THE DIAGNOSTICS
AND
TREATMENT OF TROPICAL DISEASES

The benign malarial fevers are characterized by a frank chill and well marked distinctions of cold, hot and sweating stages. In malignant tertian there is an indefinite or dumb chill with prolonged hot stage. Diagnostic of malaria are periodicity, parasites and splenic enlargement. The malignant tertian parasite is the one responsible for the so-called cerebral and algid manifestations of perniciousness. Man is the intermediate host of the parasite while the sexual cycle or sporogony goes on in some species of mosquito of the anopheline subfamily, the definitive host.

History.—Hippocrates, who considered malaria as intimately connected with bile, divided the disease into quotidian, tertian and quartan, differentiating such types of fever from continuous fevers. It is interesting to note that Celsus recognized two types of tertian fever, the one benign and similar to quartan fever, the other far more dangerous, with a fever occupying thirty-six of the forty-eight hours, not entirely subsiding in the remission, but being only mitigated.

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In the time of Caesar views were expressed by Varro that swamp air might be the cause of malaria and furthermore that animals, so small that the eye could not follow them, might transmit diseases by way of the mouth or nose.

In the view of our present knowledge it is remarkable that Lancisi, in 1718, should have associated marshes with the development of gnats, which insects he thought could not only introduce with their proboscides the putrefying organic matter of such swamps but animalcules as well.

In 1638 Countess del Chinchon, the wife of the Viceroy of Peru, was cured of an intermittent fever by the employment of the bark of certain trees which bark was introduced into Europe in 1640. The origin of the name cinchona is thus explained.

While Morton and Sydenham in 1666 noted the specific action of cinchona in certain fevers it remained for Torti, in 1753, by the use of cinchona, clinically to differentiate those fevers which were cured by cinchona from those which failed to yield to this specific. Quinine was not introduced until after 1820. Audouard, in 1803, was the first to draw attention to the splenic enlargement of malaria.

The views of Nott and Beauperthuis as to transmission of malaria and yellow fever by insects are considered under the latter disease.

In 1847 Meckel announced that the dark color of malarial organs was due to a pigment and in 1848 Virchow noted that this pigment was contained in cells. In 1875, Kelsch observed pigmented bodies in malarial blood and in 1880 came to the conclusion that these pigmented cells were diagnostic of malaria.

The year 1880 is the most important one in the history of malaria for on November 6, 1880, Laveran, at Constantine, first saw the parasites of malaria while carrying on investigations as to the origin of the pigmented bodies and melaniferous leucocytes. He not only noted the findings of spherical pigmented bodies but also of crescents and in particular the flagellation of the male gamete which demonstrated to him that these were living bodies.

The name Oscillaria malariae was proposed on account of the movements of the flagellate body, but had to be dropped as not valid, the generic name Oscillaria having been previously applied.

When these bodies were demonstrated to various Italian authorities, in 1882, they were thought by them to be degenerated red cells.

It may be stated that at this time the Italians, influenced by the work of Pasteur, were convinced that an organism, Bacillus malariae, reported by Klebs and Crudeli (1879) to have been isolated from water and soil of malarious districts, was the cause of malaria. This bacillus was said to be cultivable on ordinary media and to be capable, when injected into man, of producing malaria.

By 1885 the Italians were convinced that the bodies discovered by Laveran were the cause of malaria and Marchiafava, by staining with methylene blue, noted the ring forms and the increase in size up to that of the sporulating parasites. To Golgi we not only owe the discovery that the malarial paroxysm coincides with the period when the sporulating forms (merocytes) simultaneously reach maturity but also the exact working out of the cycle of quartan malaria. He even showed three stages of development of the parasites in a triple quartan. It may be stated that Golgi, Marchiafava and Celli are the ones to whom we owe our first knowledge of the existence of different species of parasites for different kinds of malaria. In these investigations they showed that as a rule they could reproduce a certain type of malaria by[3] injecting the blood of such a case of malaria into a well man. Gerhardt, in 1884, was the first to produce malaria by the injection of malarial blood. Laveran insisted all this time that there was but a single species of malaria. About this period a great deal of research was carried on as to the origin of malarial parasites and it was found that many animals harbored parasites similar to the malarial parasites of man. In 1891 the chromatin staining method of Romanowsky was introduced which by bringing out the variations in chromatin distribution led to more accurate study of species and cycles.

Our present exact knowledge as to the existence of 3 species of malaria is largely due to the careful examinations made by Koch of fresh and stained malarial blood preparations.

In 1894 Manson formulated the hypothesis of the mosquito transmission of malaria. He based this upon the fact that the flagellation of the male gamete does not take place for several minutes after the removal of the blood from the peripheral circulation. He also suggested that larvae might feed upon infected mosquitoes dying upon the water and thus acquire the disease.

Ross for two years had mosquitoes feed upon the blood of malarial patients which contained crescents but as he used insects of the genera Culex and Stegomyia he failed to observe development in the tissues of the mosquitoes. In 1897 he used 8 dappled-wing mosquitoes (Anopheline) and in two of these, upon dissection, he noted pigmentary bodies different from anything he had observed in hundreds of dissections of other mosquitoes. At this time he was forced to discontinue this work for about six months.

In 1886 Metschnikoff from observation of sporulating parasites in the brain capillaries at the autopsy of a malarial case considered them to be coccidial in nature. In 1892 Pfeiffer, studying the Coccidia showed that there was an endogenous cycle going on in the epithelial cells as well as the long known exogenous cycle connected[4] with the ingestion of oocysts passing out in the feces of an animal infected with coccidiosis. He suggested that malaria might similarly have an exogenous cycle as well as the well-known endogenous one. Opie noted hyaline and granular forms of parasites in the blood of crows and MacCallum, working with this malaria-like disease of birds (Halteridium), observed the fecundation of a granular female parasite by the flagellum-like process of the hyaline male cell.

In 1898, in India, working with a malarial disease of sparrows (Proteosoma), Ross infected 22 out of 28 healthy sparrows by mosquitoes which had previously fed on sick sparrows. He noted in the culicine mosquito employed for transmission the same cycle of development as that subsequently worked out for human malaria, in anopheline mosquitoes, by Grassi and Bignami, in Italy.

Koch’s great work in connection with malaria was to demonstrate that the malaria-like infections of other animals had no part in the causation of human malaria and that the malarial parasite could only circulate between man and certain mosquitoes.

In order to demonstrate conclusively the connection between infected mosquitoes and malaria Sambon and Low lived for three of the most malarious months of 1900, in one of the most malarious sections of the Roman Campagna, in a mosquito screened hut and did not contract malaria.

Infected mosquitoes were also sent to London from Italy and allowed to feed upon Doctor P. T. Manson and Mr. George Warren. After a period of incubation these volunteers came down with typical malaria with parasites in the blood.

In 1911 Bass first cultivated the parasites of malaria.

Geographical Distribution.—Malaria is so widely distributed over all parts of the tropical and subtropical world that it would require too much space to give its geographical distribution other than as given in the accompanying chart. The malaria belt may be said to extend from 60° N. to 40° S. Many of the islands of the Pacific are exempt.

This type of Haemosporidia is characterized by invasion of red cells, amoeboid movement, pigment production and the extrusion of flagellum-like processes from the male sporont after the blood is taken from the animal and allowed to cool.

Other Haemosporidia which are very important in diseases of domesticated animals, but not for man, are those of the piroplasm type.

These parasites of the red cells do not produce pigment and do not “exflagellate.” It is to parasites of this type that some authorities have ascribed the cause of blackwater fever, a condition undoubtedly connected with malaria.

Craig recognizes a quotidian form and a tertian form for the aestivo-autumnal parasite. Manson formerly held the view that three different species of crescent-bearing parasites were concerned in malignant infections; one, of tertian periodicity, Laverania malariae, and two, of quotidian periodicity, L. praecox, a pigmented form, and L. immaculata, a form in which pigment is only observed in the crescent formation and does not exist in the ring form schizonts. He has abandoned this view. Stephens has noted a parasite which has more nuclear material than P. falciparum (P. tenue).

Malaria of Animals.—Other Haemosporidia of the haemamoeba type are found in birds, monkeys, bats, squirrels and possibly in reptiles (the parasites of reptiles, while intracorpuscular and pigment producing, do not exflagellate). Of particular interest is the so-called bird malaria or Proteosoma, a parasite very similar to the human malarial ones.

The life cycle of this parasite was demonstrated before that of the malarial parasites of man.

Although Koch in his work showed that these malaria-like parasites of other animals were not infectious for man, Fermi has recently carried out well-controlled experiments, by feeding laboratory bred anophelines on the blood of various animals showing such infections, and subsequently on men, with invariably negative results.

Malaria-Transmitting Mosquitoes.—In the United States, Cellia albimana, C. argyrotarsis, Anopheles crucians, A. quadrimaculatus and A. pseudopunctipennis are efficient transmitters of malaria. Rather remarkable is the experience of Beyer in New Orleans that A. crucians will only transmit P. falciparum while A. quadrimaculatus will transmit P. vivax and P. malariae, but not P. falciparum. Further experiments have shown that A. crucians will transmit P. vivax as well as P. falciparum.

As showing the uncertainty attaching to the question of a certain anopheline species being efficient hosts for malaria may be cited the case of A. punctipennis. This species has been frequently reported as incapable of transmitting malaria and quite recently Mitzmain reported experiments on 219 females of the species which had fed on crescent containing blood and which were dissected from three to thirty-eight days after such feedings with negative findings in stomach and salivary glands. Furthermore, these mosquitoes failed to transmit malaria to healthy persons. Control experiments with A. quadrimaculatus and A. crucians were successful. In June, 1916, Dr. King reported 33% of positive findings after dissection of A.[6] punctipennis which had fed on malignant tertian cases and 85% of success where the man bitten had benign tertian malaria. These results showed as high a degree of success as that obtained with the control A. crucians and A. quadrimaculatus.

From the above it must be evident that there are other factors involved besides that of the host species as both Mitzmain and King are expert epidemiologists.

A species which may be the chief transmitter in one country may be unimportant, though present, in another country. Thus Cellia albimana is the chief malarial transmitter of Panama although C. argyrotarsis is present. In Brazil the conditions are reversed, probably due to C. albimana thriving best where slightly brackish pools of standing water abound, as in Panama.

In the Philipines A. febrifer seems the important transmitter. It freely enters houses and is a vicious biter.

In India the species which seem most active in transmitting malaria are Myzomyia culicifacies and M. listoni; while in Africa, M. funesta is very efficient.

In Europe A. maculipennis and A. bifurcatus are important.

Anopheles maculipennis.—Wings with four spots located at bases of both forked cells and of second and third longitudinal veins. No costal spots. Palpi yellowish brown and unbanded. Legs unbanded.

Anopheles punctipennis.—Wings with black costa showing yellow spots at apical third and at apex. The apical spot involves the first long vein and upper branch of first fork cell. The larger spot at the apical third passes through the first long vein and to the second vein just before it branches. In A. pseudopunctipennis the markings are as above but the fringe has yellow spots.

Myzomyia funesta.—Wings with four yellow spots on a black costa and two black line spots on third longitudinal vein. Palps with three white rings. Proboscis unbanded. Legs with faint apical bands.

Pyretophorus costalis.—Costa black with five or six small yellow spots. Palps with two narrow white bands and white tip. Femora and tibiae with yellow spots. Apical tarsal bands.

Myzorhynchus pseudopictus.—Black costa with two pale yellow spots. Wing fringe unspotted. Black palps with four pale bands. Apex of palps white.

Nyssorhynchus fuliginosus.—Black costa with three large yellow spots. Numerous black dots on the longitudinal veins. Palpi black with white tip and two narrow white bands. Last three hind tarsal segments white.

Cellia argyrotarsis.—Black costa with two distinct and several smaller white spots.

Another factor in their becoming an efficient host appears to rest in the feeding habits of such anophelines, one which is voracious and fills and then ejects by rectum[7] the blood taken from the malarial patient is more apt to be a transmitter than a species less greedy.

When man is first infected by sporozoites we have starting up a nonsexual cycle (schizogony) which is completed in from forty-eight to seventy-two hours, according to the species of the parasite. The falciform sporozite bores into a red cell, assumes a round shape and continues to enlarge (schizont). Approaching maturity, it shows division into a varying number of spore-like bodies. At this stage the parasite is termed a merocyte. When the merocyte ruptures, these spore-like bodies or merozoites enter a fresh cell and develop as before.

Rosenau, by injecting, intravenously, filtered blood, taken from a patient at the time of sporulation of the parasites caused a malarial paroxysm. No parasites developed later. Another man who received a small amount of unfiltered blood allowed a slight paroxysm and four days later showed parasites in his blood. Hence the parasite will not pass through the pores of a Berkefeld filter.

Gametes.—After a varying time, whether by reason of necessity for renewal of vigor of the parasite by a respite from sporulation, or whether from a standpoint of survival of the species, sexual forms (gametes) develop. Some think that sporozoites of sexual and nonsexual character are injected at the same time. It is usually considered,[8] however, that sexual forms develop from preexisting nonsexual parasites. The developing gametes are often termed sporonts. Strictly, the sexual parasites in the blood should be called gametocytes. The gametes take about twice as long to reach maturity as schizonts. The life of a crescent has been estimated as about ten days and that of the gametes of benign tertian and quartan about one-half this period.

Sporogony.—The gametes show two types the one which contains more pigment, has less chromatin, and stains more deeply blue is the female—a macrogametocyte; the other with more chromatin, less pigment, and staining grayish green or light blue is the male—a microgametocyte. When the gametes are taken into the stomach of the Anophelinae, the male cell throws off spermatozoa-like projections, which have an active lashing movement and break off from the now useless cell carrier and are thereafter termed microgametes. These fertilize the macrogametes and this body now becomes a zygote. (Following nuclear reduction with formation of polar bodies the macrogametocyte becomes a macrogamete). This process of exflagellation can be observed in a wet preparation under the microscope. There is first seen a very active movement of the pigment of the male gamete and finally long delicate bulbous-tipped flagellum-like processes are thrown off (exflagellated) and push aside the red cells by their progressive motion. MacCallum saw a female Halteridium fertilized by the microgamete, after which it was capable of a worm-like motion (vermiculus or ookinete).

By a boring-like movement the vermiculus stage of the zygote goes through the walls of the mosquito’s stomach, stopping just under the delicate outer layer of the[9] stomach or mid-gut. In three or four days after fertilization the zygote becomes encapsulated and is then often called an oocyst. It continues to enlarge until about the end of one week it has grown to be about 50µ in diameter and has become packed with hundreds of delicate falciform bodies. Some only contain a few hundred, others several thousand.

Zygotes.—In some of his observations Darling has noted that the zygote of benign tertian malaria grows larger and more rapidly than that of aestivo-autumnal and that the pigment is clumped rather than in belts or lines as with aestivo-autumnal. Darling has also noted that mosquitoes do not tend to become infected unless the gamete carrying man has more than 12 gametes to the cubic millimeter of blood. Rouband notes that the oocysts of P. vivax are feebly refractile with fine granules of gray pigment in loose chains while P. falciparum ones are highly refractile with large grains of black pigment. At a temperature of 25°C. vivax completes its cycle in 11 days while the zygote of the crescent requires 14 days. Apparently it is possible for a mosquito to carry both types of parasites.

The capsule of the mature zygote ruptures about the tenth day and the sporozoites are thrown off into the body cavity. They make their way to the salivary glands and thence, by way of the veneno-salivary duct, in the hypopharynx, they are introduced into the circulation of the person bitten by the mosquito, and start a nonsexual cycle. As the sexual life takes place in the mosquito, this insect is the definitive host and man only the intermediate host. The sexual cycle or sporogony in the mosquito takes about ten to twelve days.

With M. culicifacies, however, 12 in 259 showed infection. A mosquito which is capable of carrying out the complete sporogonous cycle is an efficient host and in the case of malaria the mosquito is the definitive host (sexual life of parasite).

Barber working in the Philippines with children from five to ten years of age obtained a spleen index of 13.3 and a parasitic index of 11.

Multiple Infections.—Variations in cycles may be produced by infected mosquitoes biting on successive nights, so that one crop will mature and sporulate twenty-four hours before the second. This would give a quotidian type of fever. In aestivo-autumnal infections anticipation and retardation in the sporulation cause a very protracted paroxysm, lasting eighteen to thirty-six hours; this tends to give a continued or remittent fever instead of the characteristic intermittent type.

Plasmodium Vivax.—In fresh, unstained preparations, taken at the time of the paroxysm or shortly afterward, the benign tertian schizont, or nonsexual parasite, is seen as a grayish white, round or oval body, whose outlines cannot be distinctly differentiated from the infected red cell. They are about one-fifth of the diameter of the red cell and are best picked up by noting their amoeboid activity. In about eighteen hours fine pigment particles appear and make them more distinct. After twenty-four hours the lively motion of the pigment and the projection of pseudopod-like processes, in a pale and swollen red cell, make their recognition very easy. When about thirty to thirty-six hours old the amoeboid movement ceases. Approaching the merocyte stage the pigment tends to clump into one or two pigment masses and one can recognize small, oval, highly refractile bodies within the sporulating parasite.

The gametes or sexual forms do not show amoeboid movement, but the fully developed gamete, which is generally larger than the red cells, has abundant pigment, which is actively motile in the male gamete and nonmotile in the female. The male gamete is more refractile, is rarely larger than a red cell and shows yellow-brown, short rod-like particles of pigment. About fifteen minutes after the making of a fresh preparation these male gametes throw out four to eight long, slender, lashing processes, which are about 15 to 20 microns long. These spermatozoon-like bodies now break off from the useless parent cell and with a serpent-like motion glide away in search of a female gamete, knocking the red cells about in their passage through the blood plasma.

The female gamete is larger than a red cell, is rather granular and has more abundant dark-brown pigment than the male.

Stained Smears.—In dried smears, stained by some Romanowsky method, as that of Wright, Leishman or Giemsa, we note small oval blue rings, about one-fifth of the diameter of the infected yellowish-pink erythrocyte. One side of the ring is distinctly broader than the rather fine opposite end, which seems to hold a round, yellowish-brown dot, the chromatin dot, and has a resemblance to a signet ring. These small tertian rings of the nonsexual parasites (schizont) are seen about the time of the commencement of the sweating stage of the paroxysm. Two chromatin dots in the line of the ring are rare as is also true of more than one ring in a red cell.

When the parasite is about twenty-four hours old we note that it contains much pigment and has an amoeboid or multiple figure-of-eight contour, is about three-fourths the size of a red cell and that the infected red cell is about one and one-half times as large as in the beginning and presents a washed-out appearance. It is an anaemic-looking cell. We also note, as characteristic of a benign tertian infection,[11] reddish-yellow dots in the pale red cell, which are known as Schüffner’s dots. These, practically, are characteristic for benign tertian.

A few hours before the completion of its forty-eight-hour cycle the contained pigment begins to clump, the chromatin to divide and, finally, we have a sporulating parasite, in which the 16 to 20 small, round, bluish bodies, with chromatin dots, are irregularly distributed over the area of the merocyte.

The gametes, or sexual parasites, show a thicker blue ring and have the chromatin dot in the center of the ring. The pigmentation of the half-grown gametes is more marked than that of schizonts of equal size. The shape of the gametes is not amoeboid, as is that of the twenty-four to thirty-six-hour-old schizont, but round or oval. The full-grown gametes have the pigment distributed and the chromatin in a single aggregation—just the opposite of nonsexual parasites. The male gamete stains a light grayish blue and has a very large amount of chromatin, usually centrally placed. The female gamete stains a pure blue, has only about one-tenth as much chromatin as plasma, with the chromatin often placed at one side. The pigment of the female gamete is dark brown while that of the male is yellowish brown.

Plasmodium Malariae.—In fresh preparations the young quartan schizont has only slight amoeboid movement and, as development proceeds, the rather dark brown, coarse pigment tends to arrange itself peripherally about the band-shaped or oval parasite.

The infected red cell shows but little change. At the end of seventy-two hours the rather regular daisy form of the merocyte is more distinct than that of the benign tertian merocyte.

The distinctions between the male and female gametes are similar to those of the benign tertian gametes. In Romanowsky-stained smears it is difficult to distinguish the young quartan schizont from the benign tertian one but, after twenty-four hours, the tendency of the quartan schizont to assume equatorial band forms across a red cell of normal size and staining characteristics and without Schüffner’s dots makes the differentiation easy. In the fully developed sporulating parasite or merocyte the eight merozoites assume a regular distribution, giving it a daisy appearance.

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The gametes show practically the characteristics of the benign tertian ones but are smaller.

Plasmodium Falciparum.—The young schizont of malignant tertian is extremely difficult to detect in fresh preparations, there being noted early in the rather long continued, hot stage, as small crater-like dots, about one-sixth of the diameter of a red cell which, however, show an active amoeboid movement.

Malignant tertian blood tends to show rather marked vacuolation of the red cells and these central vacuoles have a resemblance to young ring forms. The malarial parasites are most often peripherally placed and they do not enlarge and diminish in size on focusing up and down as do the vacuoles.

Later on in the hot stage these ring-like dots enlarge to become about one-third of the diameter of a red cell, most often occupying the periphery of the infected red cell. About this time, or at the very commencement of the pigmentation, the schizont-containing red cells disappear from the peripheral circulation so that the further development is rarely observed in blood specimens.

The infected cell is brassy in color and shrunken in shape—it shows evidences of degeneration. The gametes appear as crescent-shaped bodies, which are absolutely characteristic of malignant tertian, the male gamete being more hyaline and delicate while the female one is more granular and larger.

In Romanowsky-stained preparations we see, while the fever is sustained, small hair-like rings, with geometrical outline, with frequently two chromatin dots in one end of the ring and a single red cell often showing two or more of these young rings. The rings are often seen as if plastered on the periphery of the red cells or as if having destroyed a rounded section of the rim of the red cell. As the fever declines the rings tend to disappear from the peripheral circulation. The infected red cells often show polychromatophilia and distortion.

In old aestivo-autumnal cases, or those with severe infection, we may see adult rings and merocytes, which latter are smaller than those of benign tertian, show from 10 to 12 irregularly placed merozoites and a sharply clumped mass of pigment.

The gametes are the striking crescent-shaped bodies and these show the distinctions of blue-staining for the female, with lighter gray-blue to purplish staining and[14] abundance of chromatin for the male. The chromatin staining of crescents does not stand out so well as that of the round form gametes of benign tertian and quartan.

The black pigment of the female tends to be clumped toward the center while the rather generally distributed pigment of the male is reddish brown rather than black in a stained preparation.

This variation of pigment color may be due to the effect of chromatin staining, as the black of the pigment is the same in male and female gametes in fresh blood preparations.

Central vacuolation of red cells is common in malarial anaemia and may be mistaken for nonpigmented parasites.

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Malarial rings are usually peripheral and do not vary in size as one focuses up and down as do the central vacuoles.

Quinine-affected Parasite.—A very puzzling but well-recognized finding in cases treated with quinine or salvarsan is the so-called quinine-affected parasite. Such parasites lack definiteness of outline and show poor chromatin staining. The gametes do not seem to show these effects from the drug.

Certain questions connected with the life history of the malarial parasite in man which are of interest.

1. Extracellular location.—It is usual to consider the parasite as developing within a red cell and in this position to destroy the red cell. Rowley-Lawson, however, thinks that the parasites are exclusively extracellular and that they adhere to the red cells by loop-like pseudopodia which encircle a portion of the red cell and digest the haemoglobin of such an area.

2. Relapses.—There are several views as to the etiology of relapses in malaria. These views are taken up under relapses (see page 35).

3. Malarial toxin.—Nature of the toxic material thrown off by the parasite at the time of simultaneous sporulation. Rosenau’s experiments tend to show that there is a fever-producing toxin thrown off at this time. Other authors have thought that a haemolysin and an endotheliolysin were thrown off at the same time. Brown considers that the pigment produced by the parasite, in its metabolism of the haemoglobin of the red cell, may act as a haemolysin, he having found that intravenous injections of haematin were capable of producing marked anaemia. It is well known that a far greater number of red cells are destroyed in a paroxysm than would be accounted for by the actual percentage of red cells destroyed by parasites. The endothelial cells take up actively this malarial pigment or haemozoin and are damaged or destroyed thereby. Haematin injections also tend to destroy leucocytes and platelets.

Rowley-Lawson is of the opinion that the greater red cell destruction than would be represented by percentage of cells showing parasites is explained by parasites migrating from cell to cell so that many red cells may be destroyed by a single parasite.

4. Transmission to larvae.—There has been an idea that sporozoites might enter the ovaries and ova as well as the salivary glands so that a second generation of mosquitoes might transmit malaria. There is no proof that such a method is ever operative.

5. Congenital malaria.—There has been some question as to the possibility of congenital malaria. Heiser has recently reported the case of an infant which showed crescents in its blood by the end of one week from birth. The mother showed the same infection and the child must have been infected through the placental circulation.

Clark in numerous examinations of the blood of the new-born failed to find infection even when the mother’s blood teemed with parasites. In one case where the child showed infection shortly after birth there had been an accident to the placenta and he believes that instances of so-called congenital malaria are to be explained in this way.

6. Cultivation of parasite.—As to cultivation of malarial parasites. Bass takes from 10 to 20 cc. of blood from the malarial patient’s vein in a centrifuge tube which[17] contains 1/10 cc. of 50% glucose solution. A glass rod, or a piece of tubing extending to the bottom of the centrifuge tube is used to defibrinate the blood. After centrifugalizing there should be at least one inch of serum above the cell sediment. The parasites develop in the upper cell layer, about 1/50 to 1/20 inch from the top. All of the parasites contained in the deeper-lying red cells die. To observe the development, red cells from this upper 1/20 inch portion are drawn up with a capillary bulb pipette.

Should the cultivation of more than one generation be desired, the leucocyte upper layer must be carefully pipetted off, as the leucocytes immediately destroy the merozoites. Only the parasites within red cells escape phagocytosis. Sexual parasites are much more resistant. Bass thinks he observed parthenogenesis. The temperature should be from 40° to 41°C. and strict anaerobic conditions observed. Aestivo-autumnal organisms are more resistant than benign tertian ones. Dextrose seems to be an essential for the development of the parasites.

Bass considers that P. vivax has a disc-like structure which enables it to squeeze through the brain capillaries while adult schizonts of P. falciparum have a solid oval form which causes them to be caught in the capillaries.

The Thompsons have rather simplified the method of Bass. They draw 10 cc. of blood into a test tube containing the usual amount of glucose solution. They then defibrinate the blood by stirring with a thick wire for about five minutes and remove the wire with the adhering clot. They then pour this defibrinated blood into several small sterile test tubes, which should contain at least a one-inch column. Rubber caps are adjusted over the cotton plugs and the tubes placed in the incubator. They note the tendency of cultures of P. falciparum to agglutinate which is not true of P. vivax.

They think this agglutination the great cause of the plugging of capillaries in pernicious malaria. They note 32 merozoites as maximum number in sporulation of P. falciparum while P. vivax has usually 16 or more, but never as many as 32.

This would explain the shorter incubation period of malignant tertian. The pigment of P. falciparum clumps much earlier in the developing schizont than that of P. vivax and is much coarser and more discrete.

While Bass thought he noted parthenogenesis in cultures others have failed to observe any evidence of it.

7. Immunity.—As to immunity. There is no real immunity to malaria, it is a continuance of the infection, but the parasites are not in sufficient numbers to give rise to fever. If, however, the patient becomes chilled or fatigued or otherwise depressed, fever results.

This apparent immunity is also kept up by reinfection, because if natives leave the locality for a length of time they lose it. Patients who show this apparent immunity to one form of malaria have no such resistance to the other types. Bass states that immune bodies are produced in malaria and that immune processes contribute to control of the infection, but that it is not lasting and is not effective against new infection.

8. Perniciousness.—Causes of perniciousness. This is taken up under perniciousness in malaria. (See page 31.)

9. Quinine-affected parasite.—Effect of quinine on malarial parasites. It is usually thought that the merozoites at the time of being thrown off from the merocyte[18] are most vulnerable, while the gametes are only slightly affected, if at all. Still, the young forms from which gametes develop are destroyed. Quinine causes parasites to disappear from the peripheral circulation and produces degenerative changes in such parasites as may remain. Bass thinks that quinine makes the red cell permeable to the lytic action of serum. Anaemia may cause degenerative changes in parasites similar to that from quinine.

10. Anaphylaxis and the paroxysm.—Abrami has brought forward evidence in favor of the malarial paroxysm being due to the outpouring of merozoites into the blood plasma which act as foreign antigen. It is noted that the dissemination of merozoites takes place some hours before the cold stage which is one of the manifestations of anaphylactic shock. They note a leucopenia and lowering of the blood pressure preceding the paroxysm as evidence of a haemoclastic crisis.

The larval stage is the most important one to be acquainted with because in this stage one can most readily distinguish the anopheline or possible malaria transmitter from a culicine species. One can more readily and quickly make a survey for anophelines by examining the collections of water for larvae than in any other way. The anopheline larva seems to prefer the surface, on which it lies flat and out of the water. To keep it from turning over on its long axis, it has little rosette-like hair tufts on the dorsal surface of the 5 or 6 middle abdominal segments (palmate hairs). There are feathered lateral hairs projecting from thorax and abdominal segments. The head is very small in comparison with the thorax and can be rotated with lightning-like rapidity. There is no projecting breathing tube or syphon from the next to the last abdominal segment, as is characteristic of Culex, Stegomyia or any other culicine genus.

In addition, culicine larvae do not float parallel to the surface of the water, but hang suspended at an angle, with only the tip of the syphon pushed upward to the surface. The lateral hairs or bristles are not feathered and the head is much larger than that of the anopheline larvae. It is the fact of the surface position of these anopheline larvae which enables them to worm their way over film layers of water or between blades of grass, in grass or rush studded pools or swamps.

In the pupal stage it is rather difficult to differentiate species of mosquitoes from each other, so that, other than to recognize that the bloated shrimp-like body is a mosquito pupa, is unnecessary.

The male anopheline.—While certain characteristics of the male are used to separate the Aedinae from other subfamilies, yet it is only with the female that we concern ourselves in differentiating the Culicinae from the Anophelinae. Therefore, it is first necessary to distinguish the male from the female. If the antennae have not been torn off, this can be decided by the highly adorned plumose antennae of the male, those of the female being sparsely decorated with short hairs. The palpi of the male Anopheles tend to be clubbed, while those of the Culex are straight. If the antennae have been broken off, look for the claspers at the end of the abdomen.

The female anopheline.—Having determined that the insect is a female, we then proceed to place it either in the subfamily Culicinae or Anophelinae by a study of the relative length of the palpi to the proboscis. If the palpi are much shorter than the proboscis, it belongs to the Culicinae; if about as long or longer, to the Anophelinae. The palpi of the female Megarhininae are also long, but the proboscis is curved.

Anophelinae show abundant upright forked scales on occiput. The mesothorax shows sparse hairs or scales with a smooth scutellum. As a rule, the wings are spotted (dappled) and the location of these spots gives the best clue to the different[21] species of the genera. With the exception of Bironella the first submarginal cell is large. This cell is longer than the second posterior one.

In the resting position Culex allows the abdomen to droop, so that it is parallel to the wall. The angle formed by the abdomen with head and proboscis gives a hunchback appearance.

Anopheles when resting on a wall goes out in a straight line at an angle of about 45°. It resembles a bradawl.

The scutellum of Anopheles is simple, that of Culex trilobed. Anopheles has but one spermatheca; Culex has three.

Note.—Of the above genera only Cycloleppteron and Aldrichia are unproven malarial transmitters.

The female anopheline mosquito alone bites man, the male feeding on fruits and flower juices. The female absolutely requires blood for the development of her eggs after fertilization by the male mosquito.

The anopheline mosquito bites at night or toward evening and selects some dark place or dark colored wall to sleep against during the day. Hence the advantage of a buff colored wall interior. It is well to remember that the malarial incidence may be kept down by killing the mosquitoes inside of a house by striking them with a folded paper or piece of wire gauze on a handle (fly swatter).

It is not a bad plan to have a dark colored surface in a room to attract them and make their destruction easy.

Anophelines do not like wind and seek protection of underbrush. As regards distance of flight from breeding places Metz has noted that A. crucians were not distributed generally over 7000 feet and rarely were found between 7000 and 9000 feet beyond which distance they were not found. Some anophelines get accustomed to feeding exclusively on animals. Mosquitoes may hibernate through the winter and[22] possibly cause new infections the following spring. Cases of malaria in the spring are however usually due to relapses. Mitzmain’s negative experiments with hibernating mosquitoes prove man to be the winter carrier.

Wenyon has found experimentally that mosquitoes which had fed on malarial blood and kept at incubator temperatures for a week to allow development of zygotes showed inhibition of development of zygotes when kept at temperatures corresponding to hibernating ones. This treatment did not kill the zygotes but[23] complete development took place when subsequently the mosquitoes were again subjected to incubator temperatures. From this it would seem that the zygotes remain viable during the winter hibernation. This is at variance with Mitzmain’s views who regarded hibernation as destructive to zygotes.

It is a well recognized fact in the tropics that the natives seem to have an immunity to malaria yet may carry parasites in their circulation and serve as carriers. The native children to a striking degree harbour parasites and to them malaria is a prime cause of death. After repeated infections, if not fatal, a temporary immunity is acquired. Many localities in the tropics owe freedom from malaria to an absence of anophelines, as for instance Barbadoes. Again malaria-bearing mosquitoes may acquire the habit of feeding on animal blood other than that of man. It is well recognized that rural populations are more liable to malaria than those of towns and as the population of a country moves to the industrial centres human blood may become difficult to obtain and the anophelines turn to other sources of blood supply. It has been suggested that mosquitoes may suffer from other infections which may be inimical to the development of malarial zygotes (black spores of Ross). Anophelines bite chiefly at sunset and at night from which fact there would seem to be some value in shutting the windows towards nightfall as is the custom in many malarious parts of the world.

[25]

Pools containing a border growth of grass or rushes are often selected by anophelines for depositing eggs. The small fish or tadpoles, which prey on the larvae, cannot work their way through the obstacles and, again, petroleum oil cannot be easily distributed in a network of grass. Anophelines of different species and of different countries seem to vary in their selection of water for depositing their eggs. We should not generalize but go out and search for breeding places.

Anophelines seem to prefer small collections of water or sluggish clear streams. The pools made by excavations following railway or other similar construction are favorite breeding places. Proper cultivation of rural districts makes the country more healthful and Carter has stated that tile drainage is the key to rural malaria control.

The most practical method for the identification of anopheline species is to collect the larvae and later to study the adults which develop from the pupae. On the whole culicines do not seem to object to foul collections of water while anophelines avoid such breeding places.

The brain has a leaden hue caused by the black pigment. As discussed under pernicious manifestations the blocking of the capillaries may be explained in several ways. When examining sections of a malarial brain one often encounters punctiform haemorrhages.

The spleen is enlarged and the surface dark. In acute cases it may be diffluent instead of hard, as in ague cake. Microscopic sections show a striking absence of pigment in the Malpighian corpuscles, the haemozoin being pushed off into the surrounding spleen pulp. Bone marrow is dark from deposit of pigment. In the liver the endothelial and Kupfer cells are packed with black pigment. The parenchymatous cells do not contain this pigment but may show grains of a yellow pigment, haemosiderin, which gives the iron reaction. Haemozoin, although it contains iron, does not give this reaction. Haemozoin is soluble in alkalis, but not in alcohol while haemosiderin is soluble in alcohol but not in alkalis.

The finding of pigmented mononuclears or pigmented parasites in a cross section of a blood vessel makes for a diagnosis of a malarial infection.

Malarial manifestations are common in tropical autopsies and one must be very chary about reporting malaria as the real rather than contributing cause of death.

[27]

There is usually a marked increase in large mononuclears in malaria and if this is noted along with a leucopenia it is very suggestive. Melaniferous leucocytes occur in malaria only.

The kidneys may show degenerative changes and the presence of urobilin in the urine is an important indication of latent malaria.

While these benign infections rarely or never exhibit pernicious manifestations, they may, equally with the more dangerous aestivo-autumnal parasite, lead to the production of malarial cachexia, in which the clinical manifestations are similar whether produced by a benign or malignant species.

Such malarial fevers are caused by the small hair-like ring parasite with its crescent sexual forms. There are many designations for this type of malarial fever of which the best recognized are: malignant tertian, subtertian, aestivo-autumnal and tropical. It is preëminently the malarial fever of the tropics and, from its appearing in temperate climates chiefly in the late summer and through the autumn months, received from the Italians the designation aestivo-autumnal.

Depending in great part on the number of sporozoites introduced by one or more infecting anophelines at the time of biting we have with quartan fever (8-12 merozoites) a period of incubation of approximately three weeks, for benign tertian (16-24 merozoites) two weeks and for malignant tertian (32 merozoites in culture) eight to twelve days. These periods however may be much longer.

It is only when a sufficient number of parasites sporulate simultaneously and pour out into the circulation sufficient toxic material to cause a well-marked paroxysm that such occurs—with less poison we may only have vague suggestions of an attack of ague.

When there are two generations of tertian parasites, each maturing on successive days, we have a paroxysm every day—a quotidian fever. Such a tertian infection is called a double tertian. In quartan infections, with the seventy-two-hour cycle of development, if we have two generations of parasites sporulating on succeeding days, but with an apyretic day intervening, we have a double quartan. If three generations of quartan parasites sporulate on three successive days we have a triple quartan infection. When two species of parasites are present in the same case we have a mixed infection. Mixed infections of malignant tertian and benign tertian are the most common, next, those of quartan and malignant tertian and very rarely those showing quartan and benign tertian. All three species have been found in a single individual.

Notwithstanding the fact that the rectal temperature is steadily rising five or six degrees during this cold stage there is a desire on the part of the patient to cover himself with all the wraps obtainable.

At first there is a feeling of slight relief from the misery of the chill but this is soon lost sight of in the increasing headache and feeling of intense heat.

An attending bronchitis is not uncommon.

The fever remains high, from 105° to 106°F., and continues so elevated for from four to six hours to be succeeded by the sweating stage. In this the dry skin becomes moist and perspiration breaks out first on the forehead to be followed by a more or less marked profuse sweating of the entire body. The pulse becomes slower, the temperature falls rapidly and the patient falls asleep to awake slightly exhausted but feeling well.

The sweating stage lasts usually about four hours so that the entire paroxysm of cold, hot and sweating stages occupies approximately eight to twelve hours.

While most cases of the benign infections show the typical stages yet we meet cases where the cold and sweating ones are absent or but slightly marked.

Blood examination will show the parasites of the benign infections to be in the peripheral circulation during the entire apyrexial period. During the paroxysm we have a moderate leucocytosis and during the afebrile period a leucopenia with an increased percentage of large mononuclears.

Billet thinks that quartan paroxysms can be distinguished from benign tertian ones by their showing a less abrupt fever rise and a more rapid fall of temperature with a shorter duration of the paroxysm, four or five hours as against eight to twelve hours for benign tertian.

The temperature of a malignant tertian paroxysm may fall to normal during the first attack but succeeding attacks only show the tertian periodicity by an exacerbation of the more or less continuous fever.

To explain the continuous type of fever it is often stated that anticipation and retardation are characteristic of malignant tertian infections. This simply means that the new paroxysm tends to come on before the tertian periodicity of forty-eight hours has expired and, having appeared, tends to delay its termination. At any rate there is an extreme irregularity in the course of the paroxysm. These attacks are often termed “dumb chills” and are greatly dreaded.

In a blood examination one is not apt to find any other parasites than the young hair-like ring forms which begin to appear a few hours after the onset of the paroxysm. The rings may be observed to broaden, but prior to that development in which pigment would appear in the ring, the parasite-containing red cell is caught in the capillaries of spleen or other organs. The finding of young ring forms while fever continues is suggestive of a malignant tertian infection.

As explanations of perniciousness are given: (1) the very large number of red cells infected and destroyed by the malarial parasites; (2) the throwing off at the time of sporulation of the merocyte of a large amount of toxic material owing to the presence of such a large number of disintegrating merocytes, and (3) from the plugging of the capillaries of important internal organs by adult parasites. This may arise as the result of (a) the sporulating parasites acting as emboli, being too large to pass the lumen of the capillary; (b) from degenerative changes or distension with pigment of the endothelial cells lining the capillaries, or (c) as the result of an ovoid shape on the part of the malignant tertian parasite there is an inability to pass through capillaries which the flattened benign parasites can do by infolding (Bass), or (d) resulting from the tendency of malignant tertian parasites to agglutinate.

We do not understand why in one case sporulating parasites should plug the capillaries of the central nervous system, with the production of conditions resembling well-recognized nervous diseases, while in another case the damage is done the intestinal mucosa, pancreas or lungs. At any rate these pernicious manifestations of malaria should always be kept in mind when a case of sudden cerebral involvement or acute abdominal disease shows itself in a patient in a malarious country and a blood examination should be promptly made.

Cerebral malaria may give rise to a delusional insanity. Various psychoses or amnesia at times follow cerebral types of pernicious malaria.

The dysenteric type is more common but the question always arises whether the case may not have been really dysentery lighting up a latent malaria or the lowering of resistance from the malaria favoring a dysenteric infection. Stott had five algid cases of dysenteric type but not one of choleraic. The choleraic types have often been reported during outbreaks of cholera.

When epistaxis and haemorrhages from the intestines or stomach are marked features of an attack the cases are termed haemorrhagic and, if a prostrating, collapse-producing sweat be a characteristic feature, they are called diaphoretic.

Pneumonic and Cardiac Types.—Other recognized types are when, with the symptoms of a broncho-pneumonia, we find an element of periodicity and a response to quinine—the so-called pneumonic type.

[35]

Again, usually in elevated regions, dilatation of the right heart and death have been noted as occurring in cardiac types of pernicious malaria.

Another type is one in which the sweating stage is excessive, the so-called diaphoretic type. These cases may result in collapse and such a termination may be syncopal in character.

Relapses are intimately associated with conditions which tend to lower the body resistance, so that exposure to cold or wet or hot sun may bring on an attack. Alcoholic or venereal excesses, as well as errors of diet, may be provocative. Persons returning home from the tropics often experience relapses as they approach the cooler climate of the temperate zone. It has been well stated that the old resident of the tropics owes his condition of health rather to education than acclimatization—experience has taught him discretion.

Parthenogenesis.—Schaudinn thought that, either spontaneously or as the result of treatment, there was a disappearance of the nonsexual forms and the male gametes, the female gametes however surviving and, eventually, through the process of parthenogenesis, producing a set of spores or merozoites which set up a nonsexual cycle. It would seem probable that Schaudinn saw red cells containing a merozoite along with a female gamete and interpreted his findings as a sporulating sexual form.

Craig thinks that as the result of the conjugation of two young schizonts a more resisting parasite is evolved, which under favorable circumstances for its development may start anew a nonsexual cycle.

In another paragraph there is noted the importance of examining placental smears for evidence of a latent malarial infection. Persons returning to a cool climate from the tropics, who may not have shown evidence of active malaria for months, may come down with a paroxysm upon encountering cool weather (refrigeration). Latency may be complete or there may be vague manifestations of ill health such as anorexia, malaise, irritability, headaches, anaemia and alimentary tract disturbances. Not infrequently tropical residents without symptoms may show crescents in their blood and such cases are of prime importance in connection with infection of mosquitoes. To a certain extent they are the typical carriers and should be actively treated from a standpoint of malarial prophylaxis.

There may be long periods in which the temperature is normal or subnormal but slight febrile accessions may occur from time to time and at such times the blood may show parasites.

There is anorexia and alimentary tract disturbances. A very important feature of malarial cachexia may be the occurrence of haemorrhages, particularly serious being those from the retinal vessels.

It is probable that hookworm infection has frequently been confused with the anaemia of malarial cachexia as in both of these conditions we may have a high-grade anaemia with swelling about the ankles, palpitation of the heart and shortness of breath. Some authorities have recently called attention to splenic enlargement in hookworm disease, but this is not generally accepted. There may be also[37] ascites in malaria. Urobilinuria is an important sign in malaria where other causes for red cell destruction are excluded.

General Appearance.—In the cold stage of the benign infections the face is pinched and blue to become decidedly flushed when the hot stage sets in. In malarial cachexia there is an earthy color with the pigmentation more marked about the face and knuckles. In the algid forms of pernicious malaria the skin is pale, cold and clammy, in a measure simulating cholera. Herpes labialis is very common in the benign infections, but less so in the malignant tertian ones. Jaundice is a feature of bilious remittent fever.

The Temperature.—Even in the cold stage the temperature is steadily rising and may have reached 105°F. or higher by the time of onset of the hot stage. It remains elevated during the four to six hours of the hot stage and then falls rapidly to normal during the sweating stage. The paroxysm tends to occur in the forenoon or early afternoon. In 793 typical paroxysms Stott found only 37% to occur before noon. Intermittent fever curves are characteristic of benign infections. In malignant tertian a prolonged hot stage (fifteen to thirty-six hours) is a marked feature. The onset also is more gradual and the fever tends only to remit or may remain continuous over several days, but even with such a chart there are apt to be indications of slight rises every other day.

In the hyperpyrexial form of cerebral perniciousness the temperature may rise to 112°F. and the case resemble sun stroke. In the algid forms the axillary and rectal temperatures are usually elevated.

The Circulatory System.—The pulse is small, rapid and of high tension in the cold stage to become full and bounding in the hot stage. A cardiac type of perniciousness in which the right heart dilates has been referred to.

The Alimentary Tract.—Nausea and vomiting are common manifestations of malarial paroxysms and in bilious remittent fever the bilious vomiting is an especially distressing feature.

[38]

So-called choleriform and dysenteric manifestations of perniciousness of the algid type are rarely observed.

Cases with the clinical picture of acute haemorrhagic pancreatitis have been reported as incident to excessive sporulation of malarial parasites in the capillaries of the pancreas.

The Respiratory System.—There may be a slight bronchitis in ordinary types of malarial fever. In the cerebral types of perniciousness the breathing may be markedly altered—even of Cheyne-Stokes character.

A broncho-pneumonia which shows a periodicity and responds to quinine is often considered as a pernicious type of malaria.

The Skin.—Herpes labialis is a common manifestation of benign tertian and not rarely of malignant tertian infection. Urticaria may also be noted. The skin of malarial cachexia is earthy. Of course, one must always keep in mind the skin eruptions due to quinine administered in treatment, and of these urticaria is probably the most frequent.

The Nervous System.—In both the benign and malignant infections headache is a marked feature and is accentuated during the hot stage. There may be a “flighty”[39] condition in the hot stage of benign tertian and quartan but in aestivo-autumnal infections there may be actual delirium.

Delirious and comatose states are prominent features of cerebral pernicious attacks. At times there may be an apathetic condition suggesting typhoid fever.

Almost any type of central nervous system disease may be simulated as the result of focal sporulation so that we have aphasic, epileptiform, hemiplegic, bulbar and other clinical types.

Some authors have recorded cases of multiple neuritis of malarial origin. Catto has recently examined the blood of a number of cases of multiple neuritis in Jamaica and has obtained negative malarial findings in every case. Neuralgic manifestations are features of latent malaria. Some loss of memory may be apparent after severe malaria.

The Special Senses.—Plugging of the retinal arteries may lead to blindness which may be either transient or lasting. The discs are grayish red instead of white as is the case with quinine amblyopia. The ringing in the ears is connected with the quinine treatment.

The Genito-urinary System.—In the cold stage there is apt to be frequent urination with increased secretion. Later on, there is a scanty febrile urine.

Albuminuria is rather common in aestivo-autumnal attacks and true nephritis occurs in about 2% of cases.

Plehn attaches great importance to the examination of the urine for urobilin as showing malarial infection when parasites cannot be found. The pigment particles in urinary sediment (Uriola) do not give reliable information. Bile in the urine is an important sign of bilious remittent fever.

Orchitis has been reported as a malarial complication.

The Liver and Spleen.—There is very little of importance to note in connection with the liver except tenderness and jaundice in bilious remittent fever. The spleen, however, is the organ in which centers the infection and its tenderness and enlargement are of special diagnostic value in malaria.

Even in comatose conditions pressure on the spleen may bring about indications of pain. The liability to rupture of the friable spleen of aestivo-autumnal infections is a real danger and the patient should not expose himself to injury.

The Blood Examination.—This is of prime value in the recognition of malaria, and one should examine both fresh blood preparations and stained films as well. More information is gotten from the stained films but we should also avail ourselves of the different characteristics of the 3 malarial species, which can be noted in a preparation made by taking up a small drop of exuding blood on a cover-glass and allowing it to drop on a slide and run out without any pressure on the cover-glass.

The crescents, when found, show a malignant tertian infection but there may also be present one of the benign parasites. A stained film should be used to identify malignant tertian young ring forms.

Pigmented rings are rarely observed in aestivo-autumnal fever, such parasites being caught in the capillaries as they enlarge to the stage where pigment begins to be present. Flagellated forms only develop in fresh blood preparations, 15 to 20 minutes after the taking of the blood. Of the greatest differential value is the swollen pale infected red cell of benign tertian, the normal red cell of quartan and the distorted shrunken red cell of malignant tertian.

[40]

Quinine administration may cause parasites to disappear from the peripheral circulation or it may so affect the parasite that the staining would indicate a degenerated parasite—the so-called quinine-affected parasite. It is difficult to diagnose the species of malaria from such a parasite.

Large mononuclears and transitionals containing phagocytized pigment (melaniferous leucocytes) are characteristic of malaria—the pigment however must be in the leucocyte and not free. There is a leucocytosis during the malarial paroxysm with a leucopenia and increase in the large mononuclears during the apyrexial period.

Among natives of India the large mononuclears and transitionals averaged 21% in the apyrexial stage of malaria while healthy natives rarely showed as much as a 10% count (Stott).

Some authorities have reported positive Wassermann reactions in serum of malarial patients taken during a paroxysm. All agree, however, that the serum of malarial patients at other times is negative.

In an intensive investigation Bass has shown that 55.09% of those showing parasites in the blood give a clinical history of malaria while 44.91% of those with parasites in the blood fail to be associated with clinical manifestations.

Blood platelets are the findings most frequently mistaken for malarial parasites in stained blood, and the vacuoles in fresh blood. Quartan and tertian periodicity is only found in malaria, but quotidian periodicity is a feature of a host of diseases.

Of the cosmopolitan diseases, typhoid fever, septic conditions, including malignant endocarditis, tuberculosis, influenza, pyelitis and even syphilis are to be considered in a diagnosis of malaria.

As was noted under the discussion of the pernicious manifestations of malaria, scores of diseases may be simulated by the sporulation of the malarial parasite in certain organs or areas of organs. One should always keep in mind the possibility of pain in the appendix region or in the gall bladder area as connected with malaria if in the tropics. A polynuclear increase negatives malaria and indicates appendicitis or cholecystitis. Malarial pancreatitis has been referred to before.

Provocative Measures.—Kohlbrugge’s recommendation to have patients suspected of malaria climb mountains and drink copiously of cold water, in order to bring on a relapse, is of value in the diagnosis. (Effects of fatigue and refrigeration.) It must always be borne in mind that quinine causes the parasites to disappear from the peripheral circulation. It is interesting to note that small doses of quinine given over ten days or two weeks may make a latent case active. Other provocative agents are subcutaneous injections of adrenalin (the best), or anti-typhoid inoculations. Certain physical methods, as hot and cold douches or alternating the hot air chamber at 55°C. for 10 minutes, followed by a cold bath for 3 minutes have been recommended. After injection of adrenalin the presence of parasites in the blood is at its height at the end of an hour. Sunlight is a factor in relapse.

The evenly spread stained film undoubtedly gives more accurate information as to species and stage of cycle than any other method. Still one should always examine a fresh specimen and if the parasites are very scarce, a thick film preparation. The thick film methods of Ross, Ruge and James are given under the chapter on the[42] blood in tropical diseases. During winter parasites tend to disappear from the circulation regardless of treatment.

It is the tendency to perniciousness which makes us dread malignant tertian as we can never be sure that a paroxysm may not develop cerebral or algid manifestations and these show a very high death rate, 25 to 50%, even when promptly treated.

As regards relapses quartan is the malarial fever which is most apt to show this feature and aestivo-autumnal the least. Deaderick gives the percentage of cases showing relapses in quartan, benign tertian and aestivo-autumnal as 65, 55 and 45.

Statistics vary greatly as to the percentage of fatal cases in malaria. Certain figures from tropical countries give fatal results as occurring in from 2 to 10% of cases, while statistics from temperate climates show a death rate below 1%. The mortality from pernicious types of malaria is about 25%.

It may be stated that it is frequently advisable to carry on the mosquito warfare without regard to the question of the kind of mosquitoes destroyed. In general terms the malarial mosquito breeds in the suburbs of towns or in districts more distinctly rural, while the transmitter of the more dreaded yellow fever, prefers breeding places in the immediate vicinity of city houses.

Bentley has recently noted that, with improvement in agricultural methods and utilization of marshy lands, malaria tends to disappear as much from the physical improvement and thereby greater resistance of the people as from the destruction[43] of mosquitoes by the draining of the swamps. The resulting greater prosperity makes better food and shelter obtainable.

The doing away with mosquito breeding places may be accomplished by filling in pools or by making ditches with smooth sloping sides to carry away the water. These ditches require a great deal of attention to prevent their filling up with tropical vegetation and thereby adding to breeding places. Subsoil drainage with tiled drains is better. Care should be exercised that public works operations do not raise the level of the subsoil water.

Anophelines tend to breed in sluggishly moving streams or in stagnant pools especially where there is a luxuriant growth of weeds or grass, and are not apt to be found in rapidly flowing streams, hence the necessity for constant care of ditches and the like to prevent their becoming obstructed by vegetation or silt. When filling in or drainage is not practicable the method of oiling the surface of the pool with crude petroleum is to be recommended. One uses about ½ pint for every 100 square feet of surface and the process should be repeated every two weeks.

In places where oil is not effective, Barber recommends Paris green mixed with dust and so used as to form a scant surface deposit. Anopheline larvae, being surface feeders, ingest it and are killed. It does not affect Culex larvae. On account of its ease of transportation, and adaptability to weedy places where oil does not penetrate, Paris green dust will doubtless prove a valuable selective larvicide. Mayne and Jackson recommend cresol as the best larvicide. In 1 to 1,000,000 parts it is an effective larvicide, and even in 1 to 1,000,000,000 it is destructive to young larvae.

Mixtures of soft soap and petroleum are better than petroleum alone.

Winds are apt to blow away the surface coating of oil and it is difficult to oil the surface of a pool filled with grass. Wise recommends crude carbolic acid, using 1 ounce to 16 cubic feet of water.

In using any larvicide it is well to introduce it along the banks of water collections with a long-spout can and mix it thoroughly with a stiff reed broom.

There are many enemies of mosquito larvae, such as tadpoles, water-beetle larvae and various small fish such as “millions.”

Terni suggests the using of such fish as carp and tench which have a food value as well as a larvicidal one.

It is usually stated that mosquitoes may hibernate during winter following infection in the autumn and that cases of malaria in early Spring may be explained by their bites. Examination of hibernating mosquitoes for zygotes does not give strong proof to this view but such mosquitoes, becoming active with a rise in temperature, may bite gamete carriers in the house and thus spread malaria.

Pyrethrum powder, which is set on fire with a little alcohol, may be burned, using 2 pounds per 1000 cubic feet, and an exposure of four hours. This does not certainly kill the insect and the stupified mosquitoes should be swept up and burned.

Giemsa’s spray is now considered an excellent measure for killing mosquitoes in rooms. The composition is as follows: Pyrethrum tincture (20 parts powdered pyrethrum blossoms to 100 parts alcohol), 480 grams; odorless potash soap, 180 grams; glycerine, 240 grams. Before using it dilute with 20 times its own weight of water, and spray the walls of the room with a spray pump.

The use of a small square of wire gauze on a handle (fly swatter) to kill mosquitoes as they rest on a wall is of great value in keeping them down in a screened house.

It is almost impossible to screen a ship’s hatches effectually. Then too the screening of fan intakes and ports interferes with free circulation of air, thus adding to the discomfort of the heat of the tropics.

As malarial mosquitoes bite chiefly toward evening one should not expose himself after sunset.

Houses should be far removed from native habitations.

Mosquitoes prefer the lower floors of a house so that the upper stories are preferable for sleeping.

Mosquito nets at night, with protection by veils for the face or coverings for the hands and ankles, when going out of the house, are well-known measures.

It is stated that Emin Pascha always carried a mosquito net and never suffered from malaria. He thought that the cause of malaria was too large to go through the net.

Even when mosquito nets are intact and well tucked in there is the weak point that a person sleeping on a narrow cot is apt to put his arm or leg against the net, in which case the mosquitoes readily bite the skin presenting at the open spaces.

Oil of citronella is often used to keep away mosquitoes.

Brooks recommends Neal’s method. In this daub a solution of 1 ounce Epsom salts in 10 ounces of water on the exposed parts and allow to dry.

It is just as easy to give quinine to a man in the tropics as it is in temperate climates, but when one considers the propositions of draining tropical swamps and shutting off circulation of air on a torrid night with fine wire gauze in the windows and closely woven mosquito nets around the bed, the question is decidedly different. In consequence, the tendency is for the average man to despair of accomplishing anything in the way of mosquito destruction and screening and to seize eagerly on the inferior alternative, that of quinine prophylaxis.

Ronald Ross presents this matter concisely and to the point when he states that it is not a good policy to substitute a measure which does not exclude infection, but is merely extirpative in some cases, for positive prevention. From this it will be seen that unless it is clearly recognized that quinine prophylaxis may in some cases extirpate, but does not prevent, there might be a tendency to adopt this measure and neglect the two proper ones.

As regards the relative merits of quinine prophylaxis and protection from mosquitoes Celli gives the following figures:

As an instance of this, 398 marines served in 1906 for about one month on the Isthmus of Panama during which time they were given 9 grains of quinine daily as a prophylactic.

During this month there was only an occasional case of malaria among the men. At the end of the month 298 of the original 398 returned aboard ship and sailed for the North. Two days later 20 cases of malaria developed, followed the next day by 53 and the day following that by 45. The medical officer then resumed 10-grain prophylactic doses for those not down with malaria but notwithstanding this there were 215 acute malarial paroxysms, some of them of pernicious type, among the 298 men.

It was noted that these men did not respond satisfactorily to quinine treatment even when the drug was administered intramuscularly.

Linnell states that he used quinine prophylaxis among 2000 coolies for a year, giving 5 grains or more daily with most discouraging results. It seemed to act as a slow poison and did not protect.

While quinine prophylaxis may not be desirable on board ship, where one is in a position to readily recognize and treat the onset of malaria and to more or less efficiently carry out mosquito protection methods, or in a wealthy seaport, where sufficient interest in and funds for draining and screening exist, yet on military expeditions or exploring trips in tropical or subtropical countries it is the only practical method of keeping a force efficient.

Of course, one should also utilize mosquito nets as assisting in protection from malaria, and as effective for yellow fever, dengue and filariasis.

(a) Celli’s method. In this there is given 3 grains of quinine each morning and 3 grains each night. Taken in this way Celli thinks that harmful effects from quinine are avoided, that quinine immunity does not occur and that there is no danger from quinine haemoglobinuria. For children he recommends the tannate in chocolate tablets.

(b) In 1909 Bertrand and other members of a French Commission recommended two consecutive doses of 5 to 10 grains every seventh and eighth day for benign infections and two consecutive prophylactic doses of 10 to 15 grains every third and fourth days where malignant tertian was prevalent.

(c) Ziemann gives 15 grains every fourth day with the idea that the quinine is entirely eliminated in four days. Nocht gives about 12 grains on two succeeding[47] days of each week in divided doses of 2 or 3 grains instead of the entire amount in one dose.

Koch gave 15 grains on tenth and eleventh days.

(d) Castellani’s method of 5 grains daily and a double dose once a week is the one I recommend.

Much of our knowledge of the therapeutics of cinchona bark is due to Torti. In giving the drug he used a large dose the first day and the same for the subsequent two days. After that he administered smaller doses for a week and then still smaller doses for two or three weeks. Quinine was not introduced until 1820.

Toxic Effects of Quinine.—The most important untoward manifestations of cinchonism are the very common scarlatiniform, eczematous or urticarial rashes, gastric disturbances and vertigo. Impairment of vision may be brought about by quinine and quinine haemoglobinuria is a recognized possibility. In quinine amblyopia the pupils do not react to light and the optic disc is very pale, thus distinguishing the impairment of vision due to the plugging of the retinal vessels by the malarial parasite, in which condition the pupils do react to light and the disc is a grayish red.

Quinine Idiosyncrasy.—Fortunately the taking of quinine is well borne by the great majority of persons but in exceptional cases we may have developing, even after doses as small as one grain, of (a) severe nausea vomiting or diarrhoea, (b) various skin eruptions, usually of a scarlatiniform or urticarial type, (c) marked ringing in the ears, dizziness or deafness, (d) impairment of vision, (e) dyspnoea and (f) malarial haemoglobinuria. To determine an idiosyncrasy make a scratch on the flexor surface of the forearm and apply a drop of a 1 to 10 solution of quinine. Oedema with a wide zone of erythema in about 5 minutes shows idiosyncrasy. A control with normal saline should be made. It is well to make this skin test before giving quinine intravenously. For desensitization we give 1/10 grain of quinine combined with 5 grains of bicarbonate of soda and in about 1½ hours we give 1 grain with 5 grains of bicarbonate of soda.

Dosage of Quinine.—The ordinary full dose of quinine for an adult is 10 grains repeated three times in a day or 30 grains daily. Some authorities recommend 15 grains three times daily (45 grains) at the commencement of treatment and such dosage seems to be just as efficient as the larger dose of 60 grains in a day. In cinchonism we have ringing in the ears, fullness in the head, deafness and dizziness. For children Bass recommends 1/20 of the adult dose for each year of age so that a child of 5 years age would receive ¼ of the adult dose. Beyond 15 years of age the dose is that of an adult.

There now seems to be a tendency to use the alkaloid itself instead of its salts, it having been found that the alkaloid and its very insoluble tannate are absorbed from the digestive tract equally as well as the soluble salts. Quinine is almost insoluble in water (1-1560) and hence has less bitter taste than the soluble salts. It is also less haemolytic so that it may be used with greater safety where blackwater fever is feared.

Euquinine or ethylcarbonate of quinine contains 81% quinine, and is only soluble in 1-12,000 parts of water, hence its comparative tastelessness. It is expensive.

Quinine tannate contains only about 30% of quinine and is practically insoluble in water. It is often given to children in chocolate tablet form. It can often be taken by those who suffer disagreeable effects from other salts. The dose should be 2½ times that of quinine sulphate.

Until recently the bimuriate (72% of alkaloid and soluble in 1 part of water) or the chlorhydrosulphate (74% of alkaloid and soluble in 2 parts of water) have been considered the most desirable salts for hypodermic injections or oral administration. At present, owing to its extensive use in local anaesthesia and incident availability, bimuriate of quinine and urea is to be recommended for intramuscular use. It contains 60% of quinine and is soluble in an equal amount of water.

It has been found to have a slightly greater tendency to produce amblyopia than other quinine salts and should not be used intravenously.

In a very important series of experiments on prisoners, MacGilchrist found that hydroquinine (a synthetic product of quinine) was about 20% more efficient than quinine. Cinchonine was about the same as quinine while quinidine was about one-half as potent as quinine.

Acton has praised the value of cinchona febrifuge (the combined alkaloids of cinchona) given in daily doses of 21 grains for ten days.

Golgi believes that quinine is most effective at the time of liberation of merozoites from the bursting merocytes, hence he administered quinine four hours before the attack with a view to having it in its greatest concentration in the blood at such times. When given intravenously the full concentration is obtained in a very few minutes but with other methods this is a matter of great variation.

The method usually in vogue in military services is to give quinine sulphate in acid solution. This method is trying to the stomach.

Cohen holds that quinine and urea hydrochloride controls malarial infection more rapidly and efficaciously than any other salt of quinine when given intramuscularly. In order to prevent tetanus or other infections he is very careful about asepsis. He recommends that a 10 to 15-grain dose be injected every day for a week, then once a week for a month, then once every two weeks for another month. He considers a 33% solution as best, thus one could give 10 grains in the contents of an all-glass 2 cc. syringe.

James has recommended very dilute solutions for subcutaneous injections (1-150). There are practical objections to this method. It is usual to give about 1 gram (15 grains) of a soluble salt in 10 cc. of water. The present view is that subcutaneous injections deserve condemnation.

The solution should be autoclaved before use and the skin at the site of injection painted with iodine. Dudgeon has called attention to the constant production of oedema and necrosis in the area of the injection. This tissue necrosis occurs immediately and persists for a long time. If the injection is made in the neighborhood of an important nerve, neuritis may ensue. Repeated injections should not be given in the same area.

Of course in the use of quinine salts through the medium of the hypodermic needle everything must be sterile.

In giving quinine intravenously Bass thinks that 10 grains at one time is sufficient and that a 20-grain dose is not without danger.

He does not think it necessary to give more than 30 grains daily in this way. Intravenous quinine seems to be entirely eliminated within twenty-four hours and most of it within twelve hours.

When used in cerebral malaria he repeats the 10 grains intravenously in eight hours if the drug cannot then be given by mouth. Bass thinks that theoretically amyl nitrite might relax the cerebral capillaries which are obstructed by parasite-infected red cells and thus enable the quinine in the circulation to reach such cells.

The best known method of administering quinine intravenously is that of Bacelli. In this method 1 gram (15 grains) of a soluble salt of quinine is given in 10 cc. of water.

MacGilchrist has shown experimentally that such a strength of quinine (1-10) will coagulate blood serum.

In my opinion this is a dangerous method if the injection is made rapidly. There is no doubt as to the necessity for using the intravenous channel in cerebral or algid types of perniciousness when intramuscular injections do not give results. The generally accepted method is to use a salvarsan technique with a dilute solution of quinine, giving 1 gram (15 grains) of some soluble salt of quinine in 250 cc. salt solution. Such injections should be given cautiously. Quinine hydrochloride, which is soluble in 40 parts of water, is the salt usually recommended. MacGilchrist considers the very soluble acid salts as haemolytic and prefers to give quinine base—3 pints of a solution of the alkaloid, containing about 12 grains.

Rectal Administration.—Some authorities recommend the administration per rectum of a soluble salt of quinine in about 3 times the usual dose by mouth or hypodermically. It is considered applicable in cases where there is marked vomiting. It certainly is the least satisfactory way of giving quinine.

Fayrer holds that a torpid liver interferes with the efficient action of quinine, hence the value of calomel and salts. I prefer to give 2 or 3 grains of calomel, in divided doses, followed by sodium phosphate, 2 drams, every two hours, for three or four doses.

Espach has noted that he had frequent relapses in many cases treated by this method. In my opinion the Canal Zone treatment should be followed by 10 grain doses daily for 8 weeks.

Tonics of iron, arsenic and strychnine are valuable in treating the anaemia, but it is not advisable to add small doses of quinine to such tonic mixture.

Repeated Small Doses.—In Nocht’s method we give the quinine in small doses repeated several times in the day, as 3 or 4 grains given 5 or 6 times daily. Such[52] treatment is thought advisable when there is a tendency to haemoglobinuria or when giving quinine to pregnant women.

Quinine and Pregnancy.—There is frequently hesitancy in giving quinine to a pregnant woman but unless the malaria is controlled the patient will be apt to abort. Potassium bromide is thought to control the ecbolic influences of quinine.

Clark states that the experience at Ancon Hospital would indicate that quinine can be given with impunity to pregnant women. In malarial subjects quinine after parturition is of value not only in controlling a fever due to malaria but it also favors involution and aids in the healing of perineal tears. The quinine also is beneficial in improving the quality of the mother’s milk and does no harm to the child.

For regularity he advises the quinine treatment on Sunday giving a dose of salts in the morning followed by three 5-grain doses during the day.

Manson notes the danger of large doses of quinine as producing not only serious disturbances of sight and hearing but pronounced cardiac depression as well.

There are many who speak highly of Warburg’s tincture in treatment. It is both laxative and sudorific. The dose is ½ ounce (15 cc.) which contains about 5 grains of quinine sulphate and 4 grains of extract of aloes. As a rule it is better to give the quinine and the laxative separately.

More recently the tendency has been to give large doses of quinine, not only for its greater curative value but, as well, for the prevention of relapses. Craig, however, states that in his experience with aestivo-autumnal infections he has yet to see a single case, in which treatment was promptly instituted, that did not recover with a daily treatment of 30 grains.

Intermittent Treatment.—There are those who consider a treatment in which days of quinine administration are followed by days without quinine as equally efficient and less trying on the patient. Some of the experiences of Stephens and his colleagues indicated that 45 grains on two consecutive days of each week and continued for 8 weeks gave better results than 30 grains daily over such a period. In their experiments a dosage above 45 grains in a day did not seem any more efficient than 45 grains, so that this may well be considered as a maximum dose. On the whole however there seems to be a greater tendency to relapse following an intermittent treatment and Acton, as a result of his comparison of intermittent and continuous methods, deprecates the intermittent one.

Some have thought that salvarsan aided the specific action of quinine.

Many physicians recommend arsenic in the form of Fowler’s solution or as sodium cacodylate. It is most useful in chronic cases. Some preparation of iron is, of course, indicated in malarial anaemias.

The form of methylene blue to use is that labelled “Medicinal.”

Surveyor has recommended picric acid in the treatment of malaria in doses of 2 grains two or three times daily.

Recently hectine, a remedy somewhat similar to the cacodylates, has been strongly recommended by the French. It is given intramuscularly in 2-grain doses. It is said to be valuable when there is a leucopenia as it has a tonic action. It has been recommended to combine this treatment with quinine.

It is said to be a good substitute for quinine in blackwater fever.

After rather extended trial of this drug for the above purpose and as a method of treating ordinary infections the general opinion is against its value.

General and Symptomatic Treatment.—During the course of the fever the patient should remain in bed and given only broths. In the intermissions of the benign[54] forms one may allow a more generous diet. It is important that the patient be not allowed to become constipated and as a laxative one grain of calomel in divided doses followed by effervescing phosphate of soda is very satisfactory.

For the nausea sips of an ice-cold alkaline mineral water or cracked ice will generally prove effective. In more refractory cases spirits of chloroform or even a hypodermic of morphine may be necessary. Counterirritation to the epigastrium is often a help. Phenacetine may be given for the headache although ice water compresses are generally sufficient. In algid states hot water bottles should be applied to the body. During convalescence excesses in food or drink should be avoided as well as fatigue or exposure to wet or cold.

History.—There is no reasonable doubt that the explanation of the fact that blackwater fever was first brought to the attention of the medical world, by Lebeau and other French naval surgeons, in Madagascar, in 1850-1853, was due to the confusion of this disease with the bilious remittent type of pernicious malaria as well as with yellow fever. Even after the clinical picture was well recognized, disputes as to the nature of the coloring matter of the characteristic urine were frequent, some considering that the dark color, which we now know to be due to haemoglobinuria, was due to haematuria or that the color was due to bile. Blackwater fever must have been the condition referred to in medical literature of the period, 1850 to 1870, under the names “Fièvre bilieuse haematurique,” “haemorrhagic malarial fever” and “febris remittens haemorrhagica.”

It was first described in the U. S. by Cummings of Louisiana in 1859. Other American physicians during the next ten years, described the disease from various other Southern states.

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Veretas noted the presence of the disease in Greece, in 1858.

It is rather remarkable that the disease was not noted by so keen an observer as Torti, if it existed in his time, and Manson states that it is strange that it should not have been recognized in India if it had existed there prior to recent times. Some think that its introduction into Africa has been of recent occurrence. There are two explanations of the recent greater prominence of the disease in Africa and other tropical areas, where malignant malaria prevails extensively, which are (1) that there has been a great influx of susceptible Europeans into such areas during the past twenty or thirty years and (2) that the more frequent and excessive dosing of malarial patients with quinine is responsible.

Geographical Distribution.—It is in tropical Africa that the disease is of prime importance as a cause of death and invaliding. Here it prevails chiefly in West, Central and East Africa from about 12° N. to 12° S. latitude. It is less frequent in Northern Africa although a considerable number of cases have been reported from Algeria. It is unknown in Egypt, a country where malaria is very rare in Europeans.

In India it occurs in several districts and Stephens states that in the Duars (Bengal) he saw more cases in a fortnight than he had seen in the same time in Africa. In Europe it occurs chiefly in Southern Italy, Sicily, Sardinia and Greece. Blackwater fever was frequently noted among the British forces in Macedonia and Palestine during the World War.

It is common in Central America and Northern South America, especially in the regions of the Amazon basin, in Brazil.

In the U. S. it is chiefly found in the most malarious sections of Arkansas, Mississippi, Louisiana, Texas, Alabama, Georgia, Florida and South Carolina. It would seem that it is becoming more rare in the Southern States.

As a result of malarial prophylaxis among the Americans working in the Panama Canal Zone it has almost disappeared among them although still common among[57] the white Europeans in the same region who neglect quinine prophylaxis and mosquito protection.

Brem has proposed for such cases the designation, pernicious malarial fever with haemoglobinuria.

Malaria is the predisposing cause and the exciting cause may be any of a number of different factors capable of lowering body resistance such as the occurrence of another malarial attack, the administration of quinine, particularly of the acid salts of quinine in rather large doses, refrigeration, as brought about by one’s clothes becoming wet and then later subjected to the chilling influence of a sea breeze, to excessive fatigue or dietetic or alcoholic excesses.

Quinine administration, particularly if associated with refrigeration, is the most common exciting factor.

As regards the association of malaria and blackwater fever Stephens, in a study of 390 cases of blackwater, found that 73% of the cases showed malarial parasites on the day preceding the haemoglobinuria, 47.5% on the day of the attack and 23% on the day following the appearance of the dark urine. Other workers give higher figures as 95, 70 and 20%.

Where one utilizes the methods of examining for increased percentage of large mononuclears or for melaniferous leucocytes, in those cases not showing malarial parasites, the percentage of evidence of malaria is greatly increased. It is necessary to understand that a small percentage of cases diagnosed as blackwater fever do not show evidences of malaria at autopsy and cases are recorded where blackwater has attacked persons who had never had malarial fever, such instances, however being exceptional.

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The Quinine Theory.—This idea as to the causation of blackwater fever first originated with Veretas, in Greece, in 1858. Later Tomaselli supported this view in Italy and more recently it was advocated by Koch. Just as in connection with the influence of Koch’s great prestige much harm was done in prophylaxis against bovine tuberculosis so in this matter of quinine in the causing of blackwater the influence was unfortunate because many persons with severe malaria now refuse to take the specific quinine for fear of bringing on haemoglobinuria.

It may be stated that quinine alone, even in doses which are capable of producing profound toxic effects such as disturbances of sight and hearing, weak heart and collapse does not, other than exceptionally, cause haemoglobinuria. It has even been stated that quinine base and quinine tannate tend to prevent haemolysis, haemoglobinaemia and haemoglobinuria. Blackwater fever may develop without the previous administration of quinine.

Theory as to Acidosis with a Damaged Liver Plus Malaria and Acid Salts of Quinine.

MacGilchrist has recently advanced the idea that blackwater fever is brought about by an acidosis in one with a damaged liver plus malaria and the administration of acid salts of quinine. He thinks that one can safely give the quinine when alkalis are being given and that quinine base is protective against haemolysis.

Theory as to Its being Caused by a Piroplasm.

Sambon has thought by reason of the clinical resemblance of blackwater to certain haemoglobinuric diseases in cattle, dogs and sheep that such a cause might be operative. These parasites of the red cells are easily discernible in the animal infections but have never been seen in blackwater fever.

The Chlamydozoal Hypothesis.

Leishman has recently noted appearances in the large mononuclear cells of the blood of blackwater patients of certain cell inclusions which he thought to be of chlamydozoal nature and that these chlamydozoa might be etiological factors. Such appearances may not only be absent in marked cases of blackwater but may be seen in conditions other than blackwater fever.

Overexertion leading to fatigue and chilling seem to be the most common exciting factors. Those in bad health from disease or lack of proper diet seem more susceptible. A peculiar feature of the disease is that it may not be present in a district for a number of years and then assume almost epidemic proportions. Europeans are usually exempt from attacks during their first year in endemic tropical areas. Dudgeon obtained a malarial history in every one of a hundred cases observed by him in the Balkans.

Dudgeon has demonstrated active haemolysins in the tissues and urine of blackwater fever cases which bodies he was unable to note in other conditions including malaria. There was no evidence of increased fragility of the red cells. There was no evidence of auto-haemolysis. Bile pigment in the plasma occurred in most of the cases which ended fatally.

As a rule we have the pathological findings which go with malaria. As peculiarities of blackwater noted by Whipple and others may be mentioned congestion of the kidneys with purple-colored pyramids. In the spleen the Malpighian bodies are prominent and sharply outlined. Very striking are the necroses of the Malpighian corpuscles of the spleen and focal necroses of the liver. Whipple considers that this speaks for a powerful circulating toxin in blackwater fever which is not present in malaria.

The anuria is thought to be mechanical and due to the plugging up of the tubules by haemoglobin casts.

The urine shows a reddish to black color and has a sediment made up of granular débris with haematoidin crystals and only rarely a red cell. It is not a haematuria.

The absorption bands of methaemoglobin are usually noted spectroscopically.

Urobilin and albumin are present in large quantities.

Rather profuse sweating accompanies the fall of the fever and the patient is markedly debilitated after the subsidence of the fever. There may be a recurrence of the paroxysm the following day. The fever course, however, may be more or less continuous or remittent. In other words it tends to be irregular and atypical.

The spleen and liver are enlarged and tender. Albuminuria comes on with the haemoglobinuria and shows from 1/10 to 4/10 of 1% of albumen by weight.

The pulse is rapid, 110 to 120, from the first but soon becomes feeble and of low tension. In severe cases the very rapid almost thready pulse, with pallor and cold extremities, may resemble a severe haemorrhage. Epistaxis is not uncommon. A very unfavorable symptom seems to be hiccough. Another frequent cause of death and the one against which we chiefly direct our therapeutic measures is anuria with subsequent uraemic symptoms, such as coma and convulsions. At times a nephritis may develop in the course of a blackwater attack and the case subsequently run as one of severe nephritis.

In mild cases the fever course and haemoglobinuria is over within twenty-four hours leaving the patient far more prostrated than would a malarial paroxysm. In severe cases, however, the fever runs a remittent course over several days, with more marked haemoglobinuria and jaundice.

There may be cases which only show haemoglobinuria. These apyretic cases have been considered by some as quinine haemoglobinuria.

Fever Course.—This resembles that of a malarial paroxysm and may be intermittent in character or last several days as a remittent fever. The rigor which accompanies the febrile rise is intense.

The Liver and Spleen.—As a result of the marked blood destruction the liver is unable to dispose of the haemoglobin outpouring and icterus, which usually comes on in a few hours and is intense, is almost constant together with epigastric distress, bilious vomiting and tenderness and slight enlargement of the liver. The spleen is also somewhat enlarged and quite tender.

The Circulatory System.—At first the pulse is rapid with tension but soon it becomes weak, compressible and of low tension. In severe cases it may have a rate of 150 or more or even become thready.

The Genito-urinary System.—The dark colored urine is pathognomonic of the disease and gives it its name. The reddish to almost black color is due to haemoglobin and not to bile. Bile pigments do not appear in the urine. There is but rarely a red cell to be found in the granular débris with occasional haematoidin crystals which forms the urinary sediment, hence it is haemoglobinuria and not haematuria.

The urine resists decomposition for a long time. Albumin is present in large amount and comes on with the onset of haemoglobinuria. Casts are abundant and urobilinuria is marked. As a result of the blocking up of the renal tubules with haemoglobin casts pain over the loins and anuria may occur. There may be vesical tenesmus.

The Blood.—Cases have been reported where as many as 2,000,000 red cells have been destroyed within twenty-four hours, so that rapid and marked anaemia characterizes the disease. The blood is thin and the serum tinged. The degenerative changes of the red cells are not as commonly seen as one would expect but this is probably due to the fact that degenerated cells are first destroyed in the excessive haemolysis. Hb percentage reduction generally parallels the reduction in red cells. Melaniferous leucocytes may be found and during the leucopenia, which follows the paroxysm, the large mononuclears and transitionals may be increased to 20%. There is a reduction in the alkalinity and coagulability of the blood.

The two diseases which are most likely to be confused with blackwater fever are yellow fever and bilious remittent malarial fever.

In infectious jaundice the jaundice does not appear for 48 to 72 hours, the pulse is slow, there is no haemoglobinuria, although there may be a haematuria, and we have a polynuclear leucocytosis.

A case of paroxysmal haemoglobinuria occurring in a blackwater district would[62] be impossible to differentiate from a very mild case of blackwater fever. Chlorate of potash or carbolic-acid poisoning, or snake bite, or severe burns, may produce haemoglobinuria.

Albumin is present in quantity and urobilin is usually present in large amount.

One can examine the urine for blood by the haemin-crystals, guaiac or benzidin tests.

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Burkitt has noted that his cases of blackwater have shown a very acid urine with large amounts of acetone bodies.

The serum shows haemoglobinaemia and may show reduced alkalinity.

In cases treated with quinine, Deaderick, in statistics of various authorities, gives a death rate of 25.9%; in cases not so treated, of 11.1%.

Marked and persistent vomiting and hiccough are very unfavorable signs. In particular, however, it is anuria that gives us our greatest concern in the care of a case. A severe attack is followed by a marked anaemia and convalescence is usually protracted.

In particular any exposure to chilling influences or conditions which lower resistance should be avoided. As blackwater fever is more prevalent among those who have been for 2 or 3 years in highly malarious, tropical regions than among recent arrivals, the former should exercise the greater care as to errors in diet, alcoholic excesses, exposure to wet and irregularity in quinine prophylaxis.

Of course if it be true that quinine base is devoid of haemolytic influence the fear of increasing haemolysis by giving quinine would not have to be considered. At any rate any red cells containing parasites will surely be destroyed in the general haemolysis and with them their contained parasites, so that it does not seem reasonable to give quinine during the first day or two of the attack. Quinine, if given, should not be by mouth for fear of increasing the nausea and vomiting. The majority of authorities hold that if parasites persist after two or three days from the onset quinine is indicated. Some give quinine during the first day if parasites are present but otherwise they withhold quinine.

The patients should be given alkaline waters freely, as Vichy or water containing 30 grains of bicarbonate of soda to the pint. Cracked ice often tends to lessen the nausea and vomiting. Albumin water or barley water may be retained better than milk or broths. As the condition is so asthenic one cannot disregard the nourishment of the patient during the first two or three days as is true of the sthenic first stage of yellow fever. Hot fomentations to the loins are indicated for relief of pain and the effect on the renal congestion.

Saline enemata are of particular value and may suffice in mild cases. In severe cases subcutaneous or intravenous saline injections are necessary. Sorel recommends the intravenous injection of lactose or glucose solutions in quantities of about 300 cc. (Crystallized glucose 47 grams, water 1000 cc. or C. P. lactose 92.5 grams, water 1000 cc.) He also uses these sugar solutions as enemata. Dry cupping or hot fomentations over the loins are the usual remedies in threatened suppression of the urine. If blackwater fever should be shown to be accompanied by diminished alkalinity of the serum then the intravenous injection of a 1 or 2% solution of bicarbonate of soda would be indicated. Some have recommended calcium lactate in doses of 20 grains every four hours. There is little evidence however to indicate that it is of value. Transfusion of blood has been practised but reports of such treatment indicate that while temporary improvement occurs yet this is followed by a return of haemoglobinuria. From Dudgeon’s work it would seem that the existing haemolysins would destroy the foreign red cells.

Burkitt claims excellent results by intravenous injections of alkaline solutions, similar to those recommended under “cholera.” He also finds neosalvarsan of the greatest value in treatment, as cases so treated convalesce most rapidly.

Hearsey advocates a mixture in which there is contained 10 grains of bicarbonate of soda and 1/30 grain of bichloride of mercury in each dose, to be given every two hours.

Cholesterin has been given in 15-grain doses in suspension in thick milk every four hours with the idea that it is anti-haemolytic. The dose is repeated 2 or 3 times.

Calomel in large doses has been recommended by some tropical practitioners but it would seem advisable only to use calomel to keep the bowels open and then in small divided doses.

Antipyretics should not be used from their depressing action on the heart.

For the urinary suppression, Wallace recommends salines as hot as can be borne, administered high in the colon by a double-flow tube. Since he found this treatment effective after intravenous and rectal injections had failed, it is to be inferred that the results obtained were due not to the further administration of fluid but to the action of heat applied directly to the splanchnic area.

In Brazil there is a disease caused by a flagellate, Schizotrypanum cruzi, which resembles a trypanosome and is transmitted by a bug, Lamus megistus. The disease runs an acute course with a high fever and great mortality in infants showing chiefly manifestations of involvement of brain or thyroid gland. In adults it runs a chronic course showing neurological manifestations or signs of myxoedema or even of Addison’s disease.

History.—In describing sleeping sickness, in 1803, Winterbottom brought out the importance of enlargements of the posterior cervical glands (Winterbottom’s sign).

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In 1880 Evans had found a trypanosome in the blood of horses affected with surra and several years afterward Bruce discovered that nagana, a fatal disease of cattle, was due to a trypanosome, T. brucei. In 1890 Nepveu found a trypanosome in the blood of a man in Algeria but owing to vagueness of description the discovery did not attract attention.

In 1901, Forde found a parasite in the blood of a patient in the River Gambia Colony who had a fever and in 1902 Dutton recognized the parasite as a trypanosome and gave it the name T. gambiense. In 1902, Castellani, finding a trypanosome in the cerebro-spinal fluid of a patient with sleeping sickness, brought about the establishment of the connection between the trypanosome in the blood (trypanosome fever) and the trypanosome in the cerebro-spinal fluid (sleeping sickness). In 1903, Bruce and Nabarro reported that this disease was spread by a tsetse fly, Glossina palpalis.

In 1910 Stephens and Fantham brought forward the existence of a more virulent trypanosome, T. rhodesiense.

Geographical Distribution.—The disease exists on the West Coast of Africa, from Senegal to Mossamedes. It is also present in the Congo basin and particularly in Uganda. The more virulent form is found in Rhodesia.

Bruce considers T. nigeriense as being T. gambiense. Macfie noted many short stumpy forms in animals inoculated with T. nigeriense.

These trypanosomes are blood flagellates and are typical of the Binucleata in possessing two chromatin-staining areas, the larger and more centrally situated mass being the tropho or macronucleus and the smaller, but more deeply staining one, the kineto or micronucleus (Blepharoplast). Trypanosomes have a fusiform or fish-shaped body which stains blue. Near the less pointed, nonflagellated end, usually called the posterior end, is the deeply stained blepharoplast. Adjoining this is a vacuole and, taking origin from this part of the trypanosome, is the flagellum. This borders an undulating membrane attached to the body and then, carried along to the other extremity, projects free as a long, whip-like flagellum.

In fresh preparations the body of the trypanosome progresses in the direction of its flagellated end, although occasionally it will be observed to move in the opposite direction.

T. gambiense varies much in length and breadth. The normal type, as found in the blood, varies from 14 to 20 microns, while longer forms, 20 to 24 microns, are growth ones and, in the longest ones (23 to 33 microns), we have those preparing to divide longitudinally. The normal short forms are the ones from which the development takes place in the tsetse fly. In width these flagellates are from 1.5 to 2 microns. The blepharoplast is oval and the nucleus situated about the center.

When the tsetse fly, Glossina palpalis, feeds on a man in whose peripheral circulation there are normal type trypanosomes we have an accumulation of such forms in the middle and posterior portions of the gut. From the eighth to the eighteenth day long, slender forms develop and pass forward into the proventriculus. None of the intestinal forms can cause infection when injected into animals. These proventricular[70] types work their way into the salivary ducts and thence into the salivary glands, where further development takes place. Here we have shorter forms developing, which are similar in morphology to the normal blood type. It is at this stage that the fly becomes infective by the passing of these trypanosomes down the salivary ducts and through the channel in the hypopharynx to the subcutaneous tissues of the person bitten. High temperatures, 75 to 85°F., are favorable to development, while low temperatures, 60 to 70°F., are inimical to development, but do not kill the ingested trypanosomes. This explains the long period which at times elapses before a fly becomes infective. Under favorable conditions a fly becomes infective in twenty to thirty-four days and remains infective the rest of its life, up to 185 days. The infection is not transmitted to the pupa. This is an inoculative, cyclical or indirect type of infection. It is usually considered that a tsetse fly whose proboscis has just been contaminated with trypanosome blood is capable of transferring the infection for a few hours. This would be a mechanical or direct method of infection and such power for infection only lasts for a few hours.

There are other groups of trypanosomes, not important for man, in which the cyclical development does not include the salivary glands. In the T. pecorum group of small monomorphic trypanosomes development takes place only in intestines and proboscis, while in the T. vivax group this occurs in the proboscis alone.

Both of the human trypanosomes of Africa have been cultured by using the N.N.N. medium in which rat’s blood was substituted for that of the rabbit. Human blood will also serve as a substitute. Growth however is not constant.

The tsetse fly is much like Stomoxys, but has a branching of the feathering of the arista, long palps, a bulb to the proboscis and a characteristic upbending of the fourth longitudinal vein to meet the mid-cross vein. The female deposits her larva near a shady place upon loose, dry, sandy soil. Moisture and sunlight are not favorable for pupal development, the sun being particularly injurious, so that pupae, buried only an inch deep and away from shade, are killed. This fact has been utilized in prophylaxis by cutting down the trees. The trouble is that the bush growth which soon follows is favorable as providing shade for the pupae.

Male and female flies bite and transmit the disease. They bite in the daytime, usually from 9 A.M., to 4 P.M., and will bite in the sunlight.

It has been stated that tsetse flies are attracted by persons wearing khaki clothing.

Taute, however, believes them different as he not only injected blood containing such trypanosomes into himself, with negative result, but also allowed flies which had fed on antelopes, which were infective for laboratory animals, to feed on himself, likewise with negative result. It is a well-known fact that men in good condition are refractory to trypanosome infection so that this courageous experiment does not prove the antelope strain to be different from the human one.

One measure that has been proposed is to kill off the big game from a certain area with a view to depriving the flies of their main source of infection.

The probabilities of an animal reservoir for T. gambiense however is not so well settled. Many think that we may have trypanosome carriers and that such persons in the enjoyment of health may act as reservoirs of the virus. Koch suggested that crocodiles were important factors in the life of the tsetse flies and recommended the destruction of the crocodile eggs.

This same method of infection of prostitutes has quite recently been brought to notice by Bernard.

It will be remembered that dourine, a trypanosome disease of horses, caused by T. equiperdum, is transmitted by the sexual act.

All observations however indicate that the spread of the disease is almost exclusively through the medium of the tsetse fly. Professor Lanfranchini was infected in his laboratory by a strain which was supposed to be Trypanosoma brucei.

We have a meningo-encephalitis in which the most characteristic feature microscopically is a widespread perivascular infiltration of small round cells surrounding the vessels of the pia-arachnoid of both brain and cord. The process is most marked about vessels of pons and medulla. The nerve cells are but little affected other than those of the bulbar nuclei.

In natives, trypanosomes may be present in the blood for long periods of time during which they may do heavy work; thus 7 of Koch’s 52 native porters showed trypanosomes. In Europeans however the course of the disease is rarely so insidious but rapidly enters upon the stage of trypanosome fever.

The temperature curve is of a markedly remittent type, approaching normal in the morning and going up to 103°F. or higher in the evening—a wide daily range. Very characteristic is a low-tension rapid pulse which often is as rapid when the temperature approximates the normal as when it is higher. Early in the disease there are evidences of involvement of the nervous system, as shown by headache insomnia, difficulty of concentration for mental work and cardiac instability.

Kérandel Sign.—Recently great prominence has been given to a deep hyperaesthesia, which shows itself as a lively pain, often retarded, after some slight blow upon a bony projection of the body. Kérandel, who suffered from trypanosomiasis, noted that the fear of striking against objects became with him an absolute obsession. It is called the Kérandel sign. It is during this first stage, when the trypanosomes are to be found only in the blood or gland juice that the disease would appear to be[75] curable. Upon the appearance of the trypanosomes in the cerebro-spinal fluid (second stage) we have practically a hopeless prognosis.

There may be a latent period of several months in which health seems normal, to be followed by the sleeping-sickness stage. It has also been noted that untreated cases, as well as those receiving more or less treatment, may remain in good health for periods up to several years. There is therefore reason to believe that certain cases may not enter upon the sleeping sickness stage.

The gait is one of weakness and apathy—a shuffling gait. The reflexes may be exaggerated. Romberg’s sign may be present but the Argyll-Robertson pupil has not been noted. There may be an alternation of periods of crying and laughing which with the occasional exhibition of intention tremor and rarely nystagmus may make one think of multiple sclerosis. The patient tends to sleep even when lying in a bright sunlight. Again he may go to sleep with a morsel of food in his mouth. Notwithstanding the apparent stupid state of the patient, he will, when aroused, answer fairly intelligently but with apathy and retardation. The hebephrenic and catatonic manifestations of dementia praecox may be exhibited in some cases.

Finally the patient becomes weaker and more emaciated. The pulse becomes rapid and feeble, the blood pressure being extremely low. The mouth becomes dry, the teeth covered with sordes and bed sores develop. There may be convulsions. The coma and general weakness become more marked and the patient dies. Frequently terminal pneumonias or dysenteries bring about the end.

The sleeping sickness stage rarely lasts longer than a year and even with treatment not more than two years.

The Nervous System.—Headache and lack of mental concentration may be early features of the disease. Deep hyperaesthesia, or Kérandel’s sign, often present. Patients tend to be morose and apathetic. Tremor of tongue and lips are rather constant signs about the commencement of the stage of sleeping sickness. Early insomnia gives way to the drowsiness that characterizes the second stage. There is very little disturbance of sensory or motor functions until near the end. Epileptiform convulsions may be late manifestations. Coma deepens as the end approaches.

The Temperature Curve.—The febrile paroxysms, which may not be present in natives until the sleeping-sickness stage, show great irregularity of course and a marked remission in the morning. The fever may be absent for several weeks to return later. Trypanosomes are more apt to be present in the peripheral circulation during the fever than when the temperature is normal.

The Circulatory System.—The pulse tends to run from 90 to 120 beats per minute and is fast even without fever. The tension is low and the systolic pressure tends to be extremely low during the later stages of the disease.

The Lymphatic System.—Most important in diagnosis is the enlargement of the lymphatic glands, especially those of the posterior cervical triangle (Winterbottom’s sign). Other enlarged glands may be the supraclavicular, epitrochlear and axillary glands. The inguinal glands suffer enlargements so frequently as the results of wounds and infections of the foot that their enlargement is of less diagnostic value. The natives of certain parts of Africa not only attach great diagnostic importance to gland enlargement but they imagine they cure the disease by removing the glands with various primitive cutting tools. The glands are not painful, do not become matted together and rarely suppurate. Our best means of diagnosing[77] trypanosomiasis is by withdrawing gland juice with a syringe and examining the smears.

The Skin.—Erythematous areas may be present in Europeans. Localized oedemas are rather marked features. The skin may be very dry and itch markedly.

Other Manifestations.—The spleen may be enlarged, the respirations may be more rapid than normal and the blood show a secondary anaemia. In a blood examination the large mononuclears show an increase with a normal white count.

The eye may show keratitis or irido-cyclitis in trypanosomiasis.

Trypanosomiasis seems to favor abortion and still-births, in this respect resembling syphilis.

The increase in large mononuclears goes with malaria, kala-azar and syphilis as well as with trypanosomiasis so that such findings are of little assistance in differential diagnosis.

An early history of attacks of fever, with marked fluctuation of temperature, associated with rapid pulse, even with the apyrexial morning fall, is suggestive. Then with the glandular enlargements we think immediately of laboratory examinations. As with pellagra the history is very important in the diagnosis of trypanosomiasis.

Gland Puncture.—The English workers usually prefer the gland puncture method, using a sterile but dry hypodermic needle. Water in the needle distorts both leishman bodies and trypanosomes.

In the sleeping-sickness stage trypanosomes can almost constantly be found in the cerebro-spinal fluid.

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In a diagnostic study of 336 cases Broden obtained 87% of positives from gland puncture, 80% from centrifugalizing the supernatant fluid left from the second centrifugalization of the blood and 4.5% from spinal fluid examinations.

Some prefer to inoculate susceptible animals, particularly the guinea pig or monkey, with blood or gland juice from the suspected case. A very satisfactory material is an emulsion from an excised gland which may be inoculated intraperitoneally into white rats. The further course, after animal inoculation, is the examination of the blood of these animals for trypanosomes. Usually at the time the guinea pigs die we find numerous trypanosomes.

Other tests are: (1) Trypanolysis, when unheated suspected serum and trypanosomes are incubated together for one hour. Normal serum may occasionally cause disintegration and treated cases give it in only about 45% of cases. Unfavorable untreated cases give it in about 80% of cases.

(2) The so-called auto-agglutination test is not of much value. In this the red cells of the blood of a trypanosomiasis case come together in clumps when one makes a wet preparation. It is not a rouleaux formation. (3) The attachment test is made by making a mixture of inactivated serum, leucocytes and trypanosomes and allowing them to be in contact for 20 minutes. A positive test shows attachment of the trypanosomes to the leucocytes.

There is very little hope of cure if the disease has gone on to the sleeping-sickness stage.

Isolation, in the fly-free districts, of infected natives has not proven a very practical measure but that of rendering their peripheral blood free of trypanosomes by atoxyl injections would seem more desirable. In this we aim to cure the patient as well as render him safe to others.

The most practical measure is that employed in Uganda of clearing the plant and tree growth for at least fifteen feet from the streams of water, it having been noted that the tsetse flies confine themselves to a narrow strip not more than fifteen feet from the water’s edge. The tsetse fly requires considerable moisture for its existence.

The catching of flies in traps or with a sticky lime does not offer much encouragement.

Such cases have been treated with injections of 10 cc. of 1 to 1000 solution of neosalvarsan into the spinal canal, after withdrawing about 15 cc. of spinal fluid, but without appreciable curative effect. On the assumption that trypanosomes invading the central nervous system are protected from drug action, Marshall proposed the injection of salvarsanized serum intrathecally. Three hours after the administration of 0.6 gm. of salvarsan enough blood is withdrawn from a vein to give about 20 cc. of serum. Following the withdrawal of a slightly greater amount of cerebro-spinal fluid from 5 to 20 cc. of the serum is injected in its place. Yorke in a critical article on the claims for this treatment is of the opinion that there is no satisfactory evidence that such a method sterilizes the infected cerebro-spinal fluid. He cites cases where the trypanosomes disappeared from the spinal fluid after ordinary treatment and where cases lived for extended periods after trypanosomes were found in their spinal fluid. Corbus and associates have described a new method of obtaining a high medicinal content in the cerebro-spinal fluids. Their work was done with neo-arsphenamine, but there seems to be no reason why other drugs may not be similarly administered.

The basis of the method is the observation that hypertonic salt solution, injected intravenously, will dehydrate the central nervous system, and that restoration of fluid begins at about the sixth hour. If a drug is injected into the circulation just at the time when the restorative formation of spinal fluid is taking place, it appears that a large quantity is carried into the subarachnoid spaces with the fluid, as on a flood tide.

Method:

1. 8 A.M. Patient is put to bed.

2. 10 A.M. Intravenous injection of 100 cc. of 15% saline, warmed and administered slowly by gravity. The symptoms produced by this injection are mild and transitory.

3. No food is permitted at midday.

4. 4 P.M. Neo-arsphenamine is injected with the usual technic.

5. 8 P.M. Light nourishment is allowed. Patient is kept under observation, preferably in bed, for the ensuing thirty-six hours.

Atoxyl.—The first drug to offer hope of cure was sodium arsanilate, atoxyl, which contains about 26% of As. This is best given in doses of about 0.5 gram (7½ gr.) in about 15 cc. of sterile distilled water intramuscularly. Several cases of optic neuritis were reported but the drug is still a standard treatment. We give the atoxyl at intervals of five days, Manson gives 3 grains every third day.

Intravenous injection of arsenophenylglycin, in doses of about 1.0 gram. (15 gr.) intravenously has been highly recommended. Recent reports from German East Africa state that of 35 treated with this drug six died of the effects of the drug. Salvarsan and neosalvarsan have been used but apparently without particular success.

A combination of treatments in which salvarsan, sodium salicylate and ethyl-hydrocuprein (a quinine derivative) have been used has been favorably reported by Morganroth where the action of a single drug was of little value.

Very remarkable claims in experimental animals have been made for “trixidin,” a preparation of antimony trioxide which is given intramuscularly. Even inunctions with this preparation have been quite successful in curing infected mice. In larger animals abscess formation is an objection.

Daniels has reported good results from the injection of oxide of antimony. The preparation used is Martindale’s injectio antimonii oxidi given subcutaneously in 30 minim doses (1/20 grain of the oxide). Masters gives this preparation intramuscularly and notes its greater efficiency than any other drug or combination of drugs. He gives 3/100 grain every other day until 40/100 grain has been given. If trypanosomes continue present he gives a .77 gram dose of soamin. Soamin is a drug similar to atoxyl but said to be less toxic.

In the treatment of 18 cases of T. rhodesiense infections Newham notes that tartar emetic alone was as effective as the combined treatment with atoxyl. He gave the tartar emetic injections twice weekly intravenously commencing with 1 grain and going up to 3 grains. An organic antimony preparation, “Stibenyl,” has been recommended. See kala-azar.

Very favorable reports have been made from the use of galyl and ludyl, arsenical compounds.

A drug which is reported to have exceptional trypanocidal effect on animals infected with both human trypanosomes is “Bayer 205.” Dogs infected with the dourine parasite and showing oedema and eye symptoms have been cured by the injection of the drug intravenously. A dose of 0.5 mg. causes disappearance of parasites in mice. It is stated that the drug produces a protection against reinfection which lasts for months.

The bug is a vicious feeder and, from its biting chiefly about the face, has been called barbeiro or barber by the natives. Both the male and female of Lamus bite and can transmit the disease and although the parasite is not transmitted hereditarily the nymph is capable of sucking blood and becoming infected.

It requires several months for the insect to go through the egg, larval and pupal stage to maturity. Some consider this bug to belong to the genus Triatoma. The insects may live for more than a year and tend to remain in the same house where they may have become infected but leave such house if it be abandoned by man. Brumpt thinks that the bedbug may also transmit the disease. A large proportion of armadillos in the endemic areas are infected with S. cruzi but do not seem to be affected thereby. It has been suggested that this animal may be a reservoir of virus.

Chagas thinks that the gametes for the cycle in Lamus arise from parasites developing in the lungs of the vertebrate host. Flagellated parasites enter the lungs, lose the flagellum and become oval in shape, later on dividing into 8 parts. These assume an elongated form and enter the red cells of the host. Against this is the statement of various observers that the flagellates are only to be found free in the plasma, never within red cells. The forms taken up by Lamus multiply in the intestine and then pass to the salivary glands after about 8 days. The bug is then infectious when it bites. Brumpt notes that infection may occur from inoculation of the faeces passed by the bug, especially through the conjunctiva.

An irregular fever may accompany the signs of involvement of the various important organs.

The disease is attended by a marked anaemia.

Brumpt has recently advocated the xenodiagnostic method. Thus, in a number of guinea pigs infected with S. cruzi, parasites could not be found, but by having third stage larvae of Conorhinus feed on these animals the parasites developed in the bugs. He regards the alimentary tract of these bugs as a most favorable culture medium.

The same plan of treatment as for African trypanosomiasis may be tried but such treatment is not effective with infected animals.

In the myxoedema types thyroid extract is indicated.

Note: Escomel has reported the finding of a trypanosome 20 to 40 microns by 3 to 4 microns which had a flagellum as long as the body and with a very small but distinct blepharoplast (unlike S. cruzi) in the blood of a native of Peru. The patient at the time of the blood examination was afebrile and showed a generalized firm oedema. There was noted anaemia, prostration and somnolence. This may be a new species.

Trypanosoma brucei.—This trypanosome causes a surely fatal disease in horses and one from which few cattle recover. It is called “nagana” or the fly disease, from being transmitted by the tsetse fly, Glossina morsitans. All animals except man and possibly the goat seem susceptible. The disease is characterized by fever, oedematous areas about neck, abdomen and extremities, progressive anaemia and emaciation. It is an important disease of domesticated animals of many parts of Africa.

Trypanosoma evansi.—This is the cause of a very fatal disease of horses in India and the Orient and known as “surra.” It also affects camels and even cattle. It is thought to be transmitted by biting flies (Stomoxys). The symptoms are fever, emaciation, oedematous areas and great muscular weakness.

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Trypanosoma equinum.—This trypanosome causes a fatal disease in horses in South America. There is paralysis of the hind quarters of the horse which gives the disease the name “mal de caderas.”

Trypanosoma equiperdum.—This trypanosome causes a disease of horses in many parts of the world. It is known as “dourine” and is transmitted by coitus. The genital organs show marked oedema which is followed by anaemia and paralysis.

Trypanosoma dimorphon.—This trypanosome causes a disease of horses in Gambia. It is also found in horses and cattle in other parts of Africa. The parasite shows marked variation in morphology.

Trypanosoma lewisi.—Rats in many parts of the world show this infection which is rarely fatal to them. It is transmitted by the rat flea by a process of regurgitation. It can also be transmitted by the rat louse.

Besides the above species of spirochaetes others have been reported, as S. novyi for American and S. persica for Persian relapsing fever. The view taken by Nuttall, that these various names may be of convenience in the study of relapsing fevers but that there is no adequate morphological difference to justify them as species, seems worthy of acceptance. It has been shown that the separation of these spirochaetes on the basis of susceptibility of laboratory animals and cross immunity reactions is untenable. Agglutination of certain strains by their specific sera, however, is a reliable means of separation. As with European relapsing fever, these fevers are characterized by a sudden onset, intense frontal headache, and pain of back and limbs. This fever remains high for three to five days and falls by crisis, to be succeeded by an apyrexial interval of approximately one week. There may be several of these alternating febrile and afebrile periods. The spirochaetes are in the peripheral circulation during the febrile period but not in the afebrile one. The spleen is enlarged and tender. Cases showing jaundice seem more grave.

History.—Although Hippocrates described the clinical features of relapsing fever quite accurately this knowledge seems to have been lost until about the eighteenth century.

[87]

The causative spirochaetes were first seen by Obermeier in the blood of a patient in 1868 but he did not publish his discovery until 1873.

Ross and Milne, in 1904, found that African tick fever was a spirillar fever while Dutton and Todd established the fact of its transmission by ticks.

Geographical Distribution.—Relapsing fever was epidemic in the U. S. in 1869, since which time it has not reappeared. There have been many epidemics in Ireland, Russia, Turkey and other parts of Europe. It was a disease of importance during the Balkan War of 1912-1913. China and India have frequently been visited by epidemics as well as the Philippine Islands and the Dutch East Indies. Uganda, Congo State and German East Africa, as well as Egypt and Algeria, are important centers. There is also a relapsing fever of Colombia and Central America.

Transmission by the tick.—The generic name Spiroschaudinnia is preferred by some to the more commonly accepted Spirochaeta. Recently, authorities give these organisms the name Spironema. East and West African relapsing fever, or tick fever, is caused by Spironema duttoni and the transmission is through the bite of an argasine tick, Ornithodoros moubata. Not only does the tick itself become infected by the taking in of blood-containing spirochaetes but likewise transmits the infection to its progeny. Leishman considers that when the spirochaetes are taken into the alimentary tract of the tick there is a breaking up of the spirochaetes into small granules which reach the Malpighian tubules. They also invade the ovary and the ova. It was thought that these granules were the infecting agents and that they were excreted in the fluid of the coxal glands or passed out with the faeces. More recently[88] it has been claimed that these granules have no relation to the infection, which is due to spirochaetes as such.

It may be stated that spirochaetes as such may be found in the secretion of the coxal glands as well as in the faeces. This coxal fluid dilutes the thick faeces and makes an emulsion which is smeared out by the body of the tick in the area of the bite puncture.

At any rate this infection of man seems to be the contamination method, the material from faeces and coxal glands being rubbed into the wound made by the tick-bite. The ticks hide in the cracks about the old native huts and bite the sleeping inmates. There may be quite a local reaction at the site of the bite. Spironema duttoni has been cultured by Noguchi, by utilizing his methods for culturing the organism of syphilis. In such cultures he has noted longitudinal division rather than transverse, this fact rather favoring a protozoal as against a bacterial nature. This spirochaete is from 24-30 microns long, about 0.45 micron broad and has a corkscrew motility. It is readily transmissible to a number of laboratory animals, as monkeys, white rats, etc. The spirochaete of Northern African relapsing fever, S. berbera, causes the disease as seen in North Africa and Egypt. It is transmitted by lice, Nicolle and others having shown that the spirochaetes make their way from the alimentary tract to the body cavity of the louse. They have shown that the bite alone of an infected louse is innocuous and also that the faeces are non-infective, when injected into monkeys. Emulsions of infected lice, however, when rubbed into wounds, produce the disease in monkeys.

Transmission by the Louse.—The spirochaetes taken in by a louse disappear in a few hours and the insect remains harmless until about the fifth day, when it becomes infectious, and so remains until the twelfth to fifteenth day. Spirochaetes reappear in the coelomic fluid of the louse about the sixth day and continue present until about the twentieth day.

A striking fact is that infection can be brought about a day before spirochaetes appear and that after a period of a few days these spirochaete-containing lice lose their power to infect. It would seem that the infecting stage was an invisible one. Have we then a symbiosis between a spirochaete and an invisible virus, possibly filterable? Wolbach has shown that certain spirochaetes will pass through a Berkefeld filter as spirochaetes but this would not affect the possibility of the existence of some granule or chlamydozoal stage. It may be that the infecting stage is not an invisible one but a granule one.

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Mode of Infection.—It is by crushing the louse, by scratching or otherwise, that the spirochaetes contained in the coelomic fluid reach and penetrate the wound of the bite. This is therefore a contaminative method of infection. Mackie has shown that the Indian relapsing fever, which is caused by S. carteri, is probably transmitted by the louse, and it is probable that the conditions under which the infection takes place are similar to those occurring with S. berbera infections. With the European relapsing fever, bedbugs may possibly act as transmitting agents. The probabilities however are that this infection is transmitted by lice alone.

A relapsing fever of Persia is transmitted by a tick of the genus Ornithodoros, which is also true for the relapsing fever of Panama. There is great variation in the description of the different spirochaetes, and frequently measurements are given for short forms and long forms. They also vary from wave-like lines to corkscrew spirals. Again, different species have different types and different activities of movement. As a rule they are about 20 × 0.4 microns. The spirochaetes of the relapsing fever of Panama varied in length from 4.6µ to 22µ. Of these the most common were those measuring 13µ. Transverse division of the longest forms was seen in dark-field preparations. The monkey is susceptible to all species of relapsing fever spirochaetes. White mice and white rats are readily infected by S. duttoni and the Panama spirochaete but are refractory to S. recurrentis except after passage through monkeys. S. carteri causes only a transient infection in these small rodents.

Natives seem to suffer severely from tick fever in childhood but in adult life possess a sufficient degree of immunity so that the disease shows itself in a very mild form in those harboring spirochaetes.

The immunity conferred by an attack is not lasting and a second infection may occur within a year. Such second attacks, however, do not present the relapses so important in a clinical diagnosis. As a matter of fact there may be no symptoms and such cases with spirochaetes in their blood make ideal carriers for the infection of ticks or lice. Ticks can be infected by these carriers. In some of the rest houses 50% of the ticks may be infected. While the tick does not tend to leave its habitation it may be transported in the bundles of native porters. The transmitting agent of the North African relapsing fever and probably of the Indian type is the louse. The body louse deposits about 75 eggs in the clothes of the host, which hatch out in about four days and become adults in about two weeks. The head louse deposits its eggs or nits on the hair of the host’s head. Hagler has noted that, in Servia,[91] typhus fever disappeared when lice were gotten rid of but relapsing fever continued to prevail until they also exterminated the bedbugs.

The Relapsing Fever of Panama.—Bates, Dunn and St. John have demonstrated that a tick, Ornithodoros talaje, transmits the relapsing fever of Panama. This tick seems to prefer the crevices and open joints of bamboo beds, laying its eggs and moulting in the hiding places. It comes out at night to feed on the occupants of the bed. Two white rats were inoculated with an emulsion made from ticks taken from a suspected bed. Both rats developed a spirochaete infection. A man inoculated with blood of one of these rats developed relapsing fever on the sixth day. A second man was inoculated subcutaneously with an emulsion of ticks collected from a bed and showed spirochaetes in his blood on the eleventh day.

Another man was bitten by ticks from the same source and was instructed not to scratch the bite. The ticks engorged in about 15 minutes, some of them secreting coxal fluid which mixed with blood from the bite made a scab. This man was positive for spirochaetes on the fifteenth day.

Agglutinating and lytic substances show themselves chiefly during the apyretic intervals.

There may be rather marked praecordial oppression and a bronchial catarrh. The pulse in particular and the respiration in less degree are accelerated. Herpes[92] and epistaxis may be noted. The bronchial manifestations seem to occur chiefly in the first febrile accession. The spleen is somewhat enlarged and tender but in many cases this is not noted. Spirochaetes are found in the peripheral circulation during the febrile accessions but not during the apyrexial intervals. There is great variation as to the abundance of spirochaetes. In some cases we may have to search several hundred fields before finding a single spirochaete. Severe cases may show them in abundance. A rather marked leucocytosis may be present in cases showing high fever and bronchitis. After about four days the fever falls by crisis, often below normal, and possibly with great prostration and cardiac weakness.

In European relapsing fever the second febrile accession is usually shorter and of less severity than the first. Furthermore there are rarely more than 2 or 3 relapses. In tick fever, however, there may be as many as 10 of these febrile recurrences, although there are usually only 4 or 5. In natives there is usually only one febrile period, this probably being due to an immunity resulting from previous infections.

North African Type.—In the relapsing fever of North Africa the attacks are less severe and the number of relapses rarely exceeds three. A fever of Egypt, generally known as the bilious typhoid of Griesinger, is believed to have been a form of relapsing fever. In this there was marked bilious vomiting with great tenderness of the liver, late jaundice, albuminuria, bone pains, especially about the knees, and a high death rate. The symptoms rather suggest yellow fever but this disease has never been reported from Egypt.

Indian Type.—In the relapsing fever of Asia there is a marked tendency for the patient to collapse at the time of the crisis. There are rarely more than two relapses and in probably 25% of cases there is no relapse. There seems to be a greater tendency to liver complications in the Asian types than elsewhere and such cases form a large part of the death rate from this disease. Bilious vomiting and jaundice, with a typhoid-like state and the occurrence of various inflammatory complications, especially parotiditis, are noted. The mind is usually clear, but delirium may be present in severe cases.

Relapsing Fever of Panama.—In three experimental cases the temperature of the first accession varied from 102°F. to 104.5°F. Frontal headache and general body aches were the chief symptoms. Vomiting was noted in one case. The spleen was not enlarged. The first relapse was cut short in each case by arsphenamine.

The Temperature Curve.—This is the chief point in the clinical diagnosis of relapsing fever. The onset of the first febrile accession is abrupt and the temperature[93] rapidly rises to 104°F. or higher. After a continued high temperature for three or four days the fever drops by crisis, which is at times productive of collapse. Following an apyrexial period of four to eight days we have a second febrile accession, and there may be several of these wave-like alternations of fever and apyrexia.

The Nervous System.—Very marked frontal headache is a striking feature and the pains in back and limbs may be of great severity. Cranial nerve involvement has been noted. There may be apathy, but on the whole the mind is clear.

The Digestive System.—Anorexia and vomiting are features of the febrile periods to cease in the fever-free periods. In some types bilious vomiting may be marked.

The Circulatory and the Respiratory System.—The pulse rate is much accelerated, and there may be some praecordial distress. A bronchial catarrh is frequently present in the first febrile paroxysm.

The Liver and Spleen.—Splenic tenderness and moderate enlargement are fairly constant features. The liver may suffer severely in the so-called bilious typhoid and marked jaundice may ensue with a typhoid state.

The Blood Examination.—This is the most important point in diagnosis. The spirochaetes, which are only found in the peripheral circulation during fever periods, are not so numerous in tropical relapsing fevers as in the European forms. When spirochaetes are scarce it is more satisfactory to examine Romanowsky-stained specimens, especially with the Giemsa staining. The spirochaetes show a varying number of undulations. There is no chromatin staining in the line of the spirochaetes. The disease when severe shows a well-marked polymorphonuclear leucocytosis, with at times an increase of large mononuclears. This latter, however, may be connected with malaria or amoebiasis.

The blood of a suspected case even during the apyrexial period should be injected into a mouse or white rat (guinea pigs are refractory to infection). Spirochaetes should appear in the blood of the mouse in about twenty-two hours and persist for about two days. Relapses occur but recovery is the rule.

Yellow fever has many features in common with the bilious type of relapsing fever, but there is no leucocytosis in yellow fever, and there is no characteristic albuminuria and slow pulse in relapsing fever. Influenza has many points in common with relapsing fever.

Typhus fever shows a less abrupt onset and the marked mental symptoms (stupor) and dark macular eruptions about the trunk, on the 4th to 6th day, should differentiate. If the case is first seen in the apyrexial period one may take a drop of blood from a case showing spirochaetes and one from the suspected patient. After incubation for thirty minutes the spirochaetes should lose motility and agglutinate if the case be one of relapsing fever (Lowenthal’s Reaction).

In blood examinations we may use the dark-field illumination, although the spirochaetes stain readily with Wright’s stain. The India ink method is a good one. Hagler recommends smearing out a mixture of one loopful of blood and a collargol preparation made by diluting one part collargol with two parts water. The diluted collargol should stand 24 hours and be filtered before use.

A serious feature of the disease is the length of its course, this often extending from six weeks to two months.

Destruction of the spirochaetes by salvarsan injection is important prophylactically as well as therapeutically—the reservoir of infection for lice or ticks being gotten rid of.

Conseil has treated cases with galyl and ludyl, in doses of 4 to 7 grains, with results as good or better than with salvarsan. The pains in the head and back are relieved by aspirin, although a hypodermic of morphine may be necessitated. Cool sponging and fresh-air treatment are desirable. On the whole, treatment, other than the specific one, is symptomatic.

Administration of the Arsphenamines.—Although arsphenamine (salvarsan) is probably the drug of choice when immediate therapeutic effect is desired, neo-arsphenamine is more popular because it is more simply prepared and administered, is tolerated better by the patient and has a slightly higher therapeutic index. It is, however, less stable, and both the powder and its solutions should be inspected carefully for signs of decomposition, namely, a darkening in color, a strong odor, and insolubility. Ampules containing either drug should be immersed in 95% alcohol for 15 minutes in order to detect any crack. Should a breach be found, or suspected, the ampule should be rejected.

Myocarditis, advanced non-syphilitic renal or hepatic disease, advanced arteriosclerosis and Addison’s Disease are regarded as generally contra-indicating the employment of these drugs. Cases in which the syphilis is of long standing should receive mercurials for at least a week prior to the first injection of arsenic, in order to avoid the possibility of activating lesions in vital organs (Herxheimer), and should be closely questioned regarding the occurrence of symptoms following previous injections (idiosyncrasy).

Prior to each injection, a patient should have a complete uranalysis, receive a cathartic on the evening preceding, and be allowed only liquids for the meal preceding. Subsequently to the injection, he should be allowed only liquids for the succeeding meal, and be retained under observation for at least twelve hours. Untoward symptoms following the injection are treated usually with epinephrin solution (0.6 to 1.2 cc.) or atropin.

Arsphenamines are administered intravenously, usually in the median cephalic or the median basilic vein at the bend of the elbow. This method requires aseptic technic throughout. All apparatus should be thoroughly washed before sterilization, since it is believed that symptoms may arise from substances extracted from glassware and rubber tubing. The water used must be distilled, preferably twice, and freshly boiled. The dose of arsphenamine is 0.3 to 0.6 gm., that of neo-arsphenamine is 0.3 to 0.9 gm. Until tolerance is ascertained, the dose should be small and not repeated in less than a week.

1. Only a single ampule should be dissolved at a time. The powder should be dusted over the surface of a small portion of the water and permitted to dissolve without agitation. The solution is then made up to bulk. Specimens which do not dissolve readily are to be rejected.

2. Cold water only is to be used.

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3. The solution should not be stronger than 0.1 gm. of the drug in 2 cc. of water.

4. A very small needle should be used, and the time of the injection should not be less than five minutes.

1. Cold Water Should be Used in all Cases.—(Exception. “Arsenobenzol” requires hot water. Consult instructions issued by individual manufacturers for possible departures from these directions.)

2. Neutralization and Alkalinization of the Solution.—With a graduated pipette or burette add 0.9 cc. of normal NaOH, standardized against normal acid, for each 0.1 gm. of the drug. The alkali should be added all at once, the amount specified being slightly in excess of that required to redissolve the flocculent precipitate first formed.

3. Concentration of the Drug.—It is important that the concentration of the drug is not greater than 0.1 gm. to 30 cc., i.e., 180 cc. of water for the usual dose of 0.6 gm.

4. Method of Injection.—The gravity method only should be employed. When several patients are to be injected from the same solution, the container for the solution should be graduated. A glass stopcock is of value in controlling the flow of solution, but in its absence the rate of injection can be governed by the elevation of the fluid and by the size of the needle. A needle of 18 or 20 B. & S. gauge is best.

5. Rate of Injection.—Operators should pay particular attention to the rate of administration since it is believed that rapidity of injection accounts for more unfavorable results in the use of arsphenamine than any other one thing. In no case should the rate exceed 0.1 gm. of drug (30 cc. of solution) in two minutes, i.e., twelve minutes for the average dose of 0.6 gm.

When a susceptible individual is bitten by an infected mosquito there develops, after a period of incubation of from two to five days, a rapid rise of fever, with markedly congested face and severe pains of back and head. About the end of the third day the sthenic manifestations are succeeded by asthenic ones in which jaundice, haemorrhages, particularly black vomit, and anuria are the important features.

Faget’s sign of a lack of accordance between pulse and temperature is of great diagnostic importance.

History.—It would seem probable that yellow fever was the disease from which those of Columbus’ second expedition suffered in San Domingo, in 1495. At the same time the first definite description of the disease was that of Dutertre, in Guadaloupe, in 1635. There has been much discussion as to whether the West Coast of Africa may not have been the original endemic centre and the importation to the West Indies the result of the slave traffic. While there is very little support given this view the recent recognition of the extent and importance of the African endemic area, as brought out by Boyce, is somewhat suggestive. Spinden advances evidence to show that a devastating epidemic disease, attended with bleeding from[98] the mouth and nose, raged among the Mayas and Aztecs in pre-Columbian periods. One such epidemic is recorded as of 1454. There have been numerous severe outbreaks in the United States, that occurring in Philadelphia, in 1793, being the most celebrated and that centering in Memphis, in 1878, probably the most terrible. Yellow fever has been a scourge in Brazil since its introduction in 1849, until quite recently. Lisbon experienced severe outbreaks of the disease in 1723 and in the next century in 1850 and 1856. Many of the Spanish cities have also suffered from time to time.

The history of the connection between yellow fever and the mosquito is discussed under etiology.

Geographical Distribution.—As will be seen from the chart the chief epidemic centers are the islands and coasts of the Gulf of Mexico and the West Coast of Africa. The disease has at times extended down the West Coast of South America and is now rather prevalent in Ecuador. The last epidemic in the United States was that in New Orleans.

The disease has never invaded Asia or Australia and there is fear that the opening of the Panama canal may bring this about.

Guiteras, who has recently returned from an investigation of the problem of yellow fever on the West Coast of Africa, was unable to find evidence of its existence there at the present time. He notes an absence of the extreme heat and abundance of mosquitoes which are features of yellow fever ports of South America.

Autopsies of the guinea pigs showed a fatty and yellow liver with nephritis. Some of the injected guinea pigs showed only fever but seemed to have acquired an immunity to subsequent injections of a virulent virus. In the blood, liver and kidneys of the animals showing the jaundice and albuminuria Noguchi was able to demonstrate spirochaetes by dark-field illumination. He also obtained cultures from such animals. Leptospiras were demonstrated in the blood of 3 out of 27 human cases but only after prolonged search. Cultures have been obtained from human yellow fever blood. For culturing, a medium is used consisting of 1 part of serum and 3 parts of Ringer’s solution made semisolid with 0.3% agar and contained in tall tubes. One cc. citrated yellow fever blood is introduced into the lower part of the medium. A thin layer of liquid petrolatum is poured on the top of the medium. We need partial oxygen tension but not anaerobiasis. Optimum growth temperature is 33°C. L. icteroides is from 4 to 9 microns long by 0.2 wide and tapers gradually to extremely thin sharp points. These organisms will pass the pores of V and N Berkefeld filters thus placing them in the group of filterable viruses. The virulence of different strains varies, with some strains as little as 0.00001 cc. of culture proving fatal for guinea pigs. Monkeys, rabbits and birds were not susceptible to infection but the marmoset and puppy seemed to respond as did the guinea pig.

Guiteras doubts the etiological relation of Noguchi’s leptospira to yellow fever on the ground that in view of the susceptibility of animals to this organism the disease should exist as an epizootic, which is improbable in view of the ease with which yellow fever is eradicated when measures applied solely to man and the mosquito are practiced. Among other points of objection he notes the recovery of the spirochaete from the blood later than the third day of the disease.

In the natural method of transmission the mosquito, Stegomyia calopus, is the intermediary. In order that the female of this culicine species may transmit the disease it is necessary that she bite a yellow fever patient in the first three days of his illness, after which a period of approximately twelve days must elapse before the mosquito can transmit the disease. In such case the period of incubation varies from two days one hour to six days two hours. Carroll was bitten by a mosquito which had fed on a yellow fever patient twelve days previously, and four days later experienced a very severe attack, this fact being against the views of the French[101] Commission that the disease shows a less severe form in those who may be bitten in the first period of the infectivity of the mosquito. A second case bitten five days later by the same mosquito that infected Doctor Carroll had a mild attack. Persons bitten by experimentally contaminated mosquitoes before an interval of twelve days had elapsed escaped infection.

Prior to the investigations of the American Commission our views as to the incidence and spread of yellow fever were chaotic.

Rush, in 1793, thought that the Philadelphia epidemic originated from “damaged coffee which putrefied on a wharf near Arch Street.”

In 1883, Doctor Friere reported that yellow fever was caused by a coccus, Cryptococcus xanthogenicus and claimed that he could confer immunity by vaccination with attenuated cultures. Carmona y Valle of Mexico and Carlos Finlay of Havana considered that the Micrococcus tetragenus was the cause but Sternberg, investigating these claims, showed that these cocci had nothing to do with yellow fever. In his work Sternberg isolated an organism which he designated “X.”

American Commission.—In addition to Reed and Carroll, Lazear and Agramonte were also members of the Commission.

The Commission first cultured the blood of 18 yellow fever patients with negative results for B. icteroides in every case.

B. icteroides grows as readily on culture media as does the typhoid organism.

It was also shown that yellow fever blood, which was negative for B. icteroides, could produce yellow fever when injected subcutaneously. In 11 autopsies made shortly after death cultures from various viscera were negative for B. icteroides. It was then decided to abandon, as fruitless, further investigations as to Sanarelli’s organism, and to take up the mosquito transmission theory.

Riley from a study of Nott’s original paper, thinks that the author had in mind invisible forms of insect life, which could act as disease producers, and simply cited the mosquito to illustrate his views. In 1853, Dr. Beauperthuis, in Guadeloupe, noted that malaria and yellow fever ceased to exist in regions which from their altitude fail to nourish “insectes tipulaires.”

He also thought that the virus of these diseases was introduced by the channel of insect inoculation. Furthermore he stated that the variety, zancudo bobo[102] (Stegomyia), had white stripes on the legs and was in a way the domestic species. However, there is a question whether his zancudo bobo was Stegomyia and furthermore if we translate the expression inoffensif as without result it would negate the connection between this mosquito and disease production.

From 1881 Doctor Carlos Finlay had been advocating the transmission of yellow fever by Culex fasciatus (Synonym for Stegomyia calopus).

In 100 experiments made by Finlay 13 cases of yellow fever developed.

In no instance had these experimental mosquitoes fed on a yellow fever patient more than six days previous to their biting and, knowing that a period of at least twelve days must elapse, the infections in the 13 cases could not have been brought about by these experimental mosquitoes.

The American Commission obtained ova from Doctor Finlay and from these ova mosquitoes were hatched for the experimental work. Of 11 susceptible persons, bitten by contaminated mosquitoes, the first 9 remained uninfected while the two volunteers, bitten subsequently (Aug. 27 and 31), developed the disease. One of these cases was that of Doctor Carroll, whose infection was brought about by one of these laboratory reared mosquitoes which had fed on 4 cases of yellow fever, two of which were severe cases and two mild. This mosquito had fed on one of the severe cases just twelve days previously. The other case was bitten by 4 contaminated mosquitoes, one of which was the one that had infected Doctor Carroll.

Of the 9 negative cases 6 were bitten by mosquitoes which had fed on yellow fever patients from the fifth to the seventh day of the disease and the remaining 3 failures were where the interval between contamination and biting the volunteer was from two to six days only.

At this time the medical mind was obsessed with the idea that yellow fever was transmitted by fomites.

It had been forgotten that Cathrall, in 1800, had failed to infect himself with black vomit and that Ffirth, in 1804, in order to obtain material for a graduation thesis, swallowed black vomit and smeared it, as well as blood, upon wounds he had made on his skin with negative result. (It will be remembered that the fourth proposition of the French Commission was that application of infectious serum to the abraded skin would not produce the disease—the hypodermic injection being required.)

There were other experiments with similar results.

One of the occupants of the fomites building was afterward inoculated subcutaneously with 2 cc. of blood taken from a patient in the first day of the disease and developed yellow fever after four days of incubation. This proved that he was susceptible to yellow fever.

Blood from this patient, taken in the first three days of his attack, was injected into a third man who also developed yellow fever. This experiment was to prove that the production of the disease was due to a virus capable of multiplying rather than to a toxin. Of course, it would be impossible to conceive of a toxin so potent that it could produce symptoms in a third man when diluted in the circulation of the second man.

In the other building there was a screen partition dividing the space into two compartments, one containing 15 contaminated mosquitoes, the other with the same air but without mosquitoes. Controls occupying the mosquito free section remained free from yellow fever, while those exposing themselves in the mosquito-containing compartment developed yellow fever. One of these cases was bitten by mosquitoes contaminated thirty-nine days previously, a second one with fifty-one day insects and a third, who developed a severe case, was bitten by mosquitoes contaminated fifty-seven days previously.

As above stated the Commission inoculated men subcutaneously with blood, taken from yellow fever patients in the first three days of the disease, with positive results. It was also found that if the blood was heated to 55°C., for ten minutes the virus was destroyed and, finally, it was found that the filtrate from a Berkefeld filter was infectious, thus showing that the virus was so minute as to pass through the pores of a filter which would hold back the smallest known bacterium (filterable virus).

Experiments of Guiteras.—During the summer of 1901 Doctor Guiteras, with a view to immunity production, repeated the experiments of the Army Commission and infected 8 persons, 3 of whom died. Gorgas thinks the greater severity of these infections may be explained by greater virulence of the virus developing in the mosquito during the hot season. It is known that the development of this virus requires fifteen to twenty days in winter as against the twelve days for summer.

Note.—Doctor Lazear, who had charge of the mosquito work of the Commission, tried to infect himself with experimental insects prior to his applying a twelve-day mosquito to Doctor Carroll. About three weeks later he was bitten by a mosquito which he did not at the time consider a Stegomyia. The attack of yellow fever which resulted from this bite ended fatally.

The French Commission verified these findings and in addition brought out the following points.

1. Cutaneous vaccination with infective serum is without result.

2. Infectious serum loses its yellow fever-producing power in forty-eight hours unless preserved under liquid petrolatum when it remains virulent for five days.

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3. Infectious serum if heated for five minutes at 55°C. loses its virulence but has prophylactic and curative power.

4. Besides the method of hypodermic inoculation yellow fever can only be transmitted by the bite of a mosquito in which the virus has remained for at least twelve days.

5. In one instance it was thought that the progeny of infected mosquitoes transmitted the disease. Rosenau and Goldberger, in 38 experiments, failed to obtain such result.

Paraplasma flavigenum.—In 1909, Seidelin reported certain minute protozoa as existing in the red cells of yellow fever patients. He considered them as related to the piroplasms and gave the name Paraplasma flavigenum. It is stated that the parasite has been found as late as the fourteenth day from the onset of the attack. The idea is advanced that there may be carriers of yellow fever. These claims are generally denied.

The idea that the colored race possesses immunity is now thought to be connected with the contraction of the disease in infancy or childhood, attacks at this period of life being very mild and difficult of diagnosis.

There has been some inclination to question the immunity conferred by an attack of yellow fever but Carter has shown that in quarantine practice we can admit such immunes with perfect safety. Thirty thousand such immunes were allowed to enter Key West and Tampa from Havana between 1888 and 1898 and no case of yellow fever developed from them. During the same period 450 non-immunes from Havana gave 13 cases in the quarantine stations.

The Yellow Fever Mosquito.—A knowledge of the life history of Stegomyia calopus explains the epidemiology of yellow fever. This culicine species is widely distributed in the tropical and subtropical world, extending from 38° north to 38° south latitude. It is rarely found at a greater altitude than 3000 feet. Petropolis, a railway-connected suburb of Rio, has an altitude of 2300 feet, with cool nights, at times about 9°C, and a freedom from Stegomyia. Persons having occupation in Rio during the day but returning to Petropolis in the afternoon escape yellow fever. In[106] this connection it is generally accepted that the female Stegomyia only bites between 5 o’clock P.M. and midnight. While the first feeding may occur earlier in the day, all subsequent feedings, which alone could be infectious, occur late in the afternoon or at night. (Recent observations show Stegomyia to bite in daytime,—not at night.)

These views, which were advanced by Marchoux, would explain the apparent freedom from infection of those leaving infected areas by the early afternoon. Seidelin, however, claims that these mosquitoes will continue to bite in the day after numerous feedings of blood.

It is recognized that railways are unimportant factors in transporting these mosquitoes, differing in this respect from ships which offer better conditions.

Stegomyia seem to prefer water for breeding that is slightly tainted with sewage, although developing equally well in fresh water. They will also develop in brackish water.

When once this mosquito takes up its residence in a certain room of a house it rarely leaves it and thus is explained the danger of occupying a room which has been occupied by a yellow fever patient. Then too, the warning sound, so characteristic of the approach of most mosquitoes, is not given by Stegomyia.

The female lays about 70 eggs in small groups and not in a compact egg raft as with Culex. The eggs are therefore difficult of detection. The eggs do not suffer after rather prolonged drying. Even temperatures approximately 0°C. do not seem to destroy the viability. It would seem probable that it is this stage in the metamorphosis of Stegomyia which is responsible for the survival of the species under unfavorable conditions.

The eggs the American Commission received from Finley had been deposited thirty days previously on the edge of some water in a basin. The water had meanwhile evaporated and the eggs were dry. Notwithstanding this the eggs promptly hatched out when water was poured in the basin.

The most favorable temperatures for these mosquitoes range from 29° to 31°C. Under 20°C. the eggs do not hatch out.

The larvae, which hatch out in about two days, develop into pupae in approximately one week. In about two days the fully developed insect breaks out of the pupal case. It will thus be seen that a period of ten to fourteen days suffices for a generation. The insect is almost black and has a silvery lyre or Jew’s harp pattern marking on the thorax. The legs and abdomen also have silvery bands. The female lays several batches of eggs and has been observed in one instance to live 154 days. The French Commission kept a female alive 106 days. They consider that life under normal conditions is much shorter in duration than in captivity. If deprived of water the adult insect only lives about five days. In a refrigerator, Guiteras was able to keep mosquitoes alive, without food or water, for eighty-seven days.

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On fruit and sugar vessels the conditions for the development of Stegomyia are exceptionally favorable.

These mosquitoes are prone to remain in the same house where they have been feeding. Carter has pointed out that yellow fever rarely spreads more than 75 yards from an infected house so that it is improbable that infected mosquitoes fly, or are carried by the wind, any great distance.

The same authority has also noted that ships in Havana harbor lying about 400 yards from shore never become infected when the crew have not been ashore or where infected ships have not been anchored near by.

It is probable that they are carried aboard ships in connection with coaling or provisioning rather than blown aboard by prevailing winds.

The icterus is apt to be more marked after death, and is especially prominent about the neck and eyelids. Dutroulau considers the absence of icterus in a cadaver as negativing yellow fever.

The liver is of a boxwood or chamois skin color and on section is very oily. Haemorrhagic patches may be seen dotting the yellow cut surface.

The stomach and intestines contain disintegrated blood. Petechiae and erosions are common in the cardiac end of the stomach. The upper part of the duodenum shows changes similar to those seen in the stomach but the other portions of the intestines are essentially negative.

The spleen does not show any particular change. The kidneys are enlarged, congested and on microscopical examination show fatty degeneration of the renal epithelium.

The adrenals often show fatty degeneration, especially of the cortex.

Haemorrhagic infiltrations are marked features in skin and mucous and serous membranes.

Vomiting, first of mucus and bile, comes on very early. About the second day albumin appears in the urine and by the 3d or 4th day this is present in large amount and is associated with the presence of hyaline and granular casts. The temperature remains fairly high for three or four days, with morning remissions and evening exacerbations. Of great diagnostic value is Faget’s law as to lack of correlation of temperature and pulse, in that by the 2d day, notwithstanding the high temperature, the pulse rate becomes less and by the 3d or 4th day it has probably decreased 20 to 40 beats from its initial rate.

Stage of Remission.—About the close of the 3rd day or upon the 4th day there may occur a fall in the temperature and a decided amelioration of the symptoms. This however is frequently not noted and even when present may last only for a few hours. It is often called the stage of remission or calm. By the 3d day the congestion of the facies and other sthenic manifestations have disappeared and, possibly preceded by the short period of remission, there is ushered in the second or asthenic stage.

Asthenic Stage.—It is at this time that we have the appearance of the most characteristic features of yellow fever—the jaundice and the haemorrhages. The jaundice is first noted in the sclerotics and rapidly spreads over the body as a lemon[109] to orange yellow tinging. Swelling and bleeding of the gums are the earliest signs of the damage to the capillaries. This may go on to bleeding from the nasal mucosa, the intestines and, best known and most dreaded, the coffee ground vomiting or black vomit of gastric haemorrhage. Epigastric tenderness is often marked. In very severe cases haemorrhagic extravasation into the skin may appear. The mind is peculiarly clear, the patient alert and suspicious. At times patients may be delirious even to the extent of wild struggling to throw themselves out of bed.

In favorable cases the temperature rapidly falls to normal, associated with an unusually slow pulse rate, even below 45.

Besides the typical course we may have cases so mild that the albuminuria is insignificant and the jaundice and haemorrhages entirely absent. On the other hand we may have fulminating cases with jaundice and black vomit setting in by the end of the 3rd day and rapidly going on to a fatal termination.

The Temperature.—This rises abruptly, reaching its maximum by the 1st day. Very high temperatures are not a feature of yellow fever. There is nothing characteristic in the further course of the fever chart and it should be borne in mind that the so-called intermission is transient and deceitful.

General Appearance.—On the 1st day the face is swollen and congested. This florid congestion, which may extend down the neck to the upper part of the chest,[110] is more marked in yellow fever than in any other disease. The eyes are shining, the conjunctivae injected and there is photophobia.

About the end of the 2d day the facial congestion disappears to be succeeded by an earthy tinging and subicteroid tinting of the conjunctivae. The jaundice does not appear until about the fourth day. This may be noted somewhat earlier if one blanches the skin by pressure with a glass slide. Petechial eruptions may be prominent in the later stages. The jaundice is best seen at a distance of 5 to 6 feet.

The Circulatory System.—Of peculiar value in diagnosis is Faget’s law—a falling pulse rate with constant temperature or a constant pulse rate with a rising temperature.

A markedly slow pulse, between 40 and 50, is often recorded about the time of the period of remission.

It is interesting to note that the pulse of yellow fever made a great impression upon Benjamin Rush, who called it the indescribable or sulky pulse. The systolic blood pressure is high at first, but by the 2d day begins to fall, becoming quite low in the asthenic stage (even below 70 mm.) due probably to supra-renal involvement rather than to cardiac weakness.

Haemorrhages, especially from gums, nose and intestines, are common. Black vomit is the best known of these haemorrhages.

Blood Examination.—This has generally been considered as varying but slightly from normal findings.

Noc states that in the first stages of the disease there is an increase of the polymorphonuclear percentage with a marked diminution or disappearance of eosinophiles while later on, from the 3d to the 6th day, there is an increase in the large mononuclears.

The Alimentary Tract.—The tongue may be coated in the center. Vomiting often appears early and consists of whitish or bile-stained mucus. It must be remembered that if black vomit should appear it almost never comes on before the 4th day. There is usually marked epigastric tenderness. Bleeding from the gums and intestinal canal are not rare.

The Nervous System.—The mind is unusually clear, the patient often mentally alert and suspicious. There is often insomnia. The severe cephalalgia, often frontal or supraorbital, as well as the severe loin pains (coup de barre) are striking features. There may be a marked hyperaesthesia. A delirious state may be present.

The Liver and Spleen.—There is no special alteration in the size of either liver or spleen. There may be tenderness about the liver region. The jaundice of the asthenic stage is incident to the pressure of the swollen degenerating liver cells on the bile capillaries while the fatal issue is connected with the loss of the urea formation function. It has been claimed that an acidosis may occur. The spleen is not affected.

The Genito-urinary System.—Albuminuria begins to appear about the second day and tends steadily to increase in amount. Various types of tube casts, often bile-stained, are abundant. The urine shows neither bile nor blood cells except in the later stages of the disease. The reaction is very acid. It is of the utmost importance to note the quantity of urine voided, as scanty secretion, leading to anuria, makes for a very grave prognosis.

The diseases with which yellow fever is most apt to be confused are:

Aestivo-autumnal Malaria.—In ordinary aestivo-autumnal malarial paroxysms the search for the malarial parasite is of great importance, although the finding of a malarial infection does not exclude yellow fever. Albuminuria is not a feature of tropical malaria.

In that type of tropical malaria known as bilious remittent fever the clinical picture is rather asthenic and bile pigment in the urine is an early feature. Again jaundice comes on fairly early and the slow pulse is absent. The spleen is enlarged and tender.

Blackwater Fever.—This is an asthenic disease with marked and very early jaundice. The haemoglobinuria (Blackwater) is pathognomonic. Splenic tenderness is marked.

Smallpox.—The early headache, backache and vomiting of smallpox may well confuse one before the eruption of variola appears.

Dengue.—This is probably the most difficult disease to diagnose from yellow fever. The facies, orbital pains and backache of yellow fever and dengue are similar. Dengue also shows a slowing of the pulse. The high blood pressure of the onset is not present in dengue. There is no albuminuria in dengue and there is a marked and early leukopenia with reduction of the polymorphonuclear percentage, which does not exist in yellow fever. The jaundice of yellow fever and the eruption of dengue do not show themselves until after the first three days.

Relapsing fever, typhus fever and plague have been considered by some authorities as possible of confusion with yellow fever.

Bilious Typhoid of Egypt.—In 1851 Griesinger described a disease he called bilious typhoid of Egypt in which there was a sudden onset with marked chill and rise of temperature in four or five hours to 103° or 104°F. Rachialgia and bilious vomiting were marked. There was splenic enlargement. The temperature fell on the fourth or fifth day with at about this time the appearance of icterus. Relapses were the rule and the mortality was very high.

Bone pains, especially about the knee, were common and severe. This disease is now considered a relapsing fever. It is this disease which affected the troops of Napoleon in Egypt and which was thought by some authorities to have been yellow fever. Others think it may have been epidemic jaundice.

As a general rule the earlier in the year an epidemic starts the more virulent the disease; thus the 1853 epidemic, just referred to, started in May.

High temperatures and excessive albuminuria, as well as early appearance of jaundice, are bad signs. The mortality may be considered as averaging about 20%.

It must be remembered that this mosquito not only breeds near human habitations but that it tends to remain in the same room where it has been feeding. Consequently we should use sulphur fumigations or Giemsa’s spray or killing by hand to destroy insects. The larvae breed by preference in old tin cans near the house door. To kill these one should empty every old receptacle of water, and oil or cover other collections of water.

All receptacles used for collecting and storing water draining from roofs should be carefully screened with fine copper wire gauze. Of particular importance is it to treat every suspicious case as it if were one of yellow fever and screen the patient as well as destroy any mosquitoes in the room or house occupied by such patient.

Noguchi reports success in prophylaxis by the injection of 2 cc. of a killed culture of Leptospira icteroides. Immunity is not conferred until after the tenth day. He notes that among 3607 persons vaccinated in Salvador there were no cases of yellow fever while among the unvaccinated 181 cases occurred. Killed cultures of Leptospira icteroides were first used for protective inoculation in 1918 when 427 vaccinations were carried out.

During the first three days of the disease no nourishment whatever should be given. The patient should be allowed an abundance of fluid, of which the best is Vichy, of which may be given a couple of ounces every twenty minutes or so, iced or just[113] cool, as the patient prefers. Water, to which 30 grains of bicarbonate of soda to the pint has been added, makes a good substitute. It is of vital importance to put the patient to bed and keep him quiet. When vomiting is severe cracked ice or iced champagne may be of value. Alkaline enemata are indicated when the patient cannot retain the Vichy. There would seem to be an acidosis in yellow fever.

A mustard foot bath is best given in bed, the feet and legs of the prone patient being immersed in a foot tub half full of warm water into which a pound of freshly ground mustard has been stirred. Every few minutes there should be added a quart of very hot water so that the bath may be very hot—just short of burning the feet. The blankets are kept over the patient and the foot tub, so that we also give a vapor bath which causes free sweating. This treatment relieves the headache and backache. This foot bath can be repeated 2 or 3 times in the first twenty-four hours. After the bath, the sweating patient must be thoroughly dried. Cold spongings are important means of keeping down fever. For anuria use dry cups to the loins or hot fomentations. Strychnine may be indicated in the asthenic stage and camphor in oil hypodermically for extreme cardiac weakness. The Sternberg treatment is 150 grains of sodium bicarbonate and ⅓ grain of bichloride of mercury in a quart of water. The dose is 1½ ounces every hour.

Any exertion causing a rise in blood pressure may be fatal. It is possible that the stimulation of the circulation incident to the taking of food may explain the dangers of allowing food to a patient. As before stated no food should be given for the first two or three days. Then commence with albumin water and thin barley gruel. Later on wine jelly and easily digestible broths. Even when convalescence sets in we should be very careful as to diet.

Noguchi has produced an immune serum to his spirochaete by injecting horses. He has records of 170 cases of yellow fever treated with this serum with a mortality of 13.6%, while untreated cases gave a death rate of 52%. He notes that the serum must be given before the third day of the disease to be of any value—best results in the first day. He believes also that though salvarsan and neosalvarsan have some leptospiricidal action they are both too damaging to the kidney to supplant serum in treatment.

History.—This disease was probably the form of jaundice noted in the forces of Napoleon during the Egyptian campaign. It was first recognized as a distinct disease by Weil, in 1886, who described it as a peculiar form of acute infectious disease characterized by jaundice, swelling of spleen and nephritis. Inada and his Japanese colleagues discovered the causative spirochaete in 1915 and noted the frequency of this parasite in rats. Infectious jaundice was an important disease of the soldiers of the recent war.

Geographical Distribution.—Japan and Egypt may be considered as the parts of the world in which the disease is most common. It is endemic in West Africa and cases have frequently been reported from the shores of the Mediterranean.

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During the Russo-Turkish war (1877) cases of jaundice seen in the Balkans by Sandwith were probably infectious jaundice as the disease was frequently noted in that region during the recent war. Cases were noted in Flanders during the war. A few cases have been reported from the United States.

It is insoluble in 10% saponin thus differing from the other blood spirochaetes. The constituent spirals are closely placed and the total length may reach 15 to 20 microns. The dark-field illumination is preferable for its demonstration although it shows up well by various staining methods. To culture use a medium of one part of rabbit’s serum with three parts of Ringer’s solution inoculating with citrated plasma. The organism is found in the blood during the first three or four days of the disease. It is also present in the urine. Young guinea pigs are particularly susceptible and in them we have, following injection of the blood of a case, jaundice, albuminuria and haemorrhages. At autopsy the spirochaetes are best demonstrated in a liver emulsion. Infection with this spirochaete is common among rats in various parts of the world so that it may be considered a natural infection of rats, but they do not seem to suffer from it.

In Japan it has been noted that the disease is most common in wet mines, disappearing when the mines are pumped dry. Before we knew the cause of the disease attention was directed to the connection between the infection and working about defective sewers. Trench warfare, with the accompanying rats and wet conditions, seemed to favor infection.

Jaundice appears about the third or fourth day with marked tenderness of the liver and slight or moderate enlargement of the spleen. The urine is scanty and high colored showing albumin and bile pigments. Early in the second week urine of a low specific gravity is excreted in large amounts. The pulse is rapid at first to become slow with the appearance of the jaundice. There is a tendency to sleeplessness and nocturnal delirium and in unfavorable cases the “typhoid state” comes on. Pains in the nape of the neck and calf muscles are common features.

Haemorrhages, starting as epistaxis, are commonly observed. Next to epistaxis[117] intestinal haemorrhage is the most frequent. Haematuria is rarely observed. The red cells and the haemoglobin fall in percentage with an increase in the polymorphonuclears. The leucocytosis runs about 15,000.

The spirochaetes may be found with the dark-field illumination early in the disease in a blood examination and later on in the urine.

Agglutinins appear in the blood about the end of the first week and cultures may be agglutinated by such serum diluted as high as 1 to 500.

Bilious remittent fever shows earlier jaundice, a more rapid pulse rate and malarial parasites.

In yellow fever there is more marked rachialgia and earlier and more marked albuminuria. The marked leucocytosis of Weil’s disease should be of differentiating value.

The early jaundice and haemoglobinuria of blackwater fever should distinguish this disease.

Leptospira morsus-muris is found in the blood of infected mice, rats or guinea pigs during the first two weeks and then becomes distributed in the connective tissues especially that of the lips, bridge of nose and tongue. They are not secreted in the saliva but the transfer seems to occur by a break in the spirochaete-containing tissues and thus inoculated into the bite wound. The organism may possibly be excreted in the urine.

The onset is often characterized by chills and malaise. A rapid pulse and prostration are present during the pyrexial period.

Symptoms of nephritis may appear.

After the critical fall of temperature there is usually an apyrexial period of several days during which time the local manifestations about wound and glands subside. The fever again comes on, to later disappear and reappear.

The successive paroxysms are usually of less severity.

The fever is suggestive of the relapsing fevers. The pulse is rapid and weak. There may be as many as twelve of these febrile accessions and the course of the disease may extend over several months. There is an eosinophilia and during the febrile paroxysm a leucocytosis of about 15,000. The spirochaetes should be looked for in the blood during the early febrile periods. The dark-field illumination is the best method for their demonstration.

Strychnine for the heart weakness and tonics during convalescence are recommended.

Aspirin is often necessary to relieve the headache and joint pains.

As prophylactic measures the same precaution should be taken as to cauterization of the wound as one would observe in rabies.

The visceral leishmaniases are characterized by a chronic course, marked splenic enlargement, progressive anaemia and emaciation together with leucopenia. The cutaneous leishmaniases can only surely be differentiated from other tropical sores by the finding of the leishman bodies from smears made from the granulomatous tissue of the sore.

History.—In 1869 the English medical authorities in India became familiar with a very fatal disease among the natives of Assam but regarded it as a very malignant form of malaria. The native designation for the disease was kala-azar. In 1889 Giles investigated this disease and finding hookworm ova in almost all of the cases he came to the conclusion that it was ancylostomiasis.

Rogers (1896) and Ross (1898) after studying the disease were of the opinion that it had to do with malaria, the former regarding it as a malignant form of malaria and the latter that it was malaria plus some secondary infection.

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Owing to the very similar temperature charts and misled by agglutination tests of the serum of kala-azar patients, which he regarded as showing agglutinins for the Micrococcus melitensis, Bently, in 1902, claimed that kala-azar was a malignant form of Malta fever.

In 1903 Manson suggested that the disease might be caused by a trypanosome, the absence of malarial parasites and non-response to quinine being against the then usually accepted malarial etiology.

A few months later in the same year, May, 1903, Leishman reported findings which he considered as degenerated trypanosomes in the spleen pulp of a soldier who died in 1900 at Netley Hospital of dum-dum fever. Although first noting the peculiar bodies in 1900, at the time of making the autopsy, he was at a loss to explain their significance but in 1903, while examining a trypanosome-infected rat, he came to the conclusion that there was a similarity in the parasites of the two infections and published his paper entitled “On the possibility of the occurrence of trypanosomiasis in India.”

In July, 1903, Donovan reported the finding of similar parasites in material from splenic puncture of cases of dum-dum fever and taken during life.

There was much discussion as to the true nature of these leishman, or leishman-donovan bodies, Laveran regarding them as piroplasms while others thought them to be trypanosomes.

In 1904 Rogers succeeded in cultivating these parasites in citrated salt solution and noted that the cultural forms were those of flagellates. In 1903, Wright, of Boston, found similar parasites in the granulation tissue of a tropical ulcer in a little Armenian girl.

In 1905, Pianese found leishman bodies in smears from liver and spleen of children dying with infantile splenic anaemia in Italy. About the same time Laveran in examining spleen smears made by Cathoire from an infant dying of an undetermined disease in Tunis found these bodies. Later investigations have shown this infantile[123] leishmaniasis to be rather prevalent in the Northern part of Africa and Southern part of Europe.

These parasites are grouped with the haemoflagellates and occur in their vertebrate hosts exclusively as small, oval, cockle-shell-shaped bodies, measuring 2.5 × 3.0 microns. The protoplasm stains a faint blue and contains a rather large trophonucleus which is peripherally placed and gives the appearance of the hinge of the cockle shell. Besides this macronucleus we have a second chromatin-staining body which is often rod-shaped and set at a tangent to the larger nuclear structure. It is called the blepharoplast or micronucleus and stains a more intense reddish than the rather fainter stained pinkish macronucleus. One or more vacuoles are common in the cytoplasm.

Some consider these nonflagellated bodies, which are usually found packed in endothelial cells of spleen, liver, lymphatic glands and bone marrow, as resting stages, the flagellate existence occurring in some other host than its vertebrate one. Patton has carried on an immense amount of experimental work with the bedbug and has noted the development of flagellate forms from the 5th to the 8th days in bugs which fed on kala-azar patients showing leishman bodies in their peripheral circulation. If the bugs are allowed a second feeding after the infecting blood meal the flagellates disappear within twelve hours, so that for full development in the bedbug a single feeding is requisite. He states that the flagellate forms change to post-flagellate ones by the twelfth day. At the same time, although much evidence exists in favor of the bedbug as host for the flagellate forms, it has not been shown experimentally that the bedbug is definitely connected with the transmission of the disease.

Donovan is disposed to incriminate Conorhinus rubrifasciatus as the transmitting agent and furthermore he feels that there has not been sufficient investigation of mosquitoes along this line.

Wenyon, however, tried to infect two young dogs with great number of fleas which had previously fed on dogs infected with canine leishmaniasis and at autopsy, five or six weeks later, was unable to find parasites in smears from spleen, liver or bone marrow and did not succeed in obtaining cultures from this material inoculated into tubes of N. N. N. medium.

Basile states that a temperature of 22°C. is necessary for the development of the parasite in the flea and that negative experiments have been due to their not having been conducted in the winter. Patton has had fleas feed on a heavily infected dog, whose peripheral blood showed hundreds of parasites per film. These experiments were made in the winter and although examining 200 of these fleas he failed to find any evidence of the flagellates after eight hours.

Views have been entertained that the canine infection is one with a flea herpetomonad distinct from Leishmania, but as dogs can be infected with L. infantum and then show manifestations similar to canine leishmaniasis the parasites are probably the same.

Patton fed great numbers of fleas on a dog experimentally infected with L. donovani and found that the flagellates had entirely disappeared from the alimentary tract of fleas dissected after eight hours, although fleas dissected within four to six hours showed degenerating Leishmania.

As regards oriental sore Wenyon has found that bedbugs and Stegomyia will feed from the sores and take up parasites which develop into flagellate forms in the gut of the insects.

Proof of transmission by these agents however is lacking and others are inclined to suspect the house fly or some species of moth midge.

In Brazil there exists some evidence that the cutaneous leishmaniasis found there may be transmitted by species of the tabanid family.

It must be understood that there is always a suspicion that the flagellate forms noted in arthropod experiments may be those of nonpathogenic herpetomonad or crithidial species as such forms are common in arthropods and are difficult to distinguish from the flagellate stage of leishman bodies.

Cultural Forms.—Very definite is our knowledge of the cultural forms of Leishmania. Rogers first cultured material from splenic juice of kala-azar patients in 10% sodium citrate solution at a temperature of 17° to 24°C. The medium was slightly acidulated with citric acid. There was no satisfactory development at blood temperature. In forty-eight hours the oval parasites have developed into herpetomonad flagellates, from 20 to 22 microns long by 3½ microns broad, with a 20-micron flagellum which takes origin from the blunt anterior end of the body near the blepharoplast. The peripheral blepharoplast and centrally placed macronucleus are at a distance from one another as opposed to the approximation of the crithidial blepharoplast to the centrally placed nucleus in a body with pointed anterior end.

It is absolutely essential in culturing L. donovani or L. infantum that the blood agar or citrated blood be sterile, as any bacterial contamination prevents growth. With the parasite L. tropica, however, bacterial contamination does not inhibit development and statements have even been made that growth is favored by a staphylococcal symbiosis. L. tropica, it would seem, will develop into flagellated forms in cultures at 28°C. while it will be remembered that Rogers in his original experiments failed to obtain other than commencing signs of division at 27°C., 22°C. being the temperature necessary for the development of flagellate forms.

L. tropica from South American cutaneous leishmaniases seems to grow more luxuriantly on N. N. N. medium than does that of oriental sore of Asia and Africa.

Giugni tried N. N. N. media made with human, rabbit and dog blood, respectively. The parasites grew well on dog and rabbit blood media but not on that made with human blood. He found growth best when he added salt in quantity from 5 to 9 grams per liter. When red corpuscles are laked in a medium the growth is less favorable.

Animal Inoculation.—With animal inoculations we formerly thought that the parasite of kala-azar could be differentiated from that of infantile leishmaniasis by the fact that dogs could not be infected with L. donovani, while they were susceptible to infections with L. infantum. Recently Donovan and Patton have successfully inoculated dogs with kala-azar splenic material. Patton found the parasites in the liver, spleen and lymphatic glands as well as bone marrow of the inoculated dogs. Consequently we cannot separate the two visceral leishmaniases from a standpoint of susceptibility of the dog. Monkeys are susceptible to both diseases. It is important to recognize the fact that animal inoculations, even with spleen-juice, rarely give rise to infection.

As regards separating oriental sore from the visceral leishmaniases Gonder has shown that white mice may be infected with both kala-azar and oriental sore, there being produced in each case a general infection with the presence of parasites in spleen and liver. A point of difference, however, is that the oriental-sore mice develop lesions on feet, tail and head which was not observed with the kala-azar mice. There are some reasons for thinking that in human cutaneous leishmaniasis a generalized infection may precede the local manifestations.

Dogs and monkeys can be infected with L. tropica as well as mice, but in them we have only cutaneous lesions produced. Inoculation should be made intraperitoneally.

Morphology.—As regards morphology it is usually stated that the parasites of the three species of Leishmania are practically identical. In cultures it has been noted that the flagella of L. tropica are longer and more twisted than those of L. infantum. Again it has been observed that the parasites of the Oriental and South American skin lesions may at times show a flattened or band-like trophonucleus instead of the constant round or oval one of the visceral leishmaniases.

Escomel has reported the finding of flagellated Leishmania in the South American sores.

It has been suggested that the Mediterranean basin may have been the original focus of visceral kala-azar and that it spread thence to India by way of Greece and the Russian Caucasus, cases having been reported from districts which would join the two foci.

Just as children bear the brunt of malaria in old malarious districts and adults suffer in places in which the disease has been more recently imported, so by analogy we may consider the disease as of more recent introduction in India. We now know that visceral leishmaniasis is widely distributed in China, north of Yangtse, as well as in the Sudan, and quite recently a case of kala-azar has been reported from South America, in an Italian, who had lived in Brazil from 1897 to 1910.

In the Mediterranean basin there is a natural canine leishmaniasis and some think the human form may be contracted from the dog through the medium of the flea. This dog kala-azar exists in two types, one acute and the other chronic.

Manson has suggested that as oriental sore is common in camel-using countries it might be that a passage through the camel lowered the virulence of the parasite as passage through the bovines does variola, so that such an infection was of a mild type.

More recently there has been some evidence to indicate that oriental sore may simply be a manifestation of a visceral infection as shown in Gonder’s work with mice and from the fact of the long period of incubation in oriental sore with the appearance in some cases of general symptoms as well as the cutaneous ones.

The South American leishmaniases differ clinically from oriental sore in that, following the primary lesions, ulcerating granulomatous processes of nasal and buccal cavities frequently set in subsequently, at times even after the primary manifestations have healed.

In 195 cases reported from Assam, by Mackie, 100 were in children between six and ten years of age so that it is hardly true to call Indian kala-azar a disease of adults.

On the other hand, Mackie dissected 322 bedbugs which he had fed on kala-azar cases with practically negative results. He also injected material from 588 bugs into two monkeys with negative results. Mackie was likewise unsuccessful with lice, mosquitoes and sand flies.

At the same time various observers have frequently noted instances where an advanced case may associate intimately with his relatives for months or years and yet none of these develop the disease.

There is little to support the view that it is a contact infection, as such does not occur in hospitals where verminous insects are absent. By isolating the sick and moving the uninfected to new houses, only a short distance away, there is no spread of the disease. The disease practically appears only in those Europeans who live with or among natives.

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In view of the fact that Leishmania may be found in the intestinal ulcerations or in the kidneys there have been suggestions that the disease may be spread through the medium of faeces or urine. There is not the slightest evidence that the parasites could live in water which they might contaminate and the view that some sort of transmitting host might take up parasites from the faeces or urine is improbable, as the parasites have never been found in faeces or urine.

The fact that a distance of 300 yards seems to suffice for permanent protection of the uninfected excludes from consideration such transmitting agents as the mosquito or house fly.

The tendency of some to incriminate soil factors can be explained by the well-known fact that bedbugs can live for months without food, being ready to bite those entering an infected house even after long disuse as a habitation of man.

Infantile kala-azar may possibly be connected with the disease in dogs and may be transmitted by the agency of the flea but there is nothing like the evidence for this view that obtains for the bedbug theory in Indian kala-azar.

When the phagocytic endothelial cells rupture the parasites are taken up by other cells and if by large mononuclear or polymorphonuclear cells may appear in the peripheral circulation. In possibly 80% of cases the parasites may be found after prolonged search in smears of peripheral blood. The leucopenia and large mononuclear increase are the blood features.

Rogers attaches particular importance to the fact that four-hour charts will show a double or even triple rise of fever in the twenty-four hours instead of the single one in typhoid fever. The patients also show a striking absence of typhoid malaise and apathy often stating that they feel well when the temperature may approximate 104°F.

In the early stages of the disease the loss of weight is apt to be marked. Later on, owing to improvement in appetite and increase in spleen, this is not so manifest.

The spleen begins to enlarge early in the disease and has usually reached the level of the umbilicus by the third month. In some cases there is little if any enlargement of the spleen even in the chronic stages. At times we note only an irregular fever with weakness, anaemia and emaciation. The liver does not usually become distinctly enlarged until about the sixth month.

The course of the disease in India is chronic often covering a period of one or two years. In the Sudan, however, Bousfield noted that the symptoms ran an[130] acute course, the average duration being only about 5 months. Rarely he encountered chronic cases with greatly enlarged spleen.

As the disease progresses anaemia and emaciation become marked so that the bulging spleen and liver in a dusky or earthy colored, skeleton-like native (black fever) make a striking picture. The lymphatic glands of cases in North China show enlargement.

Symptoms referable to intestinal ulcerations, such as diarrhoea or dysentery, are often noted at the end. Bleeding from the gums and nose is not infrequently noted.

These complications frequently bring about a fatal termination so that we do not get the typical terminal cachexia with emaciation, exhaustion, dry brittle hair, petechiae, oedema and ascites. On the other hand the tendency of a bacterial infection to cause a leucocytosis may bring about a cure.

The onset is insidious with some fever and gastro-intestinal upset. The spleen enlarges, the child becomes apathetic, anaemic and emaciated. Irregular attacks of fever occur and the child often suffers from epistaxis, bleeding from the gums or haemorrhages into the skin. According to Nicolle a peculiar pallor of the skin is characteristic. Ulcerations of the intestines and noma may bring about a fatal termination. The liver does not enlarge to the extent that the spleen does. The finding of the parasites is necessary for the distinction of this infantile splenomegaly from those of other origin. The lymphatic glands are not usually enlarged.

Onset and Fever Chart.—The disease commences in a rather indefinite manner, often with gastro-intestinal symptoms or possibly daily rigors. The fever chart is that of a remittent fever with rather marked oscillations and in particular a double rise in the 24 hours, which Rogers regards as characteristic. The absence of a high continued fever and this double daily rise assist in differentiating typhoid. Waves of fever separated by apyrexial periods often simulate the fever chart of Malta fever.

The Spleen, Liver and Lymphatic Glands.—The splenic enlargement, which may reach the umbilicus by the third month, is the most characteristic clinical sign of kala-azar. The diagnosis was formerly made by spleen puncture but owing to many fatalities the liver puncture is to be preferred, although the results of such exploratory examinations are often negative, the liver being involved to a less extent than the spleen and rarely showing appreciable enlargement before the third month. It is during the pyrexial periods that the spleen and liver enlarge.

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Cochran has brought forward the importance of examining smears from excised lymph glands for the parasites and others have shown that gland puncture is of value. The glands in the infantile type of the disease often do not show enlargement.

The Blood.—Marked anaemia is only found in the later stages and the color index is about normal. The number of red cells rarely falls below 2,000,000.

Leucopenia is characteristically marked, this having been below 2000 in 62% of Rogers’ cases. This authority considers the finding of 1 white to 1000 red cells, in a case of fever, very significant of kala-azar.

There is also an increase in the large mononuclear percentage which would aid in differentiating typhoid.

The coagulability of the blood is decreased and this may be a factor in the fatal results which at times follow spleen puncture.

Parasites are found in the peripheral circulation in about 80% of cases, after prolonged search, and may be phagocytized by either large mononuclears or polymorphonuclears.

Patton found parasites in the peripheral blood in the examination of a single slide in 42 out of 84 cases and with three slides in 25 of those not showing parasites with the first slide. By repeated examinations up to the seventeenth slide, he got positive results in all 84 cases.

The Sudan commission found that the alkalinity of the serum of their patients was diminished.

Rogers has noted an acidosis in unfavorable cases of kala-azar while those showing improvement only showed slight or no acidosis.

Respiratory and Circulatory Systems.—There is very little that is constant, the lungs being quite normal in 90% of Rogers’ cases. The pulse rate is rather variable, although usually accelerated.

In children showing splenomegaly the probability of the case being kala-azar rather than malaria is indicated if the case has shown progressive deterioration of health.

Malta fever shows a rather similar succession of febrile and afebrile periods but the spleen of the former rarely shows marked enlargement and the bronchial catarrh, sweatings, transient joint swellings and neuralgic manifestations are characteristic of Malta fever. Kala-azar may show muscular pains and slight sweatings and the differentiation has at times only been made by the laboratory diagnosis.

Typhoid and the paratyphoids are best differentiated clinically by the presence of a continued fever, the absence of a double daily rise and the existence of a more marked apathy.

The recent statements that hookworm disease may show enlargement of the spleen would make this a condition to differentiate. Hookworm ova and an eosinophilia indicate ancylostomiasis but there is always the question here as with malaria as to the existence of kala-azar and some other affection.

While malaria may at times show a leucopenia below 4000, a polynuclear percentage below 50 and a large mononuclear one of 20 or more, yet the simultaneous appearance of all three is rare in malaria while common in kala-azar.

Malta fever, typhoid and the paratyphoids are best differentiated by blood cultures or agglutination tests.

Until recently it was recommended that for diagnosis our best procedure was to make a splenic puncture. Manson and others have pointed out the dangers from splenic puncture in kala-azar and have rather preferred puncture of the liver, although recognizing that the chances of obtaining parasites from a liver puncture, are less than from a splenic one.

Statistics have been given where a mortality approximating 1% has followed spleen puncture. Bousfield, however, using an all-glass syringe with a 1½ inch needle did not have a fatality in 120 spleen punctures.

Cultures on N. N. N. medium can also be made.

Human blood seems to inhibit growth so that N. N. N. medium for cultivating Leishmania should be made from rabbit blood.

The culture should be kept at a temperature of about 22°C.

One should always first examine a smear of the peripheral blood for parasites in polymorphonuclear or large mononuclear leucocytes. The Sudan Commission found leishman bodies in the peripheral blood of 13 out of 15 cases so examined, but rarely did they find more than one parasite-containing leucocyte to a slide.

It is well to select a time when some pyogenic infection causes a leucocytosis.

It has been noted that artificial pustulation might assist in diagnosis by giving a multitude of polymorphonuclear leucocytes for examination for phagocytized Leishmania.

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Cochran has recently noted the advisability of excising a lymphatic gland and making gland smears to examine for Leishmania. Others have reported success with gland puncture as utilized in the gland of trypanosomiasis.

Animal inoculation has no place in diagnosis as such a procedure is but rarely successful. Ray has recently proposed a turbidity test in which about 2 drops of blood are added to 20 drops of distilled water. Instead of giving a clear solution of haemoglobin we have a turbidity followed later by a white flocculent precipitate. It is now thought that this turbidity is due to excess of serum globulin in the blood of this disease and the test can be carried out with serum instead of whole blood.

The mortality is usually given as about 95% although Rogers states that he has reduced this to 75% by large doses of quinine. The action of antimony is that of a specific. Patients often succumb to complicating septic conditions or pneumonia.

Castellani recommends a combination of quinine and atoxyl, while Manson has reported success with atoxyl in 2 cases, giving 3 grains intramuscularly every other day.

Salvarsan has been tried, but without much success, as is also true of X-rays.

Some have tried cinnamate of soda with the idea of increasing the leucocytes.

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With the purpose of increasing leucocytes Rogers has tried hypodermic injections of sodium nucleate and killed staphylococcus vaccines as well as splenic substance tablets. The sodium nucleate injections were most painful and did not increase the leucocytes. He had some success with tabloids of spleen substance.

If the blood serum shows a lessened alkalinity the intravenous injection of solutions of bicarbonate of soda should be tried.

Rogers reports very favorable results from the administration of alkalies by mouth.

Recently hectine has been recommended in infantile kala-azar.

Following the successful employment of intravenous injections of antimony tartrate in American leishmaniasis it has been used in Indian and infantile kala-azar.

Rogers has used the same treatment in Indian kala-azar with a considerable degree of success. He has also used a 5% ointment of finely divided antimony. The treatment should be continued until the temperature has been normal several weeks and the leucocyte count approach the normal.

Knowles, at Shillong, has had long experience and striking success with the intravenous administration of tartar emetic in kala-azar. The heavy powder alone should be used—not the light powder. A 1% solution is prepared in normal saline and the solution autoclaved for 10 minutes at 110°C. If there is any opalescence or deposit discard the solution. Knowles begins with the intravenous injection of 3 to 4 cc. for an adult and gives the injections on alternate days, increasing the dose until we are giving from 10 to 12 cc., the maximum dose. It will be noted that the dosage ranges from 3 to 10 centigrams (½ to 1½ grains). The amount of drug given for a complete course of treatment is 200 cg. (33 grains). In the latter part of the course of treatment the effects on the patient are more marked so that caution must be observed, and it may be necessary to lengthen the interval or reduce the dose. The injections should not be given within two hours of a meal. Organic disease of the heart or kidneys contraindicates the antimony treatment. Coughing, a metallic taste in the mouth and constriction of the chest are frequently noted following the injection. Nausea, colic and diarrhoea show that the limit of the drug has been reached and albuminuria and jaundice are signs of warning to decrease the dose or stop the treatment. Christopherson considers that 5 to 8 grains will cure oriental sore, but for kala-azar 60 grains may be necessary. This authority considers 3 grains of tartar emetic as the maximum dose intravenously. For children under 1 year of age the intravenous dose of the 1% solution is ¼ to 1 cc., from 1 to 5 years old 1 to 3 cc. and from 5 to 10 years of age 1 to 5 cc.

Manson-Bahr has reported the successful use of an organic preparation of antimony, the sodium salt of p-acetylaminophenylstibinic acid. It is a powder, readily soluble in water and has the trade name of “stibenyl.” It can be injected intravenously up to 0.8 gram. The drug contains 36% of antimony. Knowles advises the use of tonics and, when indicated, of anthelminthics. He also recommends cod liver oil to increase the weight.

As the result of our knowledge that such lesions are caused by leishman bodies, Leishmania tropica, we have been forced to include among such sores clinical types entirely different from the classical oriental sore of Fayrer or Tilbury Fox. Even a keloid type of lesion described by the workers in the Sudan is known now to be caused by leishman bodies. In 1909 leishman bodies were demonstrated in ulcerative processes from Brazil and since that time we have divided cutaneous leishmaniasis[136] into two groups, according to geographical distribution, that of the East, or oriental sore, and that of the West, or American leishmaniasis.

Oriental sore is found chiefly in North Africa, Asia Minor, Syria, Persia and India, and more recently cases have been reported from Italy and Greece and New Caledonia. American leishmaniasis is found chiefly in Central America, Brazil, Peru and the Guianas.

There has been a great deal written about the origin of the disease in drinking water, various inorganic constituents having been incriminated as factors. In certain places, as Delhi, oriental sore has decreased among the British troops with the discontinuance of the use of water from certain city wells. We know that oriental sore is rather easily inoculable, it having been stated that certain people of Bagdad inoculated their children in order to insure against the possible appearance of the sore on the face with the resulting scar disfiguration. Wenyon found that the virus would not pass through the unabraded skin.

The disease is most prevalent about the end of summer and in the autumn. It is a disease of towns. Some have thought that it might be transmitted through the medium of the laundry. Not only can man be infected by inoculation but this is also possible with monkeys and dogs when a scarified area about nose or over eyebrows is inoculated with virus from a sore.

The lesions are similar to those in man but last a shorter time.

It has been suggested that the dog may be the reservoir of this virus as well as for that of infantile kala-azar. There is some experimental evidence to show that an animal which has recovered from a visceral leishmaniasis is immune to a cutaneous one.

There has been an idea that lizards or snakes might serve as the reservoir of virus for oriental sore and that species of Phlebotomus feeding on these reptiles might take in the flagellates and subsequently transmit them to man. Laveran, however, has been unable to infect lizards with L. tropica. Patton’s observations point to infection from the crushing of infected sandflies when biting the exposed surfaces of the skin.

As regards the American sores there is a great deal of difference of statement as to the probable transmitting agent. These sores seem to occur in forest regions where clearing of the trees is going on. Infections occur in late summer or autumn. Marshy districts appear to favour infection. Brumpt thinks the fact that dogs, which are susceptible as well as monkeys to inoculation with the American leishmaniasis,[137] are often bitten by ticks without the production of the sore, is against the view that ticks act as transmitting agents. He rather favors a tabanid fly and in a case reported by Darling the patient incriminated a tabanid fly.

Five cases are reported by Cerqueira as following the bite of Phlebotomus lutzi.

The disease seems to occur naturally in the dog in the infected regions.

In the keloid type of leishmaniasis noted by the Sudan Commission epithelial cell nests were characteristic although there was no other evidence of epithelioma.

The period of incubation is usually given as about two months, although in some instances it may be as short as a week. Usually the earliest appearance of the sore is similar to that of a mosquito bite. The papule continues to enlarge, becoming purplish in color with a glazed surface. It somewhat resembles an inflamed acne lesion. Growing larger, the surface of the blind boil-like lesions now becomes covered with brownish scales and, either from scratching of the rather pruriginous spot or from the development of vesicles, it becomes covered with a yellowish crust, beneath which is an ulcer with raised edges and discharging a thin offensive pus.

The ulceration does not generally occur before the third or fourth month. The ulcer is painless and may be an inch or more in diameter. Healing comes on in about seven to ten months, the yellowish unhealthy granulations giving place to healthy pink ones. The sore tends to run a course of about one year, hence the French designation bouton d’un an.

According to Déperet and Boinet the number of sores to a case was one sore in 30%, 2 to 4 sores in 50% and from 4 to 20 in about 20% of cases.

Just as with oriental sore one or more pruriginous papular lesions appear on the uncovered parts of the body. In a few days it develops a pustular summit. This undergoes ulceration and after several months or even after the primary lesions have healed nodules may make their appearance in nose and mouth.

These ulcerate and form fungoid granulations. Even the larynx may be involved. The nasal septum and other cartilaginous portions of the nose are often destroyed and the overlying tissues become swollen and often eroded by ulceration, so that the[139] patients present the appearance of similar cases where syphilis, tuberculosis or leprosy may be the cause.

A point of distinction between syphilitic and leishmaniasis lesions of the nasal mucosa is that the latter do not involve the bony structures.

Rabello noted that a positive Wassermann may be present in cutaneous leishmaniasis which is in agreement with Sutherland’s findings of 27% positives in cases of kala-azar.

The patients suffer from fever, joint pains, bronchitis and general symptoms. After a long period of ten to twenty years, during which they often die of some intercurrent affection, there may be a terminal cachexia.

It has been recommended to paint the spot of insect bites with tincture of iodine.

Atoxyl and salvarsan have been tried in oriental sore and American leishmaniasis without any particularly striking curative results. Attempts have been made to excise the early lesions but unless one goes well beyond the infected area, severe recurrences may result. Bier’s passive congestion method has been tried without success.

An expectant treatment is usually resorted to, the crusts being softened and removed with antiseptic fomentations with subsequent disinfection of the ulcer with bichloride or potassium permanganate solution and the application of some antiseptic ointment or powder. Thorough cauterization with pure carbolic acid followed by rapid neutralization with alcohol can be tried. The injection of killed cultures of Leishmania does not seem to have been effective.

Wenyon has had good results from an ointment of equal parts of methylene blue, lanoline and vaseline in an American sore.

Carbon dioxide snow has been shown by Mitchell to be an efficient local application for oriental sore.

Although Hippocrates was the first accurately to describe the disease we now know as dysentery yet there is good ground for believing that the disease existed in Egypt and India for centuries before Christ.

Many of the older writers failed to differentiate conditions which showed admixtures of mucus and blood in the stools from those with blood alone.

Commencing with the last century, authorities have considered the association of mucus with the blood as essential in clinical diagnosis.

It is interesting that with a better knowledge of etiology we are now recognizing as of dysenteric nature diarrhoeal conditions in which there is an absence of the typical stool of dysentery.

Our views as to the etiology and epidemiology of bacillary dysentery have been fairly definite for at least twenty years, while those relating to amoebic dysentery, notwithstanding the important researches of Kartulis, Councilman and Lafleur, Schaudinn and others have remained rather chaotic until quite recently.

As a rule the stool is composed of one or more teaspoonfuls of greenish yellow or dirty brown mucus, the altered blood being intimately admixed with the mucus, or we may have a whitish to grayish muco-purulent mass with streaks or flecks of blood on the outside. These mucoid masses may be found suspended in serous, sanguineous or more or less feculent discharges which are usually small in amount and passed with much frequency.

The terms tormina and tenesmus are the ones used to designate the characteristics of the pains of dysentery, tormina for the griping colicky pains, which center about the umbilicus or run in the direction of the large intestine, and tenesmus for the painful spasmodic contractions of the sphincter ani to which is due the sensation of lack of ability to complete the act of defecation leading to straining and justifying Manson’s description “glued to the commode.”

It is usually stated that the nearer the dysenteric process is to the rectum, the greater the tenesmus and the nearer to the caecum, the greater the tormina.

Owing to the great importance of the two main kinds of dysentery, amoebic, or that caused by Entamoeba histolytica, and bacillary, or that caused by some strain of Bacillus dysenteriae, we shall consider them separately from the other causes of the dysenteric symptom-complex.

While in adults these intestinal flagellates usually cause only a diarrhoea, with at times marked nervousness, they may produce dysenteric symptoms in young children. The onset in children under three years of age may be insidious and attended with fever. The stool contains much mucus with only a little blood.

In diagnosis it is important to recognize the encysted Lamblia. These are oval cysts, about 10 × 7µ and show a curved central line, with two lateral dots. When stained these dots show as chromatin areas. These cysts may be found in the faeces in great numbers. The vegetative Lamblia has 4 pairs of flagella, is about 15µ long and has a tumbling motion. Calomel alone or calomel and ipecac give good results at times. Enemata of organic silver salts may be of benefit.

Porter recommends bismuth salicylate. Low has noted the tendency of lambliasis to recur and thinks many of the reported cases of cures are only temporary. His experience with bismuth, salol, thymol and cyllin has not been encouraging.

It is well known that lambliasis is of rather frequent occurrence in mice and rats so that these rodents may be factors in spreading the infection through the agency of their faeces deposited about human food.

Of other drugs recommended in treatment Dobell and Low have had no success with methylene blue, turpentine or beta-naphthol. These authors failed to find any increase in either large mononuclears or eosinophiles in a case of the infection.

Since Lamblia inhabit the upper parts of the small intestine, it may be that the administration of drugs by the duodenal tube will prove an effective method of treatment. Owens reports successful results in the treatment of amoebic dysentery from ipecac so administered. Stiles has recommended sulphur in lambliasis.

The parasite is so large and has such an active motility that it would be impossible to fail to detect it in a microscopic examination of the faeces. Encysted parasites are round. The onset is rather insidious with diarrhoea which may be followed by dysentery. A severe form of anemia may be noted.

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Ipecac, emetine, arsenic and quinine appear to be of little value in the treatment, but Walker considers the organic silver compounds, as protargol, etc., of value. Methylene blue enemata (1-3000) and 2-grain pills by mouth have been recommended.

Wenyon noted a case of coccidial infection (Isospora hominis) in which there was a dysenteric syndrome. There have been about seventy cases of infection with this parasite reported, chiefly from soldiers serving in Gallipoli. The usual opinion is that they are nonpathogenic parasites. The oocysts are ovoid, with one end narrowed, and measure 28 × 14 microns. There are two sporocysts, each of which contains four sporozoites. The cyst when first passed is unsegmented.

2. Infections with Gastrodiscus hominis also give rise to dysenteric manifestations.

3. A very small cestode, Heterophyes heterophyes, has been noted to cause a condition suggestive of dysentery.

4. In 1902, Brumpt noted the finding of a nematode, Oesophagostomum brumpti, in the large intestine of an African native, which caused dysenteric symptoms and, more recently, another species, O. stephanostomum, has been reported as causing a fatal dysentery in a Brazilian at Manaos.

5. There have also been reported cases with dysenteric manifestations which were apparently connected with intestinal myiasis.

Paratyphoid infections may give the clinical picture of a colitis and such cases at times show a large amount of blood in the dysenteric stools. Usually the symptoms are rather those of an entero-colitis or a gastro-enteritis.

In a Pyocyaneus infection the color of the stools would be suggestive. This cause should be borne in mind in the dysenteric infections of debilitated children in the tropics. Some of the cases of so-called ptomaine poisoning due to members of the Gärtner group have clinical similarities to dysentery especially at the commencement of the attack.

A very interesting form of poisoning which gives rise to serious illness or death and is attended with marked abdominal pain and manifestations of dysentery is that reported from North China through the use of short lengths of bristles which are given mixed with the food.

Various irritant metallic poisons as arsenic, antimony and mercury may give rise to dysenteric symptoms. In cancer and syphilis of the rectum there may be a suspicion that the process is an ordinary dysenteric one.

Intussusception shows marked tenesmus with bloody rather than muco-sanguineous stools.

While dysenteric symptoms may be present in the terminal stages of various chronic diseases, especially tuberculosis and cardiac affections, yet it is in chronic nephritis, leading to uremia, that we may see symptoms of a marked catarrhal or even diphtheritic colitis.

In 1879 Grassi noted the encysted forms of amoebae, but as he found them in well people, he denied their pathogenic importance. Cunningham found amoebae in the stools of cholera patients and Perroncito in those of typhoid cases, both of these authorities, however, viewing the question of their pathogenicity as did Grassi.

This was the general attitude of the medical mind until Koch, in 1883, while investigating cholera in Egypt, was impressed with the striking penetration of amoebae in the walls of intestinal ulcers and considered that this fact favored the view that amoebae were pathogenic.

Kartulis continued the work of Koch and in 1886 published his findings in 150 cases of dysentery, noting the presence of amoebae in the stools of all these cases. In 1887 he noted the presence of amoebae in liver abscess. In 1891, Lutz noted that amoebae in dysentery contained red cells. In the same year Councilman and Lafleur came to the conclusion that there were two species of amoebae in man, one harmless and the other, which was found in the submucosa of intestinal ulcers, pathogenic, Casagrandi and others put forward the view that amoebae only acted as carriers for bacteria, but in 1893 Kruse and Pasquale injected all the bacterial species isolated from a dysenteric stool into a cat’s rectum with negative result. Hlava and Kartulis first produced dysenteric lesions in cats by injecting per rectum, amoebic stools. Kruse and Pasquale produced dysentery in cats by injecting per rectum bacteria-free pus from a liver abscess which however contained amoebae.

A stumbling block as to the connection between amoebae and dysentery was the fact that many cases of typical dysentery failed to show amoebae. In 1898 Shiga settled this matter by reporting a group of bacilli which were concerned in the production of dysentery. His findings were confirmed all over the world and the distinction gradually obtained of cases of dysentery from bacillary as well as from amoebic infections.

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In 1903 Schaudinn reported the existence of two species of amoebae, one harmless and named Entamoeba coli, the other pathogenic and named E. histolytica. In 1907 Viereck described a pathogenic amoeba which, by reason of its four nuclei in the encysted stage, he called E. tetragena.

Geographical Distribution.—Amoebic dysentery seems to be especially prevalent in Indo-China, China and the Philippines, as well as in parts of India. It is also very common in Egypt and Northern Africa. In South America, especially Brazil, it is common, as is also true of the West Indies and Central America. It is an important disease in the Southern States of the United States, as well as in Italy and other parts of Southern Europe. On the whole it is probable that it exists in greater or less degree in most of the tropical and subtropical parts of the world.

Etiology.—For a long time the authorities in Manila held that it was impracticable to differentiate between a pathogenic and nonpathogenic species, taking the view that the principal factor in the production of dysentery was that of symbiosis between amoebae and suitable bacteria, it having been thought that they observed in cultures of amoebae evidences of both symbiosis and antagonism on the part of amoebae to certain species of bacteria. They furthermore were convinced that pathogenic amoebae could be cultured on a medium of about 1/10th the strength of ordinary nutrient bouillon or agar and that dysentery could be produced by such cultural amoebae. Such views had an important bearing on epidemiology as it was thought that where amoebae could be cultured from green vegetables, fruit, or water supply there was positive evidence of the possibility of infection with amoebic dysentery from such a source.

For the nonpathogenic E. coli he noted: (1) No distinction between a granular endoplasm and refractile ectoplasm; (2) centrally placed and sharply outlined nucleus, rich in chromatin; and (3) encystment with the formation of eight nuclei, which cysts with their nuclei or amoebulae form the infecting stage.

The pseudopodia of E. histolytica are actively projected as long finger-like processes which show the ectoplasm quite distinctly, while the pseudopodia of E. coli are lobose and sluggishly projected and show a uniformly opaque grayish color. In dysenteric stools E. histolytica tends to show contained red cells. E. coli never contains them but instead shows bacteria and food particles.

All authorities now consider that Schaudinn made an error in observation as to the existence of peripheral budding for E. histolytica, so that we recognize but two types of encystment, one with a larger cyst and thicker cyst wall, with eight nuclei and an absence of chromidial bodies—E. coli—the other, smaller, with a thin cyst wall one to four nuclei and chromidial bodies in the encysted stage, the pathogenic amoeba, E. histolytica. Synonym, E. tetragena.

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In the vegetative stage the human amoebae are best differentiated by the nuclear structure as shown in stained specimens. In E. coli the nucleus is vesicular with a thick nuclear membrane and the chromatin chiefly deposited on the under surface of the nuclear membrane. This chromatin often seems deposited in quadrant aggregations. The karyosome is eccentric.

The histolytica nucleus has a thin nuclear membrane and is poor in chromatin while the tetragena nucleus has more chromatin, showing radial projections from the inner surface of the nuclear membrane, and a loose central spherical karyosome, which contains a central chromatin dot or centriole, with a clear halo surrounding it. Dobell states he has not been able to note this centriole.

Animal experimentation upon kittens with E. coli by Schaudinn, Craig and Wenyon have been unsuccessful as to production of dysenteric manifestations. On the other hand all of these experimenters produced typical lesions and dysenteric manifestations in kittens injected rectally or fed with material containing pathogenic amoebae.

Wenyon as previously stated produced a liver abscess in one of his experiments.

Darling has been so successful in his experimental work with kittens that he compares the colon of a kitten to a test tube and suggests the procedure of rectal injections of material containing amoebae as a means of differentiating the two human amoebae.

On the other hand Walker was unable to infect kittens and monkeys with material containing pathogenic amoebae and he makes the statement that such failures would indicate the greater susceptibility of man to infection, as he was able to infect 17 out of 20 men with one feeding of such material.

Sellards and Baetjer note that inoculation of kittens per rectum or by feeding dysenteric stools rich in amoebae has resulted in infection in about 50% of experiments.

By inoculating the material directly into the caecum they were able to infect every one of their kittens. They were also able to propagate a strain of amoebae through a series of animals for several months.

The intracaecal inoculations yielded positive results in diagnosis of human amoebiasis when the clinical manifestations were obscure and the amoebae in the discharges so few and atypical as to make such an examination unsatisfactory.

Other Intestinal Amoebae.—It is a remarkable fact that one of the most common of the intestinal amoebae, Endolimax nana, has only recently been reported (Wenyon and O’Conner in 1917). In the examination of the stools of American soldiers Kofoid found it present in 28% of his examinations while E. coli was present in 23% of cases and E. histolytica in 9.3%. In examining 156 British soldiers Dobell noted its presence in 33% of them. The general view is that it is not pathogenic but its great importance is in the possibility of its being mistaken in its cyst form for E. histolytica. The living amoeba averages about 8 microns but in stained specimens it is somewhat smaller. In freshly passed faeces the amoeboid motion is sluggish and the nucleus indistinct. This amoeba is best identified by haematoxylin stained specimens when the nucleus shows a measurement of about 2 microns with a large eccentric karyosome which exhibits a variety of form. Unless perfectly fresh material is stained the degenerative changes in the amoebae may give a signet ring appearance of karyosome and ring nucleus. Such an appearance may suggest the limax nucleus. The mature cysts are usually oval, but sometimes round, and contain 4 nuclei, but when newly formed may only have one nucleus. The nucleus is large in the uninucleate form (up to 3 microns) but in the quadrinucleate forms it is about 1.2 microns with a large eccentric mass of chromatin. Chromidial bodies are rarely, if ever, present in these cysts.

Iodine Cysts.—These bodies which stain a deep brown colour when treated with iodine are now recognized as amoebae and have been named Iodamoeba bütschlii. They are most probably nonpathogenic. It is a small amoeba (9 to 13 microns, rarely up to 20 microns) and shows the sluggish movements of E. coli. The nucleus is very difficult to discern, thus differing from E. coli. In stained specimens it has a[152] vesicular nucleus about 2 microns in diameter with a fairly large central karyosome. The cysts are spherical or oval, often of irregular outline and are about 10 microns in diameter. The nucleus is large and eccentrically placed and has a karyosome which tends to show as a peripherally placed mass. There is almost always present a large glycogen mass in the cyst which stains intensely with iodine.

Dientamoeba Fragilis (Jepps and Dobell 1918).—A rare binucleate amoeba averaging 8-9 microns in size. Nuclei show a fairly large, central granular karyosome and no peripheral chromatin. Strands of linin may be seen radiating from karyosome to nuclear wall. This organism is said to be frequently mistaken for Blastocystis when the vacuoles coalesce leaving a thin ring of cytoplasm. Cysts unknown. Considered nonpathogenic. Recently Kofoid and Swezy reported another species of amoeba parasitic in man, Councilmania lafleuri. The adult and cystic stages resemble in many respects the E. coli. Adult said to ingest red blood cells. Stated to be pathogenic but that more evidence is needed on this point.

The first series of experiments was with cultural amoebae, in order to refute statements that amoebae cultivated from water or other nonparasitic sources, as well as from dysenteric stools, are capable of living in man parasitically or of producing dysenteric symptoms. Twenty feeding experiments on ten men were made by Walker and Sellards with cultures of amoebae without the development in a single instance of dysentery or the finding of such amoebae in the stools upon microscopical examination. In 13 cases they recovered the amoebae in cultures from the faeces from the first to the sixth day, but never afterwards. They stated definitely that cultural amoebae are nonpathogenic.

The next experiments were with Entamoeba coli. In the 20 cases fed with material containing Entamoeba coli there was a uniform failure to recover them culturally and in no instance was dysentery produced. Seventeen became parasitized as the result of a single feeding in from one to eleven days, the entamoebae being found in the stools and persisting in their appearance in the stools for extended periods. They concluded that Entamoeba coli is an obligate parasite, nonpathogenic, and cannot be cultured.

The third series of 20 feedings, carried on by Walker alone, was with Entamoeba histolytica. The material was mixed with powdered starch or magnesium oxide and given in gelatin capsules. In these experiments they obtained tetragena[153] cysts in the stools of men fed only motile Entamoeba histolytica, and motile Entamoeba histolytica in the stools of men who were fed only tetragena cysts and, finally, an alternation of motile E. histolytica and tetragena cysts in the stools of a man having a recurrent attack of amoebic dysentery.

Results.—Seventeen of the men became parasitized after the first feeding; 1 required three feedings, and 2, who did not become parasitized at the first feeding, were held as controls. The average time for parasitization was nine days. Only 4 of the 18 parasitized men developed dysentery, which came on after twenty, fifty-seven, eighty-seven, and ninety-five days, respectively, after the ingestion of the infecting material.

In 4 cases fed with material from acute dysenteric stools or from amoebae-containing pus from liver abscess, and containing motile amoebae, there was no resulting dysentery, the 4 cases of experimental dysentery resulting from feeding of material from normal stools of carriers.

As regards the cases which became parasitized, but did not develop dysentery, it is suggested that the amoebae live as commensals in the intestine of the host and only penetrate the intestinal mucosa and become tissue parasites when there occurs depression of the natural resistance of the host or as the result of some lesion of the intestine. That the pathogenic amoebae are more than harmless commensals, however, is shown by the fact that they alone, and not the nonpathogenic Entamoeba coli, are capable of penetrating a possibly damaged intestinal mucosa.

This probably explains the endemic rather than the epidemic characteristics of the spread of amoebic dysentery because, if the innumerable vegetative amoebae in dysenteric stools were equally operative with the more sparsely eliminated cysts, there would be epidemics of amoebic dysentery similar to those of bacillary dysentery. The old idea that water, fruit or vegetables, from which one can isolate amoebae on culture, are sources of infection must be abandoned, as such cultural amoebae are known to have no pathogenic relation to man.

Vegetative amoebae undergo disintegration in a short time after the stool is passed, so that they are probably rarely concerned in amoebic infections but the resisting cysts may be washed from a dried stool into a water supply or even be transported in dust to lodge on unprotected foodstuffs.

Flies may possibly act as transmitting agents. As bearing on the probable importance of such flies as Musca domestica and Fannia canalicularis in transmitting amoebic infections may be noted the findings of Wenyon that the faeces of such flies, as well as Lucilia and Calliphora, after feeding on cyst-containing human faeces, teem with such cysts. In a dissection of 1027 house flies caught in Mesopotamia Buxton found ova of parasites of man in 4.09%. The percentage of infection with E. histolytica cysts was O.3%.

Small hemispherical elevations of the overlying mucosa mark the location of the deeper-lying necrotic process. With the multiplication of the amoebae and the extension of the necrotic process in the submucosa we have thrombi formed in the terminals of the portal vein and possibly in those of the mesenteric arteries, which in the former case may result in emboli being swept up the portal vein to lodge in the liver and form a starting point for a similar necrosing process there or, as the result of interference with the blood supply of the overlying mucosa, cause this to undergo necrosis and be cast off as a slough, leaving an oval or irregular ulcer with deeply undermined edges and a floor formed by the muscular coat. The ulcers may be no larger than a pin’s head or they may be 1 or 2 inches in diameter or by coalescence be still larger. The gelatinous necrosis in the submucosa always extends beyond the limits of the necrosis of the mucosa, thus explaining the undermining. At times the muscular coats of the intestines are involved thus leading to a slough which involves all coats except the serous one. Bacterial infection, with coagulation necrosis of the mucosa overlying the amoebic process, is also responsible for some of the tissue destruction.

The appendix was involved in 7% of the Manila autopsies. Often mild cases may only show lesions in the caecum. When there is a tendency to perforation the omentum will often be drawn over to the location of the threatened perforation. There is often thickening of the intestine in one place with cicatricial contraction of the lumen and thinning in another, so that there is an appearance of great irregularity.

Fever is absent and there are very few of the toxic manifestations which often accompany bacillary dysentery, such as headache, nausea and a mildly delirious state. There is progressive loss of weight and strength with the development of neurasthenic symptoms. The skin becomes dry and earthy and we have the picture of a more or less marked secondary anaemia. It is in these cases that we should be on the lookout for grayish green or grayish brown mucoid masses which can usually be found during an exacerbation. Sloughs of the gelatinous-like necrosis in the submucosa usually contain amoebae.

Such cases usually show a moderate leucocytosis in which the percentage of large mononuclears is increased and a very important point is that with tenderness about the caecum, plus a leucocytosis, one may diagnose appendicitis and operate on a normal appendix. Autopsy records however have shown that the appendix is not infrequently invaded by amoebae but in some of these cases, other than finding amoebae in the lumen of the appendix, I have been unable to note any change. Cases of amoebiasis confined to caecum and ascending colon may only show symptoms of slight anaemia.

Very confusing cases are those in which a bacillary dysentery sets in upon an amoebic one and this possibility should always be thought of when a severe bacillary dysentery does not respond to serum therapy or an amoebic one to emetine.

Gangrenous lesions may occur in amoebic dysentery although more common in bacillary infections. Such cases will show extreme prostration and even give the clinical picture of cholera.

The pus of such abscesses is viscid and blood-tinged, resembling liver abscess pus. The amoebae are found in the abscess wall. The symptoms are those of brain tumor, meningitis not occurring. Necrotic processes of skin and muscles have also been reported in which amoebae have been found.

Perforation of the large intestine is not rare, Strong having noted 12 perforations in 77 autopsies. These usually occur in the region of the sigmoid flexure.

Adhesions are common complications of amoebic dysentery.

We can as a rule differentiate bacillary from amoebic dysentery by the more sudden and acute onset of the former together with fever and other evidences of toxaemia. The pulse rate is more rapid in bacillary than amoebic dysentery. Again the number of stools in bacillary dysentery is usually greater and the amount of each stool less in quantity. The stool of bacillary dysentery is of a milky whiteness from the large number of pus cells or composed of gelatinous, reddish mucus, while that of amoebic dysentery is tinged with disintegrated blood giving it a grayish-green or brown color. The mucopurulent mass in bacillary dysentery may be flecked or streaked with blood. The therapeutic results following emetine injections are of value in diagnosis.

Gangrenous types of dysentery are similar whether due to bacillary or amoebic infection. Chronic dysentery of bacillary origin is much like amoebic dysentery clinically.

Manson-Bahr and Gregg recommend the use of the sigmoidoscope in the diagnosis of chronic amoebic ulcerations. In the evening the patient takes ½ ounce of castor oil and the next morning a soap and water enema is given followed by 15 minims of laudanum. The patient is put in the lithotomy position. No anaesthetic is used. The pain in introducing the instrument is greater in chronic bacillary ulceration cases than in amoebic ones. Scrapings can be made for microscopic examinations. Nisbet has reported the diagnosis of a case of balantidial ulceration by use of the sigmoidoscope.

These large cells which resemble amoebae are often vacuolated, thus intensifying the similarity. They are nonmotile, however, and do not show the small ring nucleus which is so characteristic of the vegetative human amoebae. The nucleus of the confusing cells is also larger, approximating one-fourth the size of the cell.

Bacillary dysentery stools show an absence of Charcot-Leyden crystals which are often present with amoebic stools.

For bringing out the nuclear characteristics of human amoebae Walker recommends fixation of thin moist smears in Giemsa’s sublimate alcohol (absolute alcohol 1 part, sat. aq. sol. bichloride 2 parts) for 10 to 15 minutes. These smears are then well washed with water and stained with alum haematoxylin for five minutes. The nuclear characteristics are noted under etiology. In such staining the preparations, which are best made on cover-slips, should never be allowed to become dry.

Rapidly smear out with a toothpick a small particle of faeces or other material containing protozoa and, while still moist, fix by Giemsa’s method and, after getting rid of the mercury with iodine solution followed by 95% alcohol, treat smears with a 3.5% solution of iron-alum in distilled water for one-half hour or overnight, then wash thoroughly in distilled water.

Then stain from five to twenty minutes in the following haematoxylin stain: (1) 1% solution of haematoxylin in 95% alcohol. It takes at least ten days to ripen. (2) A saturated solution of lithium carbonate. Add to 10 cc. of the haematoxylin solution 5 to 6 drops of the lithium carbonate one. Next wash well and differentiate with about 1% solution of the iron-alum. Again wash in water, pass through alcohols to xylol and mount in balsam. With vegetative amoebae I have obtained beautiful results with vital staining which can best be done by tinging the faeces emulsion with a 1% aqueous solution of neutral red. I have also had good results by emulsifying the faeces in a drop of 1 or 2% formalin and then adding a drop of 2% acetic acid. The mixture is then tinged with either neutral red or methyl green.

For distinguishing the encysted form of Entamoeba coli one can obtain excellent results by emulsifying the faeces in Gram’s iodine solution. Owing to the glycogenic reaction given by E. coli, the round amoeba, with its 8 nuclei stands out very distinctly.

Walker also notes the advantages of examining a specimen with a ⅔ inch objective as encysted amoebae are easily picked up. In opposition to the usual recommendation of text-books to report only on motile amoebae, he recommends the making of a differential diagnosis on nonmotile encysted forms. This however is now generally accepted by experienced workers as true.

As a matter of fact there is a question as to the possibility of the emetine treatment acting as a factor for the increase of carriers.

Vedder considers that while emetine will kill the amoebae deeply placed in the submucosa it has no effect on the more superficially located cysts and suggests that it may be possible to treat carriers by colonic irrigations with quinine or silver salts.

Emetine bismuth iodide has recently been highly recommended as our best agent for eradication of E. histolytica cysts of carriers.

In 1910 Vedder found that emetine was practically without power in its action on dysentery bacilli but that it would kill amoebae, even in dilutions of 1 to 100,000. He also found that deëmetized ipecac was quite inert in its action on amoebae.

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In 1912, Rogers, who had for years been an ardent advocate of the ipecac treatment of amoebiasis, took up the treatment of amoebic dysentery and its liver complications with emetine. Reports from all over the world now attest the value of this drug in the treatment of the acute manifestations of amoebiasis but unfortunately note the inefficacy of this treatment on the encysted forms of amoebae.

It was found by Baermann and Heinemann that subcutaneous injections of from 2 to 2½ grains daily caused indisposition and anorexia. The subcutaneous injections are less painful than the intramuscular ones.

Rogers has used emetine intravenously in doses of 1 grain without bad effect.

Vedder calls attention to the fact that the minimal fatal dose of emetine is several times less when administered to rabbits intravenously than when given subcutaneously, so that after seeing rabbits die with what was apparently centric paralysis immediately after intravenous doses of comparatively small amounts of emetine hydrochloride he would hesitate before administering 1 grain intravenously in a human case.

Levy and Rowntree think emetine should not be given intravenously except in extreme cases. Among ill effects of emetine they note peripheral neuritis. Kilgore has reported such cases where even wrist-drop was seen.

Low has treated cases successfully with keratin-coated tabloids of emetine hydrochloride, giving ½ grain every night. Vedder has not obtained satisfactory results with the drug by mouth.

It was customary to give 20 to 50 grains of powdered ipecac in capsule, cachet or keratin-coated pills to a patient with an empty stomach and who had had a dose of morphine or laudanum about 20 minutes before the time for giving the ipecac. The salol-coated ipecac pills are generally used in America. The patient should be in bed and should try to yield to the soporific influences of the opiate. Any flow of saliva should be removed with gauze as its swallowing would provoke nausea. Some use a mustard poultice to the epigastrium. It is remarkable the change which this treatment will effect in the number and character of the stools.

Many now think it advisable to give emetine hypodermically to reach the amoebae deeply seated and, at the same time, to give ipecac by mouth to destroy more superficially situated ones, or those in the lumen of the gut. Alcresta ipecac has been recommended as a good method of giving ipecac by mouth.

We do not have now the same confidence in emetine injections that we formerly entertained. In Egypt the combination of emetine injections with ½ grain keratin coated tablets of emetine by mouth seemed to give better results in the more chronic stages of amoebiasis.

Many drugs have been recommended for colon irrigation of which the favorite is probably quinine muriate in dilution of 1 to 1000 or 1 to 2500. Inject 2 or 3 pints slowly by gravity. Protargol in 1 to 500 solution is better than silver nitrate in 1 to 2000. Emetine enemata do not seem to be of much value.

In a discussion as to certain surgical considerations in connection with appendicostomy Muller notes that the right rectus incision is to be avoided on account of danger of gangrene from pressure of rectus on the stitched-up appendix. He also thinks that appendicostomy is much safer than caecostomy on account of the frequent thinning of the walls of the caecum. For irrigation he prefers a 1 to 500 solution of collargol.

In treating dysentery cases rest in bed and the use of a nonirritating diet are advisable.

The return of the increase of large mononuclears to normal may be used as an index to cure.

In liver abscess, as with blackwater fever, it is education rather than acclimatization that brings about a diminution of these tropical diseases.

For several years subsequent to the American occupation of the Philippines amoebic dysentery and liver abscess were common but in more recent years liver abscess has become rare in Americans and amoebic dysentery much reduced in prevalence.

More temperate living results in less storing up of fat in the liver and an organ more resistant to infection.

As to obtaining a history of amoebic dysentery in liver abscess cases we have the following statistics:

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Amoebic liver abscess is exceedingly rare among children and probably 10 times less common among women than men.

Natives of India very rarely develop liver abscess but it has been noted that when they begin to follow the customs of Europeans, as to eating and drinking, such lesions become more common in them.

As to the proportion of cases of amoebic dysentery which give rise to liver abscess only the statistics of those who have differentiated between bacillary and amoebic dysentery are of any value. Such statistics would indicate that about 20% of the cases of amoebic dysentery are complicated by liver abscess.

Liver abscess may be present without demonstrable lesions in the large intestines, such lesions having healed or the intestinal involvement having been so slight as not to have caused other than microscopic changes.

It is a well-known fact that liver abscess may set in years after a patient has left the tropics and years after the occurrence of any dysenteric manifestations.

Another view is that the amoebae may wander across the abdominal cavity and enter the liver in this way. This seems as improbable as that view which considers a possible entrance by way of the bile duct. Bile is toxic to amoebae and it would be difficult to explain their presence in the small intestines.

In 639 cases Roux found the abscess in the right lobe in 70% of the cases.

Other statistics give about 75% for the right lobe, 10% for the left lobe, 4% for the lobus Spigelii and in about 10% of cases abscesses are found in both right and left lobes.

The abscesses vary enormously in size, some being no larger than a walnut while others may contain a quart or more of pus, exceptionally as much as a gallon. The pus is typically of a chocolate color and contains degenerated liver cells, granular débris and often haematoidin and Charcot-Leyden crystals. There is an absence of polymorphonuclears. It may however be creamy in color.

In Strong’s cases about 50% of the abscesses showed bacteria upon culturing, the organisms noted being staphylococci, streptococci, B. coli and B. pyocyaneus.

The walls of liver abscesses are rather shaggy and the amoebae are found deeply located.

It is probable that the necrotic process, set up by the amoebae, begins in the interlobular capillaries although it may at times begin within the lobule.

Surrounding the abscess wall there is a zone of marked hyperaemia. Amoebae may be found in this area as well as in the abscess wall.

If the liver abscess is not treated by emetine or with this drug and some surgical procedure the tendency is for rupture to occur and Cyr’s statistics show that of 159 cases rupture occurred as follows: lungs 59, pleural cavity 31, peritoneal cavity 39, intestines 8, stomach 8, vena cava 3, kidneys 2, bile ducts 4, pericardium 1 and externally 2.

Tropical Liver.—There is also much evidence to be obtained from statistics and otherwise to support the view that the amoebic infection of the liver is only possible in a person whose liver has been functionally impaired. To this condition the designation tropical congestion of the liver or simply tropical liver has been applied. There is much to support the view that, in the tropics, the intestines and liver take the place of the thoracic organs in being subject to congestion. In temperate climates excesses and exposure to debilitating influences result in coryza or pneumonia. In the tropics we have diarrhoea and congestion of the liver. Tropical[167] liver is recognized by vague digestive troubles, high-colored urine, loss of energy, irritability, with a sensation of fullness in the region of the liver which is generally described by the patient’s statement that he feels his liver. There may be pain referred to the right shoulder and the liver may be tender on palpation.

Rogers recognizes a condition which he terms the pre-suppurative stage of amoebic hepatitis in which the amoebae from dysenteric lesions have lodged in the portal terminals of the liver but in which abscess formation has not taken place.

At this stage we have a leucocytosis in which the polymorphonuclears are but little increased in percentage with a low remittent fever. At this time Rogers considers that the disease may be cured by emetine or ipecac and liver abscess avoided.

Insomnia is a marked feature in many cases. Jaundice is rare, but an earthy color or subicteroid tinging is often noted. The superficial veins may be enlarged.

The urine is scanty and high-coloured, frequently with a marked increase in the ammonia nitrogen. Urobilin may be present in considerable amount.

This pus does not contain pus cells but only granular débris, cholesterin crystals and is often bacteriologically sterile. The amoebae, being in the abscess wall, are not apt to be found when pus is at first withdrawn. Owing to the tendency of liver abscess to rupture into the lungs the first indication of the true nature of a prolonged hectic fever may be obtained when the characteristic pus is expectorated by the patient.

Attended with progressive emaciation and exhaustion the patient, as a rule, after a prolonged illness, dies, unless operative procedures cure him or some intercurrent disease brings about his death.

Onset and the Fever Chart.—The onset is at times so insidious that there may be no symptoms and yet a liver abscess be found at autopsy. Usually following convalescence after amoebic dysentery an irregular fever sets in which becomes hectic in character. Profuse sweats accompany the evening rise. The morning temperature is frequently normal and there may be frequent apyretic intervals.

The Respiratory System.—Crepitation at the right base, a dry cough (tussis hepatica) and shallow respirations are features of the disease.

The Nervous System.—Pains in the right shoulder are connected with irritation of the branches of the phrenic nerve.

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The patient is irritable and often complains of insomnia.

The right rectus tends to be somewhat rigid and decubitus is dorsal or toward the right side.

The Liver and Spleen.—The liver is tender and as the abscess in nine-tenths of the cases is located in the right lobe and generally toward the upper convex surface we have an enlargement upward. There is very rarely any jaundice.

The urine shows an excess of urobilin and of nitrogen eliminated as ammonia. When the abscess is in the left lobe the condition is apt to be considered as some gastric disturbance. The spleen, as a rule, shows no enlargement.

Examination of the Blood.—There is usually a moderate leucocytosis with normal polymorphonuclear percentage and increase in the large mononuclears.

The X-ray may confirm the diagnosis of upward enlargement which may be as high as the angle of the scapula. The majority of conditions causing enlargement of the liver give a downward enlargement.

Syphilitic gummata may give the picture of liver abscess, especially as regards the fever and loss of weight. Iodide of potash is said to be of use in differentiating, as it controls the fever of syphilis. The gummatous enlargement, however, is irregular and projects downward.

Suppurative pylephlebitis generally arises from infections of the colon or appendix. This condition as well as pyaemic (multiple) abscesses of the liver is apt to show jaundice.

In suppurative cholangitis and cholecystitis we get a history of biliary colic, jaundice and usually a marked point of tenderness at the tip of the ninth rib and a tumor in the region of the gall bladder. Abscess of the left lobe may give the symptoms of gastric trouble.

In differentiating empyema we usually have a history of pleurisy or pneumonia.

Suppurating hydatid cyst which may be confused with liver abscess is most surely differentiated by finding echinococcus hooklets.

Then too the complement fixation test for hydatid disease will differentiate.

Tuberculosis is often thought of, particularly when a liver abscess ruptures through the lungs. Malaria is also usually suspected. Abscess in the kidney or perinephritic region may be very confusing. In an abscess of the abdominal wall an exploring needle does not move up and down with respiration as it does when penetrating a liver abscess cavity.

According to Schilling-Torgau we may have a perfectly normal white count and polymorphonuclear percentage and yet have evidence of the presence of liver abscess in his modification of Arneth’s index, so that in an apparently normal differential count we may find that ½ or more of the polymorphonuclears are of a less mature type and in cases where there are many immature polymorphonuclears we have indications which force a very cautious or unfavorable prognosis.

Thus a differential count of 33% band-form polymorphonuclears and 39% of normal nucleated ones would make us give a cautious prognosis, while one with 1% myelocytes, 22.5% immature polymorphonuclears, 21% band-form nucleated ones[171] and 30% of normal ones would make for a very bad prognosis. We have a displacement to the left. Normally there are 63% of normal polymorphonuclears, 4% of band-form and no immature ones or myelocytes.

One may find an iodophilia in liver abscess.

Of the functional liver tests we may determine the ammonia quotient, the percentage of N eliminated as ammonia being increased in abscess of the liver. The same is true of the lipase test. Probably the most specific test for disturbances of the hepatic function is that for urobilinogen. The test is made by adding 5 to 10 drops of Ehrlich’s aldehyde reagent to 5 cc. of perfectly fresh urine when a positive reaction gives a fine cherry-red color.

It is well to remember that abscesses may occur months or even two or three years after an attack of amoebic dysentery, consequently it is well to give a grain of emetine on two or three successive days of each month following an acute attack.

Until recently surgical authorities condemned severely the trocar and cannula method of operation, but with the introduction of emetine there are now those who believe that such a procedure may suffice and a more radical operation not be necessitated.

Prior to introducing the trocar and cannula the usual procedure is to use an aspirating needle of about ⅛ inch bore and 3½ inch length. If the needle happens to be longer it should not be passed deeper than 3½ inches, in a person with a 32-inch chest, in order surely to avoid the vena cava. If there are no distinct localizing signs the needle should first be introduced in the eighth or ninth interspaces in the anterior axillary line and pushed backward, inward and slightly upward. Manson recommends at least 6 punctures before abandoning exploration. Cantlie does not think that a moderate degree of haemorrhage from the puncture of the liver will do harm in a case which is simply a liver congestion. One should always be ready to operate in case pus be found in the exploring needle. Leaving the needle in situ a small skin incision is made and a 4 or 5 inch by ⅜ inch trocar and cannula introduced along the line of the needle. Withdrawing the trocar some of the pus is allowed to escape through the cannula and there is then introduced a 6 × ½ inch piece of strong[172] rubber drainage tubing, one end of which has lateral fenestrations but a closed tip in order that a long steel pin may put the tubing on the stretch so that it passes the smaller lumen of the cannula.

The cannula is then slipped out over the tubing and the external stretched end of the tubing released so that the contracting rubber fills the puncture. The steel pin used for introducing the rubber tube is then withdrawn and the tubing transfixed close to the skin with a safety pin.

After the cavity has drained of pus a dressing is applied. There are some who advocate aspiration alone without subsequent drainage. The dressing should be changed frequently and a connecting tube, draining into an antiseptic-containing bottle, should be attached to the tube in the cavity in order to obtain a syphoning action. Some aspirate and inject into the cavity about 2 ounces of 1 to 1000 emetine solution.

Some report favorably from the use of 1 to 1000 quinine irrigations. At present the hypodermic use of emetine will probably obviate the necessity of any irrigation.

There are those who think that a preliminary aspiration, followed by incision, after a few days of improvement in general condition, is the best method in serious cases.

It is usual to recommend a general anaesthetic when introducing the aspirating syringe or trocar and cannula. Local anaesthesia with quinine and urea hydrochloride, however, will usually suffice and lessen the dangers of shock in bad cases. Rib resections and even intra-abdominal procedures are best done under local anaesthesia provided the operator is familiar with the technic.

Newman has recently warned against the use of the small aspirator for diagnosis, pointing out that it is unreliable and that the diagnosis should be made by other diagnostic aids, including hypodermic use of emetine. He notes the occurrence of death from internal haemorrhage, the interference of the needle with the surgical incision and, further, the obscuration of the field of operation by pus where no adhesions exist and, finally, the danger of general peritoneal infection from a leak. He notes that the cavity may be under tension and that the pus may force itself along the track of the needle. He recommends incision and packing with gauze where adhesions do not exist and the exploration of the liver with dressing forceps instead of cutting into the liver with the knife.

Where the abscess is situated far back or high up in the liver the transpleural route is to be preferred to the abdominal one. Make a 3 or 4 inch incision over the 9th rib with its center in the line of the angle of the scapula. Excise about 2 inches of rib subperiosteally. An assistant presses a roll of gauze against the tissues above the line of incision to prevent air entering the pleural cavity. Later the upper flap may be sutured to the endothoracic fascia. Even if the pleural cavity should be opened and air enter no serious result will follow although it is an accident to be avoided if possible. The diaphragm is now cut through and the liver exposed and after packing gauze around the area to be opened, the abscess cavity is entered and drained as previously described.

McDill prefers to resect 2 or 3 inches of both 9th and 10th ribs in the midaxillary line. The muscle wounds made in resection are then closed by catgut. This movable wall is now forced against the diaphragm with a roll of gauze pressed inward by an assistant. A 3-inch incision is now made through this bone-free wall near the upper border of the 11th rib, going through diaphragm and exposing the liver. The edges of the wound in the thoracic wall and diaphragm are now clamped together by haemostats to close off the pleural cavity. Later catgut sutures are substituted for the forceps. The liver often bulges into the wound. Finding the abscess by a palpating finger as a rather firm area in a less resistant liver surface we introduce a forceps or aspirating needle or trocar and proceed as above noted.

There are indications that the use of emetine subcutaneously may make the more radical operations unnecessary. In a recent symposium on liver abscess many of the papers would indicate a preference for aspiration without drainage coupled with emetine subcutaneously.

Rogers, in a recent article, notes that a case of liver abscess was cured by emetine without any form of operation. Recent experience, however, would indicate that it is necessary to evacuate the pus to effect a cure.

Herodotus referred to an epidemic of dysenteric nature in the Persian Army and Hippocrates described the dysenteric syndrome. It has been known in India since remote times.

While the etiology of amoebic dysentery was thoroughly investigated and its connection with amoebae fairly well established during the decade from 1880 to 1890 it was not until 1898 that Shiga isolated the causative organism of bacillary dysentery. It is true that Chantamesse and Widal drew attention to a bacillus isolated from large intestines, mesenteric glands and spleen of cases of tropical dysentery but the organism was not clearly differentiated from Bacillus coli. Celli isolated an organism which coagulated milk and produced gas in glucose media. This organism which Celli called B. coli dysentericus, differs culturally from B. dysenteriae.

Geographical Distribution.—Bacillary dysentery differs from the amoebic form in that it tends to appear in extensive epidemics spreading over temperate as well as tropical and subtropical parts of the world.

It is peculiarly liable to follow the movements of armies in any part of the world and like typhoid fever its distribution is one of hygienic rather than geographical influence.

Infections with various strains of dysentery bacilli are important factors in morbidity among infants and young children in whatever part of the world the question has been investigated. The disease is prone to prevail in lunatic asylums whether in temperate or tropical parts of the world.

In 1903, Hiss and Russell isolated an organism from a fatal case of diarrhoea in a child to which they gave the name “Y”.

The characteristic of nonmotility is of greatest differentiating value and the reports of slight motility are probably from misinterpretation of molecular movement as motility. The dysentery bacilli do not form those thread or whip-like filaments so characteristic of typhoid cultures and are somewhat plumper. The dysentery bacillus is not found in the blood and hence is not eliminated in the urine, although recently there have been reported rare cases where dysentery bacilli were isolated from the blood. It is found in mesenteric glands. In dysentery patients agglutination phenomena do not show themselves until about the tenth day from the onset. Hence, this procedure is of no particular value in diagnosis. It is of value, however, to identify an organism isolated from the stools at the commencement of the attack, using serum from an immunized animal or a human convalescent for the agglutination test.

Dysentery bacilli produce a coagulation necrosis of the mucous membrane of the large intestine and occasionally of the lower part of the ileum. Polymorphonuclears are contained in the fibrin exudate.

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It was formerly thought that these lesions were of local origin, but the present view is that toxins are produced which, being absorbed, are eliminated by the large intestine with resulting necrosis. Flexner, by injecting rabbits intravenously with a toxic autolysate, produced characteristic intestinal lesions. The toxin withstands a temperature of 70°C. without being destroyed. The toxin may cause joint trouble.

In immunizing horses for the production of antidysenteric serum it is customary to use both Flexner and Shiga strains, thus producing a polyvalent serum.

Lentz recognizes 4 types of dysentery bacilli for the differentiation of which he uses mannite, maltose and saccharose bouillon with litmus as an indicator.

The following table gives the more important cultural characteristics of the intestinal bacilli which might be confused with the various strains of dysentery bacilli.

Of the above tabulated nonspore bearing, Gram-negative, intestinal bacilli only B. lactis aerogenes shows capsules and only B. cloacae and B. proteus vulgaris liquefy gelatin. In the table + = positive, - = negative, O = no change, A = acid, Alk = alkaline, G = Gas and Fl = fluorescence in neutral red bouillon.

Not only is there the danger from a patient ill with bacillary dysentery but as well that from the convalescent or chronic carrier. Such carriers are particular sources of danger where they take part in the preparation of food for others. It is now thought that the striking prevalence of the disease in insane asylums is associated with the difficulty of making such patients observe the proper care of their hands as well as their persons.

Friedmann has recently noted an outbreak of dysentery due to the Shiga type of bacillus which was instituted by a soldier returning to the barracks from a furlough.

There resulted 86 cases in the man’s regiment of which 49 belonged to his own squadron. The spread of the disease was traced to the latrines. The epidemic was suppressed by the enforcement of the most rigid rules of cleanliness especially as regarding washing of the hands after leaving the latrines.

The stools of the convalescents were examined and no man was discharged from hospital until his stools were negative for dysentery bacilli upon 3 successive tests in fourteen days.

Isolation of the bacilli from convalescents was obtained in 40 patients only for periods under fourteen days while with 27 others such carrying of bacilli lasted from two weeks to one month.

There have been reports of isolation of Flexner and “Y” type bacilli from monkeys and rabbits but there is nothing to indicate that any other host than man is of importance.

The possibility of infection through the medium of soiled clothes, sent out for washing, is to be thought of.

There have been several instances of transference of the disease by the water supply.

It is possible that infectious material may be disseminated as dust and thus contaminate food.

In the rabbit lesions similar to those in man are obtained as well as paralysis of the limbs.

Cases have been reported where the adrenals showed congestion and necroses, as if subjected to the action of a toxin.

In man we have an acute inflammation of the mucosa of the large intestines and, in the tropics, we frequently find the lower third of the ileum involved as well. In amoebic dysentery the process rarely extends beyond the ileo-caecal valve. A catarrhal process with hyperaemia and sero-purulent exudate is first noted, to be succeeded by fibrin formation in the mucosa, a process of coagulation necrosis. When the process invades the ileum there is no involvement of Peyer’s patches. Virchow noted the greater intensity of the process in the region of the rectum, sigmoid flexure and ileo-caecal valve.

As a rule, however, the entire large intestine is grayish red, looking like lustreless red velvet. Later on we may have irregular islands of grayish membrane formation surrounded by the red swollen congested gut. The solitary glands are usually swollen and may soften and ulcerate, having the submucosa as a base. Ulceration in bacillary dysentery is superficial rather than deep as with amoebic dysentery. The ulcers of bacillary dysentery involve the free folds of the intestine and extend transversely while amoebic ulcers run longitudinally. The intervening mucosa is unaffected in amoebic ulcerations while in bacillary ones it is inflamed.

In the mucosa we find an outpouring of pus cells which are entangled, along with the glandular structures of the mucosa, in a fibrinous exudate which causes necrosis of the mucosa (coagulation necrosis).

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In chronic bacillary dysentery, according to Rogers, the lesions are limited to the lower portion of the large gut and rarely extend above the descending colon.

In this region one finds serpiginous ulcerations separated by islands of mucosa. Willmore and Savage have noted autopsy findings of what was practically a large granulating surface over the whole large intestine, in cases which had apparently recovered, with the exception of a prolonged convalescence.

In temperate climates and in particular when the infecting organism is a Flexner type the case may appear as a watery diarrhoea associated with colicky pains and anorexia. The stools soon become more scanty in amount, frequent in number and associated with straining. This is followed by mucous stools more or less tinged with blood. The temperature is normal or but slightly elevated and the patient does not seem ill.

In the tropics and in temperate climates where the Shiga type bacillus is the infecting organism the onset is usually rather sudden with malaise, abdominal pain and a diarrhoea, which only temporarily relieves such pain. This initial diarrhoea is soon followed by the characteristic dysentery stool and the pains, which latter tend to centre about the umbilicus and to become continuous. There is usually loss of appetite and slight nausea and the patient may at times show a very slight tendency to flightiness. The mind however is usually clear. Fever of moderate degree is not uncommon and it may be quite marked,—up to 104°F. Ingestion of food or drink or any movement of the body brings on a desire for defecation.

Vesical tenesmus may be present and the urine may be diminished in amount.

At times, however, the lymphocytes may be the leucocytes showing the greatest relative increase.

In severe cases of the more typical dysentery or colodysentery, as designated by Shiga, the stools may change from the mucopurulent mass to a serous discharge which is very rich in albumin and of an albuminous odor. In such cases emaciation of the patient is very rapid. Such cases may show signs of collapse with cold clammy skin and the clinical picture one associates with cholera.

It has been suggested that such cases may be due to action of the dysentery toxins on the adrenal.

In some epidemics of dysentery gangrenous manifestations have been common. This is a very fatal type and is recognized by the passage of dark-brown serous discharges containing ashy gray to black sloughs or even tubules of gangrenous mucosa, the stool having a putrid odor. The general symptoms are pronounced, there being a dry glazed tongue, and low muttering delirium with a thready pulse. It is the typhoid state.

Rogers has called attention to the importance of bearing in mind a chronic condition as well as the acute one. In these chronic cases the ulcerations are usually located in the descending colon, sigmoid flexure or rectum and give rise to frequent stools containing blood and mucus and causing a progressive loss of strength and weight. There is marked digestive disorder and the patient becomes weak, anaemic and neurasthenic.

It is important however to remember that either bacillary or amoebic dysentery may show gangrenous manifestations and in such cases the clinical picture of the typhoid state is the same whether the process is amoebic or bacillary. Fulminant bacillary dysenteries may greatly resemble cholera in its algid stage.

It is important to remember that chronic dysentery may result from bacillary as well as amoebic infections, although a chronic process is more a feature of amoebic dysentery.

A fresh specimen of the muco-purulent stool of bacillary dysentery shows, in addition to pus cells, numerous large, phagocytic cells, which may show vacuolation and strikingly resemble amoebae. Such cells never show motility but, under conditions of lowered temperature of specimen or from prolonged standing and beginning disintegration, the amoebae too fail to show motility. If mounted in Gram’s iodine solution these large cells show a much larger nucleus than that of amoebae and take the yellow staining of iodine more intensely. The best method, however, is to make a smear, fix it by heat and stain by Gram’s method or with Loeffler’s blue or dilute carbol fuchsin. These confusing cells stain easily and perfectly and in the Gram specimen we note the Gram-negative bacilli in the cytoplasm. Giemsa’s stain, with methyl alcohol fixation, or the usual Wright or Leishman technique answer equally well. On the other hand it is rather difficult to obtain satisfactorily stained amoebae in this way, it usually being necessary to fix moist thin smears of the stool with some bichloride fixative, as Zenker’s fluid, and then carry out the staining with haematoxylin.

The Stained Smear.—The presence of pus cells as well as endothelial cells in a stained smear of material from a bacillary dysentery stool is of value in differentiating from an amoebic stool smear in which pus cells are rarely seen. The amoebic dysentery smear gives more the picture of granular débris.

If the microscopical examination indicates a bacillary infection we should take a small mass of the stool, wash it in sterile water and then drop it in a tube of sterile bouillon or salt solution. After emulsifying in this tube of bouillon we take up 2 or 3 loopfuls of the emulsion and deposit them on a poured plate, later smearing out with a glass rod, either by successive parallel strokes or by revolving the plate while smearing the surface with the glass rod. It is in the first two or three days of an attack of acute dysentery that we obtain the best cultural results, often noting a pure culture of dysentery bacilli from proper material taken at the onset. Manson-Bahr states that he has never recovered true dysentery bacilli from a purely faecal stool. Even faecal contamination of the mucoid mass makes it difficult to recover the organism. Dysentery bacilli rapidly die out if the stool is acid so that it has been recommended to make the stool strongly alkaline where it has to be sent to a laboratory from a distance.

It has seemed to me that litmus lactose agar gives results more surely than the more restraining faeces-plating media. Still I generally use Endo’s fuchsin agar because it is always at hand for typhoid or paratyphoid culturing and gives good results. The dysentery bacillus colonies on this medium are like those of typhoid—grayish white. In England they prefer MacConkey’s neutral red bile salt agar[184] while others use the Conradi-Drigalski medium. We are now using the Teague medium, which is taken up in the chapter on Faeces. On all these media the colonies resemble those of typhoid and the differentiation is most easily made by examining for motility. At the same time one not infrequently finds lack of motility in bacilli from colonies just isolated on Endo’s medium which later on in subculture show motility and are found to belong to the typhoid or paratyphoid group. For the sure determination of dysentery bacilli or for differentiating the Flexner and Shiga strains one should carry out agglutination tests.

Although some observers have noted the appearance of agglutinins in the serum of cases of acute bacillary dysentery within three or four days from the onset of the disease, yet it is usual not to obtain agglutination with the patient’s serum before the tenth day. With the Shiga strains agglutinating power in 1 to 50 is usually accepted as evidence of specificity but for Flexner strains we generally have a higher titre so that a dilution of 1 to 150 should be required for the test.

Willmore and Savage tried heating serum to 56°C. for thirty minutes, but found that such a procedure was of no practical value with dysentery, thus differing from Malta fever serum where such a procedure is of value in destroying coagglutinins and thus increasing the specific action. The work of Ohno would indicate that we should trust to the acid-producing effect on mannite for differentiating Flexner and Shiga strains rather than on agglutination because it was found that agglutinins for an acid strain were not always more specific for such strains than for nonacid ones.

At the same time it is the rule for a Flexner type bacillus to show specificity for its serum and the Shiga type for the serum of the more toxic, nonacid-fast Shiga strain cases. The statement of Willmore and Savage that the differentiation of bacillary dysentery infections is a refinement of technique seems a proper view because with a polyvalent serum for treatment one only needs to know that the case is one of bacillary dysentery for proper treatment. Of course with a monovalent serum, effective only for the Shiga bacillus, one would have to determine whether the organism producing the dysentery was of that strain.

From a practical standpoint we can use the therapeutic polyvalent serum for agglutination and any organism recovered on the plate made from the faeces which agglutinates in 1 to 50 or 1 to 100 may be considered as diagnostic of bacillary as against amoebic dysentery. Often one does not see a case of dysentery until late in the disease and then, provided the condition is serious and the diagnosis points to a bacillary infection it would be better to inject the curative serum rather than await laboratory confirmation.

Great care should be given to the washing of one’s hands prior to eating. The greatest care must be taken with rectal tubes when used for treatment. It is better to make an invariable rule to confine the use of a single tube to a single patient, as the rubber tubes are difficult to disinfect other than by boiling and such treatment, especially in the tropics, soon ruins the tube. For disinfecting tubes a 5% solution of liquor cresolis compositus is good. The tubes should be thoroughly washed of the disinfectant before using again. For disinfection of faeces one can use an equal portion of the above disinfectant to a similar amount of stool leaving the disinfectant to act on the stool at least one hour before emptying the receptacle. Soiled clothes should be disinfected in a 2½% solution of the compound cresol solution. Flies must be kept in mind and water and milk supplies boiled. The carrier is of as great importance here as in typhoid or cholera, especially when assisting in preparing food.

Dean reports the value of treating the emulsion of organisms with an equal amount of 1 to 1000 eusol. Gibson treated a suspension of dead organisms with an equal amount of serum, mixing in the syringe at the time of injection. Although this method was used during the war its immunizing value was not settled.

The question of the best method of preparing vaccines for prophylactic use is still unsettled. The greatest difficulty has been experienced in making vaccines of the Shiga bacillus on account of the great toxicity of such preparations.

The serum alone is used almost exclusively for curative rather than prophylactic purposes.

Some authorities deal with the subject of treatment without referring to any other means than the administration of serum. This probably is the proper attitude when the very fatal Shiga type infections are encountered. It must be remembered that certain epidemics, which as a rule are associated with the Shiga type bacillus, give a very high mortality (20 to 40%) while other epidemics seem associated with a less virulent strain of this bacillus.

At any rate when a case is seen early it would seem advisable to give about 2 grains of calomel in divided doses of ¼ grain every half hour and then follow it up with saline treatment. Most authorities recommend a preliminary dose of castor oil. During the first day or two enemata of normal saline, boric acid or 1½% sodium bicarbonate solution in 2 pint amounts would seem indicated as assisting the salines in the elimination of toxic material. After that time the tenesmus and rectal irritation make the use of the rectal tube too trying to the patient. I have used the Murphy protoclysis method with a certain degree of success, but this procedure cannot be kept up long. Hot fomentations to the belly relieve the griping pains.

Bahr in the Fiji islands treated 53 consecutive cases, of which 41% had marked constitutional symptoms, with a mortality of 13.2%. He gave 1 dram of sodium sulphate every hour for the first day and subsequently the same dose every four hours.

In a second series of 106 cases, of which 42% had marked constitutional symptoms, he treated 34 with salines plus the administration of capsules of cyllin. The remaining 72 cases received in addition to this treatment injections of a polyvalent serum obtained from the Lister Institute. The mortality in this series was 1.8%. He notes that 5 of the cases in this second series were of the severest type as evidenced by the gangrenous stools and toxic condition and yet not one of these five serum-treated cases died. He notes that the stools of those who received serum injections became normal in five days for an average while for those treated with saline alone the average period was eight days.

Bahr strongly recommends the combined treatment of salines and serum. In very severe cases Bahr used 50 to 70 cc. of the serum but ordinarily 20 cc. for adults and 10 cc. or less for children.

In the use of serum Shiga recommends a dose of 10 cc. for a mild case or two injections of 10 cc. at intervals of ten hours for cases of medium severity, while in very toxic cases he uses 60 cc. in 3 daily doses of 20 cc. each. It is important to use serum early as it has little or no effect if used after the 7th day (Klein).

The best known sera are those of Shiga, Dopter and that prepared by the Lister Institute.

Animal charcoal and bolus alba are considered of value by some physicians. Opium should be avoided. Intravenous saline injections are of value in cases showing collapse signs. Again, such cases, from the standpoint of possible adrenal insufficiency, may be helped by adrenalin. Where there is a very small rapid pulse with marked cardiac weakness injections of camphor in oil may be of value.

Ross considers opium as of value in dysentery and states that he regards ipecac as of value not only in amoebic but in bacillary dysentery as well. I have often given salol-coated pills containing 1 grain of ipecac and ⅙ grain of calomel every two hours to cases of bacillary dysentery with apparent benefit.

Unless given in small amounts liquid diet is apt to increase evacuations and some cases seem to do better on ordinary diet.

In the tropics there are many brands of sterilized natural milk and these can be inoculated with a culture of B. bulgaricus.

In chronic bacillary dysentery Rogers recommends 1 to 1½ pint enemata of albargin in strength of 1 to 500. Protargol seems to be equally efficient in the same strength. Owing to the effect of organic material on silver nitrate this salt does not seem so reliable as the organic silver compounds. It has also been recommended to flush the colon with warm boric acid solution. Another recommendation is to use milk for this purpose. Vaccine treatment has been employed, in cases of chronic bacillary dysentery. Either eusol-treated organisms or those sterilized by 0.25% trikresol are to be preferred.

History.—Ancient writers were accustomed to apply the designation “plague” to any disease which was epidemic in character and attended with great mortality. This explains why the plague of Athens and that of Marcus Aurelius, which epidemics did not possess the characteristics of oriental plague, were so designated. There exist however writings which show that fatal epidemic diseases attended with buboes and prostration were noted prior to the Christian era.

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It is probable that the biblical description of a disease among the Philistines which was attended with buboes and killed the mice of the field referred to plague.

In the 6th century, during the reign of Justinian, a disease which was unmistakably plague started from Egypt and reaching Constantinople caused the death of 10,000 persons in one day. It spread throughout the entire Roman empire.

The “Black Death.”—The most noted epidemic of plague was that of the “Black Death” of the 14th century. The disease seems to have originated in the East, possibly in China, and eventually invaded Asia Minor, Egypt and Europe. The disease was called “Black Death” in Germany, on account of the petechial spots or “tokens” and in Italy, the “Great Mortality.”

In the records of the epidemic we note that it was attended with great stupefaction, the sick losing their speech from palsy of the tongue. Others noted buboes of groins and arms while some noted a putrid inflammation of the lungs with the expectoration of blood. In the plague at Avignon it was noted that at first, for six or eight weeks, the sick expectorated blood and that to come near them was certain death. Afterwards buboes appeared in groin and axilla and some of the sick recovered.

Quarantine.—It was during this epidemic that quarantine became a recognized procedure in Europe. The adoption of a period of detention of forty days probably originated in the medical idea that the 40th day was the last day of ardent diseases, this being one of the critical days. The lazarettos, where strangers were held in quarantine, appear to have first been established on some island near Venice, in 1485.

It has been estimated that one-fourth of the population of Europe succumbed to the “Black Death,” but estimates in certain parts of Europe would indicate a mortality approaching 70% of the inhabitants.

In 1665 occurred the Great Plague of London, during which year it was estimated that approximately 60,000 out of a population of 450,000 died. It was thought that this epidemic was introduced from the Levant by way of Holland.

There was much plague in Europe in the 18th century but it would seem to have completely disappeared by 1841 and only to have returned with the present pandemic.

The Present Pandemic.—The plague epidemic with which all parts of the world are now so concerned is supposed to have originated in China, in the province of Yunnan, and from that center to have reached Canton, in 1894, causing the death of 60,000 people in a population of 1,500,000. In the same year it extended to Hong Kong and from that great seaport has spread over the entire world. India has suffered more than any other country, there having been years when the plague deaths exceeded 1,000,000.

In a recent article by Low it is noted that the highest death rate was reached in 1907 when 1,315,892 persons died. From the time of the introduction of plague into India to the end of 1917 there were 9,841,396 deaths from this disease.

In its spread it has invaded Europe, Egypt, South Africa, Australia, Japan, Philippine Islands, California and parts of Central and South America. It has recently made its appearance in New Orleans.

Geographical Distribution.—At present there are only two important foci of endemicity, one Mesopotamia and another in the region of the Himalayas (India, Thibet and Yunnan). There also seem to be less important centers in Uganda, in Africa, and in the trans-Baikal region of Siberia. In view of the rather widespread[190] infection of the California ground squirrels, from which rodents the disease has from time to time spread to man, it would seem probable that California might be considered another focus of plague.

As now recognized the plague bacillus, when in smears from pathological material, shows the form of an oval bacillus, the ends of which stain more intensely than the central portion (bipolar staining). When cultured on ordinary agar, the morphology is more rod-shaped with a tendency to pleomorphism.

These agar cultures are very sticky and mucilaginous. If 3% of NaCl is added to the agar, this pleomorphism is exaggerated, there occurring coccoid, root-shaped and various bizarre involution forms.

A bouillon culture, upon the surface of which there has been deposited drops of oil or melted butter, shows a string-like downward growth from the under surface of the oil globules. This “stalactite” growth is very fragile and is difficult to obtain.

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Ordinary bouillon cultures show a rather powdery deposit at the bottom and a hanging-drop preparation from such a culture shows chains of plague organisms resembling streptococci. Gelatine is not liquefied. Bacillus pestis grows readily at room temperature as well as at 37°C, and one may be struck with the fact that colonies on agar plates may show variations in degree of development so that the suspicion of a contaminated culture may arise. Human plague material for cultures or smears is best obtained from the bubo prior to suppuration in bubonic plague, from the blood in septicaemic plague and from the watery sputum in pneumonic plague.

Confusing Organisms.—Other organisms which may be obtained from plague-suspected material are those of the proteus or colon group, which may show bipolar staining, but culturally are quite different. Klein has noted that a nonmotile rod, which gives a striking bipolar staining and named Bacillus bristolensis, may be mistaken for the plague bacillus. Its growth in bouillon is similar to that of B. coli and it coagulates milk.

An organism, B. pseudotuberculosis rodentium, resembles the plague bacillus in a striking manner but is without virulence for rats. It is virulent however for guinea pigs and these animals can be immunized against plague with this closely related organism. Litmus milk cultures of plague show a very slight acidity while with B. pseudotuberculosis rodentium there is a high degree of alkalinity produced.

Wherry has reported two cases of ulcerative conjunctivitis with lymphadenitis of cervical glands, fever and marked prostration, due to infection with B. tularense, occurring in persons who had handled rabbits which had died of this plague-like infection. The organism was first noted by McCoy in squirrels in California. The symptoms and lesions in these animals are those of plague. Guinea pigs succumb after the cutaneous inoculation of material and show lesions markedly resembling plague. The organism, however, will not grow on ordinary simple media as does the plague bacillus. As will be noted in the chapter on Tularaemia the disease has a very limited geographical distribution.

Fleas and Plague.—In 1897, Ogata infected mice by inoculating them with an emulsion of crushed fleas taken from plague rats. In 1898 Simond showed that if a rat, dead of plague, were placed in a large bottle and a healthy rat confined in a small cage introduced into the bottle and suspended above the dead rat, so that there could be no contact between the dead and the living animal, the well rat would contract the disease. If however the fleas were removed from the dead rat, before the introduction of the caged rat, no infection took place.

On the other hand in 35 experiments, when fleas had access to the spaces, plague infections were the rule. Again, guinea pigs in cages which were suspended only two inches above a plague flea infected floor, became infected, but other animals, which were suspended so high that the fleas could not jump up to them, remained well. Two cages, each containing a monkey, were placed in a plague flea infected room. One was surrounded with a protecting zone of 6 inches of “tanglefoot” fly paper, this being the limit of the distance a flea can jump, while the other cage was not so protected. The monkey in the cage without the sticky paper contracted plague while the second monkey remained well. It is only when there is a great incidence of plague among rats that we have outbreaks of bubonic plague in man, and it has been noted that the greater the epizootic, the more heavily infected was the blood of the sick rats with the plague bacilli. A flea with a stomach capacity of about ½ c.mm. could take in several thousand plague bacilli in a feeding on a rat whose blood was teeming with bacilli. The blood of a rat dying with plague may contain as many as fifty million bacilli to the cc. Human blood rarely contains more than a million to the cc. There is a multiplication of the organisms in the flea, so that when it defecates, thousands of plague bacilli are deposited near the puncture wound made by the flea when subsequently feeding on a man. The infected faeces are rubbed into the wound by the man in scratching the site of the bite, so that we have here an instance of a contaminative method of infection as contrasted with the inoculative method by the mosquito in malaria.

Upon taking in plague septicaemia blood the bacilli multiply about the site of the proventriculus as well as distending the oesophagus. This makes an obstruction to the entrance of the stomach resulting in starvation of the flea. This naturally makes the flea more voracious and in the ineffectual muscular efforts to take in blood, regurgitation of the contents of the oesophagus occurs, thereby infecting the person upon whom the flea is trying to feed. This obstruction apparently may be overcome in some way as the plague-infected flea does not necessarily die. Still from lack of sufficient fluid such fleas are liable to be killed off if the relative humidity is low, as in dry weather. Further investigations have shown that the proventricular plug may be channeled, but in such case valve action is lost and the contents of the stomach are regurgitated, thus making such a flea more dangerous than one with an obstructed proventriculus. Such fleas may continue infectious for 67 days.

Very interesting in this connection is the fact that Heiser found plague-infected fleas in the desk of a European at Manila who died of plague. A mummified rat was found in one of the drawers of this desk, from which successful animal inoculations for plague were made. Heiser notes that data would indicate that these fleas probably remained alive 2 weeks after the death of the rat which brought about their infection. Another very striking finding during the same Manila plague outbreak (1912-1913) was that bedbugs found on the sleeping mat of a human victim of plague showed bipolarly staining bacilli.

Bacot has carried on experiments in which fleas infected two months previously and kept in a cool place could transmit plague. This would indicate the danger from plague-infected fleas which had been held in material packed away in boxes.

The house rat is rarely found in Europe while in many parts of the tropics it is common and in close association with man. The fact that the sewer rat avoids the upper portions of houses probably explains the greater infrequency of plague epidemics in Europe where this rodent is common. In former ages when the house rat was prevalent in Europe we had great epidemics there. Mus (Rattus) norvegicus is of stout build with a blunt nose and small opaque ears which barely reach the eyes when laid forward. The tail is shorter than the length of the head and body together (89% of such length). With Mus rattus we have a delicately built rat with a slender head and sharp nose. The ears are translucent and large and reach beyond the middle of the eye when extended. The rather delicate tail is about 25% longer than the length of the head and body taken together.

Recently it has been found that a guinea pig set free in a house suspected of having plague fleas becomes infected if such fleas are present. The fleas would probably prefer the guinea pig to man and such a measure would in some degree be protective to man. It is however for the detection of plague infection that the measure is employed and the guinea pig is termed the “Plague barometer.” In Madras there is practically an absence of Mus norvegicus although Mus rattus is present in numbers and the comparative freedom of the city from plague is striking.

The principal rat flea of the Orient is Xenopsylla cheopis. This flea is without combs like Pulex irritans, the human flea, but is of a lighter color and has an ocular bristle near the upper margin of eye and two bristles posterior to the antennae. In Europe and the United States Ceratophyllus fasciatus is the common rat flea. Many other species of fleas transmit plague and it is also possible that the bedbug may play a part in spreading infections from man to man. Vergbitski has transmitted plague from man to the rat by infected bedbugs. In Siberia, a marmot, the tarabagan, is supposed to play the part of the rat in plague transmission. In California, the ground squirrel, Citellus beecheyi, has become infected and may transmit the disease by its flea, Ceratophyllus acutus. In the Tropics plague tends to prevail only at times when the temperature is between 10° and 30°C. It is the effect on the flea of cold weather which causes the disappearance of bubonic plague at such times. The bacillus of plague can withstand freezing temperatures. Sunlight and drying are the especially inimical factors for B. pestis. Dry seasons are inimical to the spread of plague and it is especially in very rainy seasons that epidemics rage.

In the necrotic material plague bacilli can be found in approximately one-half of these rats although frequently the bacilli are nonvirulent. It is possible that[197] this chronic plague in rats may serve as the reservoir of infection which keeps up plague epizootics from year to year. Plague in India, according to White is less virulent now than formerly and this is attributed to a greater immunity of the rats.

In the recent epidemic of pneumonic plague in North China, it was at first thought that the hunting of the tarabagan for its valuable skin, which led some of the Chinese to even capture tarabagans, possibly sick with plague, was the origin of the epidemic. This view is no longer held and we now know that the outbreak was independent of any disease in rats, tarabagans or other animals. Strong has shown that the bacillus which was isolated from these cases of pneumonic plague was identical with that isolated from cases of bubonic plague; its virulence was no greater and animals infected cutaneously or subcutaneously died of bubonic plague. Experiments by Teague and Barber, with emulsions of plague bacilli, showed that with a room temperature of 32°C. plague bacilli were quickly destroyed when the air was comparatively dry. In such an atmosphere, saturated with moisture, the viability would be greatly prolonged. In the plague wards in Manchuria the extreme cold which prevailed, together with the saturation of the atmosphere of the unventilated rooms by the moisture of the breath of the patients, made conditions most favorable for the viability of the plague bacillus. They note that in the plains of India, although about 3% of bubonic cases assume a pneumonic type, yet epidemics of plague pneumonia do not occur; this is probably due to the fact that the higher temperatures and open rooms make evaporation occur 30 times more rapidly there than was the case in the plague wards in the bitter cold weather of the Manchurian winter. The possibility of carriers of plague bacilli in those who might go on to convalescence need not be considered, as practically all cases of plague pneumonia die. Other material from the patient than sputum does not seem to be a source of danger in the spread of plague, so that there is no need for the disinfection of urine and feces. There has recently been an outbreak of septicaemic plague in Ceylon in which there was an absence of plague in the rats. The infection was possibly transferred directly through bedbugs or human fleas. As a matter of experience the transference of plague from place to place generally occurs from infected rats or infected fleas which have been transported by ships. A case of bubonic plague in a ward with other patients would not be a source of danger provided there was freedom from fleas and a lack of development of secondary pneumonias. It is very doubtful as to infection ever taking place by way of the alimentary canal, although there is some evidence that rarely the tonsil may be primarily involved. Monkeys are very susceptible to plague and the possibility of an epizootic among them should be thought of during plague epidemics.

The chief points noted in a plague autopsy are: (1) The marked involvement of the lymphatic system as shown by intense congestion and haemorrhagic oedema of the lymphatic glands. Not only are the glands tributary to the site of inoculation involved, thus forming the primary bubo, but there is secondarily more or less inflammatory change in all the lymphatic glands of the body. There is also a marked periglandular oedema, with haemorrhagic extravasations of the connective tissue surrounding the primary bubo, this mass being made up of a group of glands matted together by this periglandular exudate.

(2) The destructive effect of a toxic product of the plague bacillus, which may be designated an endotheliolysin, upon the endothelial cell lining of blood vessels as well as lymphatic ones. This causes the extensive blood extravasations so characteristic of plague as shown by petechial spots, not only of the skin but of the serous and mucous membranes as well.

The meninges of the brain are deeply congested and there may be haemorrhagic extravasations in the brain substance itself. Crowell has reported two cases of plague meningitis in which plague bacilli were found in the ventricular pus. The spleen is generally markedly congested and enlarged to 2 or 3 times its normal size.

There may be haemorrhagic extravasations throughout the spleen pulp. The bacilli are chiefly scattered throughout the venous sinuses.

There is also active congestion of the liver. The kidneys are intensely congested and we often find fibrin thrombi in the tufts of the Malpighian bodies.

In a study of the pathology of primary pneumonic plague Strong noted pericardial and pleural ecchymoses with fibrinous pleurisy over the affected lung areas.

The process was at first lobular but later involved the entire lobe.

There was marked congestion of the bronchial mucosa with involvement of the bronchial glands. The larynx and trachea are also intensely congested. Microscopically there is a distension of the alveoli and bronchial passages with a haemorrhagic exudate. There is practically no fibrin in the alveolar exudate. The process seems to extend by continuity along the bronchi and bronchioles.

Plague bacilli pack the exudate found in the bronchi and bronchioles.

In a report on the autopsy findings of septicaemic plague in Ceylon in cases[199] where plague bacilli were demonstrated in smears and cultures from spleen and blood, Castellani noted that other than meningeal congestion and some splenic enlargement there was nothing abnormal.

Ordinarily, man is so susceptible to plague that there is no reaction at the site of inoculation but in these mild cases there is an inflammatory reaction resulting in a vesicle or pustule, which may teem with plague bacilli. In such cases it is extremely important to search for such primary vesicles and examine for plague bacilli. It is usually stated that only about 5% of cases of bubonic plague show these vesicles.

Both of these types of plague tend finally to show an invasion of the blood stream with plague bacilli, the case then becoming one of septicaemic plague. Many authors, however, recognize an overwhelming plague septicaemia in which the manifestations of buboes or pneumonia are absent and such cases are designated septicaemic plague, or pestis siderans.

Typhus fever alone shows an equal degree of early mental hebetude, so that it is stated that Clot Bey, who had seen much plague in Egypt, when elsewhere shown cases of typhus with parotid involvement, remarked “In Egypt one would call such cases plague.”

The speech is thick and difficult, the gait is staggering, so that, with the stupid mental state and tendency to wander aimlessly about, one has the symptom-complex of an alcoholic intoxication. In some cases a delirious tendency may be marked, especially as the disease develops. After a few hours, or within a day, the fever begins to rise rapidly and is often associated with shivering attacks. The face now becomes hot and flushed, the conjunctivae markedly injected, the pupils dilated, and the eyes rather staring. The temperature is as a rule from 102° to 104°F., occasionally higher, with a tendency to rather marked remissions and, on the whole, of great irregularity of the fever curve. The pulse is rapid and shows early indications of the extreme toxic effect exercised upon the heart. Cardiac weakness is a marked feature of plague.

The urinary secretion is diminished but there is rarely more than a slight amount of albumin.

The Pathognomonic Bubo.—About the second or third day the development of an extremely painful bubo practically gives the diagnosis.

There is a question whether the tonsil ever serves as the site of infection from which cervical buboes result. It would seem that the greater frequency of inguinal buboes is because a greater area of skin drains into these glands. There may be multiple buboes and it must not be forgotten that the lymphatic glands of any region may become enlarged. There may also be lymphangitis. Only one gland of a group may be involved or the whole group may show enlargement. Very characteristic for plague buboes is the oedema of the periglandular tissues, which is largely responsible for the great size of some of these buboes; they may vary from the size of an almond or walnut to that of a child’s head. The patient tends to assume an attitude to relieve any tension on the very painful bubo. Particularly over these buboes, but at times elsewhere, the skin may show areas of inflammation, often several inches in diameter. Necrosis of this area occurs and a slough separates. These lesions are often termed carbuncles but are really not such, but only gangrenous patches of skin.

Petechiae or large purpuric spots may be conspicuous in some epidemics and it was from these “tokens,” as they were called, that plague received the designation “black death.”

Cases with buboes in the axillae give the gravest prognosis, as for example, 80% mortality for axillary, and 70% for inguinal. The buboes may suppurate towards the end of a week or they may undergo a slow resolution. Secondary broncho-pneumonia may develop in the course of bubonic plague. Pulmonary congestion is however not infrequent and may cause dyspnoea, accelerated respiration and cough. Owing to the tendency to degeneration of the endothelial lining of capillaries, various haemorrhagic manifestations, other than those of the skin, may be observed, such as epistaxis, haematuria, etc. There is usually a rather marked leucocytosis in which the increase is chiefly of the polymorphonuclears.

Although the characteristics of pulmonary involvement, with expectoration of blood, were noted by many observers of the 14th century and later as manifestations of plague, yet in the present pandemic, which started in 1894, such cases were at first overlooked as being plague. The recognition of a primary pneumonic plague was made by Childe in 1897. The onset is sudden, with a rise of temperature to 103°F., or higher, during the first day. The marked physical exhaustion and clouding of the consciousness, characteristic of any type of pestis major, are intensified[202] in pneumonic plague. In fact the occurrence of manifestations of such profound toxaemia in the presence of only slight physical signs, should make one suspicious. Crepitation over small areas, without demonstrable dulness on percussion, may be the only sign. There is often early dyspnoea and rapid shallow respiration. Cough, with the expectoration of rather abundant watery sputum, which soon becomes blood-stained or absolutely sanguineous, may be present by the second day.

It is fortunate that this watery sputum teems with bacilli early in the disease as smears from such sputum give an early and sure diagnosis of this terribly contagious and fatal malady. The knowledge that this infection is transmitted from man to man by the droplets of sputum expelled in coughing demands the protection by some form of mask of anyone coming near such a patient. Some observers noted splenic enlargement and tenderness over the superficial lymphatic glands.[203] Strong has noted that the course of the disease rarely extends beyond the fourth day and that death is the invariable termination.

In 1919 thirteen cases of plague pneumonia occurred in California starting from an at first unrecognized case of bubonic plague of squirrel origin. These pneumonias were diagnosed as influenza pneumonias but later the true diagnosis was determined. McCoy notes in this connection that there is a strong tendency to pulmonary localization of plague in the squirrel which is not true of the rat.

The patient may be so overwhelmed from the start that there may be only a slight rise of temperature. Occasionally, plague bacilli may be recognized in blood smears, a finding that practically never obtains in any other bacterial disease. At the same time blood cultures are solely to be depended upon in diagnosis and even such examinations may be negative. Liston has noted that plague patients always die if more than 40 bacilli per cc. are present in the blood. In a recent outbreak of septicaemic plague in Ceylon the only clinical manifestations were intense headache, and fever. The patients died within forty-eight hours. Until properly diagnosed bacteriologically the disease was thought to be pernicious malaria.

General Appearance.—The face is at first drawn and pallid, the eyes injected and the expression one of fear or anxiety. As the temperature rises the pallor is succeeded by a flushed and dry hot skin. Later on in the disease the expression is more one of apathy. The staggering gait and the tendency to wander give the impression of alcoholic intoxication.

Temperature Curve.—The fever course of plague is very irregular. The temperature usually rises rapidly to 103° to 104°F., but tends to exhibit marked remissions by the third day. After a fall, it may rise to a very high degree just before death. Cases which recover often show a fall by lysis.

Nervous System.—Very characteristic for plague is the intense and early disturbance of the mental condition. The patient presents the characteristics of alcoholic intoxication, thick speech, lack of mental concentration and giddiness which causes a staggering gait. Later on an apathetic or stuporous stage may ensue or there may be delirium.

Rarely a case of bubonic plague may show marked involvement of the meninges, giving the clinical picture of meningitis.

Circulatory System.—The pulse is at first soft, dicrotic and rapid, 110 to 120 beats per minute. Later on, as the heart begins to show the toxic effects of the disease, the pulse becomes thready and irregular, to be followed by cardiac failure.[204] There is a marked tendency to congestion of various internal organs and to haemorrhages from the capillaries.

Respiratory System.—Pulmonary congestion and even broncho-pneumonia may supervene in bubonic plague. In pneumonic plague, however, the lungs seem to be the primary seat of the bacterial development. Plague pneumonia is characterized by intense toxaemia and few physical signs. The abundant, watery sanguineous sputum is loaded with plague bacilli. Dyspnoea and cyanosis appear early.

The Lymphatic System.—It is the presence of the plague bubo which differentiates bubonic plague. There is no relation between the size of the bubo and the severity of the attack. Axillary buboes are the most fatal. A characteristic of these buboes is their extreme tenderness, the pain causing the patient to draw up the legs or assume any attitude which will relieve tension upon the bubo. The size is mainly due to the periglandular infiltration or oedema, which causes the glands of a group to be matted together.

The elevation of a plague bubo is rather diffuse, not pointed as with venereal buboes. Femoro-inguinal buboes are about 6 times as frequent as cervico-maxillary ones. There may be lymphangitis as well as lymphadenitis.

Cutaneous System.—The skin over the buboes often tends to become necrotic and slough off. This however may occur elsewhere and such lesions are termed[205] “carbuncles.” Capillary haemorrhages of the skin may cause petechiae and when the area is large they have been designated “tokens.” In about 5% of cases there is a small vesicle or pustule at the site of the flea bite as an indication of reaction. The contents teem with plague bacilli. It is often termed the primary lesion.

The Liver, Spleen and Alimentary Tract.—The spleen may show enlargement and tenderness on deep pressure, as may also the liver, these organs being markedly congested. The tongue at first is coated, with clean tip and sides. Nausea and vomiting frequently occur and, as a rule, there is constipation. Haemorrhages from the bowel may occur.

One should be suspicious of any case of fever of rapid onset in which there is marked dulling of intellect and impairment of speech, as of one intoxicated, together with evidences of rapidly developing heart weakness. In septicaemic plague we practically have no other symptoms to guide us—there is not the exquisitely tender bubo of bubonic plague nor the abundant, watery, sanguinolent sputum of pneumonic plague.

An influenza pneumonia may show the general prostration and cardiac weakness of plague. In influenza pneumonia we have an onset with the features of ordinary influenza, which, however, in the influenza epidemic in 1918 was often short. In plague pneumonia we have pneumonia from the start. The pulse in plague is early weak and rapid and the tendency to a stuporous state more marked. The early appearance of thin watery sputum, which quickly becomes blood-tinged and always contains plague bacilli is noted in plague pneumonia. Only a few hours elapse before we have bloody sputum which in influenza is a later and not constant sign. The dyspnoea is earlier and much more pronounced in the pneumonic plague. At autopsy Crowell notes the almost invariable presence of pleural exudates in plague while an acute vesicular emphysema is a feature of influenza pneumonia.

Malaria and septicaemic conditions may be confused with septicaemic plague. The sudden onset and prostration of relapsing fever may make one think of plague.

Many have thought climatic bubo a form of ambulant plague but the gradual onset, only slight tenderness of the swollen glands and slight prostration should differentiate. Venereal bubo cases are apt to be regarded with suspicion during epidemics.

Markedly toxic cases of typhoid fever with an exceptionally rapid onset may give rise to confusion.

In a case of suspected pneumonic plague we stain the smear of watery or thin blood-tinged sputum as above.

Plague is practically the only bacterial disease where there is likelihood of finding the causative organism in smears. In septicaemic plague the blood culture is the proper procedure and one should take 5 to 15 cc. of blood in 15 to 25 cc. of normal saline containing 1% of sodium citrate. This prevents coagulation and at one’s leisure 1 or 2 cc. can be added to tubes of melted agar and plates poured or other portions added to bouillon or 3% salt agar. This same blood emulsion can be used to infect guinea pigs subcutaneously or to infect them cutaneously by rubbing on the shaven surface.

In smears from material from buboes, from sputum, or in blood smears, as well as from blood or spleen smears from experimental animals, we obtain the typical morphology of a cocco-bacillus (1.5 × 0.5 microns) with very characteristic bipolar staining, there being an intermediate, unstained area. Very characteristic also is the appearance in these smears of degenerate types which stain feebly and show coccoid and inflated oval types. The presence of these involution forms associated with typical bacilli is almost diagnostic for one with experience. Inoculating tubes of plain agar and 3% salt agar with this same material, we obtain in plain agar cultures organisms which are, typically, small, fairly slender rods, which do not stain characteristically at each end and are not oval. The smear obtained from the salt agar presents most remarkable involution forms—coccoid, root-shaped, sausage-shaped forms, ranging from three to twelve microns in length, more resembling cultures of moulds than bacteria. Another point is that on the inoculated plain agar we are in doubt at the end of twenty-four hours whether the dew-drop colonies are really bacterial colonies or only condensation particles. By the second day,[207] however, these colonies have an opaque grayish appearance, so that now, instead of questioning the presence of a culture, we consider the possibility of contamination.

The plague bacillus grows well at room temperature—its optimum temperature being 30° instead of 37°C., as is usual with pathogens. Next to the salt agar culture, the most characteristic one is the stalactite growth in bouillon containing oil drops on its surface. The culture grows downward from the under surface of the oil drops as a powdery thread. These are very fragile, and as the slightest jar breaks them, it is difficult to obtain this cultural characteristic.

A pocket made by cutting the skin of a guinea pig with scissors and extended subcutaneously with scissors or forceps, into which a piece of the suspected plague tissue is thrust with forceps, is more practical than injecting an emulsion with hypodermic syringe.

Mice inoculated at the root of the tail succumb quickly. Rats, this being primarily a disease of rats, are of course susceptible.

When a guinea pig is inoculated with plague material the animal should be placed in a galvanized iron garbage can or other similar container and the opening covered with cheese cloth to prevent the fleas or other vermin which it might harbor from escaping. Again a 6-inch band of tanglefoot fly paper should be attached around the interior of the upper part of the can to further prevent escape of fleas. It must be remembered that every precaution must be taken in the laboratory to prevent the escape of plague-infected fleas. The guinea pig usually dies in from two to five days and shows glandular enlargements, and marked congestion of viscera with a swollen spleen, smears from which may show a profusion of plague bacilli.

If guinea pigs are not available one may use white mice which die within forty-eight hours or white rats which live about as long as guinea pigs.

One of the most important points in fighting plague is the detection of plague in the rats and, from noting the locality in which such plague-infected rats were caught, to direct our rat destruction efforts to that particular section of the city. These dead rats should be dropped into a bichloride solution or petroleum preparation in order to destroy the rat fleas. In the laboratory they are dissected and plague-infected ones most easily recognized by the marked subcutaneous injection of the widely reflected skin flap. Oedematous or haemorrhagic glandular swellings are characteristic. The liver shows a yellowish appearance, and as if sprinkled with[208] small whitish dots and the spleen is swollen and congested. There may be effusion into the pleural cavities. Material from the swollen glands or spleen should be stained, cultured and inoculated into animals as for a human case.

Agglutination is not very practical owing to the frequent absence of agglutinins from the serum of plague patients. Then, too, there is a marked tendency to spontaneous agglutination on the part of the plague bacilli. Strong states that culturing at 37°C. lessens this tendency to spontaneous agglutination. Again, even when present, the titre of plague-agglutinating sera is usually quite low so that one must work with dilutions of from 1 to 10 or 1 to 20.

As regards bubonic plague the mortality averages 75%. The Egyptian epidemic of 1900 gave an average mortality of 50%. The mortality in natives is much higher than that among Europeans, these latter often showing death rates under 25% while in the same epidemic natives show from 75% to 95% mortality. Plague pneumonia, however, is absolutely fatal for Europeans as well as natives.

The attendants are protected by bag-like masks or successive layers of gauze and cotton wool applied as bandages over face and neck. Motoring goggles make a good protection for the eyes and small rolls of cotton should be placed along the sides of the nose to absolutely prevent the possibility of bacilli being drawn down to the entrance of nose or mouth. These masks should not have any weak spot in their armor.

Spread of plague pneumonia.—It has been noted that when secondary pneumonia develops in the course of bubonic plague in India, the Philippines, or other hot countries, it is not followed by primary plague pneumonia outbreaks. This is thought to be due to the fact that the windows are wide open and the relative humidity[209] low, conditions which are the opposite of those which existed in Manchuria where the intense cold made the closing of windows necessary and where the air of rooms or wards was saturated with the moisture from the occupants. As the main consideration for the spread of pneumonic plague seems to be high relative humidity it would seem that hospital wards could be constructed so that the air supplied by artificial ventilation would be very dry.

Spread of bubonic plague.—With bubonic plague, unless it should in its course become pneumonic or septicaemic, there is almost solely the question of the rat and its fleas. Many authorities consider that pure bubonic plague can be treated safely in a general ward of a hospital provided there is sure freedom from bedbugs or other verminous insects.

The various species of fleas which the rat may harbor may be attacked by the use of various petroleum preparations containing naphthalene. One preparation known as pesterine, which consists of kerosene 20 parts, soft soap 1 part and water 5 parts, the soap being dissolved in the water and the oil being gradually stirred into the hot mixture, is often recommended as a flea insecticide. A 5% solution of compound cresol to which naphthalene has been added is also of value.

This may explain why a high death rate among rats, as the result of a plague epizootic, may act as a factor in the outbreak of human plague.

The first measure in rat extermination is the regulation of the disposal of garbage. It is most important that only cans with securely fitting tops be used so that rats cannot secure any food from the contents of the can. Again no particle of food should be left accessible to the rat. Unless the ordinary food supply of the rat is denied him he will not eat poisoned bait or bait in traps. Again rats are not only carnivorous but will eat any kind of cereal or vegetable, in fact they will eat almost anything and in addition are cannibals. In a plague outbreak especial attention should be directed to flooring in stables, under surfaces of board walks, sealed-in[210] attics of houses, wharves and sewers. Where sewers have catch-basins at street openings the rat has a means of egress from the sewer. These sedimenting catch-basins also serve as a breeding place for mosquitoes. It has been estimated that a sewer rat can jump 2 feet but not 3 feet.

In rat-proofing houses, double walls should be eliminated and houses raised well from the ground—at least 18 inches. In plugging up rat holes with concrete we should add broken glass to the concrete. Sheets of galvanized iron driven down several feet have been used as a protecting barrier around grain elevators or warehouses. Concrete is the proper material to use in rat proofing.

Hydrocyanic acid gas is a most efficient destroyer of rat and flea life. The great objection to its use is its danger to those using it in fumigation. Liston allows this gas, developed from ½ ounce KCN, to act for four hours in a space of 100 cubic feet. The great danger from the use of this gas in holds of ships is that it tends to collect in detached spaces or pockets and remains following ventilation of the hold so that persons entering such spaces suffer the poisonous effects of the gas. Some cargo ships have a rat-run built to extend fore and aft and leading to a receptacle in which the rats are caught. Rats naturally choose a tube or similar opening so they get into this little passageway which is so constructed that their return is obstructed. This scheme is used in setting traps, either covering the traps with hay and leaving a small opening or placing the trap under an inclined plank or placing it at the end of an iron or terracotta pipe. There is not much danger of rats getting aboard a ship lying out from the dock. It is when a ship goes alongside a dock that we can expect rats to come aboard.

Phosphorus paste made up with a glucose base and containing about 4% of phosphorus is spread on pieces of stale bread, 1 inch square and ¾ inch thick. Whatever poison is used, whether strychnine, arsenic or phosphorus, it should be placed in boxes which have openings large enough to let the rats in but too small for domesticated animals. Barium carbonate is a useful rat poison.

Cats will very rarely attack the fierce sewer rat.

Danysz virus.—Many workers, during plague outbreaks, have tried to exterminate rats by impregnating bread or other bait with bacterial cultures. The best known of these viruses, as they are called, is that of Danysz. The organism is closely related to B. enteriditis of Gaertner and is supposed to bring about a fatal infection in the rats. As a matter of fact the cultures quickly cease to be virulent and their use has been generally abandoned. Simpson, however, thinks well of this measure and employed it with success in South Africa. He kept up the virulence of his cultures by frequent passage through animals.

Recent reports show that of 118,148 inoculated persons the plague incidence was approximately 8 per 1000 while among 321,621 noninoculated the incidence was 34 per 1000.

Statistics from Sagaing show 19 cases with 7 deaths among 4284 inoculated persons while there were 134 cases and 128 deaths among 4467 not inoculated.

The plague mortality in cases which had previously been inoculated was 40% while that among the noninoculated was 78%.

Besides this killed culture other material has been used. Lustig and Galleotti used the nucleo-proteid from plague bacilli for subcutaneous injection. Kolle and Strong have recommended a vaccine of living but nonvirulent plague bacilli. A higher degree of immunity seems to be conferred by this living vaccine but there are certain dangers in the use of living organisms which outweigh the advantage noted above.

Yersin’s antiplague serum, which is prepared by injecting horses at first with killed cultures and later with living plague bacilli, may be used as a prophylactic as well as in treatment. One point to consider is that such serum, if used immediately after taking from the horse, might contain living plague bacilli. The phenol preservative prevents this. It must be remembered that this is a passive immunization as against the active one with Haffkine’s prophylactic, hence the protection is very short, only ten days or two weeks as against the more enduring immunity of a year or so following Haffkine’s prophylactic. It must be remembered that anaphylactic manifestations may follow the repeating of the dose of Yersin’s serum. It is probably advisable for one who is to be exposed to plague for a short time only to receive an injection of the serum. As regards pneumonic plague there seemed to be little protection attaching to either active or passive immunization.

Salvarsan, as might be expected, has been tried but did not prove of any value.

Connor has reported success with the intravenous injection of one dram of a dilution of 1 part of tincture of iodine in 10 parts of sterile water. He gave 6 such injections to a severe case with good result.

In the way of symptomatic treatment one should use ice-bags to head and cold sponging to the body.

Morphine seems to be the best drug to calm the patient. Cardiac stimulants, especially strychnine, are indicated for the heart weakness so much a feature of plague. Some consider incision or enucleation of the bubo of value in treatment but it has always seemed to me that the going into the periglandular exudate might serve to set up a septicaemic condition when otherwise it might not supervene.

The site of the bite in man is usually marked by a punched-out ulcer, which is associated with swelling and suppuration of the glands draining the area. The general symptoms are sudden onset, with rigors, followed by an irregular fever of three or four weeks’ duration and by a prolonged convalescence. Several cases have been reported in the middle west due to handling infected rabbits. There have been a number of infections in laboratory workers where the local signs have been absent. In man death rarely results from the disease.

History.—In 1911 McCoy and Chapin discovered the B. tularense in a plague-like disease, first described by McCoy in the California ground squirrel. They described the organism, succeeded in cultivating it on special media, transmitted the infection to various rodents by feeding, nasal inoculation and injection of infected blood, and demonstrated the probable natural mode of transmission by the squirrel flea.

In recent publications, Francis, Lake and Mayne, and Wayson have recorded the transmission of the disease experimentally by the house fly (Musca domestica), the horsefly (Chrysops discalis), the stable fly (Stomoxys calcitrans), the rabbit louse, the mouse louse and the bedbug, and have shown that the freshly recovered organism can be grown on other than the special media previously recommended.

Geographical Distribution.—The first case of infection occurring in man was reported from Ohio by Wherry and Lamb in 1914. Since then a number of cases have been reported by Francis among rural residents of Utah and by Francis and Lake among laboratory workers handling animals infected with B. tularense.

Recently Francis has shown that the organism will grow scantily on serum or blood agar. However, by adding a piece of fresh sterile spleen to such media he has obtained a more satisfactory culture medium, although for routine work the egg yolk medium is preferred. The organism refuses to grow on ordinary media such as nutrient broth or agar. Material from a culture, or pus from bubo, or an emulsion of the spleen of an infected guinea pig, when rubbed into the abraded skin of an experimental animal brings about infection, in this respect showing a similarity to plague infection. Upon autopsy of such an experimentally infected guinea pig we find haemorrhagic oedema at the site of inoculation with caseation of lymph glands and small necrotic foci in spleen and liver. Smears from the spleen show the organism in varying numbers. In infected rodents the organism is often found abundantly in the blood and in man a bacteriaemia may occur.

As a result of accidental laboratory infections it would seem that almost 100% of those carrying on extensive animal experimentation with this organism become infected.

The louse infesting jack rabbits Haemodipsus ventricosus, can transmit the infection from rabbit to rabbit so that the infection in the jack rabbits is probably kept up by this agency. Recent experiments have shown that the infection in white mice can be transferred by the bites of the mouse louse and also by bedbugs. Again if the mice are fed on infected bedbugs transmission is found to take place by such feeding experiments. The faeces of such bedbugs prove infectious. Guinea pigs injected subcutaneously with the urine of white mice suffering from the disease die acutely with typical lesions of tularaemia.

Mice fed on the liver of a rabbit dying of the disease succumbed to the infection within five days.

Wherry reported the infection as manifested by conjunctivitis with glandular involvement and due to handling infected wild rabbits.

Lake and Francis have reported that of six investigators from the Hygienic Laboratory working with this infection all have contracted the disease. There were fortunately no fatalities. Such an experience demonstrates the great infectivity of this virus and must lead to the conclusion that the few cases so far reported of the disease do not represent the importance of tularaemia in man. With a knowledge of the existence of such an infection and with satisfactory methods of laboratory diagnosis we shall probably have other reports of the infection. We now know that the ground squirrels of California and Utah, the jack rabbits of Utah and the wild rabbits of the middle west furnish important reservoirs of virus.

In experimental animals we have a definite bacteriaemia but in man the organism has only in rare instances been obtained from the blood.

Physical examination is almost invariably negative. The spleen is not palpable. The pulse is rather rapid and the blood pressure uninfluenced.

The white and differential counts vary but little from normal.

The main feature of the disease, aside from local lesions when these are present, is prostration and this continues marked during the several weeks or months of convalescence.

In the six laboratory infections above referred to, there were no local lesions except in the case of one man who had had previously an attack of the disease. In the second attack, two years after the first one, there was noted a papule on one finger with subsequent involvement of the epitrochlear and axillary glands. A guinea pig inoculated with blood taken from the papule became infected and showed the typical lesions of tularaemia.

There was no fever or malaise in this second attack, thus showing a degree of immunity. In cases showing conjunctival ulcerations with glandular involvement Wherry and Lamb obtained cultures of B. tularense from inoculated animals.

Material from ulcers or glands should be inoculated into guinea pigs or white mice. The organism is almost invariably absent from the blood of human cases so that blood cultures or animal inoculation from such blood are almost always negative.

Complement fixation and agglutination tests are the methods of diagnosis to be relied on. In the Hygienic Laboratory an antigen is prepared by washing off the 72 hour growth from egg yolk medium with small amounts of saline. The suspension is heated for 30 minutes at 56°C. and then preserved by the addition of O.3% tricresol. Such an antigen is used for each type of test.

Detailed accounts of the presence of cholera in India were published from the 16th to 18th centuries when the Portuguese, English and French were carrying on their wars of conquest in India. These wars naturally spread the disease all over India.

It is thought that true cholera did not exist in China until 1669 when it was carried there from India. It is first described from Japan in 1821 although an epidemic which devastated Tokyo in 1718 may have been cholera.

A great pandemic of cholera started in India, in 1817, extending over Asia but not invading Europe. The second great pandemic is of importance as being the first to invade Europe. It started in India in 1826 and advancing slowly reached Persia in 1829, going thence by way of Astrakhan to Russia, Sweden, Northern Europe and England. By 1832 it had spread over the whole of Europe.

In the same year, 1832, it reached Canada and thence spread to Fort Dearborn where it infected the soldiers who subsequently carried the disease down the Mississippi valley. It was also introduced into New York and spread thence South and West so that by 1836 cholera was present all over the U. S., not disappearing until 1838. It disappeared from Europe in 1839.

The next European outbreak or third pandemic lasted from 1846 to 1862 and was traced to India by way of land and sea, that by land following the caravan route by way of Persia and Russia and that by sea from Indian pilgrims going to Mecca and there causing the infection of Mahommedan pilgrims from Egypt and European Turkey. This pandemic reached the U. S. in 1848, starting at New Orleans and going up the Mississippi valley. Central and South America and the West Indies were also invaded by the third pandemic.

The fourth great pandemic invaded Europe by the usual routes and continued from 1863 to 1875. During its continuance there were two outbreaks in the U. S., one in 1867 and another in 1873.

The fifth pandemic began in 1883 and affected particularly the Mediterranean seaports of France, Spain and Italy. It was during this epidemic, in 1883, that Koch, working in Egypt, discovered the cause of cholera, the Spirillum cholerae asiaticae.

A very serious outbreak of cholera, which originated in 1891, in pilgrims from the delta of the Ganges, reached Europe in 1892, almost a million deaths occurring in Russia. It was during this epidemic that cholera appeared in Hamburg and gave opportunity for those careful studies as to transmission of the disease to be later referred to.

It is usual to recognize a sixth pandemic which began in 1902 and spread over India, China and the Philippines. This pandemic continuing was a cause of great mortality among the soldiers of the recent Balkan war. During the World War there was much cholera among the Austrian forces in Galicia. It also prevailed in Bulgaria, Greece and Turkey.

Geographical Distribution.—Practically every pandemic when studied can be traced back to India and particularly to the delta of the Ganges, which may be considered the enduring focus of the disease.

It is Gram-negative and stains best with a dilute (1-10) carbol fuchsin. There is a single terminal flagellum, which endows the organism with great motility, which may best be termed scintillating. It has been estimated that its motility is five times greater than that of the typhoid bacillus. It grows best on media with an alkaline reaction (—0.4%) and it is this tolerance for media of high alkalinity that permits the separation of the cholera spirillum from the ordinary faecal bacteria by the use of Dieudonne’s alkaline blood agar or similar media. This is equal parts of defibrinated ox blood and N/1 NaOH, 3 parts of which are added to 7 parts of nutrient agar. It thus has 15% of normal sodium hydrate, instead of the 1% acid reaction of the usual media. Unfortunately, other spirilla tolerate this high alkalinity.

The cholera organism is strongly aerobic and grows quickly and luxuriantly in the upper part of a tube of Dunham’s peptone solution, this property enabling one to[221] separate it from other organisms of faeces by taking up loopfuls from the surface layer to plate out on agar of about 0 or -0.3% reaction. When grown in peptone solution the cholera spirillum produces a nitroso body so that one obtains an indol reaction (cholera red) by simply adding 5 or 6 drops of concentrated H₂SO₄.

When this test is employed it is necessary to determine whether the peptone used is suitable for the reaction. As a matter of fact this test is now rather discredited. Blood serum is digested. Recently much discussion has arisen as to the value of the haemolytic power possessed by noncholera vibrios on blood agar plates.

It is true that the digestive action which true cholera has on the red cells of the medium may give the appearance of a zone of haemolysis. Therefore, for the demonstration of this haemolytic action of noncholera spirilla, fluid blood media should be used. The El Tor spirillum, isolated from Egyptian pilgrims without symptoms of cholera, is haemolytic, but gives the immunity reactions of the true cholera vibrios which are not haemolytic.

Gelatine is liquefied and the stab shows an air bubble liquefaction at the summit of the stab. On gelatine plates a powdered glass center with an encircling zone of liquefaction was formerly considered characteristic of cholera, but at the present time gelatine cultures have been almost abandoned in practical work.

As a rule animals cannot be infected by feeding them cholera material unless the acidity of the gastric juice be neutralized and intestinal peristalsis checked by opium (procedure of Koch). Injected intraperitoneally, the cholera vibrio produces a fatal peritonitis. Recently monkeys have been infected after purgation with sulphate of soda and administration of bicarbonate of soda. They died in from one to forty-eight hours with symptoms of cholera.

Emmerich and Pettenkofer swallowed cholera cultures, the former experiencing a severe attack of cholera and the latter a diarrhoea in which cholera spirilla were present. On the other hand similar experiments have resulted negatively but this is what should be expected from the epidemiological facts as to carriers.

The virulence of the cholera vibrio can be exalted by passage through guinea pigs—successive culturing of the peritoneal exudate of intraperitoneally infected animals alternating with culture media growth inoculations. Such a fixed virus, the virulence of which cannot be exalted, is the material used by Haffkine in his cholera vaccine. The toxicity of cholera is supposed to be due to an endotoxin which is set free when the vibrios undergo disintegration when lying between the basement membrane and epithelial lining of Lieberkühn’s glands. Others think the vibrios may enter the blood stream, there to be immediately disintegrated with toxin production. The usual idea, however, is that the cholera spirilla never invade the blood stream—they are confined to the alimentary canal. Macfadyen obtained the endotoxin by grinding the frozen spirilla. This toxin was destroyed by a temperature of 60°C.

The inoculation of animals by cholera cultures tends to produce an immune serum which is remarkable for its high agglutinating power, the titre at times going as high as 1 to 20,000. For agglutination tests in proving spirilla isolated from stools to be true cholera ones we use a serum of at least 1 to 4000 for its specific vibrio. Such a serum should agglutinate any true cholera spirillum in a 1 to 500 or 1 to 1000 dilution. The occurrence of bacteriolysis, when a small loopful of the culture emulsified in 1 cc. of 1 to 1000 dilution of the immune serum and then introduced into the peritoneal cavity of a guinea pig, is the surest proof that a suspected organism is that of cholera.

This is shown when, upon removing a drop of the peritoneal fluid fifteen to twenty minutes afterward, there is noted an absence of motility and disintegration of the spirilla (Pfeiffer’s phenomenon).

Complement fixation tests, using the rice-water stools or peptone solution cultures as antigen, are of less value than those above noted. Agglutination is the practical test and is almost as specific as that for bacteriolysis.

It will be remembered that Pettenkofer and Emmerich insisted upon the factors of soil and ground water in the spread of cholera. Emmerich now admits that the spirilla excreted by carriers can produce cholera but that such transference never gives origin to epidemics. For this to take place he thinks that the vibrios excreted by a carrier must come in contact with a soil which has been impregnated with a suitable medium drawn to the surface from the deeper layers of the soil by capillary suction. In such medium the vibrios flourish and acquire the property of actively producing nitrites from nitrates.

Emmerich considers that the symptoms of cholera are those of nitrite poisoning so that only such organisms as possess this nitrite-forming function in high degree can produce virulent outbreaks of cholera.

[223]

All facts in connection with the spread of cholera by land or water routes can be best explained by the cholera carrier; the individual who is excreting vibrios, while in apparent health, being far more dangerous than the one excreting such organisms in the rice-water stools of a well-recognized case of the disease.

In the latter mode of infection, cases will appear from day to day and often peculiarly localized to certain definite districts of a city or to certain definite users of a particular water supply.

During a period of only about two months cholera attacked about 17,000 persons causing 8605 deaths in a city with a population of 600,000. This outbreak was attributed to the washing of clothes in the water of the Elbe River by Russian immigrants. These immigrants had come from cholera-infected districts and among them there undoubtedly were cholera carriers.

The water supply of Hamburg was taken directly from the river. The adjoining city of Altona, with a population of 140,000, is further down the river but filtered its water by a slow sand process. Although the water as taken from the river contained the sewage of Hamburg yet there were only 328 deaths or 2.1 per thousand as against 13.4 per thousand for Hamburg. There were many interesting points in connection with the exemption of certain places in Hamburg, of which may be noted the instance of the entire freedom from cholera of a group of houses (Hamburg Hof), with 345[224] occupants. This was the only section of Hamburg which was supplied with Altona water. As Hamburg and Altona are only separated by the width of a street and hence practically form a single city, the factor of food and contact transmission could easily explain the cases in Altona.

This was about the first definitely proven connection between water and cholera. In 1854 it was noted that cholera was about 10 times as prevalent in Golden Square as in other adjacent parts of London. Various factors, such as previous droughts, stagnation of lower strata of the atmosphere, sewerage defects and subsoil drainage were found to be the same in Golden Square as elsewhere. It was noted that the number of cases increased in the neighborhood of the Broad Street well. The employees of a cartridge factory where this well water was used gave a large number of cases while an adjoining brewery, which had a well of its own and served out beer to its employees, did not furnish a single case. Very striking was the case of a lady living at Hampstead, a section of London which was then free from cholera, who had acquired a liking for the water of this well and had brought out to her regularly bottles of water from the well. This lady drank some of the water on August 31 and was seized with cholera the next day. A niece drank of the same water and died of cholera as well as the aunt. A servant also contracted the disease but recovered.

Lettuce and celery are particularly dangerous because of the favorable condition of moisture in their folds and imbrications. Furthermore these vegetables are eaten uncooked and may have been fertilized with night soil (human excrement) which material, if containing cholera dejecta, would infect the plants. Milk is a splendid culture medium for cholera vibrios but, upon becoming acid, sterilizes itself of these vibrios. In sterilized milk, however, they live for extended periods, as long as sixty[225] days and, even when such milk is contaminated by faecal material containing other organisms besides the cholera vibrio, the vibrios live much longer than they do in raw milk.

Milk is liable to be contaminated by flies which have been in contact with cholera stools. Water that has been boiled and food that has been cooked should subsequently be scrupulously protected from flies or other contaminating agents. Uncooked shell fish are peculiarly dangerous in cholera outbreaks.

In India, sun-dried fish, which are frequently covered with flies during the curing process, are a factor in the spread of cholera.

Since that time these observations have been generally confirmed. In some instances as many as 20% of those who have been in immediate contact with a cholera patient have become carriers, some showing symptoms of cholera but a larger proportion excreting cholera spirilla while continuing in health.

While cholera prevailed in Manila, McLaughlin found from 6 to 7% of carriers among healthy persons living in the infected districts.

Pottevin has recently reported that of 13,000 pilgrims examined 1.7 per thousand carried cholera vibrios. The carriers were especially common among the dysenteric patients. During the Naples epidemic of 1911 it was found that on the average 10% of healthy people in contact with cholera cases became carriers. It was estimated that 90% of the cases in this epidemic were infected by sick or healthy carriers.

Sergeant has recently reported the case of a healthy carrier who continued to excrete cholera vibrios for two months and during this time was in contact with 8 persons, 7 of whom became infected and 4 died. In Manila it was found that many of the children reported as dying of meningitis or infantile beriberi were cholera cases.

With healthy cholera carriers the period of the continuance of vibrio excretion is equally short but cases have been reported where periods of from three weeks to two months have been noted. It is usually stated that 97% of carriers become vibrio free within a month.

Greig has found infection of the bile of the gall bladder or ducts in 80 cases in 271 cholera autopsies. When living organisms are injected into the ear vein of a rabbit they pass into the bile. An examination of the epithelial layers of the gall-bladder of such a rabbit shows destruction of the cells and the presence of vibrios in the underlying tissues. While cholera spirilla are soon crowded out by intestinal bacteria,[226] thus explaining the short period during which cholera spirilla are excreted by convalescents, this is not true when the cholera vibrio gets into the bile ducts or gall bladder. Greig found one cholera convalescent excreting cholera vibrios forty-four days after the attack. Of 27 persons who had been in contact with cholera patients 6 were excreting cholera vibrios although apparently well.

A very important matter is that persons who fail to show cholera vibrios may begin to excrete such organisms after the administration of a purgative or following some intestinal disorder. In fact purgatives may set up an attack of cholera in a cholera carrier.

The spread of cholera is intimately connected with the great religious festivals and pilgrimages of Oriental people. Not only do those of India keep up the dissemination of the disease there but pilgrims going from the delta of the Ganges to Mecca carry the infection and transmit it to their fellow pilgrims from Egypt and Algiers. Greig examined a number of cholera convalescents who were about to return to their homes in India and found 30 per cent of these pilgrims excreting cholera vibrios in their stools.

The intimate commercial relations between Europe and Egypt and Algiers make the introduction of the disease into European ports an easy matter. Of particular importance is the fact that so many sick people make pilgrimages, these being peculiarly liable to act as carriers.

Excesses in eating, often of badly prepared or decomposing food, following periods of religious fasts, predispose the natives of India to cholera.

The lower portion of the small intestines is the favorite location for the action of the endotoxin of cholera. Early and marked postmortem rigidity is a striking characteristic of the cholera cadaver. Muscular contractions, causing odd positions[227] of the limbs, have at times given a basis for the idea that the victim had been buried alive.

Besides marked rigor mortis the emaciation, leaden hue of skin and shrivelled hands are noteworthy.

There is congestion of the affected intestinal mucosa and the lumen is filled with the alkaline rice-water material. If the case is of some days standing we have a rather brownish, foul-smelling bowel content. There is usually a parenchymatous nephritis and on section the medullary portion is much congested.

In his studies of the pathology of cholera Greig drew attention to the frequency of the involvement of the gall-bladder. He also noted the presence of small areas of consolidation in the lungs of those developing pneumonia during the early days of convalescence. In the exudates of such areas cholera vibrios could be seen thus showing their penetration of the lung. Although rare instances of recovery of the cholera spirillum from the blood have been reported Greig was unable to accomplish this in any instance. In his opinion the spirilla travel by way of the lymphatic system. In eight cases out of fifty-five cases he recovered the spirilla from the urine.

The striking feature, however, of these movements is the sensation of prostration which accompanies them.

Early in this stage cramps of the muscles set in. The muscles of the legs, especially the calf muscles and those of the feet, are particularly liable to these very painful contractions which may cause the patient to cry out for relief. The muscles of the abdomen and back may also be involved as may at times the muscles of the entire body.

Along with the excessive loss of fluid the tissues, especially of the face, become shrunken, the eyeballs with their congested conjunctivae sink back in the orbits, and the nose becomes pinched. The pulse becomes more and more feeble and there is a steady diminution in the secretion of urine. An increasing duskiness of the skin, which is cold and clammy to the touch, denotes the setting in of the algid stage.

The vomiting, purging and cramps may or may not subside and in the patient, with his great thirst, intense exhaustion and cadaveric appearance, with mental faculties fairly well preserved, we have an example of a living death. The temperature of the sodden, inelastic, clammy skin is markedly depressed, even below 90°F., while the rectal temperature may approximate normal or be elevated.

Some authorities consider a marked difference between the superficial and rectal temperatures as of bad prognosis.

The voice becomes husky and finally so feeble that the patient can only whisper and the breath feels cold.

The sodden shrivelled hands, as those of a washerwoman, are very characteristic. Thirst is intense.

The patient now falls into a listless, motionless state in which, however, the apathy is more apparent than real. The algidity may deepen and death ensue or the stage of reaction may set in. The algid stage may last from a few hours to two or three days.

It is customary to divide the types of cholera cases into:

1. Cholera gravis. The type above described.

2. Cholerine. In this there is a more or less marked stage of evacuation with possibly the appearance of rice-water stools. The urine, however, does not become suppressed and the algid stage is not entered upon.

3. Cholera sicca. This type of the disease is more apt to be seen in old or debilitated people. The patient dies of collapse without showing symptoms of vomiting or diarrhoea. At the autopsy one may find the bowels distended with rice-water contents.

The so-called cholera ambulans is simply another designation for the more or less ill cholera carrier.

General Appearance.—A typical case of cholera, with its cyanosed, drawn, pinched face, cold, clammy skin and the eyes deeply sunken in the orbits, makes a picture rarely seen in other conditions. The washerwoman’s hands appearance should always be looked for.

Temperature Record.—The temperature of the skin surface is lowered from the normal while that of the rectum may be normal or even elevated. There may be a difference of 10° or more between rectal and surface temperature. In the stage of reaction the temperature may continue to rise to high fever points and this so-called hyperthermic type is very fatal.

Circulatory System.—The pulse is rapid and feeble in the stage of evacuation to become imperceptible in the algid stage. The circulation is practically at a standstill so that only a few drops of black tarry blood, which does not coagulate readily, flow from a wound of a vein when giving an intravenous injection. The blood is concentrated and has a specific gravity of 1072 to 1078. The systolic pressure falls greatly, even to 60 mm. of mercury in a severe, or 75 mm. in a less serious case. The red cell count is increased to 7 or 8 million red cells per c.mm. and the leucocyte count reaches 15,000 to 50,000.

Nervous System.—The mind is clear, even when the patient seems profoundly apathetic. The muscle cramps are characteristic of the disease.

Algid pernicious malaria generally shows a rather high axillary temperature and the stools are rarely so profuse as in cholera.

In ptomaine or mushroom poisoning the vomiting usually precedes the diarrhoea—the opposite of the order in cholera.

Acute intestinal obstructions may simulate but here we have faecal vomiting and constipation.

With irritant poisons as arsenic or antimony there is the metallic taste and the pains are chiefly colicky rather than muscular and the stools rather dysenteric.

I have seen severe cases of bacillary dysentery which could not be differentiated clinically from cholera, and it is interesting to note that many cases of cholera occurring in the Balkan war were diagnosed as bacillary dysentery. In children cerebral manifestations are very common so that in the Philippines many such cholera cases were diagnosed as meningitis.

It is well to first make a microscopical examination of the stool by taking one of the whitish epithelial flakes from the rice-water material and making a straight smear which is then dried and fixed with heat. This may be stained best by a dilute carbol fuchsin (1 to 10). Methylene blue makes a good stain, or more differential is that by Gram’s method which shows the Gram-negative spirilla stained by the bismarck brown counterstain, giving the appearance of fish parallel to one another in a stream. According to Koch a diagnosis can be made in this way of one-half the cases during an epidemic.

Dunbar has a quick diagnostic method in which epithelial flakes from the stool are emulsified in peptone solution. Then on a slide, according to the method to be later described, is deposited a drop of 1 to 50 normal serum dilution and on the same slide a second drop of 1 to 500 dilution of cholera serum. A loopful of the suspected stool emulsion is rubbed up in each of these serum dilutions and we should have cessation of motility and clumping in the cholera immune serum provided the organisms in the stool are true cholera spirilla.

In case of an autopsy on a suspected case of cholera one should tie off, between double ligatures, at least two 5-inch sections of small intestines, one just above the ileo-caecal valve and one taken from about the middle of the ileum. These portions of gut should be dropped into sterile salt mouth bottles, well stoppered and sent to a bacteriological laboratory as soon as possible. As the cholera spirilla, when associated with faecal bacteria, tend to die off within twelve to twenty-four hours it would probably be advisable to inoculate an agar or blood serum slant with material from the ileum at the same time the sections of gut are removed. For diagnosis of a cholera carrier with a normal stool or a cholera suspect with a diarrhoeal one inoculate 2 or 3 tubes of peptone solution with 2 or 3 loopfuls of material from the stool. With suspected carriers who are constipated and to whom one should not give purgatives we may insert into the rectum a rubber tube or a throat swab in order to obtain material immediately. The cholera spirilla grow rapidly and being strong aerobes, they grow on the surface of the fluid so that by taking a loopful from the surface, we may in three to eight hours obtain a pure culture. Should there be a pellicle present, this should be avoided in transfer by tilting the tube slightly, so that the material near the surface be obtained without touching the pellicle. Inoculate a second tube from the surface of this first and, if necessary, a third (enrichment method).

Smear the three-hour surface growth of a peptone culture on a dry agar surface in a Petri dish. From colonies developing make agglutination and, if desired, cultural tests. It is by immunity reactions and not by cultural ones that we identify cholera spirilla. The surface moisture of plates is best dried by the filter-paper top.

A practical quick method is to make smears from suspicious colonies, stain for one minute with dilute carbol fuchsin and if vibrios are present to make 2 vaseline rings on a single slide allowing ample space at one end for handling the preparation safely. Inside of one ring deposit with a platinum loop a drop of salt solution and inside the ring nearest the end which is to be held by fingers or forceps deposit a loopful of 1 to 500 or 1 to 1000 dilution of cholera serum. The emulsion in the salt solution remains uniformly turbid and under a low power of the microscope (⅔-inch) shows a scintillating motility. The emulsion made into the drop of serum quickly shows a curdy agglutination and upon examination with the ⅔-inch objective shows clumping and absence of motility. Cover-glasses placed over the two vaseline rings assist in the study of the preparation.

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The best-known selective medium for plating out cholera material is that of Dieudonne which is referred to under etiology. Apparently a more satisfactory medium is that proposed by Goldberger, this medium being transparent.

First prepare a 100% meat infusion by treating 500 grams of finely chopped lean beef with 500 cc. water and after three hours strain the infusion, adjust reaction to neutral with 5.3% anhydrous sodium carbonate, then add to each 100 cc. 2½ cc. of the 5.3% anhydrous sodium carbonate, sterilize in Arnold for one-half hour and filter. Next prepare a 3% meat extract agar and mix one volume of the alkaline meat infusion with 3 volumes of the hot melted 3% meat extract agar. Pour plates and cover with a piece of filter-paper and place in incubator for one-half hour until they are quite dry. The necessity for a surface without moisture applies to Dieudonne’s and Krumwiede’s alkaline egg media as well as this one. On this medium cholera grows well while faecal bacteria are restrained.

The cholera colony is clear, round and shows a brownish center but is without that striking bluish opalescence shown on ordinary agar plates.

While peptone solution is a more favorable enrichment medium and answers perfectly when cholera organisms are fairly abundant yet, when scarce, selective enrichment media may be desirable. Of these the best known is Ottolenghi’s alkaline bile. Goldberger prefers an alkaline egg peptone solution made as follows:

Shake up an egg with an equal quantity of water and add to this egg solution an equal quantity of a 5% solution of anhydrous sodium carbonate. Steam one hour. Then add 1 part of this alkaline egg medium to 9 parts of peptone solution, filter and sterilize. Recent reports on Aronson’s cholera medium would indicate its great value in stool examination for cholera. The organisms taken from such plates emulsify easily and there is no interference with their agglutinability. To prepare it add to 100 cc. of 3% nutrient agar, 6 cc. of 10% solution of exsiccated sodium carbonate and steam in Arnold sterilizer for fifteen minutes. Then add 5 cc. of 20% saccharose solution, 5 cc. of 20% dextrin solution, 0.4 cc. saturated alcoholic basic fuchsin and 2 cc. of 10% sodium sulphite. A precipitate forms which quickly settles and plates can be poured from the supernatant fluid. Cholera colonies develop in twelve hours and show as red colonies in fifteen to twenty hours.

In the presence of cholera one should not only drink recently boiled water, which has been protected from the contaminating influence of flies, but all forms of uncooked food should be avoided. In the first rank of prohibited foods should be raw shell fish and uncooked salads. Such articles as lettuce and celery are particularly dangerous on account of the moisture retained. Fruits such as bananas and oranges can be made safe by covering them with boiling water for two or three minutes and subsequently peeling. Care must be taken that native servants do not put fish, which may have been contaminated with cholera-infected water, on the ice in an ice box and through such a source to have the butter, etc., infected. The most scrupulous attention should be given the matter of the care of the ice-box in the tropics.

If conditions are such that boiled water cannot be obtained the water may be treated with good quality chlorinated soda. As a stock solution we use 1 teaspoonful of chlorinated soda to 1 pint of water and of this 1 teaspoonful to 2 gallons of the water to be disinfected. Pottevin recommends six hours contact with hypochlorite of soda, 1 mg. per liter.

Besides care of the food and water ingested particular attention should be paid to the washing of the hands before eating and if in contact with cholera cases careful disinfection of the hands.

Tea has been recommended as a prophylactic, as has also eucalyptus oil, 10 minims twice daily.

As acids have an inimical effect on the cholera spirilla some have recommended the use of acid drinks but as a matter of fact the best prophylactic is the normal gastric juice and there is a possibility that the use of such acid drinks might upset the digestion and thus defeat the object desired.

For disinfection of stools one requires an equal amount of a 5% compound cresol solution which when mixed with the same amount of stool becomes a 2½%[234] solution. This should be in contact with the stool at least one hour before emptying the container. Chlorinated lime, 1 pound to 4 gallons, makes a splendid disinfectant for stools—equal parts of this 1 to 16 chlorinated lime solution and stool.

Bed clothing or other material contaminated by vomitus or faeces should be immersed in a 2½% compound cresol solution. All food utensils should be disinfected by boiling.

Persons attending cholera cases should wear gowns and remove the same upon leaving the room. Particular care should be exercised in hand disinfection after attending a cholera case.

There is no danger from aerial conveyance of infectious material other than the possibility of one’s coming within the danger zone of a vomiting patient. Therefore, for disinfection of a room occupied by a cholera patient we need not use formaldehyde gas but washing of floors and lower part of walls with 2½% compound cresol solution is sufficient. The stock solution of chlorinated lime, 1 pound to 4 gallons, is suitable for mopping floors and walls.

Ferran, in 1885, was the first one to use cholera vaccines in prophylaxis. Haffkine, in 1893, adopted the use of a preliminary subcutaneous injection of an attenuated cholera organism to be succeeded later by one, the virulence of which had been exalted by passage through animals to a fixed virulence. (Pasteur’s anthrax method.) He now only uses the fixed virulence vaccine. This vaccine is not killed by heat.

The statistics indicate quite a reduction in susceptibility on the part of vaccinated persons (probably 8 to 1) but only slight lessening of mortality rate. Of 5549 nonvaccinated 198 contracted cholera and 124 died. Of 5778 vaccinated 27 contracted cholera and 14 died.

In the recent Balkan war (1913) Kolle’s vaccine was employed with considerable success. This vaccine is killed by exposure to 58°C. for one hour. It was found that this vaccine was not only of value prophylactically but diminished case mortality as well. With 91,224 persons vaccinated and 8,968 not vaccinated, the case rate among the inoculated was 0.7% and the death rate 10.2%, while among the noninoculated the case rate was 9.3% and the death rate 27.5%.

Ottolenghi prefers to sterilize with a temperature of 53°C. He gives 500 million at the first injection and 2 billion at the second.

Among 72,653 soldiers, having 2 inoculations of this vaccine, the incidence of cholera was about 13 times less than among 14,332 who were not vaccinated.

Of 2897 Greek sanitary corps men inoculated 0.45% were attacked while of 114,805 combatants, not inoculated, about 2% were attacked by cholera. One would naturally consider the greater exposure of the sanitary forces.

Cholera vaccines made from killed cultures are the ones now generally used.

During the World War a Roumanian regiment numbering 4,500 soldiers, had 386 cases of cholera develop in the course of six days, with 166 deaths. Vaccination[235] was commenced and during the interval between the first and second injections, new cases continued to appear. Two days after the second injection the epidemic ceased. In another regiment the commandant refused to have his men vaccinated. A group of Jewish soldiers, 200 in number, insisted on being vaccinated, which was done. Later the regiment was stricken by cholera and 450 cases developed. None of the vaccinated Jewish soldiers contracted the disease.

Some prefer sensitized living cultures for prophylaxis but such vaccines are less practical.

There is much to indicate that Strong’s cholera autolysate is of value prophylactically. In this cholera cultures are killed at 60°C. The killed culture is then allowed to digest itself in the incubator at 37°C. for three or four days (peptonization). The preparation is then filtered and from 2 to 5 cc. of the filtrate is injected.

Treatment.—Many of the older authorities recommended the use of various astringent medications for the checking of suspicious diarrhoeas and most of these prescriptions contained opium in some form, such as lead and opium pills or aromatic sulphuric acid and laudanum. In view of the fact that for the infection of animals Koch had to employ opium for checking peristalsis in addition to neutralization of gastric juice it would seem very undesirable to use opium by mouth. Calomel in divided doses and continued over one or two days, but not exceeding 7 or 8 grains, has been recommended.

Reports as to the use of kaolin in treatment and as a prophylactic have been favorable. The suspension in water is given as a drink and as an enema.

Rogers has recently been administering 1/100 of a grain of atropine sulphate morning and evening. His statistics would indicate a reduction in mortality of about one-half. Cases treated with atropine also rarely show collapse. Injections of adrenalin solutions have been recommended.

A great objection to any form of oral medication is the tendency to vomiting. This can in a measure be controlled by cracked ice or by a small hypodermic of morphia. The latter drug also relieves the very painful cramps.

One danger which must always be borne in mind in giving more than one dose of any drug subcutaneously is that with the slowing or cessation of circulation, coming on with the algid state, we have no absorption but, when the stage of reaction sets in and the drug, whether morphine or toxic stimulant, begins to be taken up, there may ensue a fatal poisoning.

In the Philippines the normal saline seemed to answer as well as the hypertonic solution.

Sellards had success in combating anuria, which is one of the most dangerous conditions encountered in cholera, and at the same time answered equally well with normal saline in relieving collapse, by giving 2% sodium bicarbonate injections.

There is a marked acidosis in cholera and this form of treatment seems indicated.

The objection to using sodium carbonate is that the salt has a lytic action on red cells in vitro and furthermore Sellards found that it tended to cause convulsions in one of his cholera cases. Sodium bicarbonate, even in 4 or 5% concentration, does not have any haemolysing effect on the red cells. Of course it is true that in sterilization the bicarbonate tends to be converted into carbonate but Sellards found that by sterilization in an autoclave connected with live steam, at 7 pounds pressure, this was minimized, only about 25% of the bicarbonate being converted into carbonate after 1 hour.

If the temperature by rectum is about normal or slightly below, the temperature of the fluid should be 102° to 104°F. and one usually gives about 2 quarts.

To determine the necessity for intravenous infusion in cholera Rogers has recently recommended the employment of small bottles containing aqueous solution of glycerine with specific gravities varying from 1048 to 1070, increasing the specific gravity in each successive bottle by 2°.

Drops of blood from the cholera patient are deposited at the center of the surface of the fluid in the bottles from a capillary pipette. If the specific gravity of the blood is 1062 at least a liter of saline or sodium bicarbonate solution is needed. If 1066, at least 2 liters. Formerly he estimated the indications by blood pressure, considering a pressure of 80 in Europeans or of 70 in natives as indicating intravenous injections.

Hot water bottles should be used to keep up the body heat. No food should be given during the first thirty-six hours but after that time we may give broths or albumin water.

In 1861 Marston showed on clinical and pathological grounds that the disease was different from typhoid fever.

In 1887, Colonel Bruce isolated the causative organism from the spleen at autopsy and established the demands of Koch’s postulates by reproducing the disease in monkeys with cultures from the spleen and then recovering the organism from the monkeys.

Our present accurate knowledge of the epidemiology of Malta fever and its connection with the use of the milk of goats is due to the work of a Commission appointed to investigate the disease—1904 to 1907.

Geographical Distribution.—It is usual to consider Malta as the focus of the disease, with the cities of the Mediterranean shores showing quite a degree of infection. It is probable that the spread of the disease has been in part connected with the importation of Maltese goats, these animals being desirable on account of their superior yield of milk. It is now known that outside of the Mediterranean basin the disease exists in India, East and South Africa as well as Northern Africa, China, North and South America and the West Indies.

Mohler has shown that the disease under the names of “slow fever” and “mountain fever” has existed in Texas and New Mexico for at least twenty-five years.

These minute transparent colonies become somewhat opaque and about 1/10 inch in diameter by the tenth day. Gelatine is not liquefied and litmus milk is not altered. The optimum reaction of media is about +0.75 to phenolphthalein and it grows best at the body temperature. It has great powers of resistance to drying so that it survives in dust for long periods.

Horses, cows, asses, as well as goats, are susceptible. It is very difficult to infect rabbits, mice and guinea pigs. Monkeys have been chiefly utilized in experimental work.

It would appear as if there were other organisms closely related to M. melitensis and a great deal is now being written as to confusing serum reactions from the use of M. paramelitensis.

Evans and others have studied the relationship between Bacillus abortus and M. melitensis. Morphologically and culturally these organisms are quite similar and Evans has demonstrated a marked degree of cross-agglutination. This is a probable explanation of the finding by Kennedy of agglutinating power in the sera and milk of certain cows, but inability to isolate M. melitensis from the agglutinating milk.

Epidemiology.—Many experiments have failed to show any mosquito, biting fly or louse as a probable factor in the transmission of the disease. The infection is readily transmitted by subcutaneous inoculation so that in a case in goat or man, with the cocci in the peripheral circulation, it is reasonable to suppose that a biting insect might transfer the infection by going directly from one animal to another. There have been several laboratory infections, but when we consider that of the great number of cases treated at Haslar hospital and elsewhere in England, with frequent elimination of the organism in the urine, and practically no infections among the friends or attendants, it would seem as if usual methods of infection were inoperative. There does not seem to be a carrier problem in this disease. Urine showing bacterial contamination, when dried and mixed with dust, has caused infection and contaminated urine applied to the glans penis of a monkey caused the disease.

As a large proportion of the prostitutes of Malta showed infection and as M. melitensis was found in urine and vaginal discharges of many of these it is possible that sexual intercourse may be a factor in transmission.

There are however occasional cases which Shaw has considered as due to carriers. As the organisms are excreted in faeces as well as in urine, and as the course of the disease is so protracted, as well as the convalescence, it would seem that the carrier factor should be of more importance than facts would justify.

The souring of milk does not destroy the germs of the disease, hence transmission may be brought about by butter and cheese.

Malta fever was stamped out of Port Said by destroying all infected goats.

At postmortem we have an enlarged, congested, soft spleen with swollen Malpighian bodies. The kidneys may show a nephritis and the mesenteric glands be swollen. The intestines fail to show the characteristic lesions of typhoid fever.

There may be evidences of myocarditis.

The tongue is not heavily coated and is red at the tip and sides.

There is often a slight bronchitis, with cough, which, when associated with a profuse sweating at night, may suggest phthisis.

The symptoms which aid us most in diagnosis are joint manifestations and neuralgic pains. These may come on quite early in the course of the disease or be delayed until succeeding febrile waves set in. Swelling and pain, but without redness, of a single joint may come on rather suddenly, to have the acute symptoms subside in a few hours and to be entirely normal in three or four days.

It is however the peripheral nerves, even more than the joints, for which the toxic effects of M. melitensis show a preference. The sciatic nerve seems to be most often involved and sciatica may set in suddenly and acutely, to pass off in two or three days, leaving a soreness over the course of the nerve and a tendency to recurrence. Orchitis may occasionally set in. There is usually albuminuria.

Insomnia is usually quite a prominent feature of the disease and there is a great tendency for nervous prostration to develop.

Other Clinical Types.—(1) The Malignant Form.—In such cases instead of the insidious onset we have the characteristics of a severe acute infection with high temperature from the beginning, ranging from 103° to 105°F. Such cases may show vomiting and early diarrhoea. This is followed by a typhoid state with cardiac manifestations in the way of irregularity of the pulse. An ordinary type of case may assume this malignant form and such cases may develop a broncho-pneumonia.

(2) The Intermittent Form of Hughes.—Here we have a type of case similar to the typical one but less severe. It is a subacute form which from time to time shows an intermitting fever. These cases may fail to show evidence of serious illness and the patient may continue his work although noting a progressive deterioration of health. Some very mild cases which only rarely show slight fever of a few days’ duration have been reported as ambulatory cases.

(3) The Disease in Infants.—Di Cristina and Maggiore have described various forms of the disease as observed in infants in Palermo. They note a hyperpyrexial type and an undulant type. A type with anaemia and marked cachexia is very severe. Another form shows cyanosis, irregular pulse and irregular respiration with marked sweats. Again the symptoms may be those of a cerebro-spinal meningitis.

Sequelae and Complications.—It should be borne in mind that while not serious from a standpoint of mortality this disease is to be dreaded by reason of the possibility of invalidism. The neuralgic pains, insomnia and mental depression render patients liable to the morphine habit. In pregnant women there is a tendency to abortion. In rare cases we may have intestinal haemorrhages with asthenic manifestations. Bassett-Smith has reported a case with extensive purpura. The same author in paramelitensis cases has noted the susceptibility to secondary streptococcal infections.

Temperature Chart.—Except in the malignant form of the disease, when the temperature may be rather continuous, the fever course is a step-like ascent with daily remissions for about ten days and then a similar descent. Following an evening rise of temperature night sweats may be noted.

It is the wave-like succession of such courses of fever, separated by afebrile intervals, that suggests the name undulant fever.

Circulatory System.—The disease shows rather a toxic effect on the heart as shown by palpitation and irregularity and rapidity of pulse rate.

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In the beginning of the fever, however, the pulse rate is not very fast. Anaemia is a rather marked feature.

Respiratory System.—A slight bronchitis with cough tends to suggest phthisis in those cases which show rather marked night sweats.

Nervous System.—The organism seems to have a selective action on the nervous system as shown by headache, various neuralgias, insomnia, apathy and neurasthenia. Sciatica is probably the most common peripheral nerve involvement.

Joint Symptoms.—Very characteristic are the sudden and painful swellings of various joints, especially hip, shoulder, ankle and knee. Not rarely the costo-sternal articulations may be involved. The acute symptoms subside in a few hours and the joints become normal in a few days.

Alimentary Tract Symptoms.—The tongue may have a slight furring but the edges and tip are quite clean and red. Although anorexia exists with the fever the appetite tends to return with apyrexia. Constipation is usual. There is frequently tenderness of the epigastric region.

Genito-urinary System.—Other than for albuminuria and the presence at intervals of the causative bacteria in the urine, there is nothing of note, except the occurrence of orchitis in about 3 per cent. of cases.

The Blood.—The white count is about normal or slightly reduced—6500 on the average. The cells of lymphocyte type tend to show an increase in percentage with a corresponding reduction of polymorphonuclears.

There is a secondary anaemia.

The spleen shows early enlargement and tenderness.

Besides the agglutination, complement fixation or blood culture aids, we rely upon the sudden onset of joint involvement or neuralgic manifestations as indicating Malta fever.

Usually the splenic enlargement about corresponds with that of typhoid fever but at times it may be so marked as to equal that of malaria or even kala-azar.

The presence of rose spots as well as the marked apathetic state and the tendency to diarrhoea should aid in differentiating typhoid. Unfortunately for diagnosis the leucopenia and polynuclear percentage reduction is similar in the two diseases.

The short course and more sudden onset of influenza and the more marked pulmonary symptoms of phthisis should prove diagnostic aids.

It must be remembered that the colonies only appear about the fourth day, becoming quite distinct by the tenth day.

Bassett-Smith takes about 10 cc. of blood in the afternoon during pyrexial waves and distributes this blood in several tubes of broth. He makes plates from these tubes every day. He also recommends the taking of 1 cc. of blood which he allows to clot and subsequently removes the serum and adds bouillon (clot culture).

In connection with agglutination tests Nicolle recommends that the serum be separated at once and removed from the clot and Nègre has shown that by heating the serum to 56°C., for thirty minutes, reactions are not obtained with nonspecific sera.

Some workers prefer the macroscopic agglutination.

Complement fixation methods are of value but the application of such tests is confined to large laboratories.

A rapid method of detecting infected goats is by carrying out a macroscopic agglutination of M. melitensis with the milk obtained from goats. The lacto-reaction should be confirmed by a serum one.

A serum prepared by injecting horses intravenously with the specific organism has been recommended by Sergent in doses of 50 cc.

Bassett-Smith recommends an autogenous vaccine, during the afebrile period, in doses of from 50 to 200 millions. He thinks that the best results are obtained with sensitized vaccines. During acute phases the vaccine treatment is detrimental—it is only in chronic cases that such treatment is of value. Some prefer to give doses of 10 million or so at short intervals. He also thinks yeast in 2-dram doses to be of value. Phenacetin or aspirin may be given, but the heart weakness makes extensive use of these analgesics dangerous.

The diet should be that for any acute disease but the protracted course makes it necessary to have regard to an adequate food value. Care should be taken to avoid chilling or fatigue.

Some recommend moderate use of alcoholic stimulation but this treatment is questionable.

Cold sponging and local applications to joint or nerve involvements are indicated.

Morphine should be employed with great caution.

The disease is caused by an acid-fast bacillus, which has not surely been cultivated or inoculated into animals with pathogenic result, and which is found in extraordinary abundance in the granulomatous subepithelial tissues of nodular leprosy and in scanty numbers or not at all in the perineurium and endoneurium of the ulnar, facial or perineal nerves.

History.—There are those who consider India as the home of leprosy, a condition corresponding to the disease having been described in the Rig Veda, of date of 1400, B. C.

Others regard Egypt as the original focus, a disease similar to leprosy having been described in the “Ebers papyrus” of date of about 1300, B. C.

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Any one reading chapter xiii, Leviticus, must be convinced that the disease there described as leprosy was of a different nature. We find statements to the effect that where the hair in the spot is white and the spot deeper than the skin of the flesh that it is leprosy; again, if there be a white or red rising it is not leprosy, but if lower than the skin it is leprosy.

According to Unna the term Zaarath had a theological rather than a medical meaning. At the same time other references in the Bible would indicate that leprosy was more or less prevalent among the Jews of that period.

It is very probable that the ancients confused leprosy with many other diseases where ulceration and nodular disfigurement were conspicuous features.

From the fact that leprosy was called the Phoenecian disease it would seem that Asia was the real home of the disease.

It is well established that leprosy was introduced into Europe, from Egypt, in the first century, B. C., by the returning legions of Pompey.

As a result of the crusades, leprosy was spread widely over Europe by the crusaders, so that in the 14th century the disease was so prevalent, that it required approximately 20,000 leper asylums to care for the lepers. In France alone there were about 2000 such leprosaria.

As a result of the most drastic measures of isolation the disease began to decrease in the 14th century and had practically disappeared from Europe, as a whole, by the 15th century.

Geographical Distribution.—With the exception of a limited and steadily diminishing number of cases in Norway and Sweden, with an uncertain number in the Balkan region and Turkey, leprosy has almost disappeared from Europe. Parts of Brittany and Provence in France show cases and there are a considerable number in Portugal and Spain.

Africa is heavily infected with the disease, especially in Central and East Africa. In certain portions of the Cameroons (Banyang) it is so common that one in every four persons suffers from leprosy.

[248]

Asia has many important leprosy centers, there being a very great number in China and India. There are about 100,000 lepers in Japan and about 3000 in the Philippines.

In 1902 there were 278 lepers in the United States, of which number 145 were native born. In 1912 there were only 146 distributed chiefly in three centers: (1) That of the Great Lakes, there being now 13 cases in Minnesota as against 27 in 1900; (2) among the Orientals of the Pacific Coast, and (3) in the Gulf region, especially about Louisiana and Florida.

There are 696 lepers in Hawaii and 28 in Porto Rico.

In South America, the disease is found in Columbia, Venezuela and Brazil as is also true of Mexico and Central America.

In Australia the disease is found in Queensland and New South Wales.

It also prevails in New Caledonia and the islands of the Pacific.

The leprosy bacilli are found in profusion in the granulomatous tissue of the corium and subcutaneous structures of the leprous nodules, chiefly within cells called “lepra cells” and also within endothelial and connective-tissue cells as well as lying free, packed in lymphatic channels, the so-called “globi.”

1. The presence ordinarily of huge numbers of bacilli often grouped in packets like a bundle of cigars tied together.

It will be remembered that it is very difficult to find even a single tubercle bacillus in a skin lesion. Leprosy bacilli form palisade groups but not chains.

2. The leprosy bacilli stain more solidly and when granules are present they are coarser and more widely separated than the fine granulations of the tubercle bacillus.

3. They do not stand decolorization quite as well as the tubercle bacillus. With 20% sulphuric acid in water they hold their color almost as well as tubercle bacilli but with 3% HCl in alcohol they decolorize in about two hours as against twelve to twenty-four hours for the tubercle bacillus.

4. Leprosy bacilli have neither been surely cultivated nor surely inoculated with pathogenic results into guinea pigs or other experimental animals and it is by the negative results upon cultivating or animal inoculation that we have our surest method of differentiation from tubercle bacilli.

Leprosy bacilli are chiefly spread through the lymphatics, but in nodular leprosy, their occurrence in the blood stream during the febrile accessions is so constant that this route may also be of importance. Next to the corium they are most abundant in the lymphatic glands. They stain readily by Gram’s method.

[249]

A great amount of work has been done within recent years in attempting to cultivate the leprosy bacillus.

In 1900 Kedrowsky culturing material from 3 cases of leprosy obtained diphtheroids from two and a streptothrix from one. A rabbit was inoculated first intracerebrally and later intraperitoneally with this nonacid-fast streptothrix and, when killed six months later, showed peritoneal nodules, from which both diphtheroids and acid-fast bacilli, but not a streptothrix, were recovered culturally. Injections of cultures of the acid-fast bacilli and diphtheroids into rabbits and mice produced nodules which when cultured showed acid-fast organisms or diphtheroids.

In 1901 he cultivated a diphtheroid from a fourth case of leprosy.

Fraser and Fletcher working with Kedrowsky’s culture produced peritoneal nodules with the killed as well as the living organism. They were able to produce the same results with B. phlei. With emulsions of leprous nodules, rich in leprosy bacilli, they could not produce similar lesions in the experimental guinea pigs.

Rost obtained a culture on a salt-free medium from which he prepared his leprolin by a process similar to that used for old tuberculin. It was claimed that leprolin had marked curative power in leprosy. Recently Williams and Rost have cultivated a streptothrix on a medium containing milk.

Clegg, by inoculating his medium with cultural amoebae, obtained growth of a diphtheroid organism, with acid-fast tendencies, from the spleen pulp of lepers.

Duval, by using media containing amino-acids, as result of tryptic digestion, brought forward two organisms, one of which was a diphtheroid and grew luxuriantly while the other showed a slow scanty growth and was acid-fast.

Bayon, by using placental media, isolated an organism rather resembling that of Kedrowsky. These organisms alone responded to immunity tests when such were made by Bayon and they alone gave rise to tissue changes resembling those of leprosy when injected into animals.

Professor Deycke obtained a streptothrix-like growth from the granulomatous tissue of excised leprous nodules. The ethereal extract from this culture gave a neutral fat which he called nastin and which is the basis of a leprosy treatment.

As being opposed to the possibility of culturing the human leprosy bacillus, it may be stated that most of the experiments along this line with rat leprosy, a disease occurring naturally in rats and caused by an organism almost identical, as to lesions produced, with the leprosy bacillus, have been negative. Bayon, however, states that he has cultivated the bacillus of rat leprosy.

Every book refers to the inoculation experiment by Arning, of a freshly excised leprous nodule sewn into a skin incision of the arm of a condemned criminal. In this case a neuritis developed shortly after the inoculation and the patient showed fully developed leprosy three years later. Unfortunately for the value of the experiment the man was a native of Hawaii and had lepers in his own family. Against this experiment are the numerous instances where physicians have inoculated themselves and others with leprous material with invariably negative results.

As regards those living for a long time in attendance on lepers there have been a very few instances of the contraction of leprosy as in the case of Father Damien at Molokai, and two instances in Sisters of Mercy. Such cases however are most exceptional, as the hundreds of attendants on the unfortunates continue their work for years without showing any signs of leprosy.

There are two cases which show that those who live in close relation to lepers may develop the disease; in one, a leper returned to Ireland and his brother, who had never been in a leprosy country, but who had occupied the same bed with the leper and worn his clothes, developed the disease in about five years. A similar case is reported from Germany.

In Japan, 7% of children of lepers contract the disease, 3.8% of those married to lepers and 2.7% of people living in the same house with lepers.

Just as with tuberculosis, in which all evidence points to the predominance of infection in early life and its infrequency in adult life, so does it seem to be true of leprosy. Among 10,000 lepers in the Culion leper colony, Denny notes that 35% were brothers and sisters, 27% were cousins, 11% were children of lepers, 7% parents of lepers, and only 1% husband and wife. This would indicate that the relationships involving intimate contact in childhood are etiologically most important.

This might have occurred without isolation because Hansen in investigating the descendants of 160 known Norwegian lepers, who immigrated to the North-western States of America, was unable to find trace of a single leper among their descendants.

Again, it is a well-recognized fact that leprosy is more than twice as common among men than among women. It is probable that the greater opportunity for contact with lepers by man is the explanation of the greater frequency.

Skelton was unable to find evidences of leprosy bacilli in bedbugs living in the beds of lepers. Paldrock also was unable to find any evidence of leprosy bacilli in bedbugs a few hours after feeding on leprous tissue, but did find acid-fast rods in cockroaches which had fed on leprosy nodules, even fourteen days after the feeding.

A. J. Smith fed bedbugs on Duval’s organism and recovered acid-fast bacilli for considerable periods. The question arises, however, as to the significance of Duval’s bacillus for leprosy.

Acid-fast bacilli have been reported from head lice and mosquitoes, when the insects have been feeding on leprous tissue, but little or no evidence of any multiplication has been obtained.

For many years Jonathan Hutchinson insisted that leprosy was caused by the eating of imperfectly cured or decomposing fish, a view which now has no supporters.

There is no question but that the examination of the nasal mucus for leprosy bacilli is of prime importance in diagnosis and it may be that cases showing ulcerations of the septum are especially dangerous when sneezing, but very few believe that leprosy is to any extent contracted through this channel. De Azevedo examined smears from the nasal mucosa in 59 persons who were in close contact with lepers without finding acid-fast bacilli in a single instance.

With a period of incubation covering from two to ten years it is of course manifestly difficult to arrive at any correct idea as to transmission but there is a growing belief that the free and frequent use of soap is a decided factor in preventing infection which may, like rat leprosy, be best brought about by continued contact with a skin surface more or less abraded. There has been a suspicion, but no proof, that sexual intercourse may bring about infection.

There are two types: (1) Of skin and muscles, and (2) of the lymphatic glands. In the skin form areas of alopecia are present with thickening of the site invaded. These areas are most often on the back of the head. Just as in human leprosy the epithelium is unaffected, the corium however being filled with cells packed with acid-fast bacilli, exactly similar to the picture in human leprosy. Ulceration of these subcutaneous nodules is common.

In the glandular type the glands are enlarged and the lymph sinuses packed with the causative bacilli.

In rat leprosy it has been found that infection of other rats takes places as readily through slight abrasions of the skin as when material is injected subcutaneously.

The idea is that natural infection occurs by way of the skin and through the lymphatics. There is no evidence that insects play a part in transmission.

Rat leprosy prevails extensively in Europe, Asia and America. Although similar etiologically and pathologically there does not seem to be any connection between the disease in rat and in man, as is the case with human and rat plague.

The prevalence of rat leprosy in the various parts of the world varies greatly; thus in Odessa 4 to 5% of the rats are infected while in San Francisco only ⅕ of 1%.

The leproma is a mass of cells of varying sizes and types in a connective-tissue framework. The infiltrations are chiefly about the hair bulbs, sweat glands and arteries. The epidermis is separated from the leproma by a connective-tissue layer and is uninvolved except for a thinning out of the layer and obliteration of the interpapillary epithelial pegs.

Incision of a leprous nodule shows a smooth glistening cut of a yellowish to slate gray color.

Leprous changes are common in the anterior part of the eye, as of conjunctiva, cornea and iris, but rare in the posterior eyeball. The mucosa of tongue, larynx and, pharynx is often involved. Cartilage and bone are destroyed through pressure of the granulomatous tissue.

The ovaries and testes may show connective-tissue increase.

Nephritis is rather common in leprosy but there is considerable doubt whether the lungs are invaded by leprosy, except most rarely.

Next to skin, mucous membrane and nerves, the lymphatic glands show the greatest involvement.

The liver not uncommonly in nodular leprosy and more rarely the spleen may show connective tissue or cellular infiltrations.

There are often noted (a) irregular accessions of fever (leprotic fever), attended with rather profuse sweating, so that the onset may be mistaken for a malarial infection; (b) progressive weakness, the patient being easily fatigued with a tendency to somnolence; (c) alternating attacks of dryness and hypersecretion of the nasal mucous membrane, with frequent attacks of epistaxis, and (d) various neuralgic manifestations or paraesthesias as well as headache. These prodromal manifestations usually precede but may accompany the outbreak of the spots.

It is the prominence of the nasal manifestations that has caused Sticker to insist that the primary lesion of leprosy is of the nasal mucosa, the general view, however, being that this view is without sufficient foundation and as a matter of fact some have recently suggested that the disease first manifests itself in the lymphatic glands, punctures of such structures showing bacilli rather frequently, although in less proportion than upon examination of the nasal mucosa.

These fairly distinct types tend to run into one another and in such cases we have the mixed form of the disease.

At one time a classification of the 239 lepers at San Lazaro Hospital, Manila, P. I., showed 97 cases of nodular, 42 of nerve and 93 of mixed leprosy, with two cases of doubtful nature.

They are raised and have a preference for appearing on the lobes of the ears, the nasal alae, the forehead, eyebrows, cheeks and chin.

The extensor surfaces of the forearms, thighs and buttocks are also favorite sites for the indurated spots. The palms of the hands, soles of the feet, hairy scalp, groin and axillary regions are almost never attacked.

These spots may be hyperaesthetic at first but soon show loss of pain and temperature sense with retention of touch sensation (dissociation of sensation). These spots do not sweat, they remain dry even in a general perspiration.

When the nodules are grasped between the fingers one usually finds them elastic to touch. As the result of active sebaceous secretion these nodules have a greasy appearance.

The eye is involved with frightful frequency in this form of leprosy, there being infiltrations of the eyelids, conjunctivae, cornea and iris, with subsequent ulcerations and loss of sight.

The glands in the region of the lesions become enlarged but do not tend to suppurate.

The course of the disease is essentially chronic and if some intercurrent affection does not carry off the patient, the end comes in a cachexia in about ten years, the temperature gradually falling and a state of somnolence ushering in the end.

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When nerve leprosy sets in upon a nodular type the life of the patient seems to be prolonged.

Anaesthesia of the region supplied by the ulnar nerve with contractures of the fourth and fifth fingers may be signs directing our attention to the true nature of the disease and in those cases where the appearance of smooth yellowish-brown spots precedes the neuritis manifestations we may here also find anaesthesia, provided the eruption has lasted for some time.

These spots often look like ringworm lesions, as they have an erythematous border with a paler center, but they are oval in outline rather than round and there is no scaling. Bullous eruptions, which are most frequently noted about the knuckles, are rare manifestations of nerve leprosy. They are often followed by ulceration.

These nerve enlargements are at first tender but later become painless and we have extensive areas of anaesthesia and trophic changes of the skin and nails of[260] fingers and toes such as felons, glazed skin, bullae, which latter on rupturing leave ulcers.

We also have absorption of the bones of the phalanges.

The phalangeal bones may be completely absorbed and a distorted nail cap the end of the metacarpal bone (lepra mutilans). Owing to the anaesthesia lepers often burn or injure their fingers and toes. Perforating ulcers are more common in leprosy than tabes.

Of the facial muscles the orbicularis palpebrarum is most apt to show paralysis. The eyes are affected much less frequently in nerve leprosy than nodular, 45% as against 85% for nodular leprosy. The most common changes in nerve leprosy are ectropion of the lower lid and subsequent corneal ulceration.

Mixed Leprosy.—In mixed leprosy we simply have a combination of the manifestations of the two main types and as a matter of fact the majority of cases tend eventually to assume a mixed type.

Temperature Course.—On the whole leprosy runs an afebrile course except for the accessions of irregular fever at the time of the appearance of the successive crops of spots. This leprotic fever lasts for a few days or a week or so and then the course becomes afebrile. At such times sweating may be present and suggest malaria. In the final stages of leprosy the patient may run a high fever for long periods, associated with profuse sweating and loss of weight.

Skin.—The raised spots of nodular leprosy tend to come out in numbers on lobes of ears, over eyebrows and on cheeks, as well as backs of hands and forearms and on buttocks and feet. Soles of feet and palms of hands almost never show spots. In nerve leprosy the spots are often single and flat and often appear on parts of body covered by the clothing, as trunk, thighs or arms. The spots of leprosy are anaesthetic, often showing dissociation of sensation. The indurated spots of nodular leprosy are succeeded by tubercle-like growths. The hair falls out of the areas occupied by the spots.

Mucous Membranes.—The nasal mucosa is in particular studded with nodules which later undergo ulceration. An ulcer of the septum is often the first place from which leprosy bacilli may be obtained. The pharynx and larynx are also involved early.

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Nervous System.—Besides the characteristic anaesthesia we have various manifestations of neuritis, especially involving the ulnar, facial and peroneal nerves. The affected nerves show a fusiform enlargement and are tender. Later we have trophic changes in skin, bone and nails of the fingers and toes. Absorption of bones and perforating ulcers are common. Muscle palsies and atrophies, especially the main-en-griffe, are common. The orbicularis palpebrarum is not infrequently paralyzed. The olfactory, optic and auditory nerves are rarely if ever involved. The reflexes are slightly exaggerated.

Patients often complain of a sensation of cold. Some authorities have called attention to the frequency of a mental and moral apathy in lepers.

The Circulatory System.—Honeij considers a high pulse rate, especially in the morning, as characteristic of progressive stages of leprosy.

The Eye.—In nodular leprosy eye lesions, chiefly leprotic nodules in conjunctivae or iris, with subsequent ulceration, are met with at some time in the course of the disease in almost 90% of cases. In nerve leprosy, corneal ulcerations, chiefly resulting from paralyses of the facial muscles, with ectropion, give eye symptoms in about 45% of cases.

Genito-urinary Symptoms.—Atrophy of the testicles with increase of connective tissue often result in males but data would indicate that the procreative power of the female is but little diminished. Lepers often die of renal complications, the kidney lesions being rather those of amyloid change. Bacilli may be eliminated in the urine during accessions of fever.

The Lymphatic Glands.—These tend to enlarge and show bacilli, but rarely suppurate.

The inguinal and cervical glands are most often enlarged.

The Blood.—The changes, other than those of a secondary anaemia as the disease progresses, are not characteristic. Bacilli are present in the blood of cases of nodular leprosy quite constantly but less so in that of cases of nerve leprosy. The bacilli are more apt to be found in the blood at the time of febrile accessions.

The leprous spots are at first rather oily from increased action of the sebaceous glands but subsequently become dry. In ancient times the hypersecretion of sebaceous material about the facial spots of nodular leprosy served as the basis of a test for leprosy, the suspected eruption being dashed with water. If the surface was not wetted it was a point in favor of leprosy. Of prime importance however is the pin prick for anaesthesia, which is the most important distinguishing characteristic,[262] next to the finding of the bacilli, for a leprous spot. The anaesthesia is more marked in the center of the spot and may show dissociation of sensation. It is very important to examine for enlargement of the ulnar or great auricular and the earliest signs of a nerve leprosy may be anaesthesia and a slight contraction of the ring and little finger.

In syringomyelia the dissociation of sensation is marked, as with leprosy. In syringomyelia, however, the upper extremities are, as a rule, alone affected and the muscular atrophy is more of the scapulohumeral type, with involvement of trunk muscles causing scoliosis, than of the thenar and hypothenar eminences, so that while the fingers may be more contracted and rigid than in leprosy we do not get the main-en-griffe. The anaesthetic areas of syringomyelia continue to sweat, and we may also get spastic symptoms and speech defects in syringomyelia.

Of the skin diseases the most important confusing lesions are the cutaneous manifestations of tuberculosis and syphilis. In lupus the tubercles are very much smaller, show the apple jelly appearance, the lesion spreads peripherally, is rather purplish and is not anaesthetic. Syphilitic ulcerations are more punched out, do not affect the same sites and respond to syphilitic treatment immediately. You do not find nerve enlargements in syphilis.

Fletcher obtained 22% positives in 100 cases of leprosy—28% in nodular and 17% in nerve cases. One-third of the cases gave a history of syphilis.

Sutherland and Mitra obtained 17 positive Wassermann reactions in 34 nodular cases, 16 positives in 52 anaesthetic cases and 8 positives in 14 cases of mixed leprosy. The sera of 12 children of leprous parents were negative.

[263]

The luetin reaction is negative in leprosy.

Mycosis fungoides has not the characteristic location about the face and itches markedly and does not show anaesthesia.

Vitiligo shows an abrupt margin and is not anaesthetic.

I am partial to Tschernogabow’s technique. In this, one punctures the subepithelial granulomatous tissue with a capillary pipette, the end of which has been broken off by tapping the point in order to give a cutting point, and the serum which exudes is smeared out and stained.

Some prefer emulsifying a piece of the tissue and centrifuging and staining the sediment. Quite recently the antiformin method of treating leprous tissue, as for tuberculous tissue, has been used.

Many insist that the best method is to cut out small sections of the lesion, going well into normal tissue, and putting through paraffin and cutting thin sections and staining. Gram’s method, counterstaining with bismarck brown, gives beautiful preparations. For acid-fast staining first stain with haematoxylin to obtain a histological background and then steam with carbol fuchsin, decolorize very briefly with acid alcohol, then through absolute alcohol and xylol.

Thibault examined the nasal mucus, gland juice and blood of 30 lepers. He obtained leprosy bacilli in the nasal mucus of 20, in the gland puncture juice of 18, and in the blood of 7.

Hollman detected leprosy bacilli in the nasal mucus of 90% of 58 nodular cases, of 67% of 6 mixed leprosy and of 45% of anaesthetic cases, after making 329 examinations.

Leprosy bacilli are apt to be found in the blood of nodular cases, especially at the time of the febrile accessions. The blood is best taken in 5 or 10 cc. quantities into[264] 1% sodium citrate in distilled water. After centrifuging, the sediment is treated with 10% antiformin, at 37°C. for one hour. Again centrifuging, and washing, the sediment is smeared out on a slide and stained. The bacilli are not apt to be found in the blood of cases of nerve leprosy.

Smith and Rivas add 10 vols. of 2% acetic acid to 1 vol. blood, centrifuge and make smears.

Gland puncture has recently been considered as an important diagnostic procedure in leprosy.

The Roentgen ray has been utilized in the recognition of the very early, trophic changes in bone, showing the commencing absorption of phalanges. Neve has reported a case in which there were no satisfactory indications of leprosy other than slight deformity of toes and fingers but showing marked changes in the phalanges, even to disappearance of terminal phalanx of some toes when examined with X-ray.

Nodular leprosy runs its course much more quickly than does nerve leprosy. It is in nodular leprosy particularly that intercurrent affections carry off the patients. Tuberculosis carries off about 23% of cases and nephritis almost 30%, while a combination of tuberculosis and renal disease about 10%. In the remainder, the cachexia or accidents of leprosy itself are responsible for a large portion of the deaths. Cases of nodular leprosy are more often carried off by kidney disease than those with nerve or mixed leprosy.

It must not be forgotten that lepers, especially those with the nerve form, may live for twenty to forty years.

There is some evidence that scabies favours infection so that this disease should be looked for and actively treated in endemic areas.

Leprosy tends to spread where there is marked personal uncleanliness and close contact with lepers in overcrowded quarters. Many authorities consider the free use of soap and water the most important means of avoiding infection. While segregation is generally considered the one proven prophylactic measure there are those who question its value. There does not seem to have been any very marked influence on the spread of leprosy among the native Hawaiians through the enforcement of isolation of such cases. Partial segregation at their homes has given very satisfactory results. Where a leper is not excreting bacilli, or where acid-fast organisms cannot be found after careful search there is no danger. Such patients, however, should report for examination every few months. Evidence as to contact indicates that all young children are particularly liable to the infection, as has been noted for children of lepers and brothers and sisters. Even if segregation of lepers is not carried out as regards adults, it should be the rule for children, so that infants and young children should be separated from their leper parents or parent. A very remarkable feature in connection with leprosy is the hysterical dread that many communities have of a leper, when they must know or could easily learn, that the contagiousness of the affection is so slight, that notwithstanding our efforts, we can scarcely point to a single instance to prove undoubted transmission of the disease from one person to another. At any rate knowing that immense numbers of the bacilli are given off from ulcerations and the nose, we should guard against the dissemination of leprosy bacilli from such sources.

Wise and Minett treated 244 cases with nastin for periods of from one to two years, the treatment having been at first supervised by Deycke himself. It was stated that nodular cases did not seem to be improved and that anaesthetic leprosy was not apparently influenced.

Minett mentions the efficiency of a 2½% solution of benzoyl chloride as a nasal spray and as an application to leprous ulcers, this treatment causing the bacilli rapidly to disappear from the discharges of nose or ulcers. On the other hand Scott, in Assam, reports practically 50% of cures, or cases greatly improved, in patients treated with nastin for a year or more. He gave nastin B1 injected intramuscularly at two weeks intervals.

Salvarsan does not seem to have been of any value in leprosy.

For hypodermic use Heiser makes a mixture of 60 cc. each of chaulmoogra oil and camphorated oil with 4 grams resorcin. Injections are made weekly, commencing with 1 cc. This dose is increased steadily according to tolerance, but in some patients marked reaction in the lesions, with fever, occurs after a dose of only a few cubic centimeters has been reached.

Rogers has for some time been giving subcutaneous injections of sodium gynocardate, the sodium salt of the lower melting-point fatty acids of chaulmoogra oil. Finding that large doses of sodium gynocardate could be administered to animals with safety he has recently given intravenous injections and has substituted this method for the subcutaneous one. For use in the treatment of leprosy he prepares a 2 or 3% solution in distilled water and, after sterilization in an autoclave, adds ½ per cent. carbolic acid. The solution should be quite clear. He starts with one-tenth of a grain and increases the dosage by one-tenth with each successive injection up to four-fifths of a grain. He states that this method has as great superiority over the subcutaneous one as that has over the administration of chaulmoogra oil by mouth. Rogers now uses a solution of 3% sod. gynocardate with 1% phenol and 1% sod. citrate. At first the intravenous injection is with 0.5 cc. thrice weekly, which dose is gradually increased up to as much as 5 cc.

It is possible that sodium morrhuate (cod-liver oil) may be as efficacious as the gynocardate salt. Rogers has used Hydnocarpus instead of the true chaulmoogra oil and thought he obtained better results. One explanation of the uncertainty of success with chaulmoogra oil is the difficulty of securing oil obtained from proper sources. The standard treatment of leprosy in Honolulu, as reported by McDonald, is the weekly injection of the ethyl esters of the entire fatty acids of the whole chaulmoogra oil, with 2% by weight of iodine, chemically combined. The treatment begins with 1 cc. injected intramuscularly, increased by 1 cc. at every second or third injection, until a dose of from 2 to 6 cc. is reached, according to age and weight of patient.

For internal use the mixed fatty acids, carrying 2½% iodine, chemically combined, are given in capsule. The dose by mouth is 0.25 grams per 100 lbs. weight, three times daily, an hour or two after meals. This is gradually increased every two weeks until a maximum dose of 1 gm. per 100 lbs. weight is reached.

[267]

Dyer combines hydrotherapy with the administration of chaulmoogra oil. He gives a daily bath as hot as can be borne, and, in addition to the specific treatment, gives 1/60th grain of strychnine three times daily.

Thyroid extract has seemed to benefit cases of anaesthetic leprosy in rare instances. The high frequency current with the needle applied to the nodular lesions has been recommended by Unna. Radium and X-rays have also been employed. There have been reports as to the value of the antimony treatment in leprosy.

Surgical treatment is frequently of use, as nerve stretching for the leprous neuralgias. Various eye operations are necessitated by the ectropion or leprotic iritis. The amputations of the area involved in perforating ulcer is recommended. Tracheotomy is often demanded for the laryngeal stenosis.

McCoy has combined carbon dioxide snow local treatment with chaulmoogra oil. The lesions showed decrease in size but remained bacteriologically positive.

History.—While modern knowledge of beriberi may be said to date from the writings of Bontius, in 1642, yet the disease is distinctly described by Chinese writers of the seventh century and treated in writings of the second century and possibly referred to in writings as ancient as B. C. 2697. It is probable that the disease described by Strabo as occurring in a Roman army while invading Arabia, in[269] 24 B. C., was beriberi. While mention of the disease may be found in Japanese writings of the ninth century it is thought by Scheube that this relates to the disease in China and that beriberi first appeared in Japan about the eighteenth century. Bontius described the atrophic form of the disease, Rogers, in 1808, the serous effusions, and Marshall, in 1812, noted two types, barbiers, when the paralysis predominated, and beriberi, when the dyspnoea and oedema were leading features.

In 1835 Malcolmson noted that cases of beriberi assumed the type of barbiers and vice versa, from this time the view has obtained that the two affections belong to one disease.

The disease seems to have first made its appearance in Brazil in 1866.

Geographical Distribution.—Reference to the chart will show 3 markedly endemic centers for beriberi, one embracing Japan, a second the Dutch East Indies (Java, Borneo, Sumatra), and a third, involving the Eastern coast of Brazil. In somewhat less degree the disease prevails in India, Indo-China, Malay Peninsula, Eastern China, and the Philippine Islands. It is also found in the regions of the East and West Coasts of Africa, and was devastating to the laborers on the Congo railway. It has been reported from many parts of the world among coolies from Asiatic countries. A disease of similar nature has been noted in asylums in England and America. Beriberi occurred among the British soldiers in Mesopotamia during the recent war—more than 300 cases in 1915. It is interesting to note that scurvy, and not beriberi, occurred among the Indian troops in Mesopotamia at this time. There was no scurvy in the British troops.

Manson’s Theory.—Under conditions of overcrowding, filth, warmth, moisture and lack of ventilation, as would obtain in the forecastle of a ship carrying a native crew, the development of a hypothetical germ is favored. This germ in its growth gives off emanations which like alcohol act as toxins upon the peripheral nerves. The germ itself does not infect the patient.

Wright’s Theory.—According to this view a bacillus which was given off in the faeces was ingested and locating in the duodenal mucosa gave off a toxin similar to that of the diphtheria bacillus. Instead of developing its soluble toxin in the membrane of the region of the throat this action took place in the upper part of the small intestines.

Of the bacterial causes may be mentioned: (1) The coccus of Pekelharing and Winckler. This organism was supposed to be short lived in the body and repeated infections were necessary to produce the disease.

(2) Dangerfield held views somewhat similar to those of Pekelharing and thought a coccus in the alimentary canal the cause.

(3) Isuzuki regarded a coccus isolated from the urine as the cause.

(4) Okata and Kokubo thought a coccus obtained from the blood to be the infecting agent.

Various bacilli, other than that incriminated by Wright, have been brought forward as pathogenic agents but it may be stated without further discussion that the claims of the advocates of bacterial causes have not been verified and are solely of historical interest. The same statement will hold for the plasmodium-like protozoon of Glogner which was found in the splenic blood.

Of the chemical theories may be mentioned; (1) Arsenic poisoning. In an outbreak of arsenical neuritis in England, from arsenic contained in the glucose used in making beer, Ross diagnosed the illness as beriberi. Subsequently, arsenic was found in the hair of certain patients with beriberi, hence the theory which has never been substantiated. It may be stated that a careful study of this epidemic by Reynolds and Bury indicated that the alcoholic factor was also operative as persons taking an equal amount of arsenic but without alcohol, did not develop neuritis.

(2) Treutlein’s oxalate theory.—This was based on the fact that polyneuritis gallinarum could be produced in fowls by feeding them oxalic acid.

In the old ration the ratio of N to C was as 1 to 17—32, in the new ration, 1—16. In looking over the constituents of the new ration the addition of about 100 grams of beans is noted. These are rich in vitamines.

(2) According to Fales the hypothetical germ of beriberi can only live in body fluids deficient in potassium carbonate. The high content of potash in potatoes made him greatly increase the amount of this vegetable in the dietary he recommended. Fales noted scurvy as well as beriberi in the Bilibid prisoners on a diet deficient in potash.

(3) Deficient fat. (4) Deficient phosphorus.—It was Schaumann’s idea that the phosphorus contained in the outer layers of the rice grain was essential in the prevention of beriberi. While it is now known that the beriberi-preventing substance does not contain phosphorus, yet the idea has proven of practical value as giving an index of beriberi-producing power of rice.

Schaumann now considers that the antineuritic substance in rice polishings acts as an activator in the metabolism of phosphorus.

Food Poisoning as Cause.—There are other theories as to intestinal parasites causing the disease and in particular views as to relation of fish eating to the disease, which are (1) that it is caused by the ingestion of raw fish, or again (2) from the eating of certain poisonous fish.

Miura, who is the great advocate of a fish intoxication, believes that this comes about from eating fish belonging to the Scomberidae family. As proving this, he cites the absence of beriberi in prisons in Japan, where no fish is allowed. He does not recognize that it is the diet of barley 6 to rice 4 parts which is the prophylactic factor. Barley is rich in vitamines.

There are a few points in connection with rice which should be understood. The larger part of the rice grain is starch and covering this central starch core we have the rather thin aleurone layer containing the proteid and fat constituents of the grain. Externally there is an adherent layer, the pericarp, which varies in color from red to white according to the kind of rice. The pericarp contains the salts. The grain is covered by the husk which is always removed to render the rice suitable for food. Unhusked rice is called padi in India and palay in the Philippines. In the process of removing the husk (milling) the pericarp and more or less of the aleurone layer may be rubbed off the grain. When the milling process is carried to the extent that but little remains except the starch the rice is termed polished, highly milled, or white rice. A process of parboiling causes the husk to be more easily detached and the pericarp to adhere more firmly to the grain and when milled there is less loss of the anti-neuritis principle, which is contained in the outer layers. Such rice is called cured rice. The embryo also contains the anti-neuritis vitamine as well as the fat soluble A one. It is also lost in milling. The scale-like dust is termed rice polishings and has curative value for those who have developed beriberi under a diet of polished rice. When the milling process is less complete the rice so treated is called undermilled rice or red rice. Polished, highly milled or white rice contains as a rule less than 0.4% of phosphorus pentoxide while the beriberi-preventing rices contain more than 0.4% of this compound for which reason legislation has required rice to have more than 0.4% phosphorus pentoxide.

Siam rice is a polished white rice which contains about 0.25% phosphorus pentoxide and has more often been associated with severe outbreaks of beriberi than Rangoon rice, which has about 0.32%, this latter, however, being a well-recognized beriberi-producing rice. Unpolished rice contains about 0.55% of phosphorus pentoxide. Natives generally prefer the polished rice because it is clean and free from weevils, while the undermilled kind is dirty. Parboiled rice has a disagreeable odor.

Voegtlin has recommended a P₂O₅ requirement of 0.5% for corn products and 1% for wheat ones. Thus whole wheat contained 1.12% while highly milled flour had only 0.114%. Fowls fed on this flour developed polyneuritis in twenty to thirty-two days.

Whole corn contains 0.76% P₂O₅, while highly milled corn grits has approximately 0.2%, and highly milled corn meal about 0.3%. These highly milled corn products produced polyneuritis within from thirty to thirty-five days.

With rock ground corn meal, containing 0.7% P₂O₅ the fowls remained well.

In 1909, Fraser and Stanton experimented with 493 Javanese coolies who were employed in building a road far removed from any village which might introduce the factor of bacterial etiology into the problem. They noted that the Javanese prefer white rice, and reference is made to the fact that many cases of beriberi[273] occurred among these laborers in 1906, which outbreak ceased upon requiring them to eat parboiled rice at the suggestion of Doctor Braddon. They state that they informed the coolies of the danger of white rice but, notwithstanding, they all expressed a preference for the white rice over parboiled rice. For the purpose of comparison, only one-half were allowed the white rice diet. The two parties were quartered in virgin jungle and were isolated from each other by an interval of 7 miles. Of 220 individuals on white rice there were 20 cases of beriberi recorded while among 273, who lived on parboiled rice, no cases occurred.

The Philippine scouts, numbering about 5000 natives, gave 618 cases of beriberi in 1908 and 550 cases in 1909. In 1910 undermilled rice was substituted for polished rice and they were required to eat 1-6 oz. beans daily. No other change in their mode of living was made. By 1913 beriberi had disappeared among them, although the disease still prevailed among the native population in contact with them.

The experiments were carried out in Bilibid prison. Prisoners, who had been condemned to death, were informed of the nature of the experiment and were told of the diet on which it was proposed to place them. They were also told that they might contract beriberi. Twenty-nine volunteered and each signed a statement in his own dialect that he undertook the experiment voluntarily.

In general, the groups were fed for the greater part of the time occupied by the experiments as follows: Group (1) “White rice and extract of rice polishings and special diet.” Group (2) “White rice and special diet.” Group (3) “Red rice and special diet.” Group (4) “White rice and special diet.”

Of 6 men on the Group 1 diet, 2 developed beriberi. The symptoms however, were not marked, being chiefly loss of weight, tachycardia, slight oedema of legs and tenderness of muscles of calves. Four of the 6 men of Group 2 developed beriberi and 6 out of 11, in Group 4, showed symptoms of beriberi. In Group 3, only 2 in 6 developed symptoms and these consisted in case No. 13 only in tenderness of epigastrium, paraesthesia, cardiac disturbance and marked diminution of knee jerk. In case No. 18 there was noted only slight cardiac disturbance and epigastric pulsation.[274] In none of the cases was the complete picture of beriberi obtained except in those in which the white polished rice formed the staple article of diet, but in one case, fed on red rice, the diagnosis of beriberi was almost definite.

Evidently symptoms of beriberi may also sometimes occur in individuals fed on red rice as a staple article of diet when the diet is very monotonous, comprising few articles and continued for long periods of time. From the experiments it is evident that beriberi may be produced by the prolonged consumption of white rice as a staple diet. Of 17 individuals fed on such diet 8 developed beriberi, all with distinct loss of knee jerk, as well as with other marked symptoms of the disease. Symptoms appeared within 61 to 75 days after the commencement of the diet.

Vedder thinks that the red rice used in these experiments may not have been sufficiently undermilled, as it was found most difficult to obtain such a beriberi-preventing rice for the Philippine scouts. As regards the lack of success with extract of rice polishings the same author considers that a sufficient amount of alcohol for the extraction of the vitamines was not used in the above experiments, as he found it necessary to use 30 litres of alcohol to 5 kilos of rice polishings. Strong and Crowell used only 14 litres of 95% alcohol to 5 kilos of polishings.

Braddon’s views.—Prior to the investigations of Fraser and Stanton the importance of the rice factor in the etiology of beriberi was insisted upon by Braddon who thought that a poison was elaborated by some organism which poison was contained in the beriberi-producing rice. This development was thought to occur in rice stored in damp places, but Vedder has shown that storing undermilled rice in a damp place for a year does not cause it to lose its anti-beriberi-producing properties.

Schaumann considers malt as richer in the anti-neuritis vitamine than any other article of diet, rice bran coming next. Many think that vitamines have not as yet been separated but that they are intimately combined with some mother substance in the food.

In epidemics of beriberi it has been observed that those who eat most rice are more often attacked, thus men more frequently than women. A temperature of 120°C. destroys the vitamine. Owing to the absence of rice as a constituent of other than slightest importance in the dietary of Brazilian cases of beriberi, as well as from numerous reports of the occurrence of the disease in nonrice-eating persons, the view that is now entertained is that not only polished rice, but any predominating carbohydrate article of diet, which is deficient in the neuritis-preventing substance, can produce beriberi. Wellman and Bass have shown that such articles of diet as sago, boiled white potatoes, corn grits and macaroni practically parallel polished rice in the production of polyneuritis in fowls.

Predisposing Causes.—There does not seem to be any racial predisposition other than that associated with the more varied and the more neuritis-preventing diet of the white race. For the same reason beriberi is more prevalent among the poor than among the prosperous classes of countries where the disease exists extensively.

It is customary to consider as predisposing causes bad hygienic surroundings, such as occur in jails, camps, etc., as well as the influence of warmth and dampness of the atmosphere. Beriberi is more common among men than women and affects most commonly individuals between 15 and 30 years of age. Physical exhaustion, excessive grief, digestive derangements, abuse of alcohol and tobacco are considered to have a bearing in the production of the beriberi symptoms. Surgical operations may be followed by manifestations of the disease.

In this connection Heiser, in the Philippines, has reported that with a diet in which polished rice was contained the monthly death rate at the leper colony at Culion was approximately 100, the majority of these deaths being from beriberi. As a result of the substitution of unpolished rice, about 1909, the monthly death rate fell to less than 20 and of these none were from beriberi.

Toward the close of 1911 there was a great shortage of the rice crop and the Philippine government bought quantities of rice in order to protect the people from extortionate dealers. Much of this rice was polished rice. The use of this polished[277] rice was commenced at Culion in November, 1911. In January, 1912, there were 35 deaths, of which 2 were from beriberi. In February 86 deaths with 36 from beriberi and in March 82 deaths with 60 from beriberi. In February the use of polished rice was discontinued and unpolished rice substituted. In April the deaths had fallen to 25 with 3 from beriberi and, subsequent to that month, deaths from beriberi cases developing at Culion ceased to be reported.

As regards the length of time necessary for the production of the symptom-complex, Strong’s experiments show that beriberi was produced in from sixty-one to seventy-five days. In Fraser and Stanton’s work no case developed under eighty-seven days and many of the cases did not develop for 120 to 160 days. Hamilton Wright considered that the incubation period for his toxin-producing bacillus was ten to thirty days.

Furthermore, extract of rice polishings rapidly cures the cardiac condition as well as the dropsy, but not the paresis; while Funk’s vitamine base, which will cure the paralysis, will not affect the cardiac disorder.

The blood of beriberics in the acute stage, has been shown to contain a substance capable of profoundly influencing the vasomotor functions, causing venous engorgement and a fall of blood pressure.

In deaths from wet beriberi the tissues are very moist so that incisions tend to fill with fluid. There are generally present pleural and in particular pericardial effusions. Serous fluid in the abdominal cavity may also be present. The lower end of the stomach and the upper portion of the small intestines, in particular the duodenum, show marked congestion with more or less abundant haemorrhagic extravasations. Some authorities do not admit the existence of this duodenal congestion so insisted upon by Wright.

The oesophagus is usually congested as may be also the pharynx and the larynx.

Next to the peripheral nerve degenerations, to be later considered, the most important lesions are found in connection with the heart. All chambers of the heart show a dilatation with hypertrophy as well as dilatation of the right ventricle in cases that have lasted for some time. The heart muscle has the faded-leaf appearance indicative of fatty degeneration. Microscopically there are segmentation and vacuolation of the fibres. The lungs show congestion and at times present the characteristics of pulmonary oedema. The kidneys are congested but show only exceptionally parenchymatous or interstitial changes. As would be expected, the back pressure in the right heart gives a dilatation of the central vein of the liver lobules which at times is productive of atrophy of the adjacent liver cells. The[278] muscles supplied by the affected peripheral nerves show more or less atrophy according to the duration of the disease.

Microscopically, the affected fibres show a loss of striation with a colloid degeneration. These changes are more marked in beriberic residual paralysis. The key to the disease is in the changes present in the peripheral nerves. While these may appear normal yet histological examination shows varying nerve degenerations from slight medullary degeneration in a few fibres to complete destruction of the nerve, giving a Wallerian degeneration (vacuolation and formation of myelin droplets in the medullary sheath with fragmentation of the axis-cylinder).

While it is usually stated that the central nervous system (brain and cord), remains uninvolved yet we note axonal degeneration in the cells of the nuclear centres of the affected peripheral nerves as shown by convexity of the cell sides, dislocation of the nucleus and disappearance of the tigroid substance. The striking feature of the pathology of beriberi is the involvement of the vagus nerve and there is evidence of degenerative changes in the cells of the vagal origin in the floor of the fourth ventricle.

Various investigators have shown that in fowls marked peripheral neuritis can exist long before clinical manifestations appear and that typical cases of beriberi may show striking improvement following vitamine administration, notwithstanding the continued existence of peripheral nerve degeneration. For such reasons Vedder thinks the more important changes to probably belong to cells of cord and brain.

McCarrison has noted striking changes in the endocrine glands in avian polyneuritis, particularly hypertrophy of the adrenals and atrophy of the other glands of internal secretion. He attributes the oedema to increase in adrenalin content. Shimbo has reported adrenal hypertrophy in 14 human cases of beriberi.

In fact an extensive epidemic of arsenical neuritis, or, to be more exact, a neuritis in which both alcoholic and arsenical factors were operative, was regarded by eminent authorities as beriberi.

The first record of epidemic dropsy was during a famine in Southern India in 1877. Outbreaks again occurred in 1902 and 1907. The fact that it is a disease which often shows a house infection has caused the advancing of a theory that the bedbug transmits the disease.

While greatly resembling beriberi clinically the following points of difference are usually noted by those who hold that it is a distinct disease entity.

1. The presence of fever, which rarely exceeds 102°F. and is usually only about 99° to 100°F.

2. An erythematous rash upon the oedematous portions of the extremities.

3. The frequent generalized oedema, which suggested the designation dropsy for the disease, cannot be differentiated from wet beriberi.

4. The neuritis manifestations are slight or absent. There may be formication of the feet but anaesthesia is wanting. The vagal involvement gives cardiac disturbances. There is anaemia.

In 1898 Hirota first noted the existence of a condition in infants nourished by beriberi mothers which has more recently been carefully studied by McLaughlin and Andrews and to which the name infantile beriberi is now generally given. In the Philippines it is called “taon.” Clinically there is restlessness, vomiting, altered voice, increased heart action, oedema and cyanosis. After death there is found a marked hypertrophy and dilatation of the right side of the heart with no change of the left side. The peripheral nerves also show the lesions of beriberi of adults but of less intensity.

The disease most often shows itself in an acute form, the child rather suddenly being seized with great pain, crying constantly and soon becoming cyanosed. Death, which may occur in a few minutes or hours, is often thought to be due to meningitis, although there is no fever or true convulsions. There is only rigidity of the body. Less frequently the disease appears in a chronic form in which vomiting and constipation are most marked. There is often a history of the loss by the mother, who herself may have only a rudimentary beriberi, of several children from this disease.

The infants improve rapidly when other infant feeding is substituted for the mother’s milk. An extract of rice polishings gives striking results in these cases.

Asylum Beriberi.—The beriberi outbreaks which have frequently been reported from European and American camps, prisons and asylums do not differ from the cases one may see in the classical distribution of the disease among the rice-eating populations of the Orient. The cause is the same, a deficiency in beriberi-preventing vitamines, and the symptoms are similar. These vitamines may be deficient in the[280] rice or other cereal or proteid food supplied. Again they may have originally been present in sufficient quantity but later destroyed by too great heat or otherwise.

In fact typical cases of wet or dropsical beriberi after a profuse diuresis may change in a short time, as Manson has so aptly stated, from a bloated carcass to little more than skin and bones and assume all the appearance of a case of dry or atrophic beriberi.

Even Vedder, who states that from a theoretical standpoint wet and dry beriberi may be considered separate pathological processes (deficiency in the anti-cardiac degeneration vitamine rather than the anti-neuritis one), is inclined to believe it inadvisable, from a clinical standpoint, to consider the one type apart from the other.

Again we observe cases which from the start show little if any oedema and very slight cardiac involvement, but with marked motor disturbances as shown by muscular atrophies and palsies. The sensory changes are not so marked as the motor ones. Complete anaesthesia is rarely present, it is rather paraesthesia and blunting of sensation which characterize the sensory phenomena. This is usually designated the atrophic or paraplegic type.

In such cases there may be nothing more than some weakness of the legs with vague manifestations of blunting of the sensation or variation of the reflexes. At times there may be marked anaesthesia in the region over the shin bones.

Many of these cases show cardiac palpitation on exertion and at times we may note slight evidences of oedema about the lower part of shin bone or dorsum of the foot. It is the frequency of such cases that causes physicians in the tropics to consider almost any affection showing neurological manifestations as of beriberi nature. A[281] careful study of the neurological features of cases in the tropics will show that many of these cases are not beriberi but rather the common cosmopolitan diseases of the nervous system.

As the symptoms of peripheral neuritis become more prominent we have hyperaesthesia of the calf muscles so that squeezing these muscles gives rise to rather marked pain. The thenar muscles or those of the forearm may also be more or less hyperaesthetic. Attention has been called to a circumoral anaesthesia.

In cases where the oedema is more marked and generalized and when pericardial or other effusions are developing we find a diminution in the amount of urine, but with an absence of albuminuria.

This condition of wet, dropsical or oedematous beriberi may be fairly rapidly succeeded by a disappearance of the oedema with, as a result, the making more striking of the muscular atrophy incident to the neuritis of the peripheral nerves. In this, the atrophic, dry or paralytic beriberi, the jongkok test is of value. With the hands over the head the patient squats down on the calves of his legs and attempts to rise—something impossible for the beriberic. At this time the patellar reflex probably cannot be elicited and later on there will be found foot and wrist-drop with atrophy of muscles. With complete foot-drop, the reactions of degeneration will be found.

It must always be remembered that the course of the ordinary case of beriberi is essentially chronic, running over months or years.

There is apt to be marked epigastric tenderness or even distress coming on with the onset of the acute cardiac involvement. It may be so extreme that the patient dreads the slightest palpation of his epigastrium. From a marked palpitation and praecordial distress evidences of the dilatation of the right heart become prominent. Indications of tricuspid insufficiency are seen in the pulsating jugulars and cyanosis. The cardiac dullness is greatly increased to the right and various abnormalities of sounds and rhythm may be observed. There is also dyspnoea and a sensation of constriction of the chest (beriberic corset). These are the cases which give as horrible a picture of death as one ever sees. In the final struggle for breath and praecordial agony of the last stages of decompensation in old heart lesions we have a more gradual course in a more asthenic patient. Acute pernicious beriberi may run its course in a strong, vigorous patient in a few hours. In some cases we have paralysis of the diaphragm.

There is atrophy of muscles so that the grip of the patient is enfeebled. This partial anaesthesia also accounts for the pseudoataxic gait in which the element of muscular weakness is prominent as opposed to the vigorous heel stamping gait of the ataxic tabetic. The patient drags the toes and leans forward on a cane when walking, thus suggesting the tripod.

There is no involvement of the sphincter.

Beriberic Residual Paralysis.—Hamilton Wright has used the term beriberic residual paralysis to indicate cases which, in the course of convalescence and favorable[284] regeneration of axis-cylinders and more or less return to a normal condition, become subject to some factor lowering the vital forces and body resistance and experience a return of the beriberi manifestations. To use a common expression the patient has a set-back and the favorable progress to complete recovery is temporarily in abeyance.

Nervous Symptoms.—The most common symptoms are those connected with degenerations involving the peripheral nerves of the extremities. The motor nerves are more involved than the sensory ones, there being rarely complete anaesthesia, but rather a blunting of sensation as though a piece of cloth were interposed between the examining instrument and the skin. At first there is weakening of the muscle power as shown by the grip of the hand or weakness of foot muscles. In more advanced cases we may have foot and wrist-drop. Hyperaesthesia of the muscles is prominent, especially that of the calf muscles. The unsteadiness of gait is not true ataxia as the patient does not clearly show the Romberg sign. It is muscular weakness rather than incoördination.

The Argyll-Robertson pupil is absent. The gait is the steppage one of peripheral neuritis, the patient walking as if extracting one foot after the other from clinging mud. Later on, when other muscles than the foot extensors are involved, the gait becomes a shuffling one. The mind is entirely clear. The vasomotor phenomena are often marked as shown by patchy or most extensive development of oedema and serous exudates. The knee-jerk is usually absent. Fibrillary twitchings may be observed in beriberi as well as in progressive muscular atrophy. The extensors of arms and legs are more markedly affected than the flexors. The cardiac symptoms are really connected with vagal involvement.

The Cardio-respiratory Symptoms.—Owing to involvement of the vagus the inhibitory apparatus is deranged so that we have palpitation and rapid pulse rate both of which are markedly increased by the slightest exertion.

The blood pressure is below normal. Shortness of breath is the earliest feature of respiratory trouble. This may go on to marked thoracic oppression and dyspnoea.

Aphonia may be present in acute pernicious beriberi and probably indicates laryngeal palsies. Such cases are usually fatal.

Pulmonary congestion and oedema always accompany the terminal right side dilatation of the heart which is responsible for the cyanosis, pulsating jugulars and various murmurs. The pulmonic second sound is accentuated and may be reduplicated. The rhythm of the heart sounds is replaced by the equal spacing of embryo-cardia. The diaphragm may be paralyzed as may also happen to the intercostal muscles.

Digestive and Urinary Symptoms.—Those who considered beriberi as an acute infectious disease were disposed to note frequently evidences of toxaemia as manifested by nausea, vomiting and epigastric distress. As a matter of fact these symptoms only become very prominent in pernicious beriberi and may well be connected with the cardiac decompensation. However caused vomiting is of unfavorable prognostic import.

The amount of urine is markedly decreased when oedema is advancing but is[285] succeeded by a polyuria when this diminishes. If albumin should be present it is not connected with beriberi but some other condition.

Other Features.—There is nothing characteristic about the blood other than a slowly developing anaemia.

Oedema is the most striking feature of wet beriberi. When slight this oedema may only involve the pretibial-region or sternum. Circumscribed areas of oedema may be present on the upper parts of the body as neck and trunk.

Hydropericardium is the most frequent of the exudates into serous cavities. Fever is almost always absent except in epidemic dropsy.

The urine in beriberi is as a rule normal and there are no peripheral nerve disorders in nephritis. Chagas has noted that a quartan form of malaria gives rise to oedema about the ankles and is often mistaken for beriberi by the physicians of the Amazon region.

The cardiac manifestations of beriberi differ from those of valvular disease in that the murmurs are muffled and there does not exist the definite areas for the location of the murmurs of the various valvular lesions. The rapid development of a pericardial effusion is also against valvular heart disease.

The absence of lancinating pains, typical Romberg sign and Argyll-Robertson pupil should differentiate from tabes.

In progressive muscular atrophy the palsy attacks the hand first and in a more advanced case showing the main-en-griffe there would also be deltoid involvement. Of course beriberi may show the main-en-griffe characteristic but the greater involvement of the feet with vagal phenomena differentiates.

More or less dyspnoea and cardiac palpitation are features of the disease as of beriberi. In fact death often is the result of acute cardiac paralysis. The striking point of difference is the generally reported absence of manifestations of neuritis and Nocht in an autopsy of a case failed to find evidence of degeneration of the peripheral nerves.

Another point of distinction is that once the ship arrives in port and a diet of fresh meat and vegetables is substituted for the one of sterilized canned meats and desiccated and preserved vegetables, the patient recovers rapidly so that in one or two weeks there is no sign of the disease remaining. Beriberics improve at once when put on a curative diet but the damage done the peripheral nerves makes complete recovery a matter of weeks or months. Nocht is of the opinion that ship beriberi is closely related to scurvy as he found sore gums and haemorrhages into muscles in some of his cases. He also notes that even in true scurvy there may be cases of dropsy without the spongy gums and haemorrhages. Dropsy plus sore gums is not infrequently noted in the beriberi-like affection of the men of the French fishing fleet off the Newfoundland banks.

Schaumann believes that ship beriberi is due to an acute deficiency in phosphorus, a chronic deficiency causing beriberi. It is probable that this disease is caused by a deficiency in certain vitamines, these being destroyed in the sterilization of canned meats or by drying vegetables.

The scurvy vitamine is much less stable than the beriberi one. It is contained in fresh foods only, drying destroying it.

In connection with the question of multiplicity of vitamines monkeys fed on rice will develop beriberi while if fed on a bread deficiency diet they develop scurvy.

In Mesopotamia the Indian troops suffered greatly from scurvy but not from beriberi while the British troops had many cases of beriberi. From July to December there were 11,445 cases of scurvy among the Indian forces and 104 cases of beriberi among the British. During this period the British ate white biscuits, tinned meats and horse flesh. This latter protected them from scurvy but the Indian troops would not eat the fresh meat but ate barley flour instead. The antiscorbutic vitamines are sometimes designated as water soluble C vitamines.

Infantile Scurvy.—As differing from infantile beriberi, we have in infantile scurvy, which is attributed to the use of sterilized milk instead of fresh milk, a tendency to separation of the epiphyses from the shafts of the bones and extreme sensitiveness to any movement particularly of the legs. A markedly anaemic and asthenic condition is also characteristic. The chief lesion is a subperiosteal blood extravasation.

Milk contains several vitamines some of which, as the growth vitamine, are, destroyed in boiling; others, however, are not destroyed until subjected to a temperature of about 120°C.

War Oedema.—In those areas of Europe where famine conditions were approached during the great war a condition of weakness and oedema was noted by many observers and to this symptom-complex various designations were applied such as war dropsy, war oedema, etc. The oedema was more marked than would be true in ordinary cases of starvation so that such factors as consumption of large amounts of water and salt in the thin soups so prominent in the dietary, plus hard work, must have been additional causes.

The oedema was most common in the feet and legs, at times extending to the thighs and trunk, and in about one-half the cases involving the face. Marked muscular weakness and alimentary disturbances were common. There was dyspnoea on slight exertion with a slow pulse, but cardiac disturbances were not features of the disease. The urine was pale, of low specific gravity and free of albumin. There was reduction of red cells and a tendency to leukopenia. These cases showed marked emaciation upon the disappearance of the dropsy. As is well known the deficiency in fats was marked in Central Europe so that it was to be expected that ocular manifestations should be frequently noted, deficiency of fat soluble A being the exciting cause of xerophthalmia. The cases tended to recovery under proper diet and hospital care.

In alcoholic neuritis there is the history of alcoholic excesses, long-standing digestive disorders and tremors of hands, lips and tongue. Chiefly characteristic, however, is the mental involvement, such cases almost always showing loss of memory and defective mental concentration.

Mental symptoms and tremors are practically absent in beriberi and we have here the marked feature of vagal involvement plus vasomotor phenomena.

In arsenical neuritis we have an early puffiness under the eyelids and pigmentation of the skin which first shows itself in areas normally pigmented. A dysenteric syndrome may also be present.

There would be less chance of confusing lead palsy as this chiefly involves the upper extremity. Punctate basophilia, lead colic and the blue line on the gums should differentiate.

In diphtheritic palsies the muscles of the soft palate are involved in more than 75% of cases. Ocular palsies are also not infrequent.

It may be stated that there is no laboratory diagnosis for beriberi.

We now know that a change to a beriberi-preventing diet is practically curative.

The mortality rate varies in different countries and in different epidemics, so that we have death rates varying from less than 2 per cent. to those exceeding 50 per cent. In acute pernicious beriberi the prognosis is almost surely fatal.

The epidemic of beriberi which prevailed at Manila in 1882 seems to have been attended by a great mortality, this having been as high as 60% during the early part of the outbreak.

The same result may be obtained by the employment of excessive sterilization for canning.

While boiled beef is heated throughout, with more or less complete destruction of vitamines, roast beef does not sustain a temperature above 70°C. in its interior, hence the greater portion of the vitamine content is present in such meat.

It is possible that moulds may deprive cereals of their vitamines so that spoiled cereals may be beriberi-producing. There have been many reports both from asylums and prisons which would indicate that the employed and the patients or prisoners lived on the same ration yet the guards or nurses failed to develop beriberi, which disease was prevalent among the inmates. Such statements rarely stand the test of investigation. The same is true of pellagra.

As the beriberi vitamine is apparently important in carbohydrate metabolism, a greater ingestion of carbohydrates demands more vitamine, hence an increase in carbohydrates, without corresponding increase in vitamine-containing foods, may bring on beriberi where, before the increase in carbohydrates, there was an absence of beriberi.

A combination of barley, which is rich in vitamines, with the rice is important in oriental countries, thus a diet containing 6 parts barley to 4 parts rice and used in Japanese prisons, on account of its cheapness, not only prevented beriberi but cured the disease in beriberics entering prison.

There is no doubt but that legislation against rice which contains less than 0.4% of P₂O₅ is a valuable measure of prophylaxis. Polished rice has lost in P₂O₅ as well as in vitamines.

Heiser has proposed that an excessive tax be placed on polished rice with free entry for the unpolished article. The following suggestions of Vedder in connection with prophylaxis would seem to be worthy of consideration in pellagra as well as in beriberi.

1. In any institution where bread is the staple article of diet, it should be made from whole wheat flour.

2. When rice is used in any quantity, the brown, undermilled, or so-called hygienic rice should be furnished.

3. Beans, peas, or other legume, known to prevent beriberi, should be served at least once a week. Canned beans or peas should not be used.

4. Some fresh vegetable or fruit should be issued at least once a week and preferably at least twice a week.

5. Barley, a known preventive of beriberi, should be used in all soups.

6. If corn meal is the staple of diet it should be yellow meal or water-ground meal, i.e., made from the whole grain.

7. White potatoes and fresh meat, known preventives of beriberi, should be served at least once a week, and preferably once daily.

8. The too exclusive use of canned food must be carefully avoided.

McCarrison has noted the value of onions even in a diet in which protein and vitamine constituents are sufficient. The onions seem to inhibit the growth of putrefactive bacteria.

Malt extract is very rich in vitamines and liver seems to have a higher content than beef muscle. Fat soluble A vitamine is abundant in glandular organs but scarcely present in the beef of our markets—this is probably true of water soluble B. Heart muscle is about on a par with liver. Germinating wheat and beans seem to have special value in treatment as well as prophylaxis.

Amyl nitrite inhalations or injections of 1% solution of nitroglycerine are indicated when there is evidence of extreme cardiac dilatation. Venesection is also to be kept in mind. Cardiac tonics are of less value than rest, diet and venesection.

In the feeding of such patients only small amounts should be given at a time to avoid epigastric distress. Again carbohydrates should be restricted as there is evidence that excess of carbohydrates as well as vitamine deficiency may be concerned in the disease. The bowels should be kept open with salines. Mineral oil tends to keep down intestinal putrefaction which is a factor of importance.

Strychnine is usually given as a routine treatment in the less acute cases. With muscular atrophy massage is of prime importance. Electrical stimulation is also usually employed. With the palsies there is great danger of contractures so that even the bed clothing should not rest upon the paralyzed feet. Even splints may be necessitated.

The disease is essentially chronic with periodic exacerbations but may run a rather acute course with a rapidly fatal termination. The trend of symptoms consists of (1) mild neurasthenic manifestations in the winter to be followed in the spring by (2) disturbances of the alimentary tract, consisting of stomatitis, burning sensations going up the oesophagus, gastric eructations and recurring diarrhoeas. (3) In addition to the neurological and alimentary tract symptoms we have the third and diagnostically the most important group, those of the cutaneous system. The pellagrous eruption is characterized by strikingly symmetrical, sharply delimited patches of erythema, resembling sunburn. The sites of preference are backs of hands, extending up the forearms, bridge of nose or neck. The neurasthenia tends to pass into a toxic psychosis or even a confusional insanity.

History.—Strambio considers some of the references of Hippocrates to refer to pellagra but Castellani and Chalmers state that after searching the writings of Hippocrates they have been unable to find any references to a disease showing a resemblance to pellagra.

The first definite description of the disease is generally credited to Casal who, in 1735, described the disease as it existed in the Asturias.

In his writings he notes that the peasants lived chiefly on corn and that they rarely had fresh meat.

Casal’s paper was not published until 1762 but Thitery, who visited Spain and was shown cases of pellagra by Casal, described the disease in 1755 and gave full credit[292] to Casal for the recognition of the disease. The name of the disease was given it by Frapolli, in 1771, the derivation being from pelle—skin, and agra—rough. The disease had then existed in Italy for a considerable time.

Casal called the disease mal de la rosa.

In 1810, Marzari insisted that the two diseases, pellagra and Alpine scurvy, which had a few years previously been recognized as identical, were caused by the consumption of maize and from this time on the maize theory as to etiology has been supported in Italy.

Later on (1872 to 1909) Lombroso elaborated the maize theory of etiology and so strongly presented this view that it is impossible for us lightly to set aside the arguments of this great physician.

While the zeists, as the advocates of the maize etiology are termed, insist that pellagra made its appearance in Europe following the introduction of Indian corn, after the voyages of Columbus, there does not seem to be any evidence that pellagra ever existed among the North American Indians. In 1905 Sambon insisted that pellagra was a protozoal disease and in 1910 claimed that it was probably transmitted by a midge, Simulium reptans.

About 1907 pellagra was found to be an important disease of the Southern States of the United States and since that time the number of cases has steadily increased so that it is now estimated that there have been approximately 200,000 cases in the United States.

It is generally conceded that isolated cases of pellagra had occurred in the United States prior to 1907, but they generally were diagnosed differently.

Geographical Distribution.—In Europe it is most prevalent in Italy, Balkan States, Greece, Turkey, Spain and Portugal. In Roumania there were about 100,000 cases in 1906. The disease has decreased in incidence and virulence in Italy, there having been in 1910 only 33,869 cases, as against 104,607 cases in 1881.

The disease was first recognized in Egypt by Sandwith in 1893 and is now known to be widespread in Lower Egypt. It is rare in Upper Egypt where they live on millet instead of maize. It exists in Algiers.

It has been reported from India and the Straits Settlements and prevails extensively in the West Indian Islands as well as in Mexico and Central America.

The disease in the Southern States of the United States is of a more fatal type than elsewhere, the average mortality having been 39.10%. The death rate in the United States has fallen, thus the rate in Mississippi for the years 1914 to 1916 was only ten per cent.

At present the Italian mortality is only about 3% although formerly it was much higher.

Zeists and Anti-zeists.—It is customary to divide the adherents of the different views as to the cause of the disease into two groups, the zeists, who advocate a connection between maize or Indian corn (Zea Mays) and the disease, and the anti-zeists, who claim that corn has nothing to do with pellagra.

Some claim that in the process of milling maize the vitamine-containing outer portion (bran) has been taken off just as with beriberi-producing white rice, from which the pericarp with its neuritis-preventing vitamine has been more or less completely removed.

From analyses of milled maize and millings Funk has recently suggested that pellagra in different countries is in relation to the degree of milling. Just as with rice and maize so does excessive milling of wheat get rid of vitamines, therefore, bread made from highly milled flour is dietetically deficient.

Again, as brought out by Voegtlin, alkalis tend to destroy any remaining vitamines in such bread. The practice of using sodium bicarbonate in preparation of bread is a further factor in the food deficiency problem. With the use of baking powder or buttermilk the alkaline carbonate of soda is neutralized so that there is no destructive effect on vitamine content.

The vitamine deficiency of highly milled flour and highly milled corn meal runs parallel with the phosphorus pentoxide content of such products. Whole wheat shows about 1.1% P₂O₅, while highly milled flour contains only about 0.1%. Whole corn has about 0.76% P₂O₅, while milled corn meal has only about 0.3%. Highly milled rice has under 0.4% P₂O₅.

Beriberi seems rather definitely to be associated with a deficiency in the anti-neuritis vitamine, which is probably the same as water soluble B., and in pellagra-producing diets a similar deficiency may be noted. More striking however is the deficiency in fat soluble A in such diets. This vitamine is abundant in butter fat and egg yolk, articles of diet of which pellagrins are deprived.

Leaves of plants contain it in abundance, while with seeds it is present in less degree and then contained in the embryo, which latter is lost in milling. Millet contains an exceptionally large amount of fat soluble A and it is well known that in Egypt those living on millet instead of maize escape pellagra. The protein of millet[294] has a high biological value which is the reverse with that of maize. It should be noted that besides vitamine and protein deficiencies the lack of inorganic salts should be considered.

Protein Deficiency.—Animal protein is a superior protein and maize protein an inferior one. Wilson grades proteins according to their assimilability and taking meat protein as 1 he assigns to maize protein a relative value of 3.4, which means that one must consume 3.4 times as much maize protein as that of meat to obtain the necessary protein requirements. Thirty grams of animal protein daily is sufficient to maintain nitrogenous equilibrium but Wilson considers 40 as a minimum B. P. V. (Biological protein value). We should have to consume 136 grams of maize protein to obtain a B. P. value of 40. Where hard labour is required the B. P. V. should be 50 and when associated with chronic intestinal disease it should be as high as 60.

Wilson noted a B. P. V. of 23 for males in the diet which caused an outbreak of pellagra in Armenian refugees at Port Said. The diet of the pellagrous Turkish prisoners in Egypt had a B. P. V. of 33.5. It may be stated that zein, the protein of maize, is deficient in tryptophane and lysine, two important amino-acids necessary for proper nutrition. Chick apparently produced pellagra in a monkey fed on a low protein diet (Total protein 8.2 grams, of which all but 2.7 grams was from zein.). The monkey was given an abundance of accessory food substances in butter, marmite and orange juice.

Amino-acid Deficiency.—In a recent paper Goldberger and Tanner note that a low biological protein value is not necessarily indicative of a pellagra-producing diet. In a series of experiments the deficiency of vitamines did not seem to be related to pellagra production and the same was true of the mineral elements. In studying the nature of low protein biological values they were of the opinion that this rested in certain amino-acid deficiencies in the proteins consumed by the pellagrins. Benefit seemed to result from administering cystine to two cases of pellagra and in a third case there was steady improvement following the giving of both cystine and tryptophane.

It is a question whether zein, the principal protein of maize, contains any cystine.

Goldberger and his colleagues, after a careful investigation of pellagra epidemiology, decided that such facts as the complete absence of the disease among the nurses and attendants of the pellagrous insane, or among the prison guards of institutions where pellagra prevailed extensively, as well as among those caring for pellagrous orphans, indicated that a dietary factor rather than an infectious one was operative in the disease. Even where it was stated that attendants and inmates of institutions had the same dietary investigation indicated that as a matter of fact the insane and the prisoners were not as well fed as the other group. Then too the insane frequently fail to avail themselves of the food provided.

In an investigation of the diet of the workingman’s family in the North and South it was found that the southern one consumed much larger quantities of starches and fats than the northern one, but less fresh meat. In the family of the cotton mill operative, a class showing a great incidence of pellagra, corn bread, flour biscuits, and fat pork were the chief articles of diet. There is a great deal of ancylostomiasis among these cotton mill people and the debilitating effect of this disease may predispose to pellagra. The general rise in the cost of food and, in particular, the disproportionate increase in price of meats over cereals, since 1907, may explain the greater incidence of the disease since that time. The wages of southern mill operators have also suffered on account of frequent periods of financial depression during the last ten years, thus causing them to buy cereals rather than meats.

A control was carried out with prisoners on a normal diet. The experiment was continued until Oct. 31, 1915. Of the 11 volunteers on the excessive carbohydrate diet six developed symptoms. Loss of weight and strength and mild neurasthenia were early symptoms. Definite cutaneous manifestations appeared only after five months. The skin lesions were first noted on the scrotum, later appearing on backs of hands in two cases and back of neck in one case.

There are those who believe that the methods of preserving foods, cereal or proteid, by sterilizing at high temperatures, destroy the vitamines so essential to proper metabolism so that people who subsist extensively on canned vegetables and preserved meats, instead of fresh meats and vegetables, may develop pellagra. Evidence of this sort is obtainable in the mill villages of the Southern States of the United States where pellagra is so very prevalent.

Again there would appear to be efficient resistance to pellagra in those who are in good physical condition, but when reduced by illness, or the effects of poor diet and defective hygienic surroundings, they may develop it. There are those who think that hookworm disease is an important factor in predisposing to pellagra.

Not only does alcoholism, when coexistent with pellagra, make for a bad prognosis but there are many who think that any abuse of alcohol predisposes to pellagra. Against this however is the fact that pellagra in the United States is about five times[296] as common among women as among men. It is generally recognized that pregnancy and lactation predispose to pellagra.

Pellagra in Turkish and German Prisoners.—There were (up to the close of 1919) 9257 cases of pellagra among 105,668 Turkish prisoners (1 in 11) and 79 cases among 7606 German prisoners (1 in 96). The Turkish prisoners had been on a deficient diet before capture and the diet after capture had a B. P. V. of 33.5. The labour group of the prisoners had a B. P. V. of 36.8 and the disease was much more prevalent among them than in those not working. Hammond-Searle notes that the diet of the nonworking European prisoners was probably insufficient to prevent pellagra. On the average the disease appeared among the German prisoners 4½ months after capture. They stated that while in Turkey their diet had been excellent but almost all had suffered from dysentery or malaria. In the Turkish prisoners diarrhoea was a prominent feature and Bigland suggests a possible toxin action resulting from a damaged intestinal mucosa. Stools from pellagrous Turkish prisoners showed organisms similar to B. perfringens in 90% of cases while such organisms were not found in the stools of healthy prisoners.

The statement is frequently seen that pellagra did not make its appearance in Europe until after the introduction of maize, subsequent to the discovery of the New World. There are authors who think Casal was suspicious of a maize dietary.

The zeistic views now incorporate some additional factor with the basic one of a rather exclusive maize dietary.

1. The verderame theory of Ballardini. From noting on the corn grains a covering with a greenish mould, Ballardini in 1845 advanced the view that pellagra was due to this mould and from this time on we have the so-called zeitoxic views, which hold that pellagra is caused by spoiled corn. Ceni and Fossati regard a toxin elaborated by various moulds as causative. The fungi toward which attention has been chiefly directed are Aspergillus fumigatus and A. flavescens as well as certain species of Penicillium and Mucor.

2. The Lombroso view that as a result of the action of moulds or bacteria, toxins are elaborated which, when ingested, give rise to the disease.

3. That the toxins have origin in the action of various organisms, especially B. coli, on the ingested corn, while in the intestines.

4. Recently views have been brought forward that pellagra is an anaphylactic phenomenon connected with sensitization to the maize proteins.

5. Rabitschek has brought forward a photodynamic theory which is that pellagra is due to a preponderating maize or possibly other cereal dietary which results[297] in certain photodynamic substances being introduced into the circulation. These substances become toxic under the influence of sunlight. Hirschfelder has failed to find any fluorescent body in the serum of five patients suffering with severe pellagra.

(a) Among the natives of Upper Egypt, where millet instead of maize is the staple cereal, pellagra is rare, while in Lower Egypt where much maize is eaten the disease is far more prevalent.

(b) While the natives of Corfu, prior to 1857, grew their own maize and ate only sound grains there was no pellagra but later, when the corn crop was less profitable, and the grain was imported from Roumania, much spoiled maize was brought in and pellagra made its appearance.

(c) Alsberg has shown that in recent years new methods of harvesting corn have become common in the Southern States of the United States. Instead of topping the corn it is cut and shocked with the result that conditions are more favorable for the spoiling of the corn. He also notes that varieties of corn are now planted which have a greater oil content, which means a larger embryo, and that it is this embryo which most easily spoils. Again he notes that much corn is now raised in Northern States where the season is shorter, so that there is a greater probability of immature corn being marketed. All of these facts might explain the recent appearance of pellagra in the U. S. and its previous nonexistence. Thomas has shown that where 30 grams of a superior protein, such as that of meat, would suffice, it would require 102 grams of corn protein, an inferior protein. This inferiority is due to a lack of assimilability of the amino-acids of corn protein. Protein deficiency is the outstanding feature of a pellagra-producing diet and in the corn protein we have one of inferior value.

1. The Thompson-McFadden Commission, while holding a very conservative attitude, feel that certain faecal bacteria may be the etiological factors.

2. Alessandrini believes that the causative factor may be present in certain waters.

These views are that colloidal silica in water is responsible for the disease. Voegtlin noted the great amount of aluminium in certain vegetables and suggested this as the toxic causative substance. A mixture of colloidal alumina and silica in water is supposed to be operative as well as silica alone. Against the colloidal silica hypothesis is the statement of Sandwith that the water of the Nile, the drinking water of Egypt, is low in colloidal silica content.

3. Long has suggested that amoebae may be the cause.

4. Tizzoni has incriminated a streptobacillus which he stated he found in the blood and organs of pellagrins as well as growing on maize.

Many of the peculiarities of sex and place distribution could be explained by the stable fly, Stomoxys calcitrans, a fly which bites viciously in the district in which they worked. This fly bites only by day and is intimately associated with human dwellings so that the greater incidence of the disease in the women, who stay at home, as against an incidence five times less in the men who work in the mill during the day might be explained by Stomoxys bites.

Lavinder and Francis injected 79 monkeys and 3 baboons with varying material from pellagra autopsies. Some of the animals were injected with emulsions or Berkefeld filtrates of such emulsions made from brain and cord. Other monkeys were inoculated with material from skin similarly prepared, others with stomach and mouth mucosal emulsions, and still others with intestine and faeces emulsions. Blood, urine and cerebro-spinal fluid were also injected. Feeding experiments were also carried out. With one exception, and that one only suggestive of pellagra, the experiments were negative.

Sixteen volunteers, working under Goldberger, tried to infect themselves with blood, nasopharyngeal secretions, epidermal scales, feces and urine from pellagrins. Various atria of infection were tried according to material; blood by intramuscular injection, excreta by mouth. After a period of six months all the subjects of the experiments remained well. This evidence is certainly against the infectious nature of the disease.

Before Goldberger began his experiments he was struck by the relation poverty had to pellagra epidemiology, and as diet is the chief element differentiating poverty and affluence, he chose this line of research with the results recorded under etiology. His explanation of the greater incidence in adult females, especially wives and mothers, was their act of denying themselves the more desirable parts of the food.

Sandwith has noted the great frequency of pellagra in hookworm patients, thus of 300 such cases in Egypt, 46% had pellagra.

The Thompson-McFadden Commission was unable to note any evidence that would distinctly point to corn, good or bad, as giving rise to pellagra outbreaks. They did note, however, a very limited use of fresh meats.

At autopsy we find rather marked emaciation. The wasting of all organs seems to be greater than in any other wasting disease. The skin lesions show degenerative changes in the corium with slight cellular infiltration. In the epidermis there is superficial atrophy but still some thickening in the stratum granulosum.

Warthin states that the lesions are those of a chronic intoxication. The spleen shows atrophy and in the follicles there is necrosis of germ cells as well as hyaline changes. The liver and kidneys often show fatty change. In general the changes are those of a senile character. There is atrophy of the mucosa of the small intestines and there may be small ulcers present.

The mesenteric glands are enlarged. Roaf has noted the presence of involvement of the adrenals and the Committee investigating pellagra in Turkish prisoners found a marked supra-renal inadequacy.

Degenerations in the posterior columns and crossed pyramidal tracts have been reported from certain autopsies.

The cell count of the cerebro-spinal fluid is normal and there is usually an absence of globulin increase with a negative Wassermann. The blood chemistry findings in pellagra appear solely to be low nonprotein nitrogen and urea values.

This erythema is very similar to sunburn but often follows inadequate exposure to the sun and the erythema persists instead of fading. Desquamation continues for weeks or months instead of healing. The dry scaling area usually shows a striking pigmentation at the borders even after the central portions of the erythema have cleared up. The skin lesions instead of being dry and atrophic as is usual may more rarely be moist and oedematous.

A final cachexia, with dementia, loss of control of the vesical sphincter and a terminal diarrhoea, marks the end. Recurrences of clinical manifestations each spring, or possibly skipping a year, are striking features of the disease. While the skin and alimentary tract disturbances are usually in abeyance in the winter, this holds to less degree with the nervous symptoms.

Burning sensations are noted in mouth, gullet and stomach as well as of the skin. Then too a burning sensation may be complained of in the area formerly the seat of a pellagrous eruption. The palms of the hands and soles of the feet often give a burning sensation.

One of the characteristic features of pellagra is the periodic recurrences in spring, with almost complete cessation of skin and alimentary tract symptoms in the winter and, again, the tendency in many cases for one group of symptoms to overshadow the symptoms which usually accompany them. These periodic recurrences may well be associated with seasonal variation in diet.

These stages have reference solely to the degree of severity of the manifestations and a case may never progress beyond the 1st stage, although recurring for a number of years. Again a case may rapidly progress to the 2d stage and even run through the 3d or cachectic stage in a few months. We must not consider these stages as tending to follow in sequence as we do in connection with the stages of syphilis.

In Goldberger’s cases the eruption did not appear until after five months on the experimental diet. In the study of cases of pellagra occurring among Armenian refugees, and in Turkish prisoners of war, oedema was not infrequently noted and its occurrence usually preceded the eruption.

In cases with very severe stomatitis there may be enlargement of the salivary glands. The pharynx is congested and a similar condition of the oesophagus gives rise to a burning sensation which is often described by the patient as going up the gullet from the stomach.

Gastric disturbances, especially gastralgia, pyrosis and eructations, may be pronounced. Anacidity and deficiency of pepsin are noted in gastric juice examinations. The intestinal symptoms are those of recurring diarrhoea or occasionally of a mild dysentery but in many cases there is a normal functioning of the bowels. Although the skin manifestations usually follow those of the alimentary tract they may precede them or occur simultaneously.

The pellagrous erythema shows itself most commonly during the late spring or early summer. It may appear in the early spring or late summer or early fall, but only exceptionally does it occur in the winter. There are, however, alterations in the skin previously involved which can at times be noted during the winter.

Very important were the observations of Goldberger that in his six experimental cases the eruption first showed itself as a symmetrical involvement of the sides of the scrotum.

On the feet the dorsal eruption does not usually go above the malleoli and rarely involves the dorsal surfaces of the external toes although rather commonly affecting the great toe. In the U. S. the eruption may extend up the front and back of the leg (boot). The soles of the feet and palms of the hands are not infrequently involved in American cases as is also true of the tip of the elbow.

The eruption on the elbows rarely occurs until the patient takes to his bed and is probably incident to irritation over olecranon. Sandwith states that the skin lesions in Egypt are more widespread than those seen in Italy.

In 1679 cases of pellagra Merk found 77% with eruption solely on backs of hands, 13% on backs of hands and neck, 8% on neck alone. The eruptions on dorsal surfaces of feet and calves of legs are chiefly seen in barefooted children. In the pellagra cases among Turkish prisoners Bigland noted an eruption on the hands in all but one of 232 cases. Rashes on the feet were noted in 111 cases and rashes on the face with bilateral symmetry were observed in 47 cases. One case showed a scrotal eruption.

The more advanced skin lesions are those of a dermatitis rather than an erythema. The affected skin is at first of a dull red color like a sunburn and later becomes reddish-brown or livid or chocolate-colored. Fox has likened the eruption to that of a carbolic acid burn.

The normal elasticity is lost and the area appears as a dry, scaly, atrophic[306] patch—it is the skin of a very old man. The moist oedematous skin lesions are far more common in the U. S. than elsewhere and may show bullae and even gangrene. Such cases may show the gauntlet desquamation.

Attacks of giddiness with tendency to fall forward or backward are often reported. The deep reflexes may show variations from normal and there may be variations in the reflexes of the two sides, thus the patellar reflex on one side may be exaggerated and that on the other normal or diminished. Ankle clonus is rare. Neurological manifestations are slight in pellagrous children, the main symptoms being the cutaneous ones.

In the second stage the urine shows rather marked indicanuria and the faeces contain an excess of skatol. Loss of weight is as marked a feature of pellagra as of tuberculosis. Well nourished pellagrins are the exceptions.

Pellagra often runs a rather acute course in the U. S., the patient dying within two or three months. The usual course in Europe is one prolonged over years, with at times intermissions covering one or more years.

A form of pellagra known as typhoid pellagra often shows a high fever with symptoms more or less resembling a very toxic case of typhoid.

A mental state resembling the acute delirium of paresis may be present. Such states are often terminal. The usual course of pellagra is afebrile. Such terms[307] as pellagra sine pellagra are given to cases which may not show the skin lesions and the designation pseudopellagra has usually been used by those who insist upon limiting the name pellagra to those cases which fit in with their special etiological views so that cases clinically pellagra but in which the special etiological factor does not obtain are called pseudopellagra.

The cutaneous neurological and alimentary tract disturbances have each already been separately described in detail.

The Blood.—Hillman has made very careful blood examinations of a series of cases and found a variable degree of chloranaemia which however, was not a prominent feature. He notes the occasional occurrence of a leucocytosis in the course of the disease. As a rule there is a definite lymphocytosis, the average percentage of lymphocytes being 33.99. The average percentage for the large mononuclears was 2.59. The average percentage of eosinophiles was 2.73. The determinations of the coagulation time of the blood gave normal figures.

In Ridlon’s series the average red count was 4,720,000, the white count varied from 14,200 to 4200, average 8027. The polymorphonuclear percentage averaged 68.2, that of lymphocytes 21, of large mononuclears 8 and of eosinophiles 2.

Hb percentage averaged 77 and color index 0.81. The blood serum failed to give positive Wassermann reactions.

The Urine.—There is rarely any increase in albumin. The most important urinary finding is in connection with indicanuria, 96.4% of Ridlon’s cases showing this finding. As convalescence comes on indicanuria tends to lessen.

The Temperature Chart.—We expect a normal temperature in an uncomplicated case of pellagra but in typhoid pellagra and in the terminal stages of the disease a fever of from 101° to 103°F. is generally noted. Fever makes for a bad prognosis. There is nothing special about the circulatory system other than low blood pressure and a tendency to vasomotor disturbances. With the genito-urinary system other than the rather marked indicanuria, there is nothing of note.

There is no reliable laboratory test and the reports as to positive reactions following injections of maize extracts seem unreliable. Again there do not seem to be any antibodies in the serum of pellagrins which can be utilized in serological diagnosis. A primary requirement would be a suitable antigen. Competent workers have been unable to find any bacterial organism in the blood of pellagrins.

Erythema multiforme and dermatitis venenata seem to be the skin diseases most liable to cause confusion.

In old people with arterio-sclerotic changes and consequent mental symptoms there may be lesions of the hands or feet of more or less gangrenous type, which may be a real source of confusion. The lack of sharp delimitation of such lesions and the absence of the pellagrous stomatitis should differentiate.

Poison ivy dermatitis, if bilateral, may be confusing, as may also chapping of the hands.

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In Italy a disease due to eating ergot-diseased rye meal and called ergotism may be a source of confusion as this disease shows gangrenous manifestations. The gangrene of ergotism is a dry one.

Sprue does not show the dermatitis, and the nervous manifestations are solely those of irritability or possibly slight neurasthenia. The sprue stool is not found in pellagra. See Diagnosis under Sprue.

Typhoid pellagra may be confused with severe typhoid fever or other acute infectious diseases or with conditions associated with coma, as diabetes or uraemia.

When fever comes on the prognosis of the case is unfavorable and when the mental manifestations are prominent the prognosis is bad.

Of particular importance is the question of the liability to mental trouble. Singer states that about 40% of all cases of pellagra develop mental disturbances and that this incidence is much higher in cases presenting recurrences. In Italy it is estimated that from 5 to 10% of pellagrins become permanently insane.

In the first stage the prognosis is very good but in the second, when there is more or less involvement of the central nervous system, it is much less favorable. In the third stage, or that of the terminal cachexia with marked mental deterioration, the prognosis is extremely bad. Each recurring attack makes the condition more serious. The older the patient the more serious the prognosis.

As a proper, well-balanced dietary is an important curative measure it is therefore prophylactic.

At the New York Post Graduate hospital, 17 cases were apparently cured on rest in bed and full nutritious diet. Hospital treatment, thereby removing the patients from the environment in which the disease developed, is generally conceded of the greatest benefit.

Many authorities speak highly of arsenic in various forms as Fowler’s solution, atoxyl, salvarsan, etc. Others are equally pessimistic as to the value of arsenic in any form.

Deeks prefers to eliminate sugar and starchy food from the dietary of pellagrins for a few days at a time and to give fresh fruit juices, with broths and milk. He highly recommends dilute nitric acid, well diluted, before meals. As there is almost constantly anacidity and pepsin deficiency in the gastric juice it would seem that this condition should be treated.

It is advisable to keep the patient out of the sun and require him to take his exercise after sunset.

Psychotherapy seems to be of importance in the treatment of pellagra.

With the colloidal silica etiology in view Allesandrino has recommended sodium citrate in treatment.

In an orphan asylum with 211 orphans, 68, or 32%, had pellagra. These children were divided into 3 groups and given different rations, those under six years of age receiving milk and eggs, while those over twelve years were given meat, as they assisted in the work of the institution. The children between six and twelve lived practically on a vegetarian diet in which corn products and syrup preponderated with deficiency of legumes. Of 25 young children only 2 showed pellagra, and there was but 1 case in the 66 children over twelve years of age while the 120 between six and twelve gave 65 cases or 52%.

As to the diet in pellagra Niles recommends the exclusion of all maize articles of diet. He recommends meat, eggs, milk or buttermilk with peas and beans. When intestinal symptoms are severe he gives barley gruel, rice-water, thick broths and dry meat powders. As a drug treatment for diarrhoea he uses bismuth beta-naphthol.

Babcock, recognizing the importance of the treatment of the pellagrous neurasthenia, recommends the Weir-Mitchell plan of prolonged rest in bed, nutrition, hydrotherapy and hygienic measures. “Fat and blood” should be our aims and he notes the value of cacodylate of soda in increasing fat. He also refers to the susceptibility to suggestion of pellagrins and is an advocate of psychotherapy.

Having in mind the vitamine deficiency view Voegtlin has treated cases of pellagra with extracts of substances rich in vitamines. Extracts prepared from fresh ox liver and fresh hog thymus caused definite improvement in pellagrins so treated while extracts of yeast and rice polishings seemed to be without value. It will be remembered that the glands of animals are rich in fat soluble A. For the burning of the erythema Niles recommends a lotion of calamine (4 drams), powdered zinc oxide (3 drams), in 1 pint of lime water. As regards climatic treatment the same authority believes that a colder climate is indicated and that a patient with pellagra should avoid hot weather for a year after all symptoms have disappeared.

The soreness of mouth and gullet is soon followed by erosions, especially at the site of the posterior molars, and a bare raw tongue. Exceedingly characteristic are the voluminous, frothy stools which are evacuated chiefly in the morning hours. The patient becomes weak, emaciated, irritable and of an earthy pallor.

The disease chiefly affects Europeans who have lived in Southern China, Cochin China and Java, and unless treated early tends to progress to a fatal termination.

History.—The French (1868-1872) described this disease under the name of chronic or endemic diarrhoea of Cochin China and noted its resemblance to Moore’s “Hill Diarrhoea.” In 1876 Normand incorrectly associated Strongyloides with the disease.

The physicians of the Dutch East Indies described the disease under the designation “spruw” and Manson in a very complete description of the disease called it “sprue,” a corruption of the Dutch name.

It is interesting to note that Hillary in 1766, described a similar disease of Barbadoes, W. I., which he called aphthoides chronica.

Geographical Distribution.—It is particularly prevalent in South China and the East Indies. India and Ceylon are also regions of the disease. In the West Indies it has been carefully studied, in Porto Rico by Ashford, and of particular interest is[313] the fact that Wood has recently insisted on the presence of sprue in the Southern States of the U. S. The Philippines and tropical Africa are also sections from which the disease is reported.

It seems to select those who are weakened by dysentery or other debilitating diseases, or who are compelled to subsist on indigestible food or to lead a life of exposure to hardships. Women in whom the menstrual flow is excessive or who are in the period of lactation seem to be especially susceptible. Some think alcoholics more susceptible. The idea has been advanced that the abuse of calomel has been a factor and this view is one to be given weight because it is well recognized that at the present there is much less sprue than formerly and with this there has been a more rational use of calomel. The excessive use of highly seasoned food, so common with Europeans in the tropics, may have an influence.

Some have thought that sprue was the manifestation of a tropical pancreas; at first congestion and later exhaustion of its function. The character of the stools lends support to this view.

At one time it was thought that Strongyloides stercoralis was the cause; this idea had its origin in the finding of these larvae in the stools of a patient with Cochin China diarrhoea.

Certain authors have considered bacteria giving a granulose staining reaction as the cause while others have thought cocci to be concerned.

Kohlbrugge found organisms resembling Oidium albicans in the intestines, oesophagus and tongue. He found similar organisms in the stools and tongue scrapings of cases of sprue. Beneke found bacilli in the tongue, oesophagus and intestines and considered these as causative, regarding the thrush-like membranous deposit as connected with the cachectic state and not causative.

Bahr is inclined to believe that Monilia albicans (Oidium albicans) is the cause, as he found these saccharomycetes in the deep layers of the tongue, in the mucoid coating of the intestines and in the deposit in the oesophagus. He thinks it the ordinary thrush species which may take on greater virulence in the tropics. Ashford states that he has found a species of Monilia, different from that of thrush, almost constantly in tongue scrapings and stools of sprue cases and he regards this species as the cause of sprue. He states that this organism is common in Porto Rico bread and thinks it possible that the disease is transmitted in this way. It has been called Parasaccharomyces ashfordi. It is a round yeast, 4 to 7 microns in diameter. Wood has recently expressed the view that sprue is not infrequently mistaken for pellagra in the Southern United States.

Castellani, in a study of moulds of the genus Monilia in sprue stools, holds them responsible for the excessive gas production, although not the cause of the disease. Various protozoa, as amoebae and spirochaetes, have been considered as possible causes.

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While there does not seem to be any vitamine deficiency implicated yet there is disordered assimilation, which may be due to alimentary tract infection or to insufficiency of pancreatic functioning. It has been suggested that secretin deficiency is the essential disturbance.

Sprue is usually a disease of mature life and affects women more frequently than men. While climate cannot be considered as causing sprue yet the effects of hot climates in producing exhaustion states in Europeans must be borne in mind. The sprue patient should always leave a tropical climate.

At autopsy the subcutaneous fat is found to have almost disappeared. The intestines, especially the ileum, show marked thinning, this atrophy especially affecting the mucosa, the surface of which is covered by a layer of dirty gray mucus. The submucosa generally shows connective-tissue increase. The gut is pale and diaphanous. The solitary follicles may show as small cysts filled with a gelatinous material or as ulcers.

The liver is markedly atrophied. The mesenteric glands are usually enlarged. The pancreas may show cirrhotic changes.

The diarrhoeal movements are remarkably copious and soon change from bile-colored, liquid evacuations to the characteristic putty-colored, pultaceous, gas[315] bubble permeated, offensive stool of sprue. While the patient experiences a sense of relief from the evacuation of the fermenting mass yet there is at times an excoriation about the anus which may cause pain when at stool. Neuralgic pains of the region of the anus may be present late in the disease.

When examined microscopically the stools are found to show much fat, yeasts and undigested food. The fats are chiefly in the form of neutral fats and fatty acids rather than as soaps. The reaction is acid. Nausea and vomiting, especially about noon, may be complained of.

There is also congestion and swelling of the fungiform papillae.

The gullet may be raw and very sensitive. The appetite is apt to be capricious and the patient may be very intractable, insisting upon dietary indiscretions which he knows will aggravate his condition. There is a progressive loss of strength, weight and energy. The liver progressively diminishes in size but is difficult to map out owing to the bulging, dough-like abdominal contents. The urine is usually free of albumen but shows marked indicanuria. Sprue is characteristically afebrile.

Anaemia becomes marked, the red cells going as low at times as under 2,000,000, per cmm. and the Hb. percentage less markedly reduced (color index above 1). The polymorphonuclears are reduced in percentage.

There is a tendency to depression and irritability.

The period during which sprue runs its course is very variable. Some cases drag on for ten or twelve years while others may be subacute in type, death ensuing within a year or two.

The Stomatitis.—At first we have a disagreeable bitter taste in an unusually sensitive mouth. Later there develop superficial ulcers along the sides and frenum of the tongue, which subsequently involve the buccal mucosa. The gums may be quite tender and saliva dribble from the mouth.

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In the later stages the tongue becomes bare, red, fissured and glazed.

The Stools.—Commencing as early morning diarrhoea, with at times alternating constipation, there gradually sets in that which makes for a diagnosis of sprue—putty-colored, fermenting, offensive stools which are extraordinarily copious.

They are also very fatty and of acid reaction. They show a proteid loss as well as lack of fat absorption.

The Blood Findings.—There is a marked secondary anaemia with great reduction in red cells and Hb. percentage.

The color index averages higher than normal and with the poikilocytosis resembles the blood picture of an atypical pernicious anaemia. Nucleated reds are rarely found. The eosinophiles are reduced in percentage. The polymorphonuclears often show a great number of nodes, as 7 or 8 instead of the ordinary three.

There is a mononuclear increase with polymorphonuclear reduction. The white count is somewhat below normal—4000 to 6000.

Other Features of the Disease.—The liver is notably diminished in size. The urine shows indicanuria. The patient has a dry earthy skin and may show oedema about ankles.

Mentally there is lack of concentration with marked irritability and moroseness. Tetany has been reported as occurring rarely in very severe cases. The abdomen is doughy and the temperature in the later stages tends to become subnormal.

Pellagra.—The stomatitis, diarrhoea and mental irritability are very similar in the two diseases. There is, however, absence of the sprue stools in pellagra and the periodical recurrence and skin manifestations of pellagra are absent in sprue.

Wood thinks that in the absence of any evidences of organic nervous disease in sprue we have an important differentiation as he finds that pellagra has as great a tendency to invade the nervous system as has syphilis. Salivation is marked in pellagra, not in sprue. The two diseases, however, are best differentiated by the darker, more fluid, less copious stool of pellagra as contrasted with the copious, light colored stool of sprue. Stools containing great amounts of undigested fat are most characteristic of sprue; fat absorption in pellagra is about normal (95%) while in sprue it is only about 75%.

Syphilis with its buccal mucous patches or geographical tongue may be mistaken for tongue sprue.

At first it is only the annoyance that is complained of but later on the appetite is lost and the patient becomes weak.

There is an absence of the sprue mouth. The laboratory diagnosis, other than the finding of excess of fatty acids, soaps, undigested food remnants and yeasts is unimportant.

The Milk Treatment.—A preliminary dose of castor oil is given and when this acts the patient should begin taking milk as the sole food. At first about 4 pints of skimmed milk are given daily. The milk should be given in two-hour feedings, well warmed and taken through a glass tube or with a teaspoon—it should not be drunk. As the stools become less frothy the amount of milk is increased so that the patient takes from 6 to 7 pints daily. Milk should be the sole food for six weeks from the time the stools become solid and the mouth symptoms disappear. Rele prefers buttermilk to skimmed milk. Eggs are usually well borne after the milk course. Stale bread or toast is cautiously added and then some fish or chicken.

At times the patient seems benefited by giving a meat treatment day once or twice a week during the course of the milk treatment.

Meat Treatment.—If the patient is very ill it may be advisable, after the preliminary dose of castor oil, to give meat juice obtained by expressing the juice from slightly broiled meat, about 2 teaspoonfuls every half hour. If possible however one starts in with the meat cure, which is about 4 ounces of a lightly broiled chopped-up beefsteak, every four hours. Raw meat is usually given in this treatment but there is danger of T. saginata infection.

At least 4 pints of warm water should be taken daily but not at the same time the patient eats the meat. Rest in bed and the avoidance of chilling are important measures. In all food treatments we should avoid forcing the patient to eat—it is better to give food only when the patient desires it.

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Some prefer to alternate the milk treatment with the meat one.

Fruit Treatment.—The patient is allowed fruit in great abundance. Strawberries, peaches, grapes, ripe gooseberries and fully ripe bananas are usually recommended. Papayas are particularly well suited. Pomegranates are also highly recommended. Sour or fibrous fruits should be avoided. Strawberries and milk are highly advocated. Cooked strawberries or other cooked fruits do not benefit the patient, the curative principle being apparently destroyed by heating. At all times alcoholic drinks and highly spiced foods should be avoided.

The only drug that has been advocated to any extent is yellow santonin, in doses of 5 grains, night and morning. It is very doubtful if any drug treatment is of the least value.

LeDantec, with the elimination of the granulose bacteria in mind, has recommended the cutting off of carbohydrates and the giving of a strictly albuminous diet. Subsequently he gives lactic acid producers as contained in Bacillus bulgaricus preparations.

Schmitter has recommended emetine in the treatment of sprue, but Ashford has found this drug, as well as santonin, of negative value. Brown has had success in treating a case of sprue with pancreatin, 30 grains daily. Since then he has had marked success in three other cases. He now combines the pancreatic extract with calcium carbonate.

In connection with Ashford’s work with a specific Monilia, M. psilosis, cases of sprue have been treated with vaccines made from this organism.

An autolysate of the cultures is sterilized at 56°C. for an hour and then centrifugalized. A one per cent. suspension of the sediment is used for injection increasing from about 0.1 cc. to 1 cc. at weekly intervals. Five or six injections are given.

It is stated that the symptoms at the start of the treatment are aggravated.

Goeze found a hookworm in a badger in 1782. He named the parasite Ascaris criniformis. Froelich, in 1789, found hookworms in the fox and named them hookworms from the hook-like ribs of the copulatory bursa. He proposed the generic name Uncinaria. Therefore Uncinaria belongs to the hookworms of the fox and is not valid for any human species.

In 1838, Dubini noted that these worms were generally found in very anaemic cases and that the mucosa of the duodenum or jejunum frequently showed punctate haemorrhages. On account of the four ventral teeth projecting from the mouth he gave it the name Agchylostoma or correctly Ancylostoma.

In 1854 Griesinger, as a result of frequently noting the lesions produced by the worms, stated that they were the cause of Egyptian chlorosis. In 1866, Wucherer connected hookworms with a disease of Brazil called opilacao. In 1878 Grassi noted that the disease could be diagnosed by the finding of the characteristic eggs in the stools of patients.

That the disease was very prevalent in the Southern States of the U. S., as long ago as 1849, is shown by the writings of Duncan, who noted the frequency of anaemia, often associated with dirt eating, among the slaves. He described the oedematous[320] legs, the protuberant belly and cardiac palpitation. There were several cases reported in the U. S. from 1893-1897 but they were mainly in foreigners.

From 1895 to 1901, Stiles kept insisting that hookworm disease should be of frequent occurrence in the U. S.

A. J. Smith found several cases in persons living in Texas and recognized the fact that these hookworms were different from those of Europe. It was from a study of material from Smith and Claytor in the U. S. and, later on, from Ashford in Porto Rico, that Stiles, in 1902, reported a new genus of hookworm as existing in man. It was first named Uncinaria americana but Uncinaria, belonging to the hookworm of the fox, was not valid, so he changed the name to Necator americanus.

Geographical Distribution.—The disease is rare outside the tropical and subtropical countries except in mines or tunnels where suitable conditions of warmth and moisture exist.

It is extremely prevalent in India and Egypt as well as in China and other parts of the East. It is a very important infection in Porto Rico and the Philippine Islands. It is extensively distributed in South America, especially Brazil, as well as in Central America, Mexico and the Southern States of the U. S. The inhabitants of many of the islands of the Pacific are heavily infested. Hookworm disease is common in southern Europe.

Quite recently Lane has reported a new species, A. ceylanicum, as having been obtained from 3 men in Bengal, after treatment. This species is the one that infects the civet cat in Ceylon. So far as we know the other human species belong solely to man.

The anterior extremity of Ancylostoma bends in the same direction as the general body curve while that of Necator hooks back in an opposite direction to the body curve.

By dropping the worms, while still alive, into hot 70% alcohol they readily assume the attitudes noted above.

The name hookworm was given to these nematodes from the hook-like processes of the ribs of the rays of the copulatory bursa. Dubini called the Old World parasite Agchylostoma, properly Ancylostoma, on account of the 4 formidable hook- or claw-like ventral teeth of the buccal capsule. (αγχὶλος, hook, and στομα, mouth.)

A. ceylanicum is somewhat smaller than A. duodenale and in the copulatory bursa of the male we have a deeper cleft in the dorsal ray and 2 rather long tips to each branch instead of the shallow cleft and 3 stumpy processes of the 2 branches as in A. duodenale.

As a practical point, the anaerobic conditions in the intestines seem to prevent development of the hookworm ova or at any rate the absence of the oxygen, so necessary for the segmentations preliminary to the formation of the embryo, prevents it. Therefore hookworm ova in freshly passed faeces never show other than commencing segmentation while development of the larvae of Strongyloides takes place in the intestines, so that in freshly passed faeces we find, generally, actively moving larvae or at least eggs containing fully developed embryos. Hookworm ova very rarely show more than 4 segments or exceptionally 8 segments in the freshly passed egg.

In the presence of oxygen these ova rapidly develop into larvae, particularly at a temperature of about 27°C. Beyond 37°C. and below 14°C. development does not seem to take place.

The rhabditiform larvae grow rapidly and by the 3rd day are about 300 microns[323] long and undergo a primary moulting. By the 5th day the bulb-like swellings disappear and the larva becomes possessed of a straight oesophagus, thereby becoming a strongyloid larva. It then undergoes a 2nd ecdysis or moulting, but instead of casting off this old covering, it retains it as a protecting sheath. The full grown larva is about 550 by 24 microns. At this time it ceases to take food but can move actively in its sheath so that it can crawl up blades of grass or vertical sides of mines. They can live in this state for months, when moisture and shade are present, but are rapidly killed by drying. Before becoming encysted hookworm larvae are readily destroyed by the action of the sun or chemicals or even by dilution of the faeces, especially with urine. Cort and others have found it a common occurrence for mature larvae to lose their sheaths while living in the soil, and to continue their lives in the unsheathed state. The proportion losing their sheaths varies from 52 to 98%.

Looss thought that they entered the skin by way of the hair follicles but the idea now is that they can bore into any part of the skin. It only requires a few minutes for the larvae to enter the skin. From the subcutaneous tissues they effect an entrance into lymphatics or veins, go to the right heart, thence to lungs. From the alveolar capillaries they pass into the pulmonary alveoli, thence up the bronchi and trachea, to pass out of the larynx and then down the oesophagus to the stomach. The larva loses its protecting sheath in the stomach and in a few days develops a provisional buccal capsule.

By the end of the 2nd week, after another ecdysis, the larvae have grown to be about 2 mm. long and 130 microns broad and in about 4 weeks become adults, usually in the jejunum, where, after fertilization of the females by the males, the giving off of eggs begins. The adults attach themselves to the mucosa of the intestine, feeding on the deeper structures of the mucosa, or on the tissues of the submucosa. Sambon believes that the larvae can work their way into the jejunum without going there by way of the trachea and oesophagus.

By providing an exit to the trachea, Fülleborn demonstrated that in dogs, infected with the dog hookworm, great numbers of larvae poured out of the trachea. In other dogs he stitched the oesophagus to the skin and noted larvae coming out of these openings. In these dogs, with the ordinary channel obstructed, infection did occur with, however, only a few worms, thus showing the truth of Sambon’s views but at the same time demonstrating the unimportance of such a route of infection.

The mouth cavity of the embryo is about as deep as the diameter of the embryo at the posterior end of the mouth cavity, that of Strongyloides is only about one-half as deep as the diameter. The genital anlage of Strongyloides is much larger than that of Ancylostoma.

Stiles notes that the more favorable conditions for development are in a porous, sandy soil rather than in a clay one. Where a sewerage system exists there is very little danger of the spread of hookworm disease and the same is true where there is proper disposal of the faeces by burning, boiling or treatment in a septic tank. In rural districts, however, where the stool is often deposited in the shade and retirement of a clump of trees, the soil becomes infested with myriads of larvae, so that one standing with bare feet on such a spot easily becomes infected. It is for this reason that shoes are of protective value. In infected mines with temperatures below 22°C. infection is rare (6%); from 22°C. to 25°C. more common (16.6%), and above 25°C., it may reach high figures (61%).

Those of the negro race do not suffer from the infection as do the whites. They appear to have an immunity but serve as carriers of the disease. There is difference of opinion as to the length of time the parasites may live in man in the absence of reinfection. Some consider this period one of a few months, others of two or three years. We can certainly consider that a case leaving an infested region will get rid of his parasites within seven years.

Pronounced anaemia with yellow, wax-like skin is a feature of severe cases but emaciation is rare, the subcutaneous fat still remaining. There is frequently oedema about the ankles. In the jejunum we find small haemorrhagic spots from the size of a pea to that of a half dollar. A worm may be found in the center of this spot. In sections from the tissues injured by the bite we note an infiltration of eosinophiles. The heart often shows fatty degeneration with dilatation. The liver and kidneys usually show fatty change while the spleen is generally shrunken. Sandwith noted splenic enlargement in many of his autopsies but such enlargement must have been due to other causes.

On the side of the blood we have at first a moderate leucocytosis which disappears with the anaemia. Eosinophilia and Hb. percentage reduction are often observed. In 3 cases I have known a fatal pernicious anaemia to develop.

The course of the disease is decidedly insidious and indefinite and the clinical diagnosis notoriously uncertain, as shown by many reports where physicians of experience, after examining a number of persons in a mill or school and only diagnosing 2 or 3% as infected, have been astonished, upon examination of the faeces of the group, to obtain positive evidence of infection in 70 to 80% of the number examined.

Such cases may show very slight reduction in haemoglobin and only admit of a certain lack of energy. The best indication that hookworm infection is doing the host injury is that after treatment they gain in weight and energy and show improvement in mental concentration.

These cases are very weak and show marked cardiac palpitation and dyspnoea upon the slightest exertion. There is often dilatation of the stomach and a protuberant abdomen. The red cells may fall below 1,000,000. There is also oedema, especially about the feet and ankles. Tinnitus aurium is rather frequent.

It is in children that we have the most serious effects of the disease, there being marked stunting of the growth with a corresponding mental backwardness. Such children show marked retardation and delay in answering the question asked them and often repeat it in a drawling manner. Tested by the Binet-Simon method we may find a sixteen year old child to have the mental development of a ten year old one, but at the same time we would note that from a standpoint of physical development the child only seemed ten years old.

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As the child approaches adult age we note a striking lack of sexual development and the lack of pubic hair. In girls there is delay in the onset of the menstrual periods or these may never appear.

As a rule the temperature is normal throughout the course of an uncomplicated case of hookworm disease. During the first week or so following a heavy infection there may be pulmonary manifestations when the larvae are migrating by way of the lungs.

He also notes that the pupil tends to dilate instead of to contract when the patient looks at a bright light. It has seemed to me that the condition is rather one of hippus. In severe cases retinal haemorrhages may occur. There may be night blindness. Ascites may be present in advanced cases.

Skin Manifestations.—The dermatitis following the penetration of the larvae is most often about the toes or inner side of the sole of the foot. The skin is very dry and often a pale earthy color. A tallow-yellow tinting of the alae of the nose may be observed. The hair is dry and scanty or absent in pubic and beard regions. Oedema, especially of ankles or feet, is common.

Circulatory and Respiratory Systems.—Palpitation of the heart is early and marked. Functional murmurs are frequent in the advanced stages. Pulsation of the neck veins is also common. The pulse rate averages about 110 and the blood pressure is low. There is frequently some right side dilatation of the heart. A high pulse pressure is common in severe cases. Shortness of breath on slight exertion is the most common respiratory symptom. There are at times cough and bronchitis, probably induced by the irritation of the larvae in the pulmonary alveoli.

Digestive System.—Epigastric tenderness going to the right is very characteristic. The stomach is often dilated and the gastric juice hyperacid. As the anaemia increases the acidity diminishes. It has been suggested that the desire to neutralize[329] this acidity with an alkali is the explanation of the desire for alkali-containing earth on the part of “dirt eaters.”

Patients often are pot-bellied. Constipation is rather a common feature and the stools very rarely show macroscopic blood.

Nervous System.—Hookworm patients are not only physically tired but, as well, mentally tired. The infection in children leads to a backward mental state. Patients have very little energy or initiative and are often considered stupid and lazy. Hypochondriasis is at times noted and some severe cases become melancholic.

The Blood.—The red cell count averages in marked cases 2,500,000 to 3,000,000 red cells per cu. mm. The Hb. percentage is down in such cases to between 30 and 50. The color index is well below 1, except in certain rare cases, when the color index is that of pernicious anaemia, being above 1. These latter cases are very resistant to treatment and often show very few infecting worms notwithstanding the severity of the symptoms.

There is at times a moderate leucocytosis but as a rule the white count is approximately normal.

Eosinophilia is quite characteristic and usually ranges from 15 to 35% of the leucocytes. Eosinophilia tends to disappear as the cases become advanced.

The spleen and liver very rarely give rise to any symptoms and while albuminuria is rather common in advanced cases with oedema about the feet, yet casts are but rarely found.

The signs of a multiple neuritis should differentiate beriberi, and the presence of casts or high blood pressure, chronic nephritis. Recently, there has been a great deal written about the danger of confusing hookworm disease and malarial cachexia, the statement being often made that splenic enlargement is a feature of ancylostomiasis. Most authorities, however, state that the spleen of ancylostomiasis is not enlarged, this point being of diagnostic value in differentiating it from malaria and kala-azar.

Formed stools are more satisfactory for examination than the liquid ones resulting from a dose of salts. Put about 2 drops of water or 1% trikresol solution in the centre of a glass slide and emulsify in it as much of the faeces as is held by the spatulate end of a wooden toothpick. A small piece of wood or a match stick will answer. These preparations can be readily examined without a cover-glass, using a ⅔ inch objective, with a 1-inch ocular.

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Cultural methods give a higher percentage of success than looking for ova in the stools. Put a pile of 2 inch filter papers in the center of a Petri dish. Fill the dish with water to the level of the paper island. Smear a thick layer of faeces on the paper. The larvae hatch out and can be found by centrifuging the water.

It is usually stated that about 500 worms must be present for several months to produce symptoms. Grassi has thought that the presence of 150 eggs in 0.01 gm. faeces indicates the presence of 1,000 worms, of which 25% would be males.

There may be as many as 4,000,000 eggs in a stool. Bass has proposed the following method for the examination of faeces for ova: The faeces, which have been made fluid, should be centrifuged and the supernatant fluid containing vegetable débris poured off. The sediment contains hookworm eggs. Then pour on sediment a calcium chloride solution of sp. gr. 1.050. Again centrifuge and decant. Next add calcium chloride solution of a sp. gr. of 1.250 and centrifuge. This brings to the surface the hookworm eggs which may be pipetted off. As a rule, the finding of hookworm eggs is very easy without such a technique.

Recently we have been using Barber’s technique. Emulsify the faeces in equal parts of glycerine and saturated salt solution on a slide. The eggs rise to the surface and are easily discovered with the ⅔-inch objective. As a centrifuge method, Barber emulsifies faeces in this same mixture which brings the eggs to the surface. A wisp of cotton is placed on the surface and 3 or 4 drops of melted agar dropped on the cotton. The disc of agar is removed with the cotton, deposited on a slide and examined for entangled eggs. With operculated eggs this method does not seem to be satisfactory as the salt solution loosens the operculum and floods the contents of the shell,—thus altering the specific gravity of the egg and preventing flotation.

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Lane Levitation Method.—Clayton Lane recommends a technique which he designates as the levitation method. In this procedure the concentrated sediment of a centrifuged specimen is transferred to a glass slide, where it is mixed with one cc. of water. The slide is allowed to stand for five minutes and is then immersed in water and manipulated until all coarse matter has floated free. The hookworm ova stick firmly to the slide and are not washed away. Lane reports that on an average this method results in a ten-fold concentration of ova.

In certain cases, where a microscope is not available, the diagnosis may be made by finding the worms in the stool following a thymol treatment.

Whyte has recommended the phenolphthalein test for occult blood as of value in determining the cure of ancylostomiasis. This test is so delicate that the least trace of blood from the mucosal lesion will be detected.

Charcot-Leyden crystals are often present in hookworm stools.

The presence of eosinophilia is of good prognostic significance as the absence of eosinophiles indicates an exhaustion of the haemopoietic system.

The disease shortens the life of the people in an infected district and makes them readily fall victims to intercurrent diseases. Various statistics give the mortality as from less than one-half of 1% to figures approximating 7%.

The use of some type of properly constructed privy is essential as there is nothing more favorable to the development of the hookworm larvae from eggs to infecting stage than the practice of defecating on the ground where conditions of porous, sandy soil, shade and moisture exist. Later on, such a spot teems with infecting larvae and the person stepping there with bare feet is almost sure to become infected. For this[332] reason the wearing of shoes is an important prophylactic measure. At the same time shoes are not a sure protection, as Ashford has noted infections in soldiers who wore good shoes. The fecal material, collected in a pail or tub, should preferably be burned or boiled. Otherwise it should be buried not less than 300 feet from the water supply and down hill from the same.

The use of an amount of compound cresol solution equaling the fecal mass, plus urine, is of value.

Hookworm disease tends to disappear in towns or cities where there is an efficient sewerage system.

Some authors think Ancylostoma more difficult to expel than Necator.

It is usual to prescribe the drug in 5-grain capsules or preferably in cachets, one part of thymol being triturated with an equal amount of sugar of milk. If the cachet is moistened with a little water it may be swallowed like a raw oyster.

Stiles prefers giving the treatment on Sunday so that the working days of the patient may not be lessened. By giving the patient bicarbonate of soda for a few days before the treatment it is thought that the mucus lining of the jejunum is cleared away so that the worms are more readily affected by the drug. At any rate one should give about 1 or 2 ounces of a 50% solution of Epsom salts on Saturday evening. Sodium sulphate is preferred by some.

The following morning at 6 A.M. the patient takes one-half the dose of thymol proper for his age and at 8 A.M. he takes the remaining half of the dose. At 10 A.M. he takes another dose of Epsom salts. The reason for dividing the dose of thymol is that should untoward symptoms occur after the first portion of the dose we do not give the second. Stiles now prefers to divide his dose into three portions, one to be given at 6 A.M., one at 7 A.M. and the remaining third portion at 8 A.M., followed by salts at 10 A.M. The patient should lie on the right side while taking the treatment to facilitate the passage of the drug from the often dilated stomach.

The patient should remain in bed until 12 o’clock when he may take some coffee, without milk, and crackers.

Seidell has shown that about one-third of the thymol dosage is excreted in the urine and very little by faeces. This shows absorption of the drug. It is thought some of the drug may be excreted by the lungs. Congestion of the lungs has been reported in fatal cases of thymol poisoning.

Mild symptoms of poisoning are burning in the pit of the stomach and tingling sensations of the body. More severe symptoms are those associated with cardiac weakness and respiratory distress. Coffee and strychnine are the usual remedies for thymol poisoning. Inhalation, but not swallowing, of aromatic spirits of ammonia is often of value.

The thymol dosage recommended according to the age, or rather the apparent age of the patient, is:

Total dose to be divided into 2 or 3 portions. The patient is allowed to eat only a light luncheon and supper the day of the treatment but the next day he may resume his regular meals.

As a rule most of the worms expelled by the treatment will have been passed by night of the day of treatment, although an occasional one may be passed for four or five days.

Thymol and Beta-naphthol.—Nicol in a comparison of the efficacy of various drugs, noted that thymol in 90-grain doses, taken in 3 portions of 30 grains each, at 6, 8, and 10 A.M. expelled 98% of the worms at the first treatment and the remaining worms at the second treatment a week later. With this rather large dose he frequently observed a tendency to syncope. He used Epsom salts as a purgative.

On the other hand, while using 60 grains of beta-naphthol, given in two portions at 6 and 8 A.M., followed by salts, 86% of the worms were expelled at the first treatment and 14% with the second one. He did not observe any bad effects from beta-naphthol.

The great objection to beta-naphthol is that it is a renal irritant and may damage a kidney already diseased.

[334]

Nicol found the treatment with eucalyptus oil, 2 cc., chloroform, 3 cc. and castor oil, 30 cc. vastly inferior in anthelminthic effect to the other two treatments and liable to cause severe manifestations of nausea and syncope.

It is better to divide the dose as just stated into two portions, the second half to be given about one-half hour after the first portion. This reduces the danger from the chloroform.

Schüffner tried male fern and only obtained 7 hookworms while the next day, using thymol, 1253 hookworms were expelled. He notes that thymol is dangerous when administered to patients with acute or subacute dysentery.

In Brazil a tabloid of 5 grains beta-naphthol combined with 1 grain of phenolphthalein has been generally employed. Using phenolphthalein in this way enables them to dispense with purgation.

The low diet and preliminary dose of salts, as noted under thymol treatment, are to be recommended although the commission found various purges to have little effect on the results of treatment. At 11 o’clock give a purgative dose of magnesium sulphate.

The maximum dose of oil of chenopodium is usually given as 3 cc. but a number of deaths have followed the administration of doses of from 2 to 3 cc., so that it is better to keep within 1.5 cc.

After effects of treatment, such as dizziness, depression, unsteady gait, partial loss of consciousness, tingling of hands and feet, burning sensation in the epigastric region and nausea are more frequent with chenopodium than following thymol. The toxic symptoms may be greatly delayed and even be postponed for a day or so. A large dose of castor oil seems to be the most important measure in treating a case of chenopodium poisoning. The same methods of stimulation as noted under thymol poisoning are also indicated.

Kantor has treated a large number of cases with oil of chenopodium administered through the duodenal tube. After the bucket had passed the pylorus he introduced into the duodenum about 2 cc. of oil of chenopodium and followed this in six minutes with two (2) ounces of a warm saturated solution of magnesium sulphate. The tube is withdrawn after introducing the salts. Several copious watery stools follow in a short time.

Carbon tetrachloride in a dose of 3 cc. administered in hard gelatine capsules, is recommended by Hall for the removal of hookworms and ascarids. The drug is[335] cheaper, more effective, and, when chemically pure, safer than thymol or chenopodium. It does not depress unstriated musculature or lessen peristalsis, thus eliminating the use of purgatives, which is an item of expense in extensive hookworm campaigns. The drug is of no value in treatment of tapeworms and is as unreliable as other anthelminthics for the removal of whip-worms.

In the treatment of ground itch the usual application is a zinc oxide ointment containing 10 grains of salicylic acid to the ounce.

Barlow recommends a 3% salicylic acid solution in alcohol.

It has been proposed to designate the filarial embryo by the term microfilaria, reserving the generic name Filaria for the adult parasite. This may be convenient for differentiation but zoölogical nomenclature does not permit different names for adults and embryos. While there have been almost 20 different filarial species reported for man there is, in some instances, doubt as to the correctness of the observation, and again, a well recognized species has at times been considered as a new species and given a new name.

Various well-known conditions are caused by this parasite, such as elephantiasis, varicose groin glands, chyluria, etc. This infection was formerly stated to be caused by Filaria sanguinis hominis.

Calabar swellings, irregular febrile conditions and the disagreeable sensations incident to the wanderings of the worm are clinical features of this infection.

The sheathless embryos have been surely found only within these tumors and not in the blood.

The adult is found in the retroperitoneal connective tissue or fat, while the sheathless, blunt-tailed embryo is found in the blood, both by day and night, hence perstans. The adult forms are found in the tissues behind the abdominal aorta and at the attachment of the mesentery.

An unimportant filarial worm which has been found only in the West Indies and British Guiana is known as Filaria demarquayi or F. ozzardi. The embryos have sharp tails and are without a sheath. The parasite is not known to produce symptoms.

The thickenings due to leprosy and those connected with filariasis were separated clinically by observers during the 17th and 18th centuries, Hilary, in 1750, having accurately described the progress of that form of elephantiasis connected with elephantoid fever and lymphangitis. In 1863 Demarquay discovered filarial embryos in the exudate of a chylous hydrocele and three years later Wucherer, in Brazil, found similar nematode larvae in the urine of a case of haematochyluria. Commencing with the year 1863 Lewis carried on a series of investigations in Calcutta in which he found these embryos not only in the urine of patients with chyluria but as well in the lymph and blood of those affected with elephantiasis. He called the parasite Filaria sanguinis hominis, a name still frequently employed by medical writers.

In 1876 Bancroft, in Australia, discovered the adult filarial worms in a lymphatic abscess, hence the name Filaria bancrofti. In 1878 Manson, in China, demonstrated the mosquito transmission of the disease as well as the phenomenon of nocturnal[340] periodicity. Manson’s idea, however, was that the fully developed embryo escaped from the body of the infected mosquito at the time of the death of the insect and that man contracted the infection in drinking water.

In 1891 Manson noted the presence of the larval forms which showed a diurnal periodicity in the peripheral blood.

The prevalence of dracontiasis, as the infection is generally termed, in Arabia, was well known to the Greeks and Romans.

Fedschenko, in 1870, noted the transmission of the disease by species of Cyclops.

Daniels also found these embryos, along with those of F. demarquayi, in the blood of natives of British Guiana.

It is especially in some of the Pacific islands, as Samoa and Fiji, that it is extraordinarily prevalent. Bahr has stated that Fijians in the proportion of 27% show filarial embryos in their blood. In 25% of these natives clinical manifestations of the disease exist but the embryos are absent from the peripheral circulation. In other words more than one-half of the population show absolute evidence of infection.

The following developmental cycle has been demonstrated for Culex fatigans and Stegomyia pseudoscutellaris. Bahr has found that if there are too many embryos taken up by the mosquito the insect is apt to die, as the result of too heavy an infection; so that a person harboring many filarial embryos may be less dangerous than one with a smaller number. Upon reaching the stomach of the mosquito the sheath of the embryo becomes fixed in the viscid blood contents and the embryo itself by active motions is able to force itself from its sheath. This escape usually occurs within two hours but may take longer. The free embryo then bores its way through the stomach walls and within twenty-four hours has reached the thoracic muscles of the mosquito. Within forty-eight hours the embryo begins to broaden and the anterior and posterior V spots to become more prominent. About the end of the first week there commences the formation of an alimentary canal, by which time the developing larva is about 0.5 mm. long. When the larva is about 0.6 mm. long an ecdysis apparently takes place. Later on these larvae develop 3 or 4 terminal papillae and make their way to the fleshy labium of the mosquito’s proboscis. An occasional larva may enter other structures than the labium but in such case they would be unable to effect an entrance to their definitive host, man. These larvae in the proboscis are about 1.5 mm. long and about 20 microns broad.

The mosquitoes have two terminal processes, the labella, separated from the labium by a thin membranous partition called Dutton’s membrane. The larvae,[343] having completed their developmental cycle in the mosquito, which takes about three weeks, and moving down the labium, break through this membrane when it is put upon a stretch by the wide separation of the labella at the time of feeding on the part of the mosquito. It was formerly supposed that the larvae entered man through the puncture made by the biting parts of the mosquito, but Bahr has shown by experiments that they effect an entrance through the intact pores of the skin as does the ancylostome larva.

The sheath is simply the egg membrane which from being oval at first becomes stretched by the developing embryo to finally become a long, narrow sac encasing the fully developed embryo as it exists in man. From the lymph stream they reach the general circulation. In a case of a man with filarial embryos in his peripheral circulation, who committed suicide one morning, Manson found the embryos, in large part, contained in the vessels of the lungs. There were 675 embryos per slide in blood from the lungs for one from blood from the spleen or liver. It would thus appear that during the day, when the embryos are absent from the peripheral circulation, they retire to the lungs. In the case of the filarial embryo of persons in the Pacific Islands there does not appear to exist any periodicity. Bahr thinks this absence of nocturnal periodicity to be connected with the habits of its principal intermediary host, Stegomyia pseudoscutellaris, which feeds by day. Culex fatigans feeds at night.

With the filarial embryos found in patients in the Philippines there is also a lack of nocturnal periodicity. In the opinion of Ashburn and Craig the Philippine filarial worm is a new species, Filaria philippinensis.

Walker, however, recently examined four adult filarial worms in the Philippines and was unable to note any differences from F. bancrofti.

Bahr notes the influence of adult filariae in producing an increase in connective tissue in glands and considers such glands as less resistant to bacterial infection.

It has often been claimed that various cocci were the exciting factors in the lymphangitis associated with filariasis. Recently Dutcher has reported the isolation of an organism resembling B. subtilis as the cause of filarial lymphangitis (Bacillus lymphangiticus).

As the result of the lymphangitis and blocking of the channels the embryos cannot reach the peripheral circulation; hence when obstruction does occur and symptoms of lymph stasis appear, there may be an absence of embryos in the circulation.

These lymph channel obstructions may at one time cause dilatations or varices and at another bring about solid oedemas of the tributary parts. The treatment will be considered under each special form of the disease. It may be stated however that salvarsan, arsenophenylglycin and other similar remedies have been without special effect in destroying the filarial worms.

Johnson, in examining 400 people, in Charleston, S. C., found 19% with filarial embryos, yet only 5% showed any symptoms of filariasis. Croll states that 11.5% of 4000 Europeans admitted to the Brisbane Hospital (Australia) showed filarial infection but practically none had symptoms. In South Queensland cases of lymphangitis, chyluria and varicose groin glands are occasionally seen and rather frequently hydrocele and filarial abscesses. There is an absence of elephantiasis.

Thus in Barbadoes, where there is no malaria, a condition in which there occurs a high fever of sudden onset with rigors and associated erysipelatous redness of leg or scrotum, accompanied by lymphangitis and painful lymphatic glands, has given a suggestion of a malarial paroxysm. The tense inflamed area, after several days, shows an exudation of lymph and the redness disappears, but with some resulting thickening of the affected tissues. Such attacks may terminate with profuse sweating.

Ordinarily local applications with suspension of the scrotum is the proper treatment. Should the thickening increase to a great extent the blubbery tissues may be excised, care being exercised to avoid the testicles and to bring together sound tissue for the enclosing flaps. These wounds usually heal readily, although there may be delay in healing from the outpouring of lymph in cases where the flaps include diseased tissue.

If such glands are punctured with a hypodermic needle lymph, which may contain embryos, exudes. This test together with their slow disappearance on lying down and slow return on assuming the upright position should differentiate hernia. When the contents of a hernial sac are omental there is some difficulty in diagnosis. As a rule it is not advisable to interfere surgically in this filarial condition.

As regards location, these filarial abscesses were found 31 times in the pelvis of the kidney, 18 times in the epididymis, 12 times in the retro-peritoneal tissues, 25 times in the inguinal glands, 4 times in the ilio-psoas muscles and 8 times in the lymphatic vessels.

They regard the endemic funiculitis to which attention has been directed by Castellani as simply a similar process involving the tissues about the spermatic cord. The treatment of filarial abscesses is similar to that of other abscesses.

Chylous urine coagulates rapidly and we have in such a specimen of urine, upon standing, an upper fatty layer and pinkish sediment at the bottom, with a clot between.

The sediment shows lymphocytes and at times filarial embryos. When the exudate is lymph mixed with blood the term haematolymphuria would be a better one.

Clots may form in the bladder and give rise to obstruction to the flow of urine from the bladder.

The appearance of the chyluria is often preceded by heaviness about the loins and pains in the region of the bladder.

The morning urine in such a case is apt to be clear while that passed later in the day is milky in appearance.

A feature of chyluria is its tendency to disappear and reappear so that when treating such a case one should be conservative in considering the treatment as effecting a cure.

It is difficult to understand why chyluria should be common in India and China while almost unknown in the filarial infections of the Pacific islands.

In treating a case of chyluria one should enjoin rest in bed, laxatives and a restriction of fluids and fats. Patients subject to the condition should refrain from active exercise and other conditions which might cause fatigue. Drugs are of little value.

On account of the lymphatic stasis incision into the blubbery tissue causes the outpouring of much lymph.

Elephantiasis of the lower extremities is by far the most common situation, giving us probably 90% of such affections. In Fiji elephantiasis of the upper extremities is quite common.

Other favorite sites are the scrotum, vulva, breasts and penis. Rarely the scalp or areas about neck or trunk may show involvement.

Surgical treatment is the one usually followed. When an extremity becomes too much of a burden, amputation may be indicated. The employment of the method of lymphangioplasty, which consists in the introduction of silk threads into the subcutaneous tissues, to make a channel to the normal lymphatics, does not seem to have been attended with any degree of success or at any rate permanent results. These wounds tend to become infected and if this does not occur the new channels are speedily obliterated.

In considering the advantages of operation in elephantiasis of the scrotum it is usually stated that the only question involved is the removal of a burdensome mass which in no way is a source of danger to the life of the patient. At the same time such patients are subject to attacks of elephantoid fever, a condition not without its dangers. There is one factor not usually brought forward and that is the remarkable effect of a successful operation on the mental state of the patient. This is well shown in the accompanying illustrations of the patient before and after[349] operation. If sexual deficiencies are of so powerful an influence on persons of education how much greater must they weigh on an uneducated native with but few of the higher interests of life.

Prior to operation the patient should be kept in bed for a day or so to lessen the amount of fluid and to secure relaxation of tissues. Thorough scrubbing with soap and water the day of and the day before the operation and the use of alcohol as an antiseptic are important. Some prefer iodine.

For the operation the lithotomy position is employed. An assistant supports the scrotal tumor wrapped in a sterile towel. Fauntleroy, whose method I give, does not recommend a tourniquet to the base of the tumor as in his opinion it assists but little in controlling haemorrhage and endangers asepsis. Haemostats answer better and as the vessels which give most trouble are deeply situated the elastic cord would not affect them. In some cases there is very little bleeding. The upper part of the[350] pear-shaped tumor usually affords sufficient sound skin next the thighs for the flaps. As a rule the elephantoid tissue does not involve the upper 2 or 3 inches of the skin anteriorly, which is thus available to cover in the base of the penis. In addition to this covering for the penis we have a long prepuce which has been considerably stretched so that after removing all elephantoid tissue there is enough sound prepuce remaining to cover the distal 2 or 3 inches, so that usually there is sufficient sound skin for a 5-inch penis.

The flaps which are to cover the penis and testicles should be mapped out with shallow incisions and care must be exercised that only sound skin is included in these flaps. A horseshoe shaped incision is made commencing at the left side of the base of the tumor about 1 inch from the thigh and about at the level of the penis in health. The incision is carried downward and passes just below the opening of the penis on[351] the tumor surface. A similar incision on the right side completes the horseshoe curve. Next a downward incision in the sound skin is made over the posterior surface of the tumor, thus encircling the base of the scrotum. The anterior horseshoe incision is now deepened to free the penis, care being taken not to injure the spermatic cord. Next the incisions are deepened laterally until the testicles are reached. The testicles are usually in the center of the tumor imbedded in a blubbery tissue from which they can be easily stripped. The remains of the gubernacula are then hooked up and cut close to the testicles. The tunicae vaginales are often thickened and contain fluid which has to be drawn off.

In 60% of Fauntleroy’s cases it was necessary to remove one testicle on account of extensive disease. One must also bear in mind the possibility of hernial complications and undescended testicle.

A sound is now introduced into the urethra and the septum of the scrotum divided close to the sheath of the penis, then dissecting away the blubbery tissue. At this stage there may be considerable bleeding.

The testicles and spermatic cords are then dissected away from the tunicae vaginales. The penis is now freed by a circular incision around and above the opening in the anterior part of the mass. The remainder of the horseshoe flap is now dissected up and the penis freed. The proximal covering for the penis is made from this horseshoe flap which is stitched to the distal one shaped from the prepuce, carefully trimmed of elephantoid tissue.

The lateral flaps are brought together with linen or silk-worm gut sutures leaving space for a drainage tube and we thus form a new scrotum for the testicles.

The mortality is usually given as 5% but Fauntleroy did not lose a case among 149 such operations, the tumors varying from 10 to 85 pounds in weight.

Besides chylous hydrocele we may have a chylous ascites or a chylous diarrhoea. Where there is no obstruction to the thoracic duct there is less fat and the condition is more properly a lymphocele rather than a chylocele. The same distinction is applicable to the other conditions connected with lymphatic varices due to lymphatic obstructions other than that of the thoracic duct.

Smear preparations may be made by the Ehrlich method of drawing cover glasses apart or by the Daniels method on slides. Some prefer making a thick smear of a drop of blood and, after it has dried, carefully to dehaemoglobinize it with water and then staining with dilute haemotoxylin. Staining with Leishman’s or Wright’s stain gives beautiful pictures. Fixation with methyl alcohol or with heat, by burning off a film of alcohol, and then staining with Giemsa’s stain or some haematoxylin preparation, is to be recommended. On the whole I consider haematoxylin the most desirable staining reagent, as such preparations hold their color for a long time. The paper-like sheaths are seen as if twisted about the larvae with their violet-stained cells. One should note a break in the violet-stained cell column which is 50µ from the head end of F. bancrofti and 40µ for L. loa.

A V spot is seen posterior to the break in the cell column and shows best with very light staining.

Ruge’s thick film method for malarial parasites gives excellent results in staining filarial embryos. Either the Giemsa or haemotoxylin staining may be employed.

Embryos may be found in the lymph from varicose groin glands or in the exudate from a chylous hydrocele, as well as in the urinary sediment from a case of chyluria.

Adult filariae, either alive or dead and calcified, may be found in the lymphatic glands or in the contents of filarial abscesses.

The blood shows an eosinophilia.

As noted in the table previously given, the adults which are a little more than an inch long have cuticular protuberances or bosses, about 12 to 15 microns in height. The sheathed embryo is very similar to that of F. bancrofti, but has a more twisted tail and shows a complete filling up of the tail end with rather elongated cells. The lines of the curves of the embryo show irregularities and are not the smooth lines characteristic of F. bancrofti embryos.

Leiper has reported two species of Chrysops, one of the tabanid biting flies, as transmitting agents and considers that the embryos undergo development in the salivary glands of the fly.

The life history is not well understood but as a rule a period of several years elapses after infection before adult filariae or filarial embryos are found. Again, for some reason, adult filariae may be noted and when extracted be found full of embryos and yet embryos not be found in the peripheral circulation.

The adults are noted for their tendency to move about in the subcutaneous connective tissues having been found in such tissues in the region of scalp, trunk, penis and extremities.

Most frequently, however, they are noted in the tissues about the region of the eyes and even under the conjunctivae, from which location they have been frequently extracted. It is this which has caused the name Filaria oculi to be given the worm.

As a rule the appearance of the worms in the subcutaneous tissues is characterized by itching sensations and a feeling of tension. Warmth causes them to appear in the superficial tissues while cold makes them confine themselves to the deeper structures. Eosinophilia is rather pronounced.

Rarely does one note more than one swelling at a time. Eosinophilia is quite marked during the attacks. Manson thinks the oedema results from the extrusion of embryos from the female at the site of the swelling. Ward considers the cause to be toxic material excreted by the worm.

There is very little of importance in connection with treatment. When the worms, which travel in the tissues about the eye, at the rate of about ½ inch per minute, are noted, some local anaesthetic may be used and the worm seized with forceps and extracted through a small incision. Elliot recommends the application of hot fomentations to the eye and upon the appearance of the worm under the conjunctiva to instill cocaine solution, seize the worm with forceps and then pass a silk ligature through the conjunctival fold taking in the worm. The ligature is tied and an incision made through which the worm is extracted. Cooling local applications, or an ichthyol ointment, may be applied to the Calabar swellings.

It is supposed that the adult worms cause an inflammation of the lymphatic vessel in which they may lie and that a formation of new connective tissue results, giving rise to a tumor-like mass, which is most often found in the axilla or about[355] the sides of the thorax. This tissue stroma encompasses the worms except for the anterior extremity of the female, with its uterine opening, and the posterior extremity of the male carrying the spicules, which ends lie loose in a sort of cyst-like dilatation, which is filled with a viscid fluid swarming with unsheathed embryos. These tumor-like masses cause very little discomfort, last indefinitely and do not tend to ulcerate.

The cysts are usually found on the sides of the chest and are quite superficial, with the skin freely movable over them. They may be as large as a hen’s egg but usually are smaller. They are also found over trochanters or along the crests of the ilium.

The tumors are easily enucleated.

In the American infections the tumours are more common in the regions near the eye and it has been thought that certain cases of keratitis may be due to onchocerciasis.

Life History.—The male has not surely been seen in man so that the pathological condition is entirely connected with the female worm. Almost invariably the female worm, which measures about two feet long by 1/12 inch broad, tends to wander down to the connective tissue structures of the lower extremity. In about 10% of the cases the worm may present elsewhere, as scrotum, back or arms. At the posterior extremity there is a sort of anchoring hook.

With the anterior extremity the worm presses against the overlying skin and causes the formation of a blister-like lesion.

This vesicle later on bursts and, if water is applied to the spot, a delicate tube, the uterus, is extruded and there exude a few drops of a milky fluid, which swarms with the sharp-tailed, striated, sheathless embryos. It is thought that the pouring forth of embryos, when water touches the part, is in order that the embryos may reach the water of a pool through which the infected native may be wading. Once[356] in the water of such a pool, the larvae are swallowed by Cyclops and gaining the body cavity of this little crustacean, they continue to develop for about one month.

During this period there are two ecdyses, the first after about two weeks, when the tail becomes blunt.

Usually there are no other symptoms than discomfort from the blister and a feeling of heaviness about the affected extremity. At times there may be pain and fever. The parasite may fail to gain exit to the skin surface or die before reaching maturity. In such cases she may become calcified or give rise to abscess formation. The x-ray plate may show a convoluted cord-like structure with frequent breaks in the line.

These cercariae show an absence of a pharynx and upon the rupturing of the sporocyst are discharged from the mollusc and furnish the infecting stage for penetrating the skin of man or other animal.

It is probable that the earlier stages of development take place in the portal vein and that having reached maturity the female attaches herself to the male and together they go, by way of the inferior mesenteric vein, to the haemorrhoidal or vesical terminals. The male is in the shape of a narrow leaf, about ½ inch long with a ventrally turned oral sucker and a closely adjacent ventral sucker. The[358] female is a somewhat longer and cylindrical worm almost an inch in length and, like the male, has two suckers. There is a dark brown zig-zag stripe which shows prominently in the posterior part of the female and outlines the blood-filled intestinal tract. When the female applies herself to the ventral surface of the male there is an infolding of the sides of the flattened surface giving the male a cylindrical outline and resulting in the formation of a canal containing the female (gynaecophoric canal).

Both suckers are larger than those of the other species.

The eggs of S. haematobium have a terminal spine and measure from 115 to 175 by 60 microns; those of S. mansoni have a lateral spine and measure from 110 to 125 by 50 microns while those of S. japonicum are devoid of spinous projections and measure about 100 by 70 microns.

Looss claims that the two tuberculated species are identical and that the lateral spined egg is the product of an unfertilized female. He has more recently regarded the egg as produced parthenogenetically. Other helminthologists have noted slight anatomical differences as to ovaries and testicles so that the consensus of opinion is that vesical and rectal bilharziases are caused by different species of the genus Schistosoma.

It would therefore seem proven that all human schistosome infections take place following cercarial and not miracidial development. As proof that S. haematobium and S. mansoni are different species, Leiper notes that mice infected by molluscs of the genus Bullinus showed schistosomes with terminal spined eggs, the ovary lying in the lower half of the female. The male had four or five large testes. In mice infected by molluscs of the genus Planorbis, the eggs were lateral spined, the ovary was in the anterior half of the body and the male had eight small testicles.

The mollusc host of S. japonicum is Blanfordia nosophora. The shell of this snail is of cornucopia shape.

The French troops suffered greatly from the disease in 1800. It was Bilharz in Cairo, in 1851, who first associated the haematuria with the presence of the parasite and it is from his name that we get the designation bilharziasis or bilharziosis for the disease.

In 1903, Manson found lateral spined eggs in a patient from the West Indies who was suffering from rectal rather than bladder symptoms. In 1907 Sambon, considering the points of difference between the eggs and the involvement of rectum rather than bladder, established a new species, S. mansoni.

In the West Indies, as shown by the reports of Surgeon Holcomb from Porto Rico, rectal bilharziasis is rather common.

For a number of years Japanese physicians had noted the existence of a disease characterized by splenic and hepatic enlargement, ascites and cachexia. In August, 1904, Katsurada discovered ova with a ciliated embryo in the stools of patients with this disease. He found schistosomes in the portal vessels of dogs and cats containing eggs similar to those seen in the human cases. He named this trematode S. japonicum. In November, 1904, Catto discovered the parasite at an autopsy on a Chinaman. In 1910 Lambert, in China, described a disease, which he called urticarial fever, and a short time afterward Houghton established the connection between this disease and the more advanced stages of Japanese schistosomiasis.

In the bladder these terminal spined eggs cause haematuria and form the nucleus for vesical calculi. The mucosa may also show wart-like excrescences. If the eggs are swept back through the portal vessels to the liver an interlobular cirrhosis results which would seem to be due entirely to the irritation of these egg emboli and not to toxic products of the worms themselves. Marked ureteral and kidney lesions may result as complications of cystitis or primarily from irritation by ova. In women the vagina, vulva and cervix uteri may show papillomatous thickenings. Bilharzial lesions of the male urethra are not uncommon and may lead to fibroid thickenings and fistula.

In searching for the flukes at autopsy we should make a longitudinal slit in the portal vein and with a spoon scoop out the blood and search for the parasites in a glass dish.

The connective tissue increase is in the submucosa. The gut section may also present small abscess-like areas.

Eggs have been found in the appendix as well as in the large intestines and the small intestine has been found involved in one case. In rare instances ova have been found in the lungs, spleen and even in the brain and spinal cord.

By digesting selected tissues in 4% NaOH at 75°C. and centrifuging one may find eggs which otherwise would be overlooked. Statistics from Cairo usually note 30 to 40% of infection in natives but Ferguson employing all methods found 61% infected at autopsies on 600 males. In all forms of schistosomiasis but particularly in the Japanese infection, eosinophilia is pronounced.

Symptoms of cystitis and even pyelitis may follow the early bladder and urethral manifestations. Pain in the back or symptoms suggesting renal colic may be present. Anaemia and physical weakness gradually develop. An important sequel is vesical calculus. It is a question whether the eggs or some other product of the infection form the nucleus of such a stone. Not only can stone be recognized[364] by cystoscopy but rather distinctive are small, glazed yellowish nodules with areas of granulation tissue. Papillomatous growths may also be seen upon cystoscopy.

Perineal fistulae in the male and vaginitis in the female may be noted.

When reinfection does not occur the haematuria tends slowly to disappear but recovery does not usually take place for several years. The vesical schistosome (S. haematobium) often causes pathological changes in the rectum so that a case may show both vesical and rectal symptoms. The rectal schistosome (S. mansoni) does not give rise to vesical trouble.

Most writers fail to mention other than the later manifestations of rectal bilharziasis, the earlier symptoms being overlooked or attributed to other causes. The same was true of Japanese schistosomiasis in which the initial “urticarial fever” was only recognized as connected with the late manifestations of liver cirrhosis and ascites a few years ago.

In 1916 Lawton noted in a number of Australian soldiers, encamped in Egypt, a fever of about 7 to 10 days’ duration in which the evening rise approximated 103°F. A diarrhoea and abdominal pain accompanied the fever and along with this a cough and patchy consolidation. Most of the cases showed urticaria which lasted from one to seven days. All cases showed a well marked eosinophilia. The diagnosis, but frequently only after prolonged and continued search, was made by the finding of the lateral spined eggs of S. mansoni. The period of incubation in these cases seemed to be from one to three months.

Laning, in a study of 7 well-controlled cases, has shown that the disease sets in after two or three days from the time of exposure to infection, by wading through[365] paddy fields or still waters of infected ponds or lakes. The disease occurs in China, Japan and possibly in the Philippine Islands.

In the 1st stage we have headache and an evening rise of temperature to about 101°F. or 102°F. Shortly after the onset urticarial lesions, which may be 2 or 3 inches in diameter, may appear and disappear on various parts of the body.

The bladder never seems to be involved in Japanese schistosomiasis. The eggs, however may be carried to the brain and produce symptoms of Jacksonian epilepsy.

The eosinophilia is of great diagnostic value and is usually associated with an increase in the leucocyte count.

Fairley has introduced a complement fixation reaction in diagnosis, using an extract of the livers of infected snails as antigen. The reaction appears early in the infection but disappears in the later stages. It is a group reaction as the livers of Bullinus answer for the S. mansoni serum as well as for the specific S. haematobium serum.

Then, too, if a water which does not contain fresh water snails is stored for three or four days the cercariae which might have been present in the freshly pumped up water will have died out, such free cercariae only surviving for about this period. The gastric juice will destroy cercariae so that it would seem impossible for an infection to occur by the alimentary tract atrium with the exception that cercariae might bore their way through the buccal mucosa as well as through the skin. The sterilization of the urine of cases of vesical bilharziasis and of the faeces in other forms should be carried out where practicable. It is now considered practicable to eradicate carriers of the infection with antimony treatment.

Of various treatments, having in view the destruction of the worm, such as salvarsan, etc., none seem to have been of any value except antimony.

Robertson has reported relief of symptoms from the administration of 2 grains of thymol dissolved in half a drachm of benzine. The treatment is continued for a few weeks. Others have not had good results from this treatment. Local treatment is necessary in treating the cystitis and prolapse of rectum. Operative procedures are indicated where calculi exist.

Arce has recently reported cases of paragonomiasis in three Peruvians who had been in contact with Japanese immigrants.

In 1880, Baelz found the ova in the sputum of a case of haemoptysis in a Japanese, as did also Manson in a Chinaman. Manson’s case subsequently died and when autopsied showed in his lungs a fluke which was responsible for the eggs seen by Manson. The fluke itself is a little more than ⅓ of an inch (8 mm.) long and is almost round on transverse section, there being, however, some flattening of the ventral surface. The acetabulum is conspicuous and opens just anterior to the middle of the ventral surface.

The branched testicles are posterior to the laterally placed uterus and the genital pore opens below the acetabulum. The branched ovary is opposite the uterus on the other side.

It is rather flesh-like in appearance and is covered with scale-like spines. The flukes are usually found in tunnels in the lungs, the walls of which are thickened connective tissue. These tunnels result from hypertrophy of the bronchioles. There may be also cysts formed from the breaking down of adjacent tunnel walls. In addition to lung infection with this fluke, brain, liver and intestinal infections may be found.

Nakagawa has found that the miracidia infest certain fresh water molluscs and become cercariae in this first intermediate host. From this host the cercariae go to certain fresh water crabs and encyst in this second intermediate host, either in the liver or in the gills. In Japan one of these crab hosts, Potamon dehaanii, is eaten both raw and cooked.

Experimental feeding of puppies on infected crabs brought about infection with the lung fluke. It is thought that the fluke, after leaving the cyst, goes through the intestine to the abdominal cavity. Thence it perforates the diaphragm and enters the pleural cavity, finally penetrating the lung to become encysted there. The lung is the favorite site but wandering flukes may invade other tissues and organs even invading the central nervous system.

Besides man, dogs, cats and especially hogs may be infected.

The course of the disease is very chronic, often lasting many years. As a rule the patient is fairly well nourished although recurring attacks of haemoptysis may[371] bring on a rather marked anaemia. Jacksonian epilepsy has been reported as occurring in paragonomiasis, the ova being found in cysts of the brain. There is some question as to whether some of the reports as to paragonomiasis may not have been connected with infections with Japanese schistosomiasis.

Clonorchis infections are common in China and Japan, the fluke being about ½ inch long by ⅛ inch wide. There is considerable dispute as to whether we have a pathogenic and nonpathogenic Clonorchis; the name C. endemicus applying to the former and C. sinensis to the latter.

Looss considered the nonpathogenic C. sinensis to be larger (13-19 mm.), to show pigment in its parenchyma and to have breaks in the vitelline glands. C. endemicus was reported as smaller (10 to 13 mm.), and without pigment or breaks in the continuity of the vitellaria.

The eggs of this fluke show slightly concave bending of the sides at the operculated end and are about 30 × 16 microns. These flukes are found within the thickened bile ducts and may be present in great numbers. They may invade the pancreas as well as the liver.

These flukes are found in dogs and cats as well as man.

The course of the disease is insidious and chronic with periodic improvement.

Kobayashi has examined various molluscs and fish for trematode larvae. He succeeded in infecting nine kittens and two cats by feeding them with certain fresh water fishes whose flesh contained trematode larvae. These fishes were found in districts where human distomiasis was common.

Further experiments by Kobayashi have shown that the larval flukes leave the cyst and start for the biliary passages. When the flukes are very numerous the size is smaller. Maturity is reached in four weeks. This investigator believes that the primary intermediate host is a mollusc as cercariae found in these hosts are very similar to the larval forms found in fish.

He does not consider that there are two species concerned in Clonorchis infections, as he has found variations in continuity of vitellaria in small as well as large flukes. Number of parasites present influences size. Age influences pigment production.

Both Clonorchis and Opisthorchis have the testicles in the posterior end with the uterus anterior. The testicles of Clonorchis are branched (dendritic) while those of Opisthorchis show as two lobes. In Dicrocoelium the lobed testicles are anterior to the uterus, which fills up the posterior end of the fluke.

F. buski and Fasciola hepatica are much alike in size and outline. The acetabulum of the latter is only 1.6 times the diameter of the oral sucker and the alimentary tract shows branching which is best seen in the cone-shaped projection of its anterior extremity. F. hepatica is a liver fluke rarely found in man.

F. buski is found in China, Assam and India. It is a parasite of hogs as well as man. The eggs measure from 80 to 120 microns, are nearly colorless and have a thin shell with a very small operculum.

Other intestinal flukes such as Cladorchis watsoni, Gastrodiscus hominis, Heterophyes heterophyes, and Fascioletta ilocana are of less importance. Heterophyes is[374] probably a rather common parasite but owing to its very small size (2 mm.) has been generally overlooked at autopsy.

It seems to be capable of setting up quite an eosinophilia at the time the adult female is penetrating the crypts of Lieberkühn, so that it is probably of pathogenic importance.

They usually live deep in the mucosa and the embryos emerge from the ova laid in the mucosa. The embryos escape from the eggs while still in the intestines, so that in the faeces we only find actively motile embryos. The eggs, which are strung out in a chain, never appear in the faeces except during purgation. As they greatly resemble hookworm eggs this is a point of great practical importance.

It has been demonstrated by Fülleborn that infection of man takes place through the skin. If the temperature is warm, 25° to 35°C., these embryos develop into the free-living form. In this we have males and females, with double oesophageal bulbs, the male about 1/30 of an inch (¾ mm.) long with an incurved tail and 2 spicules and the female about 1/25 inch (1 mm.) long with an attenuated tail. These copulate and we have produced rhabditiform larvae, which later change to filariform ones. At this time the length is about 550 microns. These start up the parasitical generation.

For treatment thymol is usually recommended. Stiles speaks highly of sulphur.

It is known that yaws often occurred in epidemic form on board the slave ships and it is thought that this disease may have been an African importation into the new world.

In Africa it is very prevalent in the equatorial region, especially in the Congo Free State. It is also found more rarely in Tripoli and Algiers and to a less extent in the Sudan region. It is common in the West Indies and tropical America.

In Asia it is very prevalent in the Malay Peninsula, Siam, the East Indian Islands and in the Philippines. It does not exist in Japan. In many of the islands of the Pacific it is exceedingly prevalent, particularly in Samoa. It is also present in Northern Australia.