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                      PUBLISHED ON THE FOUNDATION
                        ESTABLISHED IN MEMORY OF
                            ANTHONY N. BRADY

[Illustration:

  FIG. I. AUTOPSY NO. 99. ACUTE HEMORRHAGIC AND ULCERATIVE
    LARYNGOTRACHEITIS.
]




                                  THE
                         PATHOLOGY OF INFLUENZA


                                   BY
        M. C. WINTERNITZ, ISABEL M. WASON AND FRANK P. MCNAMARA

                                  FROM
  THE BRADY LABORATORY OF PATHOLOGY AND BACTERIOLOGY, YALE UNIVERSITY
             SCHOOL OF MEDICINE AND THE NEW HAVEN HOSPITAL

[Illustration]

                               NEW HAVEN
                         YALE UNIVERSITY PRESS
          LONDON · HUMPHREY MILFORD · OXFORD UNIVERSITY PRESS
                                MDCCCCXX




                          COPYRIGHT, 1920, BY
                         YALE UNIVERSITY PRESS


The present volume is the fourth work published
by the Yale University Press on the Anthony N.
Brady Memorial Foundation, which was established
June 15, 1914, by members of the family of the
late Anthony N. Brady to enable the University
to declare operative the agreement for an
alliance between the New Haven Hospital and the
Yale School of Medicine. In addition to the
pledge of endowment for this purpose, the donors
erected for the University on the grounds of the
Hospital a clinical and pathological laboratory,
and have since, through additional gifts to
supplement the income of the Memorial
Foundation, made possible the publication of
this and other works by members of the faculty
of the School of Medicine at Yale.


                        Our grateful acknowledgment is due the Staff of
                        the New Haven Hospital, especially the members
                        of the Department of Medicine, for their hearty
                        co-operation and for the use of the clinical
                        notes. We also wish to thank the members of the
                        Medical Corps of the United States Army who were
                        stationed at the Yale Army Laboratory School
                        while the work was in progress and who aided in
                        many ways:—Colonel Charles F. Craig, Captain R.
                        A. Lambert, Lieutenants C. A. McKinlay,
                        Frederick Parker, Jr., Ellis Kellert, Henry R.
                        Muller, and J. H. Globus.

------------------------------------------------------------------------




                           TABLE OF CONTENTS


                                                                   Page

 Introduction                                                         9

    I. The Pathology of the Respiratory Tract in Influenza           13

         (A) Lesions of the Trachea and Bronchi                      13

                  (a) Gross Picture                                  13
                  (b) Histological Picture                           14
                  (c) Summary                                        16

         (B) Lesions of the Lung                                     16

             (1) Acute Diffuse Fulminating Type                      18

                  (a) Gross Picture                                  18
                  (b) Summary                                        19
                  (c) Histological Picture                           20
                  (d) Summary                                        22

             (2) Localization and Necrotization of the Pneumonic
               Process                                               22

                  (a) Gross Picture                                  22
                  (b) Histological Picture                           24
                  (c) Summary                                        26

             (3) Organization of the Bronchiolar and Pneumonic
               Processes                                             26

                  (a) Illustrative Protocols                         27
                  (b) Summary                                        30

   II. Influence of the Respiratory Complications of Influenza
         upon Tuberculosis of the Lung                               32

                  (a) Illustrative Protocols                         32
                  (b) Summary                                        33

  III. Extrarespiratory Lesions in Influenza                         34

         (A) Lesions of the Hematopoietic System                     34

                  (a) Lymphadenoid Tissue                            34
                  (b) Spleen                                         35
                  (c) Bone Marrow                                    35

         (B) Lesions of the Blood Vessels and Elsewhere in the
           Body                                                      36

                  (a) Vascular System                                36
                  (b) Skeletal System                                36
                  (c) Parenchymatous Organs                          36
                  (d) Alimentary Canal                               37
                  (e) Urinary Bladder                                37

         (C) Miscellaneous Lesions                                   38

                  (a) Parenchymatous Organs                          38
                  (b) Jaundice                                       39
                  (c) Central Nervous System                         39
                  (d) The Pregnant Uterus                            39
                  (e) Summary                                        39

   IV. A Comparison between the Respiratory Lesions of Influenza
         and those Initiated by the Inhalation of Poisonous Gases
         with Special Reference to:—                                 40

         (A) The Inflammatory Response versus the Systemic
           Capacity to Compensate                                    40

         (B) The Primary Injury                                      41

         (C) The Tendency to Organization of Bronchiolar and
           Alveolar Exudates with Bronchiolitis and
           Bronchiolectasis as Sequelæ                               42

         (D) The Importance of the Trachea and its Ramifications
           as a Protective Mechanism against Infection of the
           Pulmonary Parenchyma                                      42

    V. Peculiarities of the Histology of Influenzal Pneumonia        44

         (A) The Extent of the Initial Pulmonary Lesion              44

         (B) The Hemorrhagic Exudate—The Relation of Red to Grey
           Hepatization                                              44

         (C) The Aplastic Exudate                                    45

         (D) The Hyaline Necrosis of the Pulmonary Tissue            46

         (E) The Organization Process                                46

   VI. Infection as a Possible Etiological Factor for Malignant
         New Growths                                                 48

  VII. The Bacteriology of Influenzal Pneumonia                      49

         (A) Organisms Associated with Influenzal Pneumonia          49

         (B) The Relation of the Type of Organism to Pleural
           Involvement                                               50

         (C) The Relation of Different Organisms to the Type of
           Pneumonia                                                 50

         (D) Summary and Discussion                                  54

 VIII. Conclusions                                                   55

   IX. Bibliography                                                  56

    X. Illustrations                                                 63

[Illustration:

  FIG. II. AUTOPSY NO. 98. DRAWING OF A SECTION THROUGH A TRACHEA
    SHOWING NECROTIZING HEMORRHAGIC INFLAMMATORY PROCESS OF THE MUCOSA.
]




                              INTRODUCTION


The epidemic of influenza, prevalent in Europe during the Great War, was
watched with interest everywhere, not only because of its military
importance, but also because of the danger of its spreading to other
continents. The prediction that this would occur, made months before its
realization, was verified on an even larger scale than had been
anticipated, for in the autumn of 1918, this acute respiratory infection
passed over the United States like a huge wave, taking a tremendous toll
in human lives; later smaller waves followed leaving in their wake
corresponding degrees of devastation. The first cases of the disease
appeared on the New England coast, and New Haven was among the cities to
be early invaded, though here the epidemic was somewhat less severe than
in other cities along the Atlantic Seaboard.

Forewarned and alert to the danger, medical men spared no effort in
studying the disease; as a result, no malady, perhaps, has ever been
investigated so intensively and from so many different points of attack
in an equal length of time. Proof of this appears in the abundant
literature issuing from every quarter. Among the various contributions
to this subject, many include the anatomical changes associated with the
disease. In general, however, these are brief; and although they serve
their special purpose well, they have not been elaborated sufficiently
to close the chapter.

During a period of about three months beginning with September 18, 1918,
while the epidemic raged and waned in New Haven, there were
approximately eleven hundred cases of the disease admitted to the New
Haven Hospital. As is so often true, only the more critically ill sought
hospital care, and few, if any, patients affected by other respiratory
infections are included in these statistics. The mortality here, as
elsewhere, was very high; of two hundred eighty (280) cases that ended
fatally, eighty-two (82) were investigated at the post-mortem table. An
attempt was made to make the studies very complete, and this was favored
since the headquarters of the Yale Army Laboratory School, under the
command of Colonel Charles F. Craig, were located at the Brady
Laboratory where a large number of men were being instructed in
Pathology and Bacteriology. It was also fortunate that competent
illustrators were available who made a splendid series of water-colors
and drawings of the characteristic lesions, both gross and microscopic.

The number of autopsied cases at the New Haven Hospital was augmented by
a series of acute fatalities from the same disease at the United States
General Hospital No. 16, at Allingtown, West Haven, where the anatomical
studies were carried on by the same group of men. The latter autopsies
offered nothing new, but served to corroborate the conclusions reached
at the New Haven Hospital.

The majority of the fatalities occurred in the acute stage of the
disease, the anatomical aspects of which have been elaborated more or
less completely.[1] Other cases survived for a longer period and in
these, anatomical changes existed, which, as will appear later, were
prognosticated from the acute lesions. Moreover, these findings
suggested that certain progressive anatomical changes occur even when
the disease runs a much less severe clinical course; for example, in
cases where respiratory symptoms persist for a long period before they
are brought to a fatal conclusion.

History, too, suggests such a chain of events; namely, in the record of
the delayed crop of respiratory disorders that followed the harvest of
the epidemic of ’90.

Previous studies of experimental pneumonia in normal and aplastic
animals by one of the authors (160) give a background for the
interpretation of the histology of some phases of this disease, but more
important are the studies of the respiratory inflammatory processes
initiated by the inhalation of toxic gases. This subject, introduced
into human Pathology with the use of poisonous gases in modern warfare,
necessitated elaborate investigations which have just been concluded
(159).

The pathology produced by the inhalation of these poisonous vapors is
analogous to that found in influenzal pneumonia. This is said with a
full comprehension of the criticism that may follow such a statement,
and with the knowledge that a similar analogy has been drawn between
influenzal and plague pneumonia (Symmers, 141). It is, however, a
criticism that is welcomed and which will be met in the body of the
paper.

For the reasons just cited, it has seemed desirable to contribute to the
Pathology of various phases of influenzal pneumonia and to attempt to
correlate this with other types of acute respiratory inflammation, in
the hope that the prognostications which suggest themselves may be of
aid in the prophylaxis and possibly in the treatment of the more
insidious and progressive pulmonary changes that may follow this
disease.

A large part of the text is devoted to a description of the gross and
more minute pathology of the respiratory tract associated with influenza
and its complications, both in the acute and in the subacute or chronic
stages. Incidental lesions of less importance in other portions of the
body that have occurred in these cases are presented briefly, and
emphasis is placed upon a number of special subjects. The order of
discussion will be as follows:—

  I. The Pathology of the Respiratory Tract in Influenza.

      (A) Lesions of the Trachea and Bronchi.

      (B) Lesions of the Lung.

      (1) Acute Diffuse Fulminating Type.

      (2) Localization and Necrotization of the Pneumonic Process.

      (3) Organization of the Bronchiolar and Pneumonic Processes.

    II. Influence of the Respiratory Complications of Influenza upon
    Tuberculosis of the Lung.

    III. Extrarespiratory Lesions in Influenza.

      (A) Lesions of the Hematopoietic System.

      (B) Lesions of the Vascular System, Parenchymatous Organs,
        Alimentary Tract, and in the Walls of Other Hollow Viscera.

      (C) Miscellaneous Lesions.

    IV. Comparison between the Respiratory Lesions of Influenza and
    those Initiated by the Inhalation of Poisonous Gases with Special
    Reference to:—

      (A) The Inflammatory Response versus the Systemic Capacity to
        Compensate.

      (B) The Primary Injury.

      (C) The Tendency to Organization of Bronchiolar and Alveolar
        Exudates with Bronchiolitis and Bronchiolectasis as Sequelæ.

      (D) The Importance of the Trachea and its Ramifications as a
        Protective Mechanism against Infection of the Pulmonary
        Parenchyma.

    V. Peculiarities of the Histology of Influenzal Pneumonia.

      (A) The Extent of the Initial Pulmonary Lesion.

      (B) The Hemorrhagic Exudate—The Relation of Red to Grey
        Hepatization.

      (C) The Aplastic Exudate.

      (D) The Hyaline Necrosis of the Pulmonary Tissue.

      (E) The Organization Process.

    VI. Infection as a Possible Etiological Factor for Malignant New
    Growths.

    VII. The Bacteriology of Influenzal Pneumonia.

      (A) Organisms Associated with Influenzal Pneumonia.

      (B) The Relation of the Type of Organism to Pleural Involvement.

      (C) The Relation of Different Organisms to the Type of Pneumonia.

      (D) Summary and Discussion.

    VIII. Conclusions.

    IX. Bibliography.

    X. Illustrations.

[Illustration:

  FIG. III. AUTOPSY NO. 90. DRAWING FROM A LESION OF THE TRACHEA
    (SOMEWHAT OLDER THAN THAT ILLUSTRATED IN FIGURE II). THE MUCOSA IS
    ENTIRELY LACKING. CONGESTION AND EDEMA ARE THE STRIKING FEATURES IN
    THE SUBMUCOSA. THE NECROTIZING PROCESS HAS EXTENDED INTO THE MUCUS
    GLANDS. THIS IS SHOWN IN THE LOWER PICTURE.
]

[Illustration:

  FIG. IV. AUTOPSY NO. 205. CONGESTION AND EDEMA OF THE SUBMUCOSA AND
    REGENERATION OF THE TRACHEAL EPITHELIUM.
]

[Illustration:

  FIG. VII. AUTOPSY NO. 94. A NECROTIZING PROCESS LIKE THAT OF THE
    TRACHEA ILLUSTRATED IN FIGURE II. HERE IT IS SHOWN TO INVOLVE THE
    WALL OF THE BRONCHIOLE.
]

[Illustration:

  FIG. V. AUTOPSY NO. 95. AN EARLY LESION OF THE BRONCHIOLE
    CHARACTERIZED BY HYALINIZATION OF THE EPITHELIUM AND SEROUS EXUDATE
    IN THE LUMEN.
]

[Illustration:

  FIG. VI. AUTOPSY NO. 103. ILLUSTRATES ANOTHER EARLY BRONCHIOLAR
    LESION. THE EPITHELIUM IS LACKING, THE CONGESTED VESSELS OF THE
    SUBMUCOSA PROTRUDE INTO THE LUMEN WHICH CONTAINS DESQUAMATED
    EPITHELIUM, MUCUS, AND RED BLOOD CELLS.
]




                         PATHOLOGY OF INFLUENZA




          THE PATHOLOGY OF THE RESPIRATORY TRACT IN INFLUENZA


If the atrium of an infection and its specific etiological agent are
undetermined, the narrator of the pathology of a specific disease is
confronted immediately with serious obstacles in the elaboration of a
complete picture. Some writers assume that the respiratory tract is the
portal of entry in influenza (162), though the specific agent is still
unknown.[2] Whatever the agent, unquestionably it attacks the
respiratory tract at a very early stage in the disease and produces a
lesion which becomes responsible for the most serious aspect of
influenza, whether this phase be primary or only a complication.

Among the lesions which will be considered, therefore, those of the
respiratory tract chiefly will be emphasized. They include the changes
in the large air passages, as well as the pulmonary, alveolar, and
interstitial involvement. Unquestionably, a very close association
exists between the lesions of the larger air passages and those of the
alveoli, but probably it is equally true that the former may occur
alone; in many instances also they are the forerunners of the latter
lesions. Consequently, it seems logical to begin with an exposition of
the lesions in the trachea and its ramifications, including the
bronchioles.


                 A. LESIONS OF THE TRACHEA AND BRONCHI


                            _Gross Picture._

Early in the disease the congestion and the hemorrhages that have been
described in the mucous membrane of the nasopharynx (14 and 94) are also
conspicuous features in the lining of the trachea and bronchi (Fig. I).
This membrane is swollen, turgid, red, and covered by a copious, mucous
exudate which may be clear, but much more frequently is blood-stained or
opaque and yellowish in color. The blood, variable in amount, may be
fresh and red; and after the mucous exudate on the surface is removed,
more intense red foci stand out on the congested base (47, 90, 157).
Frequently, as the bronchi are approached, the red color of the mucosa
becomes more intense and may have a garnet tinge. Membranes such as are
encountered in the more usual necrotizing inflammatory processes, like
diphtheria, have not occurred in the trachea and larger bronchi in this
series (108, 128, 157).[3] The exudate peels off readily, and as
indicated above, leaves a velvety red surface, dotted here and there
with darker or more intensely red foci. Small ulcerations of the mucosa
occur, but are inconspicuous (82, 156). As the finer ramifications of
the bronchi are approached, the accumulation of the exudate in their
lumina becomes more and more marked, and on cross section of the lung,
they often stand out conspicuously on account of their increased size
and projecting, seromucous, blood-stained content (101, 149, 162).

It is remarkable how long this picture in the trachea and bronchi may
persist without showing any marked variation. It is encountered, not
only in the most acute and fulminating types of the disease (that have
been examined), but a similar picture may be present in cases which end
fatally only after a period of weeks of severe illness. In the latter
cases, however, the exudate, particularly in the bronchioles, assumes a
more purulent character and after this accumulation is wiped away from
the surface of the tube, the intensity of the dark red color of its
lining membrane presents an even more striking contrast on account of
the opaque, yellowish-green exudate in the lumen. At this stage, too,
the bronchioles are more distended with pus, which oozes from each one
when the lung is sectioned (1, 108, 110). In the cases still more
chronic, the terminal bronchioles may be sharply outlined with a thick
grey wall which surrounds the dilated opening from which the accumulated
yellowish exudate oozes as soon as the pressure is relieved (Figs. XXXIX
and XL).


                        _Histological Picture._

The changes are less marked, perhaps, in the trachea than in its finer
ramifications. The mucosa is constantly more or less destroyed and large
areas, usually focal, are entirely devoid of their epithelial covering.
This is replaced by a sparse exudate, composed largely of red blood
cells, mucus, a small amount of fibrin, and nuclear fragments (Fig. II).
It may dip into the submucosa for a short distance, but usually these
indentures are associated with the ducts of the mucous glands into which
the inflammatory reaction extends. A more striking feature than the
exudate, however, is the edema and the congestion of the submucosa. The
loose areolar tissue of the submucosa is spread widely apart, and
throughout it distended blood vessels are very conspicuous. Occasionally
such a vessel is broken and actual hemorrhage appears in the submucosa.
Occasionally, too, the inflammation extends down the duct to the mucous
gland itself, and here, also, aplastic inflammatory reaction is evident,
inasmuch as the acini now stain intensely red with the cells
undifferentiated from each other and specked here and there by broken
remains of the dead nuclei (Fig. III). After the disease has continued
for a short period, even at the end of five or six days, some
regeneration of the epithelial lining may be seen (3) (Fig. IV). But
despite this, the acute picture persists, and there goes on, side by
side, an attempted repair characterized by epithelial regeneration and
the same evidence of acute change. Since the lesion is essentially a
superficial one, scars or contractures of any extent are not encountered
in the trachea, even in examples of the disease that have ended fatally
only after many weeks.[4]

[Illustration:

  FIG. VIII. AUTOPSY NO. 97. ALTHOUGH THE EPITHELIUM IS STILL VISIBLE AS
    A HYALINE BAND LIFTED FROM THE UNDERLYING MUCOSA, BOTH MUCOSA AND
    SUBMUCOSA ARE INVOLVED IN A NECROTIZING PROCESS. BACTERIA ARE
    ABUNDANT IN THE DEAD TISSUE.
]

[Illustration:

  FIG. IX. AUTOPSY NO. 105. THE NECROTIC EPITHELIUM IS INVADED BY
    POLYMORPHONUCLEAR LEUCOCYTES AND THESE, AS WELL AS ROUND CELLS,
    CAUSE A THICKENING OF THE BRONCHIOLAR WALL.
]

[Illustration:

  FIG. X. AUTOPSY NO. 106. THE SMALL BRONCHIOLE IS FILLED WITH PUS
    CELLS, WHICH, IN SOME PLACES, EXTEND THROUGH ITS WALL.
]

There is considerable evidence to support the view that the disease
spreads from bronchus to bronchus, and in keeping with this view,
various stages in the inflammatory processes are more readily determined
in these smaller structures than in the trachea. Furthermore, it must be
emphasized that even the mildest and the most extreme of these stages
are not infrequently encountered in the same lung. The earliest lesion
is manifested by an increased homogeneity of the protoplasm of the
epithelial lining of the bronchus. The cell protoplasm loses its normal
granulation and the nucleus, somewhat darker than usual, becomes
conspicuous on a red base (Fig. V). In the lumen of such a tube a serous
exudate, perhaps mixed with mucus, is encountered, and there is some
spreading apart of the surrounding muscular tissue with engorgement of
the vessels. This picture merges gradually into one where the epithelium
appears as a homogeneous, red-staining ribbon, devoid of nuclei, often
exfoliated, in part at least, from the underlying submucosa (92). The
change is traceable through the larger bronchi, even to the ducti
alveolares, and not infrequently, bacteria, either as a diffuse, minute
dotting or in the form of circumscribed, colony-like formations, are
spread through the red, ribbon-like strand (Fig. XVI). With the
exfoliation of the epithelial lining, the submucous vessels become more
and more conspicuous and may bulge into the lumen of the tube (Fig. VI).
That they actually weep into the lumen is proved by the presence of red
blood cells in the exudate, now rich in mucus, broken-down nuclei, and
desquamated cells. The necrotizing process may not extend deeper than
the epithelial lining as is the status described above (140, 162), but
it also frequently involves the underlying submucous and muscular
layers, so that these lose their identity and stand out as homogeneous
masses, in which fragmented nuclei and bacterial accumulations are
prominent. Such deeper necrotizing areas may be focal (Fig. VII), or may
involve the entire circumference of the tube (Fig. VIII). Occasionally,
the epithelium, now dead and staining homogeneously, is lifted from the
underlying submucosa in the form of a blister (66), and has very much
the same appearance as the well known, early reaction which follows the
application of croton oil to the rabbit’s ear. Where this occurs, the
submucosa is less involved, as though the necrotizing agent had not
penetrated to the same depth and the serous reaction beneath were
actually a beneficent exudate. These blisters are in contrast with the
deeper areas where the fibrinous mass, mixed with the dead tissue, forms
an intensely staining ring or band, which extends through the
bronchiolar wall even to the surrounding alveoli.

In the early stage of this process one of the most outstanding features
is the absence of polynuclear leucocytes in the reactionary process, but
gradually as the dead tissue sloughs away, these cells wander into the
exudate and form a purulent ring, more intense in the lumen, but
extending for a variable distance through the still viable wall of the
structure (47) (Fig. IX). Later mononuclear cells accumulate in this
wall and occur either as a diffuse mottling or as circumscribed foci in
the muscle and submucous layer of the bronchiole, just as they do in the
trachea. Occasionally, a striking change is found in a small bronchiole
within a portion of the lung which is otherwise uninvolved by an
inflammatory process. Perhaps the alveoli were the seat of a change
which has subsided, but, whatever the history, the purulent mass in the
bronchiole and involving its wall, stands out effectively (Fig. X).

Sooner or later, with the subsidence of the irritating agent, repair
begins in the bronchus or bronchiole. If its walls have been destroyed
and the lesion has extended into the surrounding alveoli to form an
abscess of greater or lesser extent, or if the necrotizing process has
been superficial and confined to the epithelium in large part, the
reparative process is very much the same. Mitotic figures in the
fibroblasts and in the endothelial cells of the capillaries abound in
the young granulations (Fig. XI). However, the granulation tissue does
not have an unrestricted path of growth, for if a remnant of epithelium
remains, this is stimulated to grow probably in this disease as in no
other. Mitotic figures are common and the young epithelial cells stretch
across the denuded submucosa or granulation (Fig. XLVIII) and extend
downward into the surrounding alveoli, not only as strands, but also as
solid nests of cells (47) (Fig. XLIX). The bronchioles, therefore, show
changes dependent upon the extent of the damage suffered by their walls.
The vast majority, in all probability, will be restored; but if the wall
has actually been necrotized, the bronchioles may be converted into
small, saccular, bronchiectatic cavities (48, 110, 162) (Figs. XII and
L), or obliterating bronchiolitis may result from the organization of
the exudate within their lumina (82) (Fig. XI). The importance of the
epithelial proliferation cannot be ignored; in many cases, it invades
the surrounding lung tissue and a typical, histological picture
results—an infiltrating, malignant, epithelial neoplasm (Figs. XLVIII
and XLIX).


                               _Summary._

The lesions of the trachea and of the larger bronchi, even though they
persist in their acute form for a period of weeks, are superficial and
do not lead to extensive or deep scarring. In contrast to the larger
respiratory passages, that portion of the bronchial tree which is not
supported by cartilaginous rings becomes more and more intensely
involved, not only on its surface, but in its deeper structures, and the
changes in the bronchioles and the neighboring air sacs are among the
more characteristic anatomical manifestations in this disease.
Therefore, while it will be unnecessary to refer again to the larger air
passages, further consideration of the smaller ones, which are
constantly associated with the lesions of the pulmonary parenchyma, will
be included in the subsequent discussion of the pulmonic involvement.


                         B. LESIONS OF THE LUNG

In the prosecution of the scientific study of any disease, the great
temptation is to differentiate its various manifestations with the
intention of elaborating a classification. While there may be more or
less distinct types of pulmonary involvement in influenza, so many
intermediary forms appear in an extensive series of cases, that any
classification must necessarily be arbitrary. Here, such an attempt at
classification is beset with unusual difficulty, because, in the vast
majority of cases which come to anatomical observation, the disease is
fulminating. The lesions are more uniform in character than in an
experimental study where the material is arranged so as to include
intermediary and chronic stages, which in man are only encountered when
accident causes death. These gaps in the study cannot be supplemented
with experimental observations, because attempts to reproduce this
disease have failed, even in human subjects. From the literature it
appears also that variations in the extent, and perhaps in the
maturation, of the anatomical involvement may be represented in
different proportions for different localities (1, 2, 17, 55, 92, 162).
Therefore, no sharp differentiation may be drawn between the more or
less definite stages which are seen at the post-mortem table; still, for
convenience of description, certain of the lesions which occur more
frequently and are more widely differentiated may be considered
separately.

The disease, as has been indicated, may be confined to the bronchial
tree. In these circumstances, it is almost necessary to suppose that the
larger bronchi alone are involved. When the delicate bronchioles are
affected, there is always a more or less extensive involvement of the
pulmonary parenchyma (124), for the bronchioles have a more direct
communication with the alveoli, and their walls present a less
formidable barrier to the extension of the inflammation to the
surrounding air sacs.

[Illustration:

  FIG. XI. AUTOPSY NO. 140. ILLUSTRATES A LATE CHANGE IN THE BRONCHIOLE;
    THE EXUDATE IS BEING ORGANIZED AND THE EPITHELIAL LINING IS
    PROLIFERATING AND HAS INVADED THE SURROUNDING LUNG TISSUE. COMPARE
    FIGURES XLVIII AND XLIX.
]

[Illustration:

  FIG. XII. AUTOPSY NO. 209. A SMALL BRONCHIECTATIC CAVITY FILLED WITH
    PUS. THE GROSS APPEARANCE IS ILLUSTRATED IN FIGURE L.
]

[Illustration:

  FIG. XIII. AUTOPSY NO. 96. RIGHT LUNG. A WATER COLOR DRAWING OF A
    GROSS LUNG IN THE ACUTE STAGE. NOTE THE SIZE OF THE LUNG, THE
    HEMORRHAGES ON THE PLEURAL SURFACE, AND THE BLUE AREAS OF
    CONSOLIDATION.
]

Clinically, there is reason to believe that the disease may begin with a
period of general malaise, during which the respiratory symptoms may be
more or less severe. In the fulminating cases, the malaise may be
associated from the beginning, not only with a tracheobronchitis, but
also with pulmonary involvement. In less severe types the malaise may be
accompanied only by tracheobronchitis, and may present no symptoms
referable to the pulmonary parenchyma; there may follow or not, a
definite period of clinical improvement, after which pneumonic
involvement becomes evident. However, even where a fulminating type of
the disease is not associated with clinical evidence of pulmonary
involvement, the post-mortem examination may show extensive change in
the lung parenchyma (110).

Whether this grouping of the disease is correct or is based upon a
fallacious deduction from more or less satisfactory clinical histories,
is open to question; and a decision may be reached from comparison of
the opinions based upon carefully observed cases treated in different
institutions. From the report of the epidemic at the Johns Hopkins
Hospital (Bloomfield and Harrop (14)), where two hundred sixty-eight
cases were studied in which the complication of pneumonia was uncommon
as compared with cases in other hospitals—the New Haven Hospital, for
instance—and where the percentage of the deaths was low, the conclusion
was reached that the disease is primarily a general one and that the
pulmonary involvement is secondary, just as in an exanthem, like
measles. By way of comparison, at the New Haven Hospital, where more
than eleven hundred patients with influenza were observed, the type of
disease described by Bloomfield and Harrop was relatively rare. Of
course, there were cases of that type where general malaise, with or
without respiratory symptoms, was followed by a period—usually of from
two to three days—of definite improvement in the symptoms; and later
extensive and serious pulmonary complications ensued. However, in
another group, largely composed of individuals who entered the hospital
seriously ill, the histories indicate an acute onset resembling that of
lobar pneumonia and with early manifestations of pulmonary involvement
(2, 17, 52, 145). This discrepancy, probably, may be explained in part
by variations in the sensitivity to minor indisposition on the part of
the different individuals.

The preceding review should aid in the correlation of the clinical types
of the disease with the respiratory lesions. All pulmonary lesions, from
the least to the most localized, may be explained either by a subsidence
of a less acute initial and diffuse involvement of the parenchyma, or by
a less rapid and progressive spread of the necrotizing and inflammatory
process from the upper respiratory tract through the bronchioles to the
alveoli. This conception does not take into account the significance of
the period of malaise, interpreted by the clinician as the period of
invasion, but attempts to correlate the respiratory symptoms with the
pulmonary lesions and their etiology.

Our own experience, like that of other observers (26, 104, 162), is that
all fatal cases of this disease show pulmonary involvement in the form
of pneumonia. The lesion varies greatly in intensity and in the amount
of pulmonary tissue affected. In the descriptions which follow, the more
diffuse and intense processes will be discussed first, and later those
in which the inflammation localized and terminated in pseudolobar,
lobar, lobular, or peribronchial pneumonia.


            (1) ACUTE DIFFUSE FULMINATING TYPE OF PNEUMONIA

The majority of influenzal deaths have been examples of this acute type.
Out of ninety-five cases, the total number studied, forty-four belong to
this group in which the average duration of illness was nine days. They
form the basis of the description which follows.


                            _Gross Picture._

A striking feature of the external examination of the body is the
intense rigor which involves all the muscles and is broken only with
difficulty (78). This is associated with a rapid settling of the
unclotted blood in the dependent parts which gives them an intense blue
or bluish-purple color. The erythema of the skin which has been
described clinically is not recognizable at the post-mortem table. There
is, however, cyanosis of the face which reaches an intensity explained
by the fact that this disease so often affects healthy, well nourished,
muscular individuals. In a few instances the cyanosis is more extensive
and gives a plum color to the entire body. All the mucous membranes
share in the intense congestion and discoloration of the face. Slight
jaundice is common, but marked variations in intensity occur. The
external nares and the lips are almost invariably covered with
blood-stained crusts. Even in the decubitus position, a thin, sanguinous
fluid tends to escape in large quantities from the nose and mouth. The
large veins of the neck are usually prominent, and the chest voluminous.

Distinct splanchnic engorgement is evident as soon as the peritoneal
cavity is opened. The liver extends below the costal margin and is dark
in color, but otherwise the abdominal cavity presents nothing
characteristic of the disease. The diaphragm does not extend as high as
usual, and the pleural cavity almost invariably contains an excess of
fluid. Usually the quantity is small, but, on the other hand, it may be
considerable, and in twenty-one of the forty-four cases the fluid
exceeded one hundred cubic centimeters. The turgidity of the mediastinal
tissues varies somewhat in degree (27). Generally the pericardial sac is
smooth and glistening on both visceral and parietal surfaces; the
pericardial fluid is not materially changed. Frequently (seventy per
cent) there is dilatation of the right side of the heart (138, 141,
157), but aside from an occasional small endocardial or subepicardial
hemorrhage (90, 108, 156), there are no lesions of consequence in the
heart attributable to this disease[5] (162).

[Illustration:

  FIG. XIV. AUTOPSY NO. 96. LEFT LUNG. NOTE ITS SIZE AND THE PATCHY
    CONSOLIDATION.
]

[Illustration:

  FIG. XV. AUTOPSY NO. 149. ILLUSTRATES ONE OF THE MOST STRIKING EARLY
    PULMONARY LESIONS; THE DILATATION OF THE TERMINAL BRONCHIOLES AND
    THE HYALINIZATION OF THEIR EPITHELIUM. COMPARE FIGURE XVI.
]

[Illustration:

  FIG. XVII. AUTOPSY NO. 133. HYALINE THROMBI AND NECROSIS OF THE
    ALVEOLAR WALL. COMPARE FIGURES V, XV, XVIII, XIX, XXXI AND XXXII.
]

The lungs are extremely voluminous (12, 17) due in part to an
accumulation of liquid within them. This finds its way into the trachea
and completely fills the latter structure with blood-stained, syrupy
fluid, with purulent material, or with a mixture of these (2, 90, 107,
157, 162). At first the pleural surface is smooth and often quite even,
but on closer inspection, a minute granulation is suggested. In many
cases even close examination does not allow the conclusion that an
exudation of anything but serum has occurred through this membrane,
except in localized foci. These foci more frequently involve the
interlobar pleura and that of the lower lobes (112, 143). The volume of
the lungs, often great enough to obliterate the pericardial area, is one
of the two most characteristic features of the external examination. The
other feature is their color. Small, bright red hemorrhages may occur
anywhere. The larger patches are the most striking. Violet, purple, or
dark brown areas, irregular in shape and distribution, are more
frequently found on that portion of the pleura over the lower two-thirds
of the lung. Between the deeply colored zones, there are pale pink areas
which involve the lowermost edge to the least degree, the anterior
margin somewhat more, and the apex of the lung most of all. The darker
portions just referred to may project above the surface and may be
circumscribed, resembling huge, fresh hemorrhagic infarcts (41, 108).
The alveolar walls are not seen through the pleural surfaces in these
darker zones. The pale pink areas, usually at the level of the more
intensely colored zones, may be elevated and the dilated air sacs are
distinctly made out through the pleura (Fig. XIII). At the hilum, the
lymph glands are large and soft. When cut, fluid escapes and is often
blood-stained. The cross section may present a distinct, diffuse,
hemorrhagic appearance (162). At the hilus, too, the lymphatics,
distended here and there over the surface of the pleura, are most
affected. The congested bronchial mucous membrane and the exudate in
these structures has been described.

After removal, the lung retains its shape, but is more flaccid than the
consolidated lung of lobar pneumonia. It cuts with very little
resistance and immediately a large amount of a syrupy, pink fluid
escapes and obscures the entire area. With the fluid scraped away, the
variations in the consistency of the lung become visible. The pale areas
around the borders and chiefly at the apex in which the air sacs are
discernible with the naked eye, sink slightly below the remainder of the
surface, and the pleural edge inverts. The individual lobules of the
lung in these areas are more conspicuous than normal, because the
interstitial tissue bearing the lymphatics and vessels, as well as that
around the bronchi and larger blood vessels, does not lose its edematous
appearance as quickly as the alveoli (40, 92, 110, 164), and,
consequently, these grey lines and points stand up somewhat more
prominently.[6] In contrast with the paler areas which are prone to
slight collapse, the remainder of the cross section retains its more
smooth and even surface. The alveolar walls are not distinctly made out,
but the terminal bronchioles often make themselves evident by the nature
of the material which is within and by their distinct dilatation (1, 67,
110, 149, 162). The more firm areas stand out, too, on account of their
difference in color. The scheme is not unlike that seen on the pleural
surface, and while dark, almost black, infarct-like areas occur on the
cut surface, the solid areas are more likely to be translucent, dull,
light red, brown or even grey. They have a surface similar to a very
fresh, tuberculous, gelatinous pneumonia, but the color differs from the
cloudy grey of the latter on account of the admixture of blood in the
exudate and the great congestion of the vessels (Fig. XIV).


                               _Summary._

The well developed post-mortem muscular rigidity, the lividity of the
dependent parts, of the face with its mucous membranes, and often of the
trunk, the jaundice variable in extent, the crusts of blood on the nares
and mouth, and the splanchnic dilatation are features which prepare for
the gross picture presented by the thoracic organs. The increased
moisture within the pleural cavities associated with the even,
translucent pleural surface, whose dilated lymphatics become more and
more prominent towards the hilum, the large succulent lymph glands, and
the exudate in the bronchial tree, are all striking, but more
characteristic of the gross picture, is the great increase in volume of
the lung itself, mottled with brilliant colors. The lung, too, is very
wet and on section, after the syrupy, blood-stained fluid escapes from
the less definitely consolidated zones, the latter appear, not as the
usual granular, firm areas of hepatization, but have more the
consistency of a gel, and also its translucence. Characteristic of this
disease as these changes may be, the specificity of the fundamental
lesion in the respiratory tract, becomes more emphatic after study of
its histology (92, 162).


                        _Histological Picture._

No matter what the portion of the lung from which the sections are
derived, the fundamental changes found are the same. The subpleural
sheets are spread wide apart, now by empty spaces, now by coagulated
fluid. The process extends from the surface through the interlobular
septa (Fig. XX), and is accentuated where the connective tissue is more
prominent around vessels and bronchi. The nature of the infiltrate in
the subpleural and interstitial tissues becomes more evident in the
alveoli, which likewise are filled. The material varies somewhat in
appearance, probably dependent upon its proteid content. Not
infrequently the alveoli contain a homogeneous, pink-staining mass,
which resembles the colloid of the thyroid gland. Again, it may be
simply a coarse granular precipitate (Fig. XXIII), and in still other
instances, small sticks and strands form the bulk of the alveolar
content (47, 92, 140, 156). This subpleural, interstitial, perivascular,
peribronchial, and alveolar edema, which is a term applicable to this
collection of fluid, is very prominent, and although its intensity
varies in different portions of the lung; and although it may be
replaced in some areas by other types of exudate, unquestionably, this
is the dominating expression of the inflammatory process in the early
stage of the disease.

As might be expected from the gross appearance, the alveoli vary in
size. At times slightly collapsed and at other times overdistended,
their lumina are still the seat of the inflammatory exudate, although
the mechanical change may allow of some variation in the appearance of
their walls. As a rule, however, the alveolar wall is prominent and owes
its conspicuousness to the tortuous, engorged vessels within. These
vessels contain red blood cells almost exclusively, and on account of
the partial, occasionally complete, loss of the lining epithelium, the
alveolar wall appears as a huge, dilated arteriole (101) separating the
lakes of coagulated material in the spaces (Fig. XXIII). There are
areas, as indicated above, where the alveolar content may be more
definitely arranged in the form of beaded or homogeneous strands of
different caliber; the smallest resemble delicate threads. They tend to
converge toward the alveolar wall like wheat in a sheaf, and often pass
through this wall by way of the so-called pores of Cohn; as soon as the
body of the neighboring alveolus is reached, they again present a
fan-like expansion into innumerable, fine strands (Fig. XXII). Where the
exudate is more fibrinous, the alveolar wall is less likely to be
distended, its vessels are not so prominent, and their content of red
blood cells is definitely decreased. Still this is not the most extreme
type of alveolar exudate met with at this stage. Perhaps, the most
striking, although not the most frequent, exudate has a superficial
resemblance to a huge, red blood clot, and it may be difficult to make
out the alveolar walls separating the masses of well preserved red blood
cells that fill the alveolar spaces. These areas are indistinguishable
from infarcts and may be associated with thrombotic arteritis in near-by
pulmonary vessels (47) (Figs. XXIV and XXV). Among the red blood cells
an occasional strand of fibrin, a desquamated alveolar epithelial cell,
and rarely a polymorphonuclear leucocyte may be encountered. The
alveolar wall itself varies in the definition of its outline. When its
vessels are greatly distended, when its alveolar epithelium is gone, and
when its content consists largely of red blood cells, it is difficult to
distinguish from the exudate which it encloses. However, when it is more
compressed or when its epithelial lining cells are still more or less
intact, it may be seen as a blue-staining strand under the low power of
the microscope, for the well preserved nuclei lend it prominence.

[Illustration:

  FIG. XVI. AUTOPSY NO. 112. BACTERIA DEVELOP IN THE HYALINE NECROTIC
    EPITHELIUM OF THE TERMINAL BRONCHIOLES. HERE THEY FORM CIRCUMSCRIBED
    MASSES THAT SIMULATE NUCLEI. COMPARE FIGURES V, VIII, XV, AND XVII.

  HELIOTYPE CO. BOSTON
]

[Illustration:

  FIG. XVIII. AUTOPSY NO. 155. ILLUSTRATES A MILD FORM OF PULMONARY
    INTERSTITIAL EMPHYSEMA.
]

[Illustration:

  FIG. XXII. AUTOPSY NO. 175. AN ALMOST PURE FIBRINOUS EXUDATE. THE
    ALVEOLAR WALLS ARE SLIGHTLY HYALINIZED AND THEIR EPITHELIUM IS
    ALMOST ENTIRELY LACKING.
]

There are, of course, variations in the extent of the serum, the fibrin,
and the hemorrhage in the exudate of the alveoli, and while these
different types may occur as pure forms, often they are associated. In
still other areas and varying in prominence, one finds as characteristic
an exudate, not only of serum, strands of fibrin, and red blood cells,
but also a diffuse dotting of the exudate with bacteria, singly, in
pairs, clumps, and chains (92, 164) (Fig. XXI). This type of reaction is
uncommon in pulmonary disease. It resembles more closely a streptococcus
cellulitis such as is encountered frequently in the subcutaneous
tissues, for example, a woody phlegmon, or a sero-hemorrhagic exudate
like the avirile response to a rapidly fatal hemolytic streptococcus
serositis. A similar reaction has been reproduced experimentally in
animals which have been rendered aplastic with benzol previous to
pulmonary insufflation, and it is conceivable that the lack of
polymorphonuclear response in the inflammatory exudate may be associated
with some such general destruction or temporary suspension of leucocytic
formation (160).

A more striking picture, however, even than this aplastic alveolar
exudate appears in the terminal bronchioles. In many instances, these
are conspicuous on account of their size, for they are dilated to form
prominent, often irregular, sacs (Fig. XV). The distention of these
terminal bronchioles may be so great that the surrounding alveoli are
compressed. What makes them even more conspicuous is their lining, once
epithelium, but now a swollen, thick, homogeneously staining material,
with complete loss of architecture; the material forms (with hematoxylin
and eosin) a red band limiting the lung tissue and sharply demarcating
it from the exudate within the bronchioles (48, 92). However, this
ribbon of red, often thickened by fibrin deposition, is not always pure,
for bacteria thrive in the dead tissue. They occur singly, paired, in
chains, and also as circumscribed, dense masses which in size and
position, simulate nuclei (162) (Fig. XVI). This same hyalinization of
the epithelium, it will be recalled, occurs in the larger bronchi (Fig.
V), and there, too, bacteria frequently develop in the dead tissue (Fig.
VIII). In the smallest bronchiolar ramifications, acute epithelial
necrosis is not infrequently encountered, even when the surrounding lung
tissue is relatively normal (Fig. XVI). That the process does not stop
with the epithelium, but, as in the larger bronchi, may extend through
the entire structure of the bronchioles, is manifest. Even the alveolar
walls may be involved and frequently homogeneous pink or red bands, now
the phantom of the former viable lung tissue, mark the presence of the
old wall of the alveolus (Fig. XVII). Occasionally, some architecture
remains in this pink ribbon and then the involvement seems to be
primarily in the vessels of the wall. Not all the vessels are involved,
and next to a hyaline thrombus in one, there may be fresh blood, usually
red blood, in its neighbor. The alveolar epithelium is usually denuded
and thus accentuates the intensity of the change.

The acute death which involves the tracheal, bronchial, and bronchiolar
epithelium and which may extend beyond the epithelium into the walls of
these structures and kill en masse the walls of the alveoli, is a lesion
which does not occur in other types of acute pulmonary infection.
However, in influenza, as after exposure to pulmonary irritating gases,
it is the lesion of characterization (158,159). The effects of this
change, of course, where it involves the alveolar wall, will vary with
the extent of the process; but given an absolutely necrotic wall, as yet
unstrengthened by inflammatory reaction, an expected result would be its
rupture with respiratory movement. The point of rupture is important,
but where so many alveoli are involved, disturbance of continuity will
occur, occasionally in such position that the result will be the escape
of air into the interstitial tissues.[7] There is ample evidence that
this happens. Indeed, among the clinical manifestations of the disease,
interstitial emphysema of the lung spreading through the fascial planes
to the subcutaneous tissues of neck and thorax is well known; the
phenomenon is more frequent and extensive in influenza than in any other
disease (8, 17, 52, 143).

Interstitial emphysema is very striking at the post-mortem table. The
escaped air appears as beads along the interlobular septa, but on
account of their size they are always most conspicuous between the lobes
and along the vessels toward the hilum (162) (Fig. XVIII).
Histologically, a small bubble of escaped air confined to the
interlobular septum compresses the surrounding tissue with almost
complete atelectasis of many neighboring alveoli (Fig. XIX).


                               _Summary._

The diffuse involvement of all the lung tissue, chiefly with a serous
exudate in the subpleural, interstitial, perivascular, and peribronchial
tissues, as well as in the alveoli, is associated with other elements
which occur in aplastic reactions; red blood cells, fibrin, and
bacteria. Added to the aplastic exudate is an acute necrosis of
bronchial and alveolar epithelium involving at times the walls of these
structures; consequently, the histology of this disease is almost as
specific as that of any biological reaction.


      (2) LOCALIZATION AND NECROTIZATION OF THE PNEUMONIC PROCESS

In the preceding description, the gross and microscopic anatomical
changes in the lung have been discussed minutely. The picture presented
persists, even though it becomes less intense, and forms a background
upon which later variations may be superimposed. There is no
justification for the opinion that the changes described are necessarily
the most acute, but it is presumably correct to suppose that an
aplastic, inflammatory reaction will terminate fatally more quickly than
a cellular reaction (160), and upon this basis the sequential
description in this narrative is arranged.

In the group of fatal cases of influenza, now to be discussed, the
lesions of the pulmonary parenchyma are characterized by more definite
lung consolidation. Thirty-nine examples presenting an average illness
of ten days are included in the following description.


                            _Gross Picture._

The external examination of the body includes nothing not described in
the previous group.

[Illustration:

  FIG. XIX. AUTOPSY NO. 123. A SMALL AIR BUBBLE IN THE INTERSTITIAL
    TISSUE. COMPARE FIGURE XVIII.

  HELIOTYPE CO. BOSTON
]

[Illustration:

  FIG. XX. AUTOPSY NO. 90. THE ACUTE SEROFIBRINOUS EXUDATE INVOLVES NOT
    ONLY ALVEOLI, BUT ALSO SUBPLEURAL AND INTERLOBULAR BANDS OF
    CONNECTIVE TISSUE. COMPARE FIGURES XXI, XXII, AND XXIII.

  HELIOTYPE CO. BOSTON
]

The fluid of the pleural cavities varies volumetrically as described in
the preceding section. It is, however, usually not a clear fluid, but
varies from a slightly turbid, blood-stained material to a typical
purulent exudate. The cloudiness may be associated with minute flecks of
suspended material, but in no instance has this fluid been of the thick
inspissated type which formerly would have been designated as
empyema.[8] (This is mentioned with the knowledge that the term empyema
is being applied now to less viscid, purulent, pleural exudates). The
turgidity of the mediastinal tissue also persists, but it is very rare
indeed to find anything more than a small amount of clear fluid in the
pericardial sac. Only once was there a typical, fibrinous pericarditis
with effusion, and this occurred where a most extensive pleural exudate
was also present.[9] Where such complications have been described in
serous membranes, the bronchial lymph glands, particularly at the hilum
of the lung, are more involved and show, not only an increase in size
and a red color on cross section, but frequently also focal areas of
necrosis at the periphery, which appear as yellow patches and
subsequently undergo suppurative disintegration (2, 47).

The lung remains increased in volume and its surface is mottled with
vivid colors. Often these are an indication of deeper parenchymatous
change. The pale pink zones, through the pleural surface of which
distended alveoli are discernible, are still prominent in the upper
lobe, around the margins, and on the anterior surface of the lung. The
darker purple, slightly elevated, often circumscribed, infarct-like
areas (25, 34, 108) may occur anywhere, but are more frequent in the
lower lobes. Small, maroon, slightly depressed areas of atelectasis may
also involve the borders of the lung, usually the posterior borders; or
they may occur between larger and more elevated areas on either lobe.
Besides the purple, firm, projecting foci, paler pink or grey nodules of
similar consistence may be present and show no structure when viewed
through the pleura. The distribution of the different types of change is
variable, and, aside from the fact that they involve the middle and
lower lobes more frequently than the upper, no general statement is
possible. In a few instances, one lobe, almost always the lower, may be
more voluminous than the others, and although its pleura often suggests
lobular involvement, the masses tend to be confluent and suggest a
pseudolobar change. Sometimes, though rarely, this approaches a true
lobar type of consolidation. (Compare Figs. XIII and XXVII.)
Occasionally, the changes in the lung, except its increase in size, are
obscured by pleural exudate which may form a thick, buttery, rather
sticky mass on the surface (12, 19, 157) (Fig. XXXVII). Such pleural
exudates are rare, and likewise it is uncommon to find so little pleural
granulation as in the previous group. The roughening, as a rule, is not
uniform, but is more prominent over the lower lobes and in the
interlobar spaces than elsewhere. It may occur when there is no definite
increase in the fluid content of the pleural sac.

The lung, now sectioned, presents a surface in accord with the changes
suggested from the description of its external appearance. As compared
with the first stage the amount of syrupy, blood-stained exudate may be
definitely decreased, especially in the upper lobe or in those portions
of the lung where the solidification is less marked. Its character, too,
may be more cloudy, and more ropy, or viscid; it bathes the surface and
is scraped off in abundance with the blade of a knife from the
underlying consolidated foci (108, 156). The bronchi and bronchioles,
however, may be prominent, irrespective of the change in the parenchyma
itself. From their lumina, thick, yellow pus wells forth and their
mucous membrane is intensely congested. Where such involvement occurs in
unconsolidated portions of the lung, the bronchioles are even more
striking than in the hepatized areas in which the more widespread
changes obscure the process. The dilatation of the bronchioles,
especially in their smaller ramifications, is still conspicuous.

The consolidated areas vary greatly in size and number;[10] often they
are small and involve only single lobules, which now stand out as
granular, generally elevated patches on the surrounding congested plane.
Their color, as on the pleura, varies. They may be dark, almost
hemorrhagic, fading through the reds, pinks, and greys. They may be
firm, or, at the other extreme, honeycombed by small, often narrow,
cavities, from which a material similar to that described on the surface
wells forth. The latter change is more frequent if the consolidated area
is large. It has occurred most often in the pseudolobar and in the lobar
types of the process. The pseudolobar change is differentiated, not only
by the confluence of more or less definite lobular patches and by its
involvement of portions of contiguous lobes rather than a single lobe,
but also by variations in the color and consistence of the different
lobular foci. This is in contrast with lobar involvement where the
entire lobe is affected by a uniform process usually at the same stage
of development. Although the consistence may vary in different portions,
usually the same color is present throughout. (Compare Figs. XIV and
XXVIII.) In one instance where a solid, yellow lobe was found, its
center contained an irregular, fresh blood clot (Fig. XVIII), which
would be sufficient to differentiate this type of consolidation from
that of respiratory disease in which the initial lesion is less
destructive. Sometimes the softening in a hepatized lobule or group of
lobules is much more evident, and the zone becomes divided by irregular
channels filled with viscid, grey or brown material (108, 149, 162).
When such a condition lies just beneath the pleural surface, it may be
distinctly seen from without (Fig. XXXIII). The pleura bulges, the
normal topography of the local zone is lost, and it appears as a dull,
somewhat projecting, circumscribed patch, two or three or more
centimeters in diameter, the surface of which has a more or less
characteristic brown or brownish black opacity. As soon as this is
sectioned there pours from the cavity the liquefied exudate in which the
destroyed pulmonary parenchyma is mixed (Fig. XXXIV). Occasionally,
strands of tissue still traverse the cavity, but, as a rule, it empties
itself completely, and leaves a brownish black wall. The delicate, sweet
but persistent and penetrating odor is not so marked as with typical
gangrene.


                        _Histological Picture._

Sections from the least involved areas of the lung show a subsidence of
the alveolar exudate and the walls are no longer intensely engorged.
Perhaps the most prominent feature within the alveoli is the desquamated
cells, presumably alveolar cells with broken or pyknotic nuclei. Despite
the fact that so many cells of this type occupy the lumen of the
alveolus, its wall has a prominent lining of cubical epithelium. Often
mitotic figures abound in this new alveolar epithelial lining (Fig.
XLVII), an evidence of rapid regeneration in that portion of the lung
where the initial irritative process has subsided and where the
destruction has not been as deep as elsewhere (79). This picture may be
taken as positive evidence of an initial, diffuse, and general pulmonary
involvement, which, with the subsidence of the primary reaction, is
followed by localization resulting in the different types of
consolidation now encountered.

[Illustration:

  FIG. XXI. AUTOPSY NO. 95. A TYPICAL APLASTIC ALVEOLAR EXUDATE COMPOSED
    Of RED BLOOD CELLS, FIBRIN, AND BACTERIA. COMPARE FIGURES XX, XXII,
    AND XXIII.

  HELIOTYPE CO. BOSTON
]

[Illustration:

  FIG. XXIII. AUTOPSY NO. 175. NOTE THE ABSENCE OF ALVEOLAR EPITHELIUM,
    THE ENGORGEMENT OF THE VESSELS OF THE ALVEOLAR WALLS, AND THE SEROUS
    EXUDATE.
]

[Illustration:

  FIG. XXV. AUTOPSY NO. 92. THE EXUDATE CONSISTS ALMOST ENTIRELY OF A
    MASS OF RED BLOOD CELLS. THE DESQUAMATED ALVEOLAR EPITHELIUM IS
    SCATTERED THROUGH THE HEMORRHAGIC EXUDATE. COMPARE FIGURES XXIV AND
    XXVI.
]

However, in such areas of slight change, the bronchi and bronchioles may
be distended and filled with polymorphonuclear leucocytes, exfoliated
epithelium, and bacteria (Fig. X). It is, of course, possible that
infection of the parenchyma may recur from these sources. Here the
extent of involvement of the bronchiolar wall is variable and analogous
to those described previously. Occasionally, too, where the alveolar
change has subsided, the interstitial tissue, particularly that which
divides groups of neighboring lobules, may retain its increased size
with fibrous tissue framework spread apart by exudate and punctuated
with an occasional circumscribed purulent mass (92, 95, 110, 156) (Fig.
XXXVI). Such a miliary abscess within the lymphatics of the interstitial
tissue may compress the neighboring air sacs, themselves entirely free
of inflammatory involvement. That these strands of interstitial tissue,
the conduits for the lymphatics, are important barriers against the
spread of an inflammatory process from lobule to lobule by direct
extension, is evidenced by the extreme variation in the amount and type
of involvement in neighboring lobules (Fig. XXX). This variation is
repeatedly encountered and the band of interstitial tissue, often
prominent on account of its edema, separates these lobules the more
clearly. In all probability, the sharp demarcation of the lobular
consolidation as described in the gross picture depends upon the change
in the interstitial tissue which tends to localize the infection (93).
This fact suggests that the process within the pulmonary parenchyma
spreads along the bronchial tree rather than from lobule to lobule.

Sections from those areas of the lung where the involvement is more
marked may show a histological picture not unlike that described for the
aplastic stage, but, in addition, there are groups of lobules where the
exudate is typically purulent and pus cells not only form the greater
part of the exudate in the lumen, but are prominent in the distended
vessels of the alveolar wall (Fig. XXIX). Often these leucocytes are
multilobed and frequently their protoplasm is granulated with
phagocytized bacteria. The bacteria are also encountered free in the
alveolus along with other elements; namely, red blood cells, strands of
fibrin, or precipitated albumin (Fig. XXI). The bacteria, however, are
not particularly conspicuous, for generally they are either single, in
pairs, or in chains; and it is only when they become clumped to form
large masses, often larger than any normal tissue cell, that they
attract attention. When this appearance is encountered, the alveolar
wall is no longer distinct and well preserved. Although the wall may
still be made out, it often stains rather homogeneously and much of the
finer architecture is lost in the thrombo-necrotizing process that has
been instituted (Fig. XVII).

From this intermediary stage the picture of actual abscess with
mortification of bronchiolar and alveolar tissue, as well as of the
exudate itself, is readily approached (25, 48, 110, 140) (Fig. XXXI). In
the necrotic mass that forms the center of such a focus, the most
prominent feature is the bacteria. With hematoxylin they stain intensely
as black, irregular masses, and their prominence is accentuated by the
homogeneous staining qualities (with eosin) of the dead tissue, whether
lung or exudate (Fig. XXXII). These abscesses may have central cavities
which represent a discharge of their contents and may indicate the
position of a bronchiole (Fig. XXXI). The necrosis of the alveolar
walls, focal in its distribution as previously described, suggests
itself as a forerunner of the more extensive necrosis encountered at
this stage.

The most extreme form of mortification is seen in the wall of a
gangrenous cavity, and several layers can be distinguished there.
Beginning with that portion of the lung the least involved, the lesion
may be limited to congestion of the alveolar wall with a serofibrinous
exudate in the lumen, but this stage passes rather rapidly into another
where cellular exudate, chiefly of polymorphonuclear leucocytes,
predominates. Moreover, the leucocytes form not only the bulk of the
alveolar content, but also distend the vessels and accumulate in the
interstitial tissue around blood vessels and lymphatics. Passing toward
the center of the gangrenous cavity, the lung rapidly changes in
appearance. The blue zone of leucocytic infiltration makes more
conspicuous the inner area of necrosis—where nuclei no longer stain and
the alveolar wall is a homogeneous pink.

Gradually this phantom architecture, spotted only here and there with
disintegrating polymorphonuclear leucocytes, ends in a ragged compressed
border of a shaggy pink material which has no identifying qualities
(Fig. XXXV). In the inner zone of pink an occasional vessel or, at
times, a bronchiole more resistant to the process remains; frequently it
is accentuated by the presence of partially destroyed polymorphonuclear
leucocytes at its periphery. Probably these cells invade the necrotic
areas along the sheath of the bronchus or vessel and not across the dead
area. The thrombotic process described in the previous stage (Fig. LII)
associated with an acute arteriolitis, may be associated with these
gangrenous areas as well as with infarcts (82), but more likely gangrene
is preceded by the acute diffuse necrosis of the alveolar wall which
occurs in the fulminating cases. Furthermore, this is suggested where a
typical grey hepatization is associated with marked thinning, but not
actual disappearance, of the alveolar wall. Before concluding the
description of this stage of the disease, mention should be made of the
granular nodules of fibrin superimposed upon the swollen pleural cells
and also of the older pleural exudate, either typically fibrinopurulent
or more homogeneous with broken nuclear fragments (Fig. XXXVIII).


                               _Summary._

In this stage of the disease the respiratory change is characterized by
a localization of the inflammatory process with cellular invasion of the
exudate. Pneumonia results, varying in extent from peribronchial to
lobar, a pneumonia in which one of the most frequent complications is
necrosis of the lung. Consequently, abscesses, even gangrene, are found.


        (3) ORGANIZATION OF BRONCHIOLAR AND PNEUMONIC PROCESSES.

The processes described for the preceding group which involve not only
the alveoli, but also the bronchi and the bronchioles, were predicted
from the extensive hyalinization of these structures—a characteristic
change in the more fulminating and acute phases of the disease.
Likewise, it can be predicted that where death does not terminate the
process such lesions will be followed by organization, which, by
converting the exudate into scar, will produce deformities and offer
serious mechanical interference with the ingress and egress of alveolar
air and similar interference with the flow of blood through the
pulmonary circulation (82).

[Illustration:

  FIG. XXIV. AUTOPSY NO. 92. AN ALMOST PURE HEMORRHAGIC ALVEOLAR
    EXUDATE. COMPARE FIGURES VI, XXV, AND XXVI.
]

[Illustration:

  FIG. XXVI. AUTOPSY NO. 103. THE LARGER ILLUSTRATION OF AN HEMORRHAGIC
    ALVEOLAR EXUDATE IS ELABORATED BY TWO HIGHER POWER DRAWINGS. THESE
    SHOW (1) AN ANEURSYMAL DILATATION OF A CAPILLARY IN THE ALVEOLAR
    WALL AND (2a) A RUPTURE OF THE CAPILLARY WALL WITH THE ESCAPE OF RED
    BLOOD CELLS INTO THE ALVEOLUS; (2b) NECROSIS WITH EARLY THROMBOSIS
    OF THE CAPILLARY IN THE ALVEOLAR WALL.
]

It is probable that chronic processes, not sufficiently severe to
terminate fatally in a few weeks or months, may occur, but few examples
of that kind have been observed. A total of twelve cases of our series
in which organization of the bronchiolar (47), or alveolar exudate (156)
was found, include three of the lobar, three of the pseudolobar, two of
the lobular, and four of the peribronchial types. Such a
differentiation, it will be understood, is purely arbitrary. The
majority of the cases show, not only a reparative process, but also a
continuance of the acute change, and, indeed, both gross and microscopic
pictures of the lung may be complicated. It will be impossible to give
an inclusive description of these changes, and therefore a few of the
most diverse and characteristic will be presented in the form of case
abstracts.


_Autopsy No. 140._

  A white female, aged 19 years, entered the New Haven Hospital after
  five days of fever, prostration, and cough. She was moderately
  cyanotic and dyspnœic, but examination of the lungs was negative
  except for a few râles at the right base. She was delivered of a
  six-months’ fœtus two days later. On the eleventh day of her
  illness, definite signs of consolidation had developed in the
  midback on both sides and spread gradually to include the left base
  and all of the right back to the level of the 4th dorsal spine. The
  temperature varied irregularly between 100°F. and 105°F. The pulse
  followed the temperature, but averaged 102 per minute, while the
  respirations remained about 40 per minute.

  The white blood count on admission was 5,800, but rose gradually to
  28,320 cells per cubic millimeter, with 90% of polymorphonuclear
  leucocytes. The patient died on the twenty-second day of the
  disease.

  Post-mortem examination showed little of interest aside from the
  thorax. The left pleural cavity contained 75 cubic centimeters of
  slightly cloudy fluid. The right was almost completely obliterated
  by an organizing fibrinopurulent exudate which bound together the
  visceral and parietal layers. The left lung was partially collapsed
  and covered by a thickened pleura, bluish purple in color, which at
  the base and in the interlobar area was finely granular. Crepitation
  was present at the apex, the anterior surface, and the borders of
  the lung; elsewhere the consistency was increased. On section there
  was a frothy exudate from the apex and extreme base. These were deep
  red in color, while the intervening surface of the lung was paler,
  but broken by many small, white, elevated nodules which at first
  glance resembled tubercles (Fig. XXXIX). On close examination each
  of these was seen to have a small, depressed center from which pus
  could be expressed, and on dissection this was seen to be the wall
  of a bronchiole. The right lung was more voluminous and covered by a
  thick, grey, fibrinopurulent exudate except on the upper anterior
  border where there were a few small areas of interstitial emphysema.
  On section the pleural exudate was seen to be sharply demarcated
  from the lung parenchyma by a fine red line. The pseudotubercles of
  the other lung were here even more marked and from each exuded a
  yellow pus which partially obscured the pinkish-grey translucence of
  the surface (Fig. XL). The lumina of the larger bronchi were
  distended. The hilic and bronchial glands were enlarged and grey.

  Microscopic examination of sections from the lung showed an
  extensive bronchopneumonia. The alveoli of an occasional group of
  lobules were filled with serum or red blood cells, while still other
  areas showed foci of necrotizing pneumonia, actual miliary abscesses
  in which there were large clumps of bacteria (Fig. XLI). Throughout
  the sections, however, the striking change was an organization of
  the exudate, which varied from a few fibroblasts to a well defined
  connective tissue almost obliterating the normal architecture (Figs.
  XLI and XLIV). The alveolar walls in some areas showed edema only,
  in others they were almost replaced by a thin line of fibrous
  tissue, and in still others, by a hyperplasia of the epithelium
  which almost filled their lumina. The bronchi exhibited similar
  changes, their lumina were filled with an exudate of desquamated
  epithelium and leucocytes, which in some places was organizing (Fig.
  XI), and there was a regeneration of epithelium evidenced by a
  piling up of the cells and the presence of mitotic figures in them.
  The interstitial tissue showed some edema. The tracheal epithelium
  was intact, but a few leucocytes and lymphocytes were scattered
  through the submucosa.

  Pneumococcus Type II was recovered from the blood, pleural fluid,
  and lung. B. influenzæ was also demonstrated in the lung by smears
  and cultures.

In contrast to this example of a very diffuse, organizing pneumonia,
associated with a marked peribronchial organization where the illness
lasted for three weeks with hardly a remission throughout its course,
the following example of necrotizing and organizing lobar pneumonia may
be considered.


_Autopsy No. 183._

  A white male, aged 46 years, was admitted to the New Haven Hospital
  on January 9, 1919, complaining of “pneumonia.” The family history
  was unimportant. He stated that he was in the hospital twelve years
  ago with typhoid fever and again five years ago with acute
  cholecystitis.

  His present illness began two weeks previous to admission with
  chills, fever, anorexia, nausea, vomiting, and a slightly productive
  cough. He was prostrated and drowsy, but could not sleep. On
  admission his temperature was 101.5°F., the pulse 124, and the
  respirations 34 per minute. He was cyanotic and dyspnœic. The right
  chest showed signs of consolidation, and fluid below the 3rd
  interspace. The white blood count was 8,200 cells per cubic
  millimeter, 89% being polymorphonuclear leucocytes. The patient died
  eighteen hours after admission.

  The autopsy was held four hours after death and the essential
  findings were as follows:—

  Twelve hundred cubic centimeters of fibrinopurulent fluid were found
  in the right pleural cavity and the visceral and parietal pleura had
  a thick, yellow coat of fibrin. The right lung was voluminous,
  retained its shape on removal, and weighed 1,800 grams. The lower
  two lobes were consolidated and the upper lobe was atelectatic. On
  section the latter was slightly congested, but not consolidated. The
  lower two lobes were fairly smooth and grey, mixed with red areas,
  and exuded thick, sanguinous pus. They also showed several necrotic
  areas in the central portion and, in some instances, cavities 1
  centimeter in diameter filled with sanguinous pus had formed. The
  bronchi contained the same material, and on its removal a deep red
  mucosa was exposed. The left lung showed some fibrous pleurisy over
  its lateral, posterior, and diaphragmatic surfaces. There was a
  firm, puckered scar at the apex. The lung crepitated throughout, and
  on section was essentially normal except for moderately intense
  injection of the bronchi. The hilic nodes were enlarged, soft,
  succulent, moderately injected, and pigmented. The trachea was pale,
  but was covered by a mucopurulent exudate. The right side of the
  heart was moderately dilated. The spleen was not enlarged, but was
  softened and congested. The liver was pale, slightly decreased in
  consistency, and congested. The kidneys and adrenals showed cloudy
  swelling. The gall-bladder contained several stones, had a thickened
  wall, and was bound to the pylorus by firm, fibrous adhesions.

  Microscopic examination of the lung showed the alveoli filled with
  an acute inflammatory exudate in many stages of degeneration and
  hyalinization (Fig. XLII). Abscesses were frequent, but were for the
  most part small. A similar necrotic mass was contained in the
  bronchi. There were, however, features of the microscopic picture
  that outweighed those already described. The alveolar and
  bronchiolar exudates were everywhere being invaded by a young
  granulation tissue, rich in fibroblasts and capillaries. Mononuclear
  cells abounded in the new tissue. Even more striking than the
  mesodermal new growth was the epithelial proliferation which could
  be seen in many areas. It not only attempted to cover the denuded
  bronchial surfaces, but stretched over masses of exudate and
  granulation in the lumina and extended in tongue-like projections
  for a considerable distance into the surrounding lung tissue (Fig.
  XLVIII).

[Illustration:

  FIG. XXVII. AUTOPSY NO. 115. HERE THE HEMORRHAGIC CONSOLIDATION
    INVOLVES THE DEPENDENT PORTION OF THE LUNG; CONTRAST THIS WITH THE
    EDEMATOUS AND EMPHYSEMATOUS UPPER LOBE.
]

[Illustration:

  FIG. XXVIII. AUTOPSY NO. 118. THE CONSOLIDATION IS GREY IN COLOR AND
    LOBAR IN TYPE. IN THE CENTER OF THE HEPATIZED LOBE THERE IS A
    LARGE HEMORRHAGE. THE UPPER LOBE IS CONGESTED AND EDEMATOUS.
]

  Cultures of the blood, lung, and pleural fluid showed gram-positive,
  bile insoluble diplococci which formed chains, and morphologically
  and culturally were Streptococcus mucosus capsulatus.

These two examples differ widely in the distribution of the pulmonary
involvement. They show the acute inflammatory process persisting and
complicating the attempt at repair, which manifests itself, not only by
the formation of granulation tissue, but also by extensive epithelial
proliferation.

Still a third type of chronic lesion is manifested in Autopsy No. 209,
where the necrotizing and organizing process in the pulmonary parenchyma
is associated with typical saccular bronchiectatic cavities.


_Autopsy No. 209._

  A white woman, aged 55 years, was admitted to the New Haven Hospital
  complaining of weakness and ill health following pleurisy. For the
  past seventeen years she had suffered from a gradually progressing
  arthritis, which had resulted in marked deformity and disability.
  Five weeks before admission she became ill with chills, fever,
  cough, and pain on both sides of the chest. Thereafter, her general
  condition had gradually grown worse.

  Physical examination showed a markedly emaciated white woman with a
  high degree of arthritis deformans. Dullness and fine râles were
  present at the left apex. The temperature was but slightly elevated
  until three days before death, when it rose to 101°F. and slight
  dullness developed at the right base with bronchial breathing and
  fine râles. The white blood count, which on admission had been 9,200
  cells per cubic millimeter, rose to 15,000 per cubic millimeter. She
  died after a seven-weeks’ illness.

  At necropsy, with the exception of the joints, little of interest
  was found outside the thoracic cavity. On the posterior and
  diaphragmatic surfaces of both lungs fibrous adhesions were present
  binding the visceral to the parietal pleura. The right lung was
  moderately voluminous and grey in color over the upper lobe, but had
  darker red areas over the surface of the lower lobes. Patches of
  increased consistency were found in the lower part of the upper
  lobe, in the middle lobe, and at the base. On section there was a
  slight, red, serous exudate. The surface over the more solid areas
  was somewhat translucent, grey or light red, and was firm and not
  friable. The bronchi of the lower lobes were conspicuous, and at the
  extreme base so dilated as to give almost a honeycombed appearance.
  From them yellow pus exuded. The left lung was less voluminous and
  showed some increase in consistency throughout. In the lower lobe
  this was more uniform, but the upper had a shotty feeling. On
  section the upper lobe showed many hard or caseous nodules, with
  occasional patches of grey, gelatinous pneumonia. One small cavity
  was present about 3 centimeters from the apex. The lower lobe showed
  no gross evidence of any tuberculous process. Many pseudotubercles
  projected from the red surface, but from each pus could be expressed
  exposing the slightly congested wall of a bronchiole. At the extreme
  base two small cavities filled with yellow pus were present (Fig.
  L).

  Sections from the left upper lobe showed, microscopically, both a
  chronic and acute tuberculous process. Tubercles with a definite
  wall were present, but there were also large areas of caseation. The
  tissue between showed interstitial organization with mononuclear
  infiltration and occasional groups of leucocytes. The bronchial
  epithelium exhibited no marked change, but the bronchi were filled
  with pus cells.

  Sections from the left lower lobe and from the right lung showed
  both necrotization and organization. The alveoli contained an
  exudate, fibrinous, serous, and hemorrhagic, but predominantly
  leucocytic. There was slight necrotization of alveolar walls in some
  areas with infiltration of leucocytes in them and in the
  interstitial tissue. Several sections showed a marked degree of
  interstitial organization (Fig. XLVI). The bronchi were filled with
  a purulent exudate which sometimes involved the walls to form a
  peribronchial abscess. The walls of other bronchi showed great
  thickening with infiltration of both mononuclear cells and
  leucocytes, and many saccular dilatations were found (Fig. XII).

  The post-mortem blood culture showed a small, gram-negative,
  hemoglobinophilic bacillus (B. influenzæ). Cultures from lungs and
  bronchi yielded hemolytic streptococci, and Staphylococcus aureus
  was also present in the lung.


                               _Summary._

Of the ninety-five cases included in this report, twelve showed the
reparative process in a more or less marked degree. Furthermore, the
twelve showing organization had an illness averaging twenty-seven days
in duration, whereas for the eighty-three cases in which there was no
organization, the period of illness averaged nine days. Thus, it appears
that the early fatal termination of the disease in the latter group is
responsible for the absence of organization.

With one exception, when organization was encountered, the disease had
run a relatively acute course without marked remission until death. In
this instance, the fatal outcome was the result of an accident at a time
when all the clinical evidence pointed toward a subsidence of the acute
disease. The history of this patient is abstracted below, for it may
throw light upon possible relapse and upon late, chronic, respiratory
changes.


_Autopsy No. 163._

  A white male, aged 35 years, was admitted to the New Haven Hospital
  on December 5, 1918, complaining of “cough, pain in the chest, and
  headache.” For six days he had had fever, chills, and severe frontal
  headache, and for three days pains in the chest. He had also had
  “coryza” and epistaxis. The family and past histories were
  unimportant.

  The physical examination showed a well developed and well nourished
  male, who was slightly jaundiced and markedly prostrated. The
  conjunctivæ were injected. The heart, abdomen, extremities, and
  right lung were negative. In a small area outside the left nipple
  and extending into the axilla, tubular breathing and subcrepitant
  râles were heard, but no definite signs of consolidation were made
  out. The physical signs remained the same during the eight-day stay
  in the hospital. At entrance his temperature was 102.8°F. In twelve
  hours it fell to 100°F., then rose to 103°F., where it stayed for
  twenty-four hours, falling by lysis and remaining normal for the
  three last days. On his eighth day in the hospital, the patient
  suddenly collapsed and died within fifteen minutes.

  The autopsy was held one hour after death and the essential findings
  were as follows:—

  The peritoneal cavity contained 100 cubic centimeters of clear,
  straw-colored fluid and the viscera, particularly the liver, were
  acutely congested. The right side of the heart was greatly dilated;
  and on opening the pulmonary artery _in situ_ considerable blood
  gushed forth under pressure and a huge, tortuous embolus completely
  filled the vessel and its branches (Fig. LIII). The veins of the
  vesicoprostatic plexus on the right, and the right internal and
  external iliac veins contained thrombi, and it was evidently from
  this region that the embolus had been set free. The pleura of the
  lower third of the left lung over an oval area about 13 × 5
  centimeters was bound to the parietal pleura by pinkish-grey,
  translucent adhesions which were evidently of comparatively recent
  origin. Here the lung was firmly consolidated, but it was apparently
  normal elsewhere. On section the consolidated area was silvery grey,
  with a pink tinge, comparatively dry and smooth. In some areas,
  especially about the bronchi, delicate, silvery grey, translucent
  strands could be seen sweeping out into the surrounding lung, which
  contained no air. The remainder of the lung was air-containing. The
  trachea showed moderate congestion most marked near the bifurcation.
  The hilic lymph nodes were enlarged, soft, congested, and succulent,
  as well as anthracotic.

[Illustration:

  FIG. XXIX. THE VESSELS OF THE ALVEOLAR WALLS ARE CONGESTED AND
    CONTAIN A LARGE NUMBER OF LEUCOCYTES. THE EXUDATE IS COMPOSED
    ALMOST ENTIRELY OF WHITE BLOOD CELLS, IN THE BODIES OF WHICH
    INNUMERABLE BACTERIA MAY BE SEEN. COMPARE FIGURES XXI, AND XXXII.
]

  Microscopic examination of the viscera showed acute congestion and
  some degree of cloudy swelling in the liver and kidneys. The
  sections of the lung through the consolidated area showed the pleura
  replaced by a thick layer composed of large and small mononuclear
  cells, some red blood cells, a rare polymorphonuclear cell, and
  great numbers of fibroblasts and budding capillaries. Some of the
  alveoli contained many red blood cells, a few polymorphonuclear and
  mononuclear cells, some fibrin, and in many areas fibroblasts were
  organizing this exudate (Fig. XLV). Organization was also present
  around the bronchi and these contained mucus, pus, and desquamated
  epithelium. Frequently strands of fibroblasts were seen sweeping
  through the bronchiolar exudates, and in a few instances they had
  completely filled the lumina.




    II. INFLUENCE OF THE RESPIRATORY COMPLICATION OF INFLUENZA UPON
                        TUBERCULOSIS OF THE LUNG


Thirteen of the ninety-five cases included in this report occurred at
the United States General Hospital No. 16, one of the large tuberculosis
camps. In five instances the patients had active pulmonary tuberculosis.
The remaining eight were members of the detachment and may be added to
the eighty-two from the New Haven Hospital, making a total of ninety
cases in which there was no clinical evidence of active pulmonary
tuberculosis at the onset of the acute respiratory disease. When these
ninety cases are analyzed, it is found that only two of them show
definite activation of an old tuberculous focus (82). One has already
been referred to (Autopsy No. 209); the other, presenting a much more
acute exudative and ulcerative tuberculosis, deserves special
consideration.


  _Autopsy No. 194._

  A white female, aged 27 years, was admitted to the New Haven
  Hospital on November 8, 1918, complaining of “cold on the chest,
  fever, cough, and prostration.”

  The past and family histories were unimportant. Her illness began
  one week before admission with dizziness, headache, vomiting, cough,
  pains in back and legs, chilly sensations, and fever. She went to
  bed the day after. The acute onset became definitely worse and pains
  developed in her chest. On admission she was very weak, had a
  temperature of 101.4°F., a pulse of 120, and respirations of 40 per
  minute. The physical examination showed a very well developed and
  nourished woman who was cyanotic but not dyspnœic. The pharynx and
  tonsils were definitely injected. There were signs of consolidation
  at the base of the left lung. The pneumonic process gradually
  increased in the left, spread to the right, and involved the greater
  portion of both lungs. Otherwise the physical signs did not change
  greatly during her stay of thirteen weeks in the hospital.
  Thrombosis of the left femoral vein was diagnosed about two days
  before her death. The temperature curve was of interest. During the
  first two days in the hospital it remained at 104°F. For two weeks
  it was septic in character, being 102°F. in the morning and 104°F.
  in the afternoon. Then for thirty days it was practically constant
  at 102°F., only to become septic again, 98.6°F. in the morning and
  103.4°F. in the afternoon, and it remained so until death. The pulse
  curve ran essentially parallel to the temperature curve, varying
  from 100 to 140 per minute. The respirations varied between 46 and
  64 per minute.

  The sputum showed Type IV pneumococcus. The blood culture was
  negative.

[Illustration:

  FIG. XXX. AUTOPSY NO. 169 (LEFT) AND AUTOPSY NO. 97 (RIGHT). THIS
    CONTRAST IN THE EXTENT OF INFLAMMATORY INVOLVEMENT BETWEEN
    NEIGHBORING LOBULES IS FREQUENTLY ENCOUNTERED.
]

[Illustration:

  FIG. XXXIII. GANGRENE OF THE LUNG.
]

  The autopsy was held four hours after death. The body was markedly
  emaciated. The peritoneal cavity and its contents appeared normal,
  though the liver was low. The right pleural cavity contained 150
  c.c. of slightly cloudy, yellow fluid. The left was free from fluid.
  Both lungs were bound to the chest wall by silvery grey, translucent
  adhesions which were broken with slight difficulty. The right lung
  was heavy, voluminous, retained its shape on removal, and was
  consolidated throughout. Thick, creamy pus exuded from the cut
  trachea. For the most part, the lung was covered by a recently
  organized exudate several millimeters thick in which delicate blood
  vessels could sometimes be made out. Beneath the pleura of the lower
  three-fourths of the lung, were numerous, irregularly rounded,
  slightly elevated, opaque, greenish-yellow areas resembling
  conglomerate tubercles. These gave the lung a shotty or nodular
  feeling. In the lowest lobe several of these areas had fused and
  softened to form semifluctuant areas several centimeters in
  diameter. On section the lower two-thirds of the lung was studded
  with areas corresponding to those seen on the surface, which in many
  instances had broken down and formed irregular cavities filled by
  thick, green pus (Fig. LI). Between the green areas delicate strands
  of new-formed fibrous tissue could be made out in all parts of the
  lung. The bronchial mucosa was injected, the walls were irregularly
  thickened and dilated and they opened into the ragged cavities noted
  above. New-formed fibrous tissue was prominent along the bronchi.
  One chalky white, old, encapsulated, tuberculous focus was found
  near the apex of the left lung.

  Microscopically, there were two distinct processes found in the
  sections taken from various parts of the lung: an early miliary and
  exudative tuberculosis, and a necrotizing and organizing
  bronchopneumonia. Often the two processes were side by side, but
  sharply demarcated, in the same section. In others, they might be so
  intermingled that they could not be differentiated. The bronchi were
  filled with pus and often could be seen opening into large abscess
  cavities. The proliferation of the bronchial epithelium, as noted
  elsewhere, also was a striking feature in these sections. The
  pleural exudate was undergoing organization.

  Streptococcus hemolyticus was found in the cultures of the lung,
  blood, pleural fluid, and bronchi. In addition, the bronchi and
  abscess cavities also showed Type IV pneumococcus and Staphylococcus
  albus.


                               _Summary._

In this series of ninety-five cases, two examples of activation of an
old tuberculous focus by the acute respiratory process were encountered.
In both the pulmonary tubercular process was acute and played an
important rôle in the fatal outcome.




               III. EXTRARESPIRATORY LESIONS IN INFLUENZA


In all the fatal cases of influenza which came to autopsy, and this has
been the experience of others, the respiratory lesions, as indicated
above, occupy the foreground. Indeed, compared with other types of
respiratory disease, the lung involvement is so great that expression of
the disease need not be sought elsewhere to explain the cause of death.
However, there are general systemic changes which, even though
quantitatively inconstant, are sufficiently common and widespread to
support the view that the disease is a systemic one. The lesions of the
hematopoietic organs and those of the vascular system are the most
important and will now be taken up.


                 A. LESIONS OF THE HEMATOPOIETIC SYSTEM

There is ample evidence that both the lymphadenoid and myeloid tissues
of the body are affected. The lymph glands at the hilum of the lung
naturally are involved with the extensive pulmonary changes. Also, a
similar change may be found in distant nodes, perhaps associated with
drainage from focal lesions or perhaps brought about by general
intoxication.

The myeloid involvement is unassociated with focal lesions and finds its
early expression in the equation of the white blood cells of the
peripheral blood. The two groups of changes, those involving the
lymphadenoid and those of the myeloid structures, should be discussed
separately.


                        _Lymphadenoid Tissues._

By far the most extensive lesions are encountered in the lymph glands of
the lung and its hilum, and from here the mediastinal and deep nodes
along the trachea are affected to a greater or lesser extent. The glands
are very large and succulent (2, 157, 162, etc.). Very frequently,
indeed, they are hemorrhagic on cross section (34, 108) (Fig. XXXVII),
and there exudes a sanguinous fluid, usually thin and syrupy in
character. The cut surface projects slightly, and the edge of the gland
everts. The architecture is often obscured by hemorrhage—a diffuse red
color—but very frequently near the periphery, translucent or more
opaque, yellowish points are visible. Rarely, larger, opaque, yellow
foci are found in the gland; these may be softened and purulent in
exceptional cases (2, 47, 157).

Microscopically, the picture presented by the gland is that of a
non-suppurative lymphadenitis. The peripheral sinuses are markedly
distended and the channels through the gland share in the change (66).
The sinuses contain serum, red blood cells, and mononuclear cells for
the most part, but occasionally polymorphonuclear leucocytes are also
encountered. More rarely still, a megalokaryocyte finds its way into the
sinus. The most characteristic feature is the presence of phagocytosed
cells,—a picture comparable with that found in the typhoid lymph node.
The nuclei of the phagocytic cells are vesicular and usually stand out
sharply in contrast with the pyknotic nuclei of the included cells.
There is conclusive evidence that the phagocytes arise from the lining
cells of the channel wall, as in typhoid fever, for these cells are
frequently in process of division (Fig. LIV). The blood vessels of the
lymph gland, greatly congested, contain almost exclusively red blood
cells. As a rule, the lymph follicles and the lymph cords take little
part in the process. If there is any change in these structures, it is a
rarefication. Occasionally, hemorrhage is encountered in a follicle or
even in a cord, and this hemorrhage may involve not only the cells of
the cord, but its supporting reticular structure, and may form the
nucleus of a subsequent necrotizing or suppurative focus.

[Illustration:

  FIG. XXXI. AUTOPSY NO. 100. ACUTE FULMINATING BRONCHIOLITIS AND
    BRONCHOPNEUMONIA. NOTE THE NECROTIC ALVEOLAR WALLS AND THE MASSES OF
    BACTERIA IN THE EXUDATE. COMPARE FIGURES VIII, XVII, AND XXXII.
]

The picture that has been detailed is subject to modification in those
cases particularly where a leucocytic reaction is associated. Then,
there may be more polymorphonuclear leucocytes in the sinuses, and
necrotizing foci may be converted into miliary abscesses.

The change in the bronchial lymph glands cannot be considered other than
an expression of an aplastic, inflammatory reaction. It finds an
analogue especially in diseases like typhoid fever. The most constant
picture includes an edematous, hemorrhagic reaction in which there is
phagocytosis of sieved-out cells by the scavengers generated within the
gland. Where necrosis or suppuration occurs, and this is rare, it may be
considered as a complication.

Elsewhere in the body, the lymph glands rarely show the same degree of
change as those of the thorax. The same general picture, however, is
present to a greater or lesser extent, except that extensive necrosis
and suppuration have not been encountered.

The lymphadenoid tissues of the alimentary canal share in the process
only to a minor extent. In a number of cases, there is no question that
the Peyer’s patches and solitary follicles are hyperplastic. Grossly,
they stand out prominently, and are pale pinkish-grey in color.
Histologically, there is hyperplasia, chiefly apparent from the large
germinal centers in the follicles, and a slight distention of the lymph
channels. This picture, so commonly found in every type of general
infection, is in no way characteristic of influenza.


                               _Spleen._

The spleen is the seat of the usual manifestations in generalized acute
infections. In no case is the organ markedly involved, although
considerable increases in its size may occur (2, 108, 141, 157, 162). It
is not feasible to introduce a detailed discussion of this mild grade of
splenic tumor, for there are natural variations in the size of the
spleen and frequently it is modified in this respect by subsidiary
conditions. In every instance the capsule of the spleen is smooth and
there is no acute or chronic perisplenitis attributable to influenza.
The capsule usually retracts slightly and the splenic pulp, in slight
excess, is much more frequently red or garnet than grey in color.
Occasionally, the splenic tumor is grey as in pneumonia. The more minute
changes in the organ consist of congestion of the sinuses, increase of
the mononuclear cells of the pulp, and prominence of the germinal
centers of the Malpighian corpuscles (140). Hemorrhages, found
occasionally (47), are more frequent in the pulp, but also occur in the
corpuscles.


                             _Bone Marrow._

One of the clinical features of influenza is a leukopenia, which
persists often in the face of acute pyogenic pulmonary infection (12,
138, 143, etc.). In this series of ninety-five cases, the vast majority
had this type of blood picture, but occasionally a leucocytosis (14) was
demonstrable even during the early part of the disease and in those
cases which terminated fatally within a period that may be called acute.
In almost all instances where fatal termination was delayed, the
leucocyte count ultimately was elevated either with remission or to a
constant high level. The blood studies have not been sufficiently
complete to allow further discussion, though there is reason to believe
that these might have yielded interesting results. The blood changes in
this series are similar to those presented in the reports of the
epidemic from other sources.

In the majority of cases where the marrow was studied, it was aplastic
(12). Occasional, focal, hemorrhagic lesions of the marrow (47) similar
to those discussed below in the skeletal and parenchymatous systems were
encountered and there was an apparent increase in the number of
megalokaryocytes. The usual hyperplasia of the myeloid elements of the
marrow associated with pyogenic change was not present.


       B. LESIONS OF THE BLOOD VESSELS AND ELSEWHERE IN THE BODY

Here, as in the discussion of the involvement of the lymphadenoid
tissue, the most outspoken changes are in the thorax. Frequently thrombi
are encountered in the vessels of the lung (34, 138). This does not
include the capillary thrombi associated with damage to the alveolar
walls already discussed. It has not been possible to demonstrate an
association between the hemorrhagic, infarct-like foci in the lung and
these vascular complications (47). The thrombi, histologically, are most
frequently propagated, but occasionally an indication of their etiology
is found in a destructive lesion of the vessel wall (19, 47, 50, 108,
156). This arteritis or phlebitis may be embedded either in a pneumonic
zone or in relatively normal lung. The vessel wall may be obscured by a
cellular infiltrate throughout its circumference or only at one point.
The cells, on account of karyorrhexis often difficult to identify, are,
partly at least, polymorphonuclear leucocytes, and the thrombus which
forms upon the inflammatory nucleus, as a rule, is fairly rich in these
cells (Fig. LII).

This vascular lesion may involve either artery or vein and may be found
either within the lung or at distant points. Not infrequently, pulmonary
embolus terminates influenza. One instance of this is incorporated in
the group of chronic influenzal cases detailed above (Fig. LIII). In
this instance, the thrombus originated in the right iliac veins; and,
although no attempt was made to demonstrate the primary vascular lesion,
so many similar cases are recorded (7, 82), and vascular damage is so
frequent in this disease, that the hypothesis attributing pulmonary
embolus to a thrombus initiated by a phlebitis is strongly supported.

Parenchymatous and skeletal lesions of hemorrhagic type, although
variable quantitatively, are frequent and involve the muscles, the
parenchymatous organs,—the adrenal especially,—and the mucosa of the
alimentary canal. They have been described already with regard to the
pleural surface and they may occur in other serous membranes.

[Illustration:

  FIG. XXXII. AUTOPSY NO. 100. A HIGHER MAGNIFICATION OF THE LESION
    ILLUSTRATED IN FIGURE XXXI. THE ALVEOLAR WALL IS ENTIRELY NECROTIC:
    BACTERIA AND POLYMORPHONUCLEAR LEUCOCYTES ARE ABUNDANT.
]

[Illustration:

  FIG. XXXIV. AUTOPSY NO. 87. CROSS SECTION THROUGH THE AREA OF GANGRENE
    SHOWN IN FIGURE XXXIII.
]

[Illustration:

  FIG. XXXV. AUTOPSY NO. 160. MICROSCOPIC DRAWING OF THE GANGRENOUS
    CAVITY ILLUSTRATED IN FIGURES XXXIII AND XXXIV.
]

Only two examples of hemorrhage in the recti muscles[11] were
encountered in the ninety-five autopsies. In other localities this
lesion has not only been more frequent but also more extensive (2, 47,
50, 128, 140, etc.). However, it has been fortunate that the two
instances in this series represent a fresh hemorrhage and the healing
lesion, respectively. The fresh hemorrhage is quite characteristic of
Zenker’s necrosis involving muscles. Grossly, it is a small lesion and
does not involve the entire width of the rectus muscle, as may happen,
with a resulting rupture of this structure (12, 162). Microscopically,
many of the muscle cells have lost their striation, are irregularly
swollen, and, as fractures in them indicate, are apparently brittle.
Between the muscle fibers and where these are lacking, the predominating
element of exudate is the red blood cell, but there is a considerable
amount of fibrin and also some serum between these cells (Fig. LVI). The
absence of polymorphonuclear leucocytes is noteworthy. The second
example of a muscular lesion occurred in a patient who died on the
twenty-fifth day of the disease. Grossly, this also was a small lesion,
although the muscle fibers at its site were obviously ruptured.
Histologically, the lesion is a healing one. Regeneration of the muscle
fibers (47, 156), as illustrated by the formation of typical spindles,
is handicapped by the rapid development of the fibrous scar (Fig. LVII).
Suppuration had not occurred and this also has been true for the focal,
hemorrhagic, inflammatory processes which were encountered in many
different localities throughout the body.[12]

Perhaps the focal hemorrhagic lesions were most frequent in the adrenal
gland. Generally, they were located in the cortex, although medullary
hemorrhages were encountered. The extent of the process varied from
minute hemorrhages, associated with necrosis of only a few cells, to
extensive ones involving half of the adrenal. The microscopic
examination of the exudate revealed the same elements and in
approximately the same proportions as described for the similar process
in the muscles. Not infrequently, mitotic figures in the adrenal cells
indicated an attempt at repair of a minute damage.

Hemorrhages in the mucosa of the alimentary canal, including the stomach
and intestines, similar to those so common at the post-mortem table in
many different types of acute infectious disease, are, of course, common
in influenza; but, in one case especially, a lesion was encountered
which adds significance to these hemorrhages (47). Here areas of mucosa,
usually round or oval and varying from one-half to two centimeters in
diameter, often with ulceration in their centers, show, microscopically,
bacterial emboli in the vessels of the mucosa with a hemorrhagic
effusion which obliterates the architecture of this coat and extends at
some points into the submucosal and muscular layers (Fig. LVI). Here,
the occurrence of bacterial emboli in association with the lesion
suggests that they may be etiologically related to similar processes in
other parts of the body.

The above example of hemorrhage in the mucosa of the alimentary canal
has seemed of especial interest, not only for its possible value in
explaining the etiology of the lesion here and elsewhere, but as an
interpretation of the findings in Autopsy No. 185, an abstract of which
is appended below. There a hemorrhagic lesion in the wall of the urinary
bladder led to rupture and brought the patient to the surgical clinic of
the hospital.


_Autopsy No. 185._

A white female, aged 46 years, was admitted to the New Haven Hospital on
January 4, 1919, complaining of “cough and headache.” Five days
previously she had a “cold” that she was able to “break up” with quinine
and aspirin. The “cold” recurred two days ago, and since then she has
had “frequent chills, aches all over, and feels weak.” Her family and
past histories were unimportant.

Physical examination on admission showed congestion of the pharynx.
Below the inferior angle of the scapula on the right, there was
dullness, bronchovesicular breath sounds, and a few fine râles. The
examination was otherwise negative. Three days later the signs in the
lungs disappeared. The next day, after an attack of coughing, she
complained of something having “burst” within her abdomen and of
generalized abdominal pain. A diagnosis of ruptured bladder was made and
1,400 cubic centimeters of bloody urine were withdrawn by catheter.
Immediate operation was decided upon and the bladder was found a hand’s
breadth above the symphysis pubis; the posterior wall was very thin and
presented a tear extending from the trigone upward in the mid line for 7
centimeters. Fully 500 cubic centimeters of clotted blood and urine were
removed from the pelvis, but there was no marked evidence of
peritonitis. A permanent mushroom catheter was placed in the urethra,
and the tear was sutured. The abdomen was closed with provision for
drainage. The patient was returned to the ward in doubtful condition.

Her temperature at entrance was 104°F., and it fell by lysis to 99°F.
just before operation. After the operation it fell to 97°F., and in a
few hours rose to 99°F. Thirty-six hours after operation she had a chill
lasting ten minutes, and her temperature rose to 105°F. in eight hours,
when death occurred. The respirations were thirty per minute until the
rupture of the bladder when they rose to forty per minute and
corresponding to the final rise in temperature rose to 60 per minute.
The pulse ran a parallel curve to the temperature, ranging from 100 to
160 per minute.

The autopsy was held two hours after death, and the essential findings
were as follows:—

The body was that of a moderately obese woman. Rigor mortis had not
developed, but there was a distinct heliotropic hue of the face and
neck. The recent surgical wound between the symphysis pubis and
umbilicus was in good condition. The peritoneum was slightly dulled in
the lower half of the abdomen, and there was about 100 cubic centimeters
of faintly cloudy, blood-tinged, thin fluid in the pelvis. The left
pleural cavity contained about 200 cubic centimeters of slightly turbid,
amber fluid, but the right side was free from fluid. While the pneumonia
had not been prominent clinically, both lungs were found extensively
involved by a necrotizing and organizing bronchopneumonia with purulent
bronchitis similar to what has already been described. As the lesion of
the bladder is the distinctive one in this case, and as the other organs
show nothing that has not been described elsewhere, further description
will be confined to it.

The wall of the bladder was thin and soft, and grossly the sutured wound
appeared in good condition. Posteriorly there was a hemorrhagic zone
about 3 centimeters in width most marked beneath the mucosa, but
involving all of the coats. The mucosa was superficially ulcerated along
this area, and was covered by a thin, patchy, fibrinous exudate. In
addition, there were scattered beneath the mucosa several smaller
hemorrhagic foci, quite distinct from the larger one.

Microscopically, one striking feature was the erosion of the mucosa,
with hemorrhages most marked along the line of rupture but occurring
elsewhere in the subjacent tissues. This condition was found in all the
sections studied. Another feature was the lack of inflammatory exudate
and the very slight attempt to repair the injury, only a very rare
polymorphonuclear cell and fibroblast being seen. Sections of the
peritoneum showed only a patchy deposit of fibrin with a rare
polymorphonuclear cell.


                        C. MISCELLANEOUS LESIONS

In this series of cases lesions elsewhere in the body are not
sufficiently constant or important to merit emphasis.[13] Hemorrhages
have been found occasionally in other structures, especially the testes.
The usual cloudy swelling of the parenchymatous organs is, of course,
marked, and in many cases has been associated with actual cellular
necrosis both in the liver and the kidney. Such necroses are usually
focal, and occasionally mitotic figures in the cells of the renal
convoluted tubules or in the liver may be a similar expression of
previous damage. Acute nephritis was not found in our series.[14] The
swollen liver cells often show the bile canaliculi clearly, and this
appearance may be associated with a variable degree of jaundice which
has been found frequently, although the explanation of the jaundice is,
in all probability, an hemolysis of the red cells caused by the
infecting microorganisms. The only other lesion encountered and of
sufficient importance to mention, has been the congestion of the
membranes of the brain and a swelling of the cerebral substance, in all
probability dependent upon edema. One example of purulent meningitis was
encountered.[15] The dilatation of the right side of the heart with a
greater or lesser degree of splanchnic engorgement is such a common
feature in acute pulmonary diseases that it is hardly worthy of detailed
discussion.

[Illustration:

  FIG. XXXVI. AUTOPSY NO. 133. A SMALL ABSCESS IN AN EDEMATOUS BAND OF
    INTERLOBULAR CONNECTIVE TISSUE.
]

[Illustration:

  FIG. XXXVII. AUTOPSY NO. 114. ILLUSTRATES AN UNUSUAL ANATOMICAL
    PICTURE IN INFLUENZA—AN EXTENSIVE FIBRINOPURULENT PLEURISY. THE
    BRONCHIAL LYMPH GLANDS ARE PROMINENT ON ACCOUNT OF THE HEMORRHAGIC
    INFLAMMATORY PROCESS WHICH HAS INVOLVED THEM.
]

A striking feature of influenza is the occurrence of abortion in cases
complicated by pregnancy. Of the ninety-five cases included in this
report, twenty-seven were women of whom three died undelivered (three
months, six months, term), three had suffered complete abortion (one,
three months, and two, six months), and one (six months) was in process
of abortion. It is not our purpose to discuss the relation between
pregnancy and this complication. Here it is desirable simply to point
out that, although in the non-complicated cases of influenza, pregnancy
does not influence the course of the disease, if pneumonia supervenes,
the mortality for the mother, as well as for the child, is definitely
increased (57, 148, 164).

A specific placental lesion would be difficult, indeed, to establish
since hemorrhage is a part of the normal process of placental
separation. However, the hemorrhagic lesion of influenza seems a
plausible explanation for the frequency of abortions in this disease.


                               _Summary._

The most important extrapulmonary lesions in influenza are those of the
hematopoietic and the vascular systems. The first are typical of a
general non-suppurative, inflammatory process, and are characterized in
the majority of cases by a picture not unlike that encountered in
typhoid fever, although the hyperplasia of the lymphadenoid tissues, as
seen in the latter disease, is not present. The more important lesions
are associated with the vascular system; phlebitis and arteritis occur,
but are not so frequent as hemorrhages in the skeletal system, in the
parenchymatous organs, and in the mucous membranes of the hollow
viscera. These hemorrhagic necroses may be etiologically associated with
capillary bacterial thrombi.




 IV. COMPARISON BETWEEN THE RESPIRATORY LESIONS OF INFLUENZA AND THOSE
             INITIATED BY THE INHALATION OF POISONOUS GASES


Immediately preceding the advent of the influenza epidemic in New Haven,
there had been completed in this laboratory the experimental studies of
the effects of a large number of different toxic gases upon the
respiratory tract. This was begun with the support of the Bureau of
Mines, and subsequently, after the formation of the Chemical Warfare
Service, the work received the support, not only of this branch of the
Army, but also of the Surgeon General’s Office. Exceptional
opportunities for animal experimentation were offered. Every stage of
the inflammatory process in the respiratory tract was studied, from the
most acute, a few hours after the exposure of the animal to a high
concentration of gas, to the very chronic types that resulted from
sublethal concentrations and led to lesions encountered at the sacrifice
of the animals many months later.

The criticism will unquestionably be introduced, that with the
anatomical picture of the respiratory lesions initiated by irritating
gases freshly in mind, an analogy between them and those of the
pulmonary lesions of influenza may not be impartially drawn. However,
such fundamental and striking similarities exist between the two
processes (128) that the argument is simplified.


A. THE INFLAMMATORY RESPONSE VERSUS THE SYSTEMIC CAPACITY TO COMPENSATE

Symmers (141) and Oberndorfer (108) have already likened the influenzal
pulmonary complications to plague pneumonia, and it is quite possible
that others will find fundamental similarities with other fulminating,
inflammatory reactions. Inflammation, a series of processes manifested
after injury by a tissue which still retains its viability, is modified
by another important factor usually neglected; namely, the state of the
host. As a consequence, the inflammatory reaction might readily have
similar manifestations even though the primary exciting agents are
diverse. This has been amply demonstrated for many different reactive
processes, and still it may be considered as a challenge for those who
are of the opinion that specific bacterial agents necessarily produce
characteristic anatomical manifestations. Consider the state of
knowledge of the various reactions to the tubercle bacillus before this
microorganism was isolated; and then bear in mind that we are dealing
here with a disease whose causative agent, despite the present
uncertainty regarding its specific nature, produces a lesion that paves
the way for the invasion of the respiratory tract by many different
organisms. The extent of the reaction may depend upon the systemic
capacity to compensate, as well as upon the degree of primary damage in
a specific system of organs. Unquestionably, these two factors must take
their places in the balance, the opposite pan of which contains the one
or the other secondary bacillary invader.

[Illustration:

  FIG. XXXVIII. THE UPPER ILLUSTRATION, AUTOPSY NO. 116, SHOWS A FRESH,
    FIBRINOPURULENT PLEURAL EXUDATE. THE PLEURAL LINING CELLS ARE
    SWOLLEN AND CONSPICUOUS. THE LOWER ILLUSTRATION, AUTOPSY NO. 100,
    SHOWS ANOTHER AND LATER TYPE. THE ELEMENTS OF THE EXUDATE HAVE
    DISINTEGRATED TO FORM A MUCILAGINOUS MASS. COMPARE FIGURE XXXVII.
]

[Illustration:

  FIG. XLI. AUTOPSY NO. 140. IS A LOW POWER DRAWING OF THE
    CHARACTERISTIC LUNG IN THE MORE CHRONIC STAGE OF THIS DISEASE.
    NECROTIZING AND ORGANIZING BRONCHIOLITIS AND PERIBRONCHIOLITIS ARE
    ASSOCIATED WITH AN ORGANIZATION OF THE EXUDATE IN THE ALVEOLI. THE
    ORGANIZATION PROCESS IS SOMEWHAT OBSCURED BY THE EDEMA. COMPARE
    FIGURES XI, XXXIX, XI, AND XLIV.
]

[Illustration:

  FIG. XXXIX. AUTOPSY NO. 140. RIGHT LUNG. THE HISTOLOGY OF THE
    PULMONARY CHANGES IN THIS CASE IS ILLUSTRATED IN FIGURES XI, XLI,
    AND XLIV. THE NECROTIZING PERIBRONCHIAL FOCI STAND OUT PROMINENTLY
    AND THE ORGANIZATION OF THE EXUDATE IN THE SURROUNDING ALVEOLI IS
    ALSO DISTINCTLY SEEN IN THE ABOVE FIGURE.
]

Scientific medicine has reached that evolutionary period where, in
addition to the specific infecting microorganism, associated etiological
factors find an important place in the interpretation of a disease. More
and more attention is being directed toward the latter factors and the
rôle they play in respiratory infections. Many different factors open
the pulmonary portal for organisms and, in this way, terminate by a
serious respiratory inflammatory complication what otherwise might have
been a relatively mild disease. In the past two years this has been
demonstrated for measles.

For the above reasons, not only the immediate action but the
complications and sequelæ, too, of the inhalation of irritating gases by
normal healthy animals, emphasize themselves as a framework for a more
comprehensive interpretation of respiratory disease in general.


                         B. THE PRIMARY INJURY

With few exceptions, the gases studied have their most marked effect
upon the respiratory tract. They differ, however, in the localization of
the lesions and in the extent of the damage. For instance, mustard gas,
in high concentrations, has a necrotizing effect upon the entire
respiratory tract even to the pulmonary parenchyma itself. Inhaled in a
more dilute form it involves the larynx and the trachea and has spent
itself before the lung is reached. With phosgene, the opposite is true.
The upper respiratory tract is only slightly involved. The outspoken
lesions involve the bronchioles, the ducti alveolares, and extend to the
alveolar walls of the lung. Chlorine, while it produces a less severe
lesion of the upper respiratory tract, extends more often through all of
the ramifications of the tracheal tree to the lung.

With vital stains (trypan blue), it may be readily demonstrated that
these gases kill the epithelium of the respiratory tract and extend
through this superficial cellular coat to the deeper tissues of the
bronchiolar wall and to the lung tissue, killing it entirely, just as a
corrosive chemical destroys the wall of the stomach.

When chlorine and phosgene reach the lung, an intense reactive process
follows immediately. The congestive changes, the hemorrhage into the
pulmonary parenchyma both in the alveoli and in the subpleural and
interstitial tissues, and the albuminous rich, serous exudates occupy
the foreground of the acute picture and are associated clinically with
intense cyanosis, great dyspnœa, hemorrhage, bronchorrhea, and also with
pulmonary and subcutaneous interstitial emphysema. The microscope
reveals a hyalinization of the walls of the bronchioles or ducti
alveolares which are distended during this acute period and form a
picture that is very unusual in the more frequent types of respiratory
inflammation. It shows also a hyalinization of the alveolar walls,
usually those in direct continuity with the larger air passages. The
interstitial edema and hemorrhage, often perivascular in distribution,
is only overshadowed by the thick, almost colloid-like material within
the alveolus itself. Fibrin stains at this stage show this exudative
element in surprisingly large amounts. Fibrin not only covers the
alveolar wall, but crosses this structure and often forms intracapillary
plugs. In fact, besides the red blood cells, the serum and the fibrin,
one often sees, not only an excess of polymorphonuclear leucocytes in
the vessels of the lung, but these appear in process of migration within
a few hours after the animal has been exposed.

Animals surviving this stage often succumb later with a typical
pneumonic process. Although frequently pseudolobar, the process may
be lobar in extent, and as time goes on more definite lobular
involvement is frequently encountered. With the localization of the
inflammatory process, the general edema, congestion and milder
reactions in other portions of the lung tend to subside, and may be
entirely absent in a few days. The clinical picture, in the
experimental animal at least, also assumes a more typical expression
of respiratory infection,—leucocytosis, chlorine retention, etc.,
appear. Often the pneumonias, both lobar and lobular, are
complicated, grossly, by softening, and histologically, by
necrotization of the bronchiolar and alveolar walls. Recrudescence
of the active pulmonary infection is not uncommon, and perhaps is
associated with these focal necrotizing areas.


  C. THE TENDENCY TO ORGANIZATION OF BRONCHIOLAR AND ALVEOLAR EXUDATES

The sequelæ after exposure to gas may be markedly delayed. They occur,
not only in animals which have exhibited characteristic acute symptoms,
but also, and especially with phosgene, where no serious immediate
clinical effects followed exposure to the gases. They are dependent upon
the fact that the pneumonic process has a very striking tendency to
undergo organization, a process which involves not only the exudate in
the alveoli, but also that within the bronchioles. The organizing
process may be present in both these portions of the lung or may be
confined to the bronchiole alone, and lead to a progressive interference
with the ingress and egress of alveolar air, so that atelectasis and
emphysema become permanent, and in turn lead to narrowing of the
vascular bed, ultimately producing right-sided cardiac decompensation.
Bronchiectases also occur; they may be tubular, associated with
organization of the pneumonic process in their vicinity, or saccular if
death has not followed the destruction of the bronchiolar wall.

Compare this picture with that of influenzal pneumonia and its sequelæ;
in both there is, first the acute diffuse involvement of the lung,
initiated by, or occurring simultaneously with, an acute
tracheobronchitis and presenting clinically dyspnœa, cyanosis,
blood-stained, abundant sputum, and even interstitial emphysema; next,
the tendency for the pneumonic process to localize and to necrotize; and
finally, if the acute period is survived, organization of the pneumonic
and bronchiolar exudates with resulting bronchiolitis and
bronchiectasis. With even more minute comparison, the resemblance is
sustained. The initial or early dilatation of the ducti alveolares, so
characteristic in gas poisoning, also occupies the foreground of the
histological picture in influenza. These dilated structures are the more
prominent on account of the red, ribbon-like strands that cover the
surface and often involve the walls. Similar necrotization, varying in
its depth even to involve the whole of the alveolar walls, occurs in
both of these conditions. Similar hemorrhages in the early stage,
rupture of the alveolar wall with interstitial and subcutaneous
emphysema, necrotization, gangrene, and organization in the same
localities, characterize the two lesions, and are not found with the
same uniformity in any other type of respiratory disease.


 D. THE IMPORTANCE OF THE TRACHEA AND ITS RAMIFICATIONS AS A PROTECTIVE
        MECHANISM AGAINST INFECTION OF THE PULMONARY PARENCHYMA

In gas poisoning it has been demonstrated that the initial damage to the
epithelium of the larger air passages is followed by an invasion of the
pulmonary parenchyma by the bacteria of the mouth. Repeated cultures
from the mouth before the exposure of the animal to gas have been
followed by the recovery of the same organisms, including the
pneumococci, the streptococci, the staphylococci, and a gram-negative,
hemoglobinophilic, small bacillus from the pneumonic lung. They find
their way into the lung after the destruction or incapacitation of the
protective mechanism (70) of the upper respiratory tract,—into a lung
which has been so damaged by the irritative gas that bacteria innocuous
in the normal pharynx now find a favorable medium for their development.
The inflammatory reaction which develops into pneumonia, perhaps
necrotizing, perhaps later organizing, can only be explained by the
combined action of the corrosive gas and the organisms saprophytic in
the normal mouth, but now pathogenic in varying degrees in the lung
whose vital reactions have either been inhibited or impaired by the gas.

[Illustration:

  FIG. XL. AUTOPSY NO. 140. LEFT LUNG. THE HISTOLOGY OF THE PULMONARY
    CHANGES IN THIS CASE IS ILLUSTRATED IN FIGURES XI, XLI, AND XLIV.
    THESE PROCESSES, ILLUSTRATED IN FIGURE XXXIX, ARE ACCENTUATED AND
    THERE IS ALSO AN ORGANIZATION OF THE EXTENSIVE PURULENT PLEURISY TO
    BE MADE OUT IN THE ABOVE FIGURE.
]

There is no reason why this analogy should not be drawn, no reason why
we should not consider that the unknown etiological agent in influenza
produces a similar injury to, or even destruction of, the protective
mechanism of the respiratory tract. Similarly, gas and influenza damage
the pulmonary parenchyma itself, so that the bacteria of the air and of
the mouth which find their way into the damaged lung[16] initiate
processes and produce complications which may not be distinguished.




       V. PECULIARITIES OF THE HISTOLOGY OF INFLUENZAL PNEUMONIA


             A. THE EXTENT OF THE INITIAL PULMONARY LESION

One of the features differentiating the pneumonic process in influenza
from the usual types of inflammation of the lung, is diffuseness (90).
In the early cases especially, or in cases which terminate fatally at an
early period, both lungs are often involved, and, on histological
examination, only a small portion of the pulmonary parenchyma is found
unaffected. The exudate, largely acellular, presents serum as its most
conspicuous feature. The picture is one of a patchy pneumonia with
intermediary areas of what might be called edema, although fibrin is
often demonstrable in the coagulated, albuminous material. So little
attention has been paid to earlier stages of the usual types of
pneumonia, for example lobar, that it is impossible to say whether or
not diffuse involvement of the pulmonary parenchyma initiates the
process which later becomes localized in one or more lobes. The initial
edema of influenzal pneumonia is the expression of a widespread
irritation. If the injury has not extended deeply, the edema may
disappear within a relatively short time, and exfoliated lining cells
fill the alveoli; those remaining in their normal position are
frequently in process of division (Fig. XLVII). It is conceivable—and
the view has already been announced—that this edema is a disseminating
factor and perhaps responsible for the diffuseness of the pneumonic
process which may follow. If the fluid is simply a serous exudate, it
may play no essential rôle in the severe acute symptoms manifested by
these patients, for it has been shown, both in the experimental lesions
induced by pulmonary irritating gases and by pulmonary irrigation
through which extensive artificial edema of the lungs may be attained,
that the presence of fluid in the lung in itself is not harmful (161).


                       B. THE HEMORRHAGIC EXUDATE

Another striking feature of the inflammatory process in this disease is
the extensive hemorrhagic exudate expressed clinically in the fresh, red
blood of the abundant sputum. In the tissues the blood is always fairly
well preserved. It may be scattered diffusely through the cellular
exudate (Fig. XXIV) or so abundantly that the area resembles an infarct
(Fig. XXV). These hemorrhagic foci, which vary considerably in size, are
found not only in the cases that terminate fatally within a few days,
but may occur at any time during the acute manifestation of the disease.
They are an exaggerated form of red hepatization and it is difficult to
see how such red foci could ever change to areas of grey pneumonia. It
is a widely accepted statement, in textbooks of Pathology at least, that
the stage of red hepatization in pneumonia follows the period of
engorgement and precedes the grey form. This interpretation is open to
question concerning the lesions that are encountered in influenza, as
well as in those that are seen after gas inhalation. Unquestionably, in
the stage of engorgement the lung has a red appearance, enhanced by the
acellular, serofibrinous exudate in the alveoli through which the
greatly congested vessels are seen. At this stage, the lung has a
translucency on gross examination, which is not the case when the
cellular content of the alveoli is increased. This picture is not the
one spoken of most commonly as red hepatization; for, although it
appears as a relatively red lung in the gross, difficulty is encountered
in its histological correlation, for the exudate is composed, not of red
cells, but largely of serum and fibrin. The red color may persist even
when numerous polymorphonuclear leucocytes and desquamated alveolar wall
cells are within the alveoli, the walls of which are markedly engorged.
Later, as the circulation in the pneumonic zone is impaired, the
alveolar exudate determines the tone of the gross color, and a
considerable number of red blood cells may be overshadowed by the larger
percentage of white ones.

[Illustration:

  FIG. XLII. AUTOPSY NO. 133. IS A MUCH LATER STAGE OF THE PROCESS SHOWN
    IN FIGURE XXXI. ASSOCIATED WITH THE ENCAPSULATED BRONCHIOLAR AND
    PERIBRONCHIOLAR ABSCESS, THERE IS A DIFFUSE ORGANIZATION OF THE
    EXUDATE IN THE SURROUNDING ALVEOLI.
]

[Illustration:

  FIG. XLIII. THE ALVEOLAR WALLS ARE THIN AND THE EXUDATE OF RED BLOOD
    CELLS AND DESQUAMATED EPITHELIUM IS IN PART HYALINIZED.
]

The advent of red blood cells where grossly the exudate is red can
hardly be explained by the simple process of diapedesis. Indeed, there
is ample evidence that they escape by rhexis through lesions of the
vascular wall. This phenomenon cannot be demonstrated in areas where a
compact mass of red cells obliterates the alveolar space (Fig. XXV), but
in the less firmly consolidated alveoli where red blood cells
predominate (Fig. XXVI) the picture of the alveolar wall is very
instructive. The capillaries may be prominent and contain red cells
almost exclusively. Often the epithelium of the air space is exfoliated
so that there is nothing to minimize the prominence of the engorged
vessels. These capillaries, covered by such a delicate wall that rupture
seems imminent, may protrude like saccular aneurysms (101) into the
alveolar space (Fig. XXVI). In all probability, these sacs do rupture
and this result would be one explanation for the escape of large numbers
of red blood cells. In several instances such a picture was encountered,
where with little reaction at the point of rupture, red cells within the
vessel were continuous with an accumulation of similar cells in the
alveolus. Further evidence for such rupture is offered where the vessel
is collapsed. Here there is accumulation of polymorphonuclear leucocytes
in the area of destruction in contrast to the well preserved red
corpuscles in the remainder of the vessel (Fig. XXVI). The above
pictures may be utilized in the interpretation of the outspoken foci of
red hepatization which may assume infarct-like proportions. As has been
said, it is impossible to conceive that these hemorrhagic areas where
the alveoli are packed with red cells ever change to a grey type of
consolidation. Consequently, it seems more probable that the color of
red hepatization in the usual types of pneumonia depends upon the marked
engorgement of the vessels seen through a relatively acellular,
transparent, serofibrinous, alveolar mass and not upon the number of red
cells in the exudate.


                        C. THE APLASTIC EXUDATE

The absence of cellular elements in the alveolar exudate is frequently
observed in influenzal pneumonia (Figs. XXI, XXII, XXIII). This picture
has been reproduced experimentally in animals which have been rendered
aplastic with benzol, especially with reference to their myeloid
elements (160). Pneumonia produced by intratracheal insufflation is more
rapidly fatal in aplastic animals, and it is conceivable that the
absence of cellular reaction is an explanation for the lack of
resistance demonstrated by the high mortality of influenzal pneumonia.
Frequently the fibrinoserous mass scattered diffusely throughout the
lung is rich in bacteria. In the absence of cells of the
polymorphonuclear series, the bacterial development seems to be
unrestricted. The aplastic exudate is associated clinically with an
absence of a myeloid reaction in the peripheral circulation. The
leucocytic count may be definitely decreased, even though the tissues
have been invaded by pyogenic organisms to which the usual response is a
definite leucocytosis. The only explanation is that the myeloid
structures have been injured, probably by the unknown virus of the
disease.


            D. THE HYALINE NECROSIS OF THE PULMONARY TISSUE

The hyalinization of the epithelium lining the ducti alveolares (47, 48)
also merits special attention (Figs. V, XV, XVI). This process may
extend through the wall of the duct and is often seen in the alveolar
walls throughout the involved lung. The entire alveolar wall may be
homogeneous in appearance, but, occasionally, the thrombus alone, which
has formed in its vessels (41), presents this change (Fig. XVII). The
alveolar as well as the bronchiolar wall is thickened by a homogeneous
material in which cell-body and exudate cannot be differentiated. This
acute necrosis, as has been mentioned, is encountered in gas poisoning
but is unusual in other known types of respiratory infection. Doubtless,
it is a precursor to the more destructive lesions commonly found in
later stages of the disease—abscesses which extend through the
bronchiolar walls (Fig. XXXI), necrotizing areas of pneumonia in which
huge clumps of bacteria are found (Fig. XXXII), and true gangrene (Figs.
XXXIII, XXXIV, XXXV). The destruction of the alveolar wall in the early
stages of the disease plays a causal rôle in the production of
subcutaneous emphysema (Figs. XVIII and XIX). This important phase of
the histological change in influenzal pneumonia has received but little
attention and, with one or two exceptions, is not mentioned in the
literature (8, 162).

In the interpretation of this necrotization, the only helpful analogy is
offered by the acute respiratory lesions following the inhalation of
poisonous gases. With the aid of vital stains, it has been demonstrated
that chlorine quickly initiates necrosis due to the direct action of the
gas. Since necrosis also occurs with phosgene,—in the decomposition of
which hydrochloric acid is probably liberated,—there is presumptive
evidence that the halogen is responsible for the process. Studies are
now in progress to determine the relation of the acid-producing
properties of the different strains of organisms to the type and fate of
the pneumonic exudate.


                      E. THE ORGANIZATION PROCESS

The similarity between the acute lesions of influenzal pneumonia and
those following the inhalation of poisonous gases led to the prediction,
in the early studies, that if the process were not terminated by death,
the bronchiolar and alveolar changes would not result in a restoration
of the tissue to normal, but in an organization which would in its turn
bring about mechanical changes in the pulmonary tissue. This prediction
has been fulfilled; obliterating bronchiolitis (Figs. XI and XLVIII),
bronchiectasis (Figs. L and XII), and organizing pneumonia (47, 92, 156,
162) (Figs. XXXIX, XL, XLI, XLIV, XLV) have been encountered despite the
fact that the time interval for fatalities from extraneous or subsidiary
causes has been short.

[Illustration:

  FIG. XLIV. THE ALVEOLAR WALLS ARE IN PART OBLITERATED. THE ALVEOLAR
    EXUDATE IS ORGANIZED BUT THE FIBROUS TISSUE STRANDS ARE SPREAD APART
    BY EDEMA.
]

[Illustration:

  FIG. XLV. AUTOPSY NO. 163. ORGANIZATION OF THE ALVEOLAR EXUDATE AFTER
    THE SUBSIDENCE OF THE ACUTE PROCESS. COMPARE FIGURE XLIV.
]

Resolution of the exudate in pneumonia, with the restoration of the
tissue to normal, is a result at such variance with the usual fate of an
inflammatory exudate, that it has attracted a great deal of attention.
Perhaps the most striking results of the study of this subject have been
published recently by Kline (69). Arguing from previous experiments (70)
in which it was demonstrated that the circulation of the pneumonic lung
is impaired, and that for this reason sufficient serum cannot reach the
exudate to inhibit the proteolytic action of leucocytic ferments, Kline
introduced normal serum into the consolidated lung by the tracheal
route, and showed conclusively that this resulted in an organization of
the alveolar exudate. This, of course, might explain resolution, but it
is difficult to see without further study how serum can reach the
exudate to inhibit autolysis, and in this way stimulate organization, in
one case of pneumonia and not in another.

Comparison with certain processes in other portions of the body suggest
the nature of this stimulus to organization in pneumonia. For example,
it is well known that epithelial necrosis of the liver that results from
chloroform is followed by a restitution of the organ to normal. On the
other hand, if the liver necrosis is produced by a chemical agent plus a
bacterial one, the destructive lesion not only involves the liver cell,
but extends to the framework of the organ and terminates in a cirrhosis.
Unquestionably, the difference between the reaction after the chemical
alone and that after chemical plus bacterial injury is a more extensive
destruction in the latter case resulting in a stimulation of all the
elements of the organ, including liver cell, connective tissue, and
blood vessel. The connective tissue and vascular elements have a greater
capacity to regenerate than has the liver cell; consequently,
granulations form which impede the less active reparative process of the
hepatic cell. If this comparison be applied to the pulmonary changes in
influenza and after the inhalation of poisonous gases, it will be seen
that in both processes the initial damage is extensive, as has been
indicated in the discussion of necrotization. Where the lesion is
superficial, tracheal, bronchial, and alveolar epithelia rapidly
regenerate and restore the injured surface. Where, however, the lesions
are more extensive, alveolar and bronchiolar exudates are transformed
into granulation tissue, even though the epithelium may manifest unusual
activity in its attempt to repair a denuded area.




VI. INFECTION AS A POSSIBLE ETIOLOGICAL FACTOR FOR MALIGNANT NEW GROWTHS


It is rare to see such activity on the part of the epithelium as that
frequently encountered in influenza. The alveoli may be lined by newly
formed cubical cells (Figs. IV, XI, XLVII), and mitotic figures in the
injured bronchiolar lining occur in abundance. This might lead to the
supposition that, if the epithelium were restricted in its path of
development, it would pile up to form a typical nest, just as the
epithelium at the edge of a healing chronic ulcer of the skin may pile
up and extend fairly deep into the tissue. In a number of cases,
epithelial proliferation has been so extensive that it could not be
differentiated histologically from an invasive, malignant neoplasm (47)
(Figs. XLVIII and XLIX). There is no reason to believe that malignancy
might not result from the continuous stimulation of the epithelium to
proliferate, in the chronic inflammatory process of the lung in
influenza, just as chronic infection in the lung of a mouse results in a
much higher percentage of spontaneous neoplasms of the respiratory tract
in this species (132) than in those animals where chronic pulmonary
inflammatory processes are uncommon. It will be interesting, indeed, to
see whether, as a late manifestation, there is an increase in the number
of now relatively rare epithelial new growths in the respiratory tract
of man.

[Illustration:

  FIG. XLVI. AUTOPSY NO. 128. THE ORGANIZATION IS HERE LARGELY CONFINED
    TO THE INTERSTITIAL TISSUE. THE ALVEOLI ARE DISTORTED AND
    COMPRESSED, AND THEIR EPITHELIUM HAS ASSUMED A CUBICAL FORM.
]

[Illustration:

  FIG. XLVIII. AUTOPSY NO. 183. THIS DRAWING SHOWS A DILATED BRONCHUS
    UNDERGOING OBLITERATIVE BRONCHIOLITIS. THE EXUDATE IN THE
    SURROUNDING LUNG TISSUE IS BEING ORGANIZED. THE EPITHELIUM OF THE
    BRONCHUS IS MANY LAYERS THICK AND HAS INVADED THE SURROUNDING LUNG
    TISSUE. IT HAS THE APPEARANCE OF AN INFILTRATING EPITHELIAL
    NEOPLASM. COMPARE FIGURES XI AND XLI.
]




             VII. THE BACTERIOLOGY OF INFLUENZAL PNEUMONIA


           A. ORGANISMS ASSOCIATED WITH INFLUENZAL PNEUMONIA

Certain conclusions may be drawn from the literature on the bacteriology
of the respiratory lesions associated with influenza. All reports show
that a few organisms have been found more or less constantly in
influenza and influenzal pneumonia: the pneumococcus group, the
streptococci (hemolytic, non-hemolytic, pandemicus, etc.) and the
Pfeiffer bacillus. They may occur alone, together, or with less
frequently found organisms. Among the latter, the staphylococcus, the
Micrococcus catarrhalis, Bacillus pneumoniæ (Friedlander), diphtheroids,
and undetermined organisms, all have been reported (2, 48, 62, 67, 68,
92).

Another feature has been the variation of the predominating organism, or
organisms, in different localities, and in the same locality at
different times. For example, Wolbach (162) at Camp Devens,
Massachusetts, demonstrated the Pfeiffer bacillus at autopsy in
twenty-three out of twenty-eight cases. In fourteen, it was in pure
culture. Keegan (67) at Chelsea, Massachusetts, also found it in
eighty-two per cent of the lungs at necropsy, in thirty-one per cent of
which it was in pure culture. MacCallum (92), working at Camp Lee,
Virginia, found the pneumococcus, Type IV, the predominating organism
and rarely the Pfeiffer bacillus. “At the Johns Hopkins Hospital similar
methods revealed no influenza bacilli whatever.” At Camp Dix, New
Jersey, however, MacCallum found the Pfeiffer bacillus in every case. At
Camp Grant, Illinois, Hirsch and McKinney (60) state that the epidemic
was due to a virulent strain of pneumococcus and that the Pfeiffer
bacillus played no rôle. At the Puget Sound Navy Yard, Ely and
co-workers (37) did not find the Pfeiffer bacillus; they attributed the
epidemic to the hemolytic streptococcus. Goodpasture (48), working at
the same hospital as Keegan, reports that the bacteria found in
December, 1918, and January, 1919, were different from those found in
the early months of the epidemic, inasmuch as in the latter group the
hemolytic streptococcus was found in one hundred per cent of the cases
and the Pfeiffer bacillus in twelve per cent. The foreign literature
shows similar variations in the bacteriology.

The organisms associated with influenzal pneumonia are the so-called
“mouth organisms.” They are not only found in the mouths and upper air
passages of the influenza patients, but also in those of normal
individuals. This points to the fact that the bacteria of the mouth have
gained access to the lung, probably already injured by a primary agent,
in sufficient numbers to bring about a serious inflammatory process. In
this connection it is of interest to note the relatively high frequency
of the mouth organisms, pneumococcus, Types III and IV, in influenzal
pneumonia as compared to the less frequent mouth inhabitants, Types I
and II, which are responsible for two-thirds of the cases of true lobar
pneumonia (5, 45, 92, 121).

Only the eighty-two cases at the New Haven Hospital are included in the
following report. Routine post-mortem cultures were taken from blood,
lung, serous fluid wherever present, and exudates from the trachea and
bronchi in the later cases. Blood and serous fluids were cultured into
neutral infusion broth and plated on blood agar after twelve to
thirty-six hours’ incubation. Lung and bronchial cultures were streaked
on blood agar plates and for the last third of the series on Avery’s
oleate media. Cultures were examined on each successive day and were
discarded only after one week. Undoubtedly, we have failed to find B.
influenzæ in many of the earlier cases because of lack of familiarity
with the organism, of variations in its morphology (33), and of
unsuitable culture media. The organisms tabulated below include only
those determined by cultural methods; those found by direct smears or in
histopathological preparations are not considered. (See Table No. I.)


     B. THE RELATION OF THE TYPE OF ORGANISM TO PLEURAL INVOLVEMENT

The hemolytic streptococcus has been found frequently in association
with purulent pleural effusions in influenza, Thomas (146), Stone and
Swift (138), Ely et al (37); and Goodpasture (48) has suggested an
etiologic relationship between the type of effusion and the infecting
organism in influenza, as has been brought forward for the similar
post-measles empyema in the army camps. At the New Haven Hospital the
Streptococcus hemolyticus was found frequently in non-fatal empyema.
However, at post-mortem examination the frequency of this organism in
pleural effusions of various types was no greater than that of several
other organisms, but it occurred in the only two cases of frank empyema
of this series. (See Table No. II.)


    C. THE RELATION OF DIFFERENT ORGANISMS TO THE TYPE OF PNEUMONIA

Various observers have emphasized the types of organism associated with
different gross and microscopic manifestations of influenzal pneumonia.
Pfeiffer described the peribronchial type with purulent bronchitis, from
which the influenza bacillus was isolated, and the same association has
been noted by MacCallum (92), Wolbach (162), Wegelin (156), Dietrich
(34), and others. Opie et al (110), however, in a series from which B.
influenzæ was isolated in over eighty-five per cent of the necropsies
rarely found this picture. Wolbach states that the gross anatomical
picture in influenzal pneumonia is similar to that following measles,
from which a hemolytic streptococcus has been isolated in a high
percentage of cases. MacCallum (93) classified this type as interstitial
pneumonia. It is interesting to note that interstitial pneumonia has
been rare in many localities where the hemolytic streptococcus has been
prevalent during the past year. Stone and Swift (138) state that
“despite the prevalence of the streptococcus at necropsy, only eight
instances of so-called interstitial pneumonia were found in a series of
fifty-five cases,” and Goodpasture (48) failed to find a single example
in a series of sixteen cases. The pneumococci Types I and II, frequently
encountered in the usual forms of lobar pneumonia, have been found
exceptionally in this epidemic. Type II, however, has been reported (67,
107) present in about the same proportion as in true lobar pneumonia
(5). Chickering and Park (25) described a series of cases of pneumonia
due to the staphylococcus characterized by multiple miliary abscesses.
Necrotization and abscess formation, however, have been striking
features of the pathology of this epidemic, even when the staphylococcus
has not been demonstrable. Recently Wadsworth (154) demonstrated
experimentally that organization in pneumonia does not result from the
pneumococcus or the staphylococcus alone, but only follows when both
organisms are associated. On the contrary, Blanton and Irons (12) found
that “there was no difference to be made out in the nature of the
process caused by the streptococcus, pneumococcus, or influenza
bacillus.”

[Illustration:

  FIG. XLVII. AUTOPSY NO. 100. PROLIFERATION OF THE ALVEOLAR EPITHELIUM
    IN A PORTION OF THE LUNG ONLY SLIGHTLY INVOLVED BY THE ACUTE
    INFLAMMATORY PROCESS. COMPARE FIGURES IV, XI, XLVIII, AND XLIX.

  HELIOTYPE CO. BOSTON
]

                              TABLE I.
                     _Post Mortem Bacteriology._
 ════════════════════════════════╤════════════════════════════════
                                 │
                                 │       Acute Fulminating
                                 │           (34 cases)
 ────────────────────────────────┼────────────────────────────────
                                 │                   Trachea
                                 │           Pleural   and   Total
                                 │Blood Lung  fluid  Bronchi Cases
 ────────────────────────────────┼────────────────────────────────
 Strep. hemolyticus              │    8   12       7       2    12
 Strep. non-hemolyticus          │         7                     7
 Strep. “viridans”               │                               0
 Strep. mucosus capsulatus       │                               0
 Pneumococcus Type II            │    3    4       3       1     4
 Pneumococcus Type III           │    4    4       3             4
 Pneumococcus Type IV            │    4    6       2       3     6
 Pneumococcus (Type undetermined)│    2    3                     3
 B. influenzæ                    │    1    4               2     5
 Staphylococci                   │         3       2       2     4
 B. mucosus capsulatus           │         1       1             1
 M. catarrhalis                  │         2               1     2
 Diphtheroids                    │         1                     1
 Enterococcus                    │         1                     1
 ════════════════════════════════╧════════════════════════════════

 ════════════════════════════════╤════════════════════════════════
                                 │
                                 │          Necrotizing
                                 │           (36 cases)
 ────────────────────────────────┼────────────────────────────────
                                 │                   Trachea
                                 │           Pleural   and   Total
                                 │Blood Lung  fluid  Bronchi Cases
 ────────────────────────────────┼────────────────────────────────
 Strep. hemolyticus              │    8    9       3       1     9
 Strep. non-hemolyticus          │    2    5       1       5     5
 Strep. “viridans”               │         2       1       2     2
 Strep. mucosus capsulatus       │                               0
 Pneumococcus Type II            │    3    4       1       2     4
 Pneumococcus Type III           │         2       1             2
 Pneumococcus Type IV            │    6   11       2       5    11
 Pneumococcus (Type undetermined)│    3    2       5             5
 B. influenzæ                    │    1   12       0       4    12
 Staphylococci                   │    1    9       3       4     9
 B. mucosus capsulatus           │         2       1       1     2
 M. catarrhalis                  │         2               2     2
 Diphtheroids                    │                               0
 Enterococcus                    │                               0
 ════════════════════════════════╧════════════════════════════════

 ════════════════════════════════╤════════════════════════════════
                                 │
                                 │           Organizing
                                 │           (12 cases)
 ────────────────────────────────┼────────────────────────────────
                                 │                   Trachea
                                 │           Pleural   and   Total
                                 │Blood Lung  fluid  Bronchi Cases
 ────────────────────────────────┼────────────────────────────────
 Strep. hemolyticus              │    7    8       5       3     8
 Strep. non-hemolyticus          │                               0
 Strep. “viridans”               │                               0
 Strep. mucosus capsulatus       │    1    1       1             1
 Pneumococcus Type II            │    1    3               1     3
 Pneumococcus Type III           │    1    1                     1
 Pneumococcus Type IV            │         1               1     1
 Pneumococcus (Type undetermined)│                               0
 B. influenzæ                    │    1    1                     2
 Staphylococci                   │         6               2     6
 B. mucosus capsulatus           │                               0
 M. catarrhalis                  │                               0
 Diphtheroids                    │         1               1     1
 Enterococcus                    │                               0
 ════════════════════════════════╧════════════════════════════════

 ════════════════════════════════╤═══════════
                                 │ Total All
                                 │   Types
                                 │   (82)
 ────────────────────────────────┼─────┬─────
                                 │     │
                                 │     │ Per
                                 │Total│cent.
 ────────────────────────────────┼─────┼─────
 Strep. hemolyticus              │   29│ 35.4
 Strep. non-hemolyticus          │   12│ 14.6
 Strep. “viridans”               │    2│  2.4
 Strep. mucosus capsulatus       │    1│  1.2
 Pneumococcus Type II            │   11│ 13.4
 Pneumococcus Type III           │    7│  8.6
 Pneumococcus Type IV            │   18│  22.
 Pneumococcus (Type undetermined)│    8│  9.7
 B. influenzæ                    │   19│  23.
 Staphylococci                   │   19│  23.
 B. mucosus capsulatus           │    3│  3.7
 M. catarrhalis                  │    4│  4.9
 Diphtheroids                    │    2│  2.4
 Enterococcus                    │    1│  1.2
 ════════════════════════════════╧═════╧═════
                              TABLE II.
                 _Bacteriology of Pleural Exudates._
 ════════════════════════════╤══════════════════════════════════════════
                             │          Acute Fulminating (34)
 ────────────────────────────┼──────────────────────────────────────────
                             │
                             │
                             │
                             │                     Sero-
                             │            Sero-   fibrino-
                             │Fibrinous fibrinous purulent Empyema Total
 ────────────────────────────┼──────────────────────────────────────────
 Strep. hemolyticus          │        1         5        2             8
 Strep. non-hemolyticus      │        1                  2             3
 Strep. “viridans”           │                                         0
 Strep. mucosus capsulatus   │                                         0
 Pneumococcus Type II.       │        2         1        1             4
 Pneumococcus Type III.      │                  2        1             3
 Pneumococcus Type IV.       │        1         2        2             5
 Pneumococcus (Type          │
   undetermined)             │                                         0
 B. influenzæ                │        1         1        2             4
 Staphylococci               │                           3             3
 B. mucosus capsulatus       │                  1                      1
 Number of cases of pleurisy │        3        12        6            21
 Percent of cases showing    │
   excess of Pleural fluid.  │                                        53%
 ════════════════════════════╧══════════════════════════════════════════

 ════════════════════════════╤══════════════════════════════════════════
                             │             Necrotizing (36)
 ────────────────────────────┼──────────────────────────────────────────
                             │
                             │
                             │
                             │                     Sero-
                             │            Sero-   fibrino-
                             │Fibrinous fibrinous purulent Empyema Total
 ────────────────────────────┼──────────────────────────────────────────
 Strep. hemolyticus          │        3         2        1             6
 Strep. non-hemolyticus      │        1         2        1             4
 Strep. “viridans”           │        1         1                      2
 Strep. mucosus capsulatus   │                                         0
 Pneumococcus Type II.       │        2         1        1             4
 Pneumococcus Type III.      │                           2             2
 Pneumococcus Type IV.       │        5         4        2            11
 Pneumococcus (Type          │
   undetermined)             │        1         1        2             4
 B. influenzæ                │        5         4        2            11
 Staphylococci               │        3         3        3             9
 B. mucosus capsulatus       │                           1             1
 Number of cases of pleurisy │       13         7       10            30
 Percent of cases showing    │
   excess of Pleural fluid.  │                                        47%
 ════════════════════════════╧══════════════════════════════════════════

 ════════════════════════════╤══════════════════════════════════════════
                             │             Organizing (12)
 ────────────────────────────┼──────────────────────────────────────────
                             │
                             │
                             │
                             │                     Sero-
                             │            Sero-   fibrino-
                             │Fibrinous fibrinous purulent Empyema Total
 ────────────────────────────┼──────────────────────────────────────────
 Strep. hemolyticus          │        1         1        3       2     7
 Strep. non-hemolyticus      │                                         0
 Strep. “viridans”           │                                         0
 Strep. mucosus capsulatus   │                           1             1
 Pneumococcus Type II.       │                           1       1     2
 Pneumococcus Type III.      │                                         0
 Pneumococcus Type IV.       │                  1                1     2
 Pneumococcus (Type          │
   undetermined)             │                                         0
 B. influenzæ                │        1                  1             2
 Staphylococci               │        1         1        1       1     4
 B. mucosus capsulatus       │                                         0
 Number of cases of pleurisy │        1         1        5       2     9
 Percent of cases showing    │
   excess of Pleural fluid.  │                                        67%
 ════════════════════════════╧══════════════════════════════════════════

 ════════════════════════════╤══════════════════════════════════════════
                             │          Total (All Types) (82)
 ────────────────────────────┼──────────────────────────────────────────
                             │
                             │
                             │
                             │                     Sero-
                             │            Sero-   fibrino-
                             │Fibrinous fibrinous purulent Empyema Total
 ────────────────────────────┼──────────────────────────────────────────
 Strep. hemolyticus          │        5         8        6       2    21
 Strep. non-hemolyticus      │        2         2        3             7
 Strep. “viridans”           │        1         1                      2
 Strep. mucosus capsulatus   │                           1             1
 Pneumococcus Type II.       │        4         2        3       1    10
 Pneumococcus Type III.      │                  2        3             5
 Pneumococcus Type IV.       │        6         7        4       1    18
 Pneumococcus (Type          │
   undetermined)             │        1         1        2             4
 B. influenzæ                │        7         5        5            17
 Staphylococci               │        4         4        7       1    16
 B. mucosus capsulatus       │                  1        1             2
 Number of cases of pleurisy │       17        20       21       2    60
 Percent of cases showing    │
   excess of Pleural fluid.  │                                        52.4%
 ════════════════════════════╧══════════════════════════════════════════

 ════════════════════════════╤════════╤════════
                             │        │
 ────────────────────────────┼────────┼────────
                             │ Total  │
                             │ number │
                             │of cases│
                             │  with  │Effusion
                             │positive│present
                             │cultures│percent.
 ────────────────────────────┼────────┼────────
 Strep. hemolyticus          │      29│     55%
 Strep. non-hemolyticus      │      12│     42%
 Strep. “viridans”           │       2│     50%
 Strep. mucosus capsulatus   │       1│    100%
 Pneumococcus Type II.       │      11│     54%
 Pneumococcus Type III.      │       7│     71%
 Pneumococcus Type IV.       │      18│     67%
 Pneumococcus (Type          │        │
   undetermined)             │       8│     37.5%
 B. influenzæ                │      19│     52%
 Staphylococci               │      19│     63%
 B. mucosus capsulatus       │       3│     67%
 Number of cases of pleurisy │        │
 Percent of cases showing    │        │
   excess of Pleural fluid.  │        │     52.4%
 ════════════════════════════╧════════╧════════

[Illustration:

  FIG. XLIX. AUTOPSY NO. 122. HIGHER POWER ILLUSTRATION OF EPITHELIAL
    PROLIFERATION AS ILLUSTRATED IN FIGURE XLVIII.
]

[Illustration:

  FIG. LII. AUTOPSY NO. 107. THROMBUS ASSOCIATED WITH AN ACUTE
    INFLAMMATION IN THE WALL OF A PULMONARY ARTERIOLE.
]

[Illustration:

  FIG. L. AUTOPSY NO. 209. BRONCHIECTATIC CAVITIES AT THE BASE OF A
    LUNG. THE HISTOLOGY OF THIS LESION IS ILLUSTRATED IN FIGURE XII.
]

     TABLE III.—_Bacteriology in Relation to the Pneumonia._
 ═════════════════════════════════╤═══════════════════════════════
                                  │    Acute Fulminating (34)
 ─────────────────────────────────┼───────────────────────────────
                                  │      Pseu- Peri-
                                  │       do-  bron-
                                  │Lobar lobar chial Lobular Total
 ─────────────────────────────────┼───────────────────────────────
 Strep. hemolyticus               │          1             4     5
 Strep. hemolyticus and           │
   Pneumococcus II                │                              0
 Strep. hemolyticus and           │
   Pneumococcus IV                │                        1     1
 Strep. hemolyticus and           │
   Pneumococcus IV and            │
   staphylococci                  │                              0
 Strep. hemolyticus and Strep.    │
   non-hemolyticus                │                        1     1
 Strep. hemolyticus and B.        │
   influenzæ                      │          1             1     2
 Strep. hemolyticus, B. influenzæ │
   and Strep. non-hemolyticus     │                              0
 Strep. hemolyticus, B. influenzæ │
   and staphylococci              │                              0
 Strep. hemolyticus and           │
   staphylococci                  │                        2     2
 Strep. hemolyticus and M.        │
   catarrhalis                    │                              0
 Strep. hemolyticus, M.           │
   catarrhalis and B. mucosus     │
   capsulatus                     │                        1     1
 Strep. non-hemolyticus           │                        3     3
 Strep. non-hemolyticus,          │
   Pneumococcus II and            │
   staphylococci                  │                              0
 Strep. non-hemolyticus,          │
   Pneumococcus IV and            │
   staphylococci                  │                        1     1
 Strep. non-hemolyticus and       │
   staphylococci                  │                              0
 Strep. non-hemolyticus and B.    │
   mucosus capsulatus             │                              0
 Strep. non-hemolyticus and M.    │
   catarrhalis                    │                        1     1
 Strep. non-hemolyticus and       │
   diphtheroids                   │                        1     1
 Strep. mucosus capsulatus        │                              0
 Strep. “viridans” and            │
   Pneumococcus IV                │                              0
 Strep. “viridans,” Pneumococcus  │
   IV and staphylococci           │                              0
 Pneumococcus Type II             │                        3     3
 Pneumococcus Type III            │                        4     4
 Pneumococcus Type IV             │                        2     2
 Pneumococcus (Type undetermined) │                        3     3
 Pneumococcus Type II and B.      │
   influenzæ                      │                        1     1
 Pneumococcus Type II and B.      │
   mucosus capsulatus             │                              0
 Pneumococcus Type II and         │
   staphylococci                  │                              0
 Pneumococcus Type III and B.     │
   influenzæ                      │                              0
 Pneumococcus Type III and        │
   staphylococci                  │                              0
 Pneumococcus Type IV and B.      │
   influenzæ                      │                        2     2
 Staphylococci                    │                              0
 Staphylococci and B. influenzæ   │                              0
 Staphylococci, B. influenzæ and  │
   M. catarrhalis                 │                              0
 B. influenzæ and Pneumococcus    │
   (Type undetermined)            │                              0
 B. influenzæ and a pleomorphic   │
   diplococcus                    │                              0
 Enterococcus                     │                        1     1
 ═════════════════════════════════╧═══════════════════════════════

 ═════════════════════════════════╤═══════════════════════════════
                                  │       Necrotizing (36)
 ─────────────────────────────────┼───────────────────────────────
                                  │      Pseu- Peri-
                                  │       do-  bron-
                                  │Lobar lobar chial Lobular Total
 ─────────────────────────────────┼───────────────────────────────
 Strep. hemolyticus               │                        4     4
 Strep. hemolyticus and           │
   Pneumococcus II                │                              0
 Strep. hemolyticus and           │
   Pneumococcus IV                │                        1     1
 Strep. hemolyticus and           │
   Pneumococcus IV and            │
   staphylococci                  │                              0
 Strep. hemolyticus and Strep.    │
   non-hemolyticus                │                              0
 Strep. hemolyticus and B.        │
   influenzæ                      │                              0
 Strep. hemolyticus, B. influenzæ │
   and Strep. non-hemolyticus     │                        1     1
 Strep. hemolyticus, B. influenzæ │
   and staphylococci              │                              0
 Strep. hemolyticus and           │
   staphylococci                  │                        2     2
 Strep. hemolyticus and M.        │
   catarrhalis                    │                        1     1
 Strep. hemolyticus, M.           │
   catarrhalis and B. mucosus     │
   capsulatus                     │                              0
 Strep. non-hemolyticus           │    1                         1
 Strep. non-hemolyticus,          │
   Pneumococcus II and            │
   staphylococci                  │                        1     1
 Strep. non-hemolyticus,          │
   Pneumococcus IV and            │
   staphylococci                  │                              0
 Strep. non-hemolyticus and       │
   staphylococci                  │                        1     1
 Strep. non-hemolyticus and B.    │
   mucosus capsulatus             │          1                   1
 Strep. non-hemolyticus and M.    │
   catarrhalis                    │                              0
 Strep. non-hemolyticus and       │
   diphtheroids                   │                              0
 Strep. mucosus capsulatus        │                              0
 Strep. “viridans” and            │
   Pneumococcus IV                │                        1     1
 Strep. “viridans,” Pneumococcus  │
   IV and staphylococci           │                        1     1
 Pneumococcus Type II             │                        1     1
 Pneumococcus Type III            │    1                         1
 Pneumococcus Type IV             │                1       1     2
 Pneumococcus (Type undetermined) │                        3     3
 Pneumococcus Type II and B.      │
   influenzæ                      │                              0
 Pneumococcus Type II and B.      │
   mucosus capsulatus             │                        1     1
 Pneumococcus Type II and         │
   staphylococci                  │                        1     1
 Pneumococcus Type III and B.     │
   influenzæ                      │                        1     1
 Pneumococcus Type III and        │
   staphylococci                  │                              0
 Pneumococcus Type IV and B.      │
   influenzæ                      │          3             3     6
 Staphylococci                    │                              0
 Staphylococci and B. influenzæ   │                        1     1
 Staphylococci, B. influenzæ and  │
   M. catarrhalis                 │                        1     1
 B. influenzæ and Pneumococcus    │
   (Type undetermined)            │                        2     2
 B. influenzæ and a pleomorphic   │
   diplococcus                    │                        1     1
 Enterococcus                     │                              0
 ═════════════════════════════════╧═══════════════════════════════
 ═════════════════════════════════╤═══════════════════════════════╤═════
                                  │        Organizing (12)        │(82)
 ─────────────────────────────────┼───────────────────────────────┼─────
                                  │      Pseu- Peri-              │
                                  │       do-  bron-              │
                                  │Lobar lobar chial Lobular Total│Total
 ─────────────────────────────────┼───────────────────────────────┼─────
 Strep. hemolyticus               │    1     1                   2│   11
 Strep. hemolyticus and           │                               │
   Pneumococcus II                │    1                   1     2│    2
 Strep. hemolyticus and           │                               │
   Pneumococcus IV                │                              0│    2
 Strep. hemolyticus and           │                               │
   Pneumococcus IV and            │                               │
   staphylococci                  │                1             1│    1
 Strep. hemolyticus and Strep.    │                               │
   non-hemolyticus                │                              0│    1
 Strep. hemolyticus and B.        │                               │
   influenzæ                      │                              0│    2
 Strep. hemolyticus, B. influenzæ │                               │
   and Strep. non-hemolyticus     │                              0│    1
 Strep. hemolyticus, B. influenzæ │                               │
   and staphylococci              │                        1     1│    1
 Strep. hemolyticus and           │                               │
   staphylococci                  │                1       1     2│    6
 Strep. hemolyticus and M.        │                               │
   catarrhalis                    │                              0│    1
 Strep. hemolyticus, M.           │                               │
   catarrhalis and B. mucosus     │                               │
   capsulatus                     │                              0│    1
 Strep. non-hemolyticus           │                              0│    4
 Strep. non-hemolyticus,          │                               │
   Pneumococcus II and            │                               │
   staphylococci                  │                              0│    1
 Strep. non-hemolyticus,          │                               │
   Pneumococcus IV and            │                               │
   staphylococci                  │                              0│    1
 Strep. non-hemolyticus and       │                               │
   staphylococci                  │                              0│    1
 Strep. non-hemolyticus and B.    │                               │
   mucosus capsulatus             │                              0│    1
 Strep. non-hemolyticus and M.    │                               │
   catarrhalis                    │                              0│    1
 Strep. non-hemolyticus and       │                               │
   diphtheroids                   │                              0│    1
 Strep. mucosus capsulatus        │    1                         1│    1
 Strep. “viridans” and            │                               │
   Pneumococcus IV                │                              0│    1
 Strep. “viridans,” Pneumococcus  │                               │
   IV and staphylococci           │                              0│    1
 Pneumococcus Type II             │                              0│    4
 Pneumococcus Type III            │                              0│    5
 Pneumococcus Type IV             │                              0│    4
 Pneumococcus (Type undetermined) │                              0│    6
 Pneumococcus Type II and B.      │                               │
   influenzæ                      │                1             1│    2
 Pneumococcus Type II and B.      │                               │
   mucosus capsulatus             │                              0│    1
 Pneumococcus Type II and         │                               │
   staphylococci                  │                              0│    1
 Pneumococcus Type III and B.     │                               │
   influenzæ                      │                              0│    1
 Pneumococcus Type III and        │                               │
   staphylococci                  │          1                   1│    1
 Pneumococcus Type IV and B.      │                               │
   influenzæ                      │                              0│    8
 Staphylococci                    │                        1     1│    1
 Staphylococci and B. influenzæ   │                              0│    1
 Staphylococci, B. influenzæ and  │                               │
   M. catarrhalis                 │                              0│    1
 B. influenzæ and Pneumococcus    │                               │
   (Type undetermined)            │                              0│    2
 B. influenzæ and a pleomorphic   │                               │
   diplococcus                    │                              0│    1
 Enterococcus                     │                              0│    1
 ═════════════════════════════════╧═══════════════════════════════╧═════

The type of the pneumonic process, as well as the invading organism, has
varied widely in different localities. From the foregoing brief survey,
it will be seen that before the associations suggested above can be
proven, much more definite evidence must be presented.

An attempt has been made to correlate the bacteriological findings in
this series with the distribution and type of pneumonic process. These
are tabulated in Table III. It will be seen at a glance that no
relationship is demonstrable between the type of single or associated
organisms and the distribution of the pneumonia, whether it is lobar,
pseudolobar, peribronchial or lobular and whether acute fulminating,
necrotizing or organizing. (See Table No. III.)


                       D. SUMMARY AND DISCUSSION

The confusion which exists in associating different bacterial types with
well defined and characteristic anatomical lesions is true, not only for
the disease as it occurs spontaneously in man, but also for its
reproduction in experimental animals. A review of the literature teaches
that not all of the factors concerned in producing the different
anatomical types are known.

Pertinent experimental studies were reported recently by Blake and Cecil
from the Army Medical School in Washington. One cubic centimeter of a
very virulent pneumococcus (M. L. D. for a mouse in forty-eight hours
equals one-millionth of 1 cubic centimeter) inoculated in monkeys
through the skin of the neck into the trachea just beneath the larynx
has uniformly produced a lobar pneumonia, clinically as well as
anatomically the nearest experimental approach to spontaneous lobar
pneumonia of man. This work indicates, not only the possible importance
the species may play, but also points to the rôle of the infecting
organism which, when sufficiently virulent, incites a characteristic
reaction even when inoculated in a minimal quantity into the trachea as
distinct from the bronchioles or lung tissue.

Pneumonia unassociated with a simultaneous or preliminary incapacitation
of the mechanism of the upper respiratory tract, differs from the
pulmonary lesions encountered after measles, gas poisoning, influenza,
etc., and those experimentally produced by intrabronchial insufflations.
In the lobar type the virulence of the infecting organism, combined
perhaps with species variation,—implying as this does different
capacities for reaction on the part of the host,—seems to be the
fundamental principle. It remains to be determined whether other
organisms of equal virulence with that of the pneumococcus are capable
of producing characteristic anatomical reactions when inoculated in a
similar manner.

In the other group, where there is not only a free ingress to the
pulmonary parenchyma by the bacteria of the mouth, but where there is,
in all probability, also a simultaneous or preliminary pulmonary damage
furnishing a proper medium for relatively innocuous organisms, the
lesion of response will surely depend upon other factors as much as upon
the infecting organism. Among these obscure factors, the most important,
unquestionably, is the extent of the damage to the lung tissue before
the entry of the organisms, or simultaneously with it, into this area.
The systemic capacity to compensate also must be considered.

[Illustration:

  FIG. LI. AUTOPSY NO. 194. A LUNG IN WHICH INFLUENZAL PNEUMONIA AND
    PULMONARY TUBERCULOSIS ARE ASSOCIATED. THERE IS A CIRCUMSCRIBED,
    OLD, TUBERCULOUS FOCUS IN THE UPPER LOBE. COMPARE FIGURES XXXIX AND
    XL.
]




                           VIII. CONCLUSIONS


The etiology of influenza is unknown.

The portal of entry of the inciting cause is likewise undetermined.

The respiratory lesions, whether primary or secondary, are responsible
for the high mortality of the disease.

The lesions of the respiratory tract peculiar to this disease and most
frequently encountered are:

  An acute tracheobronchitis associated with diffuse involvement of
  the pulmonary parenchyma.

  Hyalinization of the epithelium of the air passages, and necrosis of
  the alveolar walls with extensive interstitial emphysema and
  occasionally with pneumothorax.

  Dilatation of the terminal bronchioles.

  Aplastic serofibrinous, and hemorrhagic, pneumonic exudates.

  Necrotizing and organizing bronchiolitis, and pneumonia: lobar,
  lobular, peribronchial, interstitial.

  The sequelæ—obliterating bronchiolitis and bronchiolectasis.

  Proliferation of alveolar and bronchiolar epithelium.

The extrarespiratory lesions of influenza are neither constant nor
characteristic. Irrespective of localization, they have the same
fundamental pathology characterized by:

  Vascular damage.

  Hemorrhage.

  Organization with or without infection.

A basis for the interpretation of the respiratory lesions of influenza
is offered by the analogous changes in the respiratory tract initiated
by the inhalation of poisonous gases.

The respiratory lesions are dependent primarily upon the damage produced
by the true etiological agent and the systemic capacity to compensate,
and only secondarily upon invasion by the bacterial flora of the mouth
and inspired air.




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[Illustration:

  FIG. LIII. AUTOPSY NO. 163. PULMONARY EMBOLUS.
]

[Illustration:

  FIG. LIV. (AUTOPSY NO. 20. U. S. GENERAL HOSPITAL.) ILLUSTRATES THE
    CHANGE IN THE BRONCHIAL LYMPH GLANDS. NOTE THE PHAGOCYTOSIS WITHIN
    THE SINUSOIDS AS WELL AS THE MEGALOKARYOCYTES AND THE MITOTIC
    FIGURES IN THE CELLS LINING THE CHANNELS.
]

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  36. Eichhorst: Ueber das Influenza Herz;—Corr. Blatt f. Schweizer
    Aerzte, 1919, 49, 225.

  37. Ely, Lloyd, Hitchcock, Nickson: Influenza as Seen at the Puget
    Sound Navy Yard;—J. A. M. A., 1919, 72, 24.

  38. Erdheim: Der pathologische-anatomische Bild der Grippe;—Wien. med.
    Wchnschr., 1918, 31, 1971.

  39. Farrar, L. K. P.: The Visitations of Influenza and its Influence
    upon Gynecologic and Obstetric Conditions;—Am. J. Obs., 1919, 79,
    229.

  40. Fildes, Baker, and Thompson: Provisional Notes on the Pathology of
    the Present Epidemic;—Lancet, 1918, 195, 697.

  41. Fischer: Pathologische Anatomie der epidemischen Grippe;—Mün. med.
    Wchnschr., 1918, 65, 1303.

  42. Flusser: Pathologie und Klinik der Grippe 1918;—Wien. klin.
    Wchnschr., 1918, 31, 1133.

  43. Forbes and Snyder: Study of the Leucocytes in an Epidemic of
    Influenza;—J. Lab. & Clin. Med., 1918, 3, 758.

  44. French, H.: “Influenza” (Clinical Lecture);—Guys Hospital Gazette,
    1919, 33, 118.

  45. Friedlander, McCord, Sladen, and Wheeler: The Epidemic of
    Influenza at Camp Sherman;—J. A. M. A., 1918, 71, 1652.

  46. Gibson, Bowman, and Connor: A Filterable Virus as the Cause of the
    Early Stage of the Present Epidemic of Influenza; Prelim. Rep.—Brit.
    Med. J., 1918, 2, 645.

  47. Glaus and Fritzsche: Über den Sektion befund bei der Gegenwärtigen
    Grippe Epidemie unter besonderer Berücksichtigung der
    Mikroskopischen Befund;—Corr. Blatt f. Schweizer Aerzte, 1919, 49,
    72.

  48. Goodpasture: Bronchopneumonia due to Hemolytic Streptococci
    following Influenza;—J. A. M. A., 1919, 72, 724.

  49. Gotch and Whittingham: A Report of the Influenza Epidemic of
    1918;—Brit. Med. J., 1918, 2, 82.

  50. Gruber and Schädel: Zur pathologischen Anatomie und zur
    Bakteriologie der influenzaartigen Epidemie im Juli, 1918;—Mün. med.
    Wchnschr., 1918, 65, 905.

  51. Hall and Dyas: Appendicitis at Camp Logan as a Sequel to Influenza
    and Pneumonia;—J. A. M. A., 1918, 72, 726.

  52. Hall, Stone and Simpson: Epidemic of Pneumonia following Influenza
    at Camp Logan;—J. A. M. A., 1918, 71, 1986.

  53. Hamilton and Leonard: Acquired Immunity to Influenza;—J. A. M. A.,
    1919, 72, 854.

  54. Hamman, L. V.: Discussion on Influenza;—Bull. Johns Hopk. Hosp.,
    1919, 30, 112.

  55. Hammond, Rolland, and Shore: Purulent Bronchitis;—Lancet, 1917,
    193, 41.

  56. Harris, D. T.: Some Observations on the Recent Influenza
    Epidemic;—Lancet, 1918, 195, 877.

  57. Harris, J.: Influenza Occurring in Pregnant Women;—J. A. M. A.,
    1919, 72, 978.

  58. Hedinger, E.: Zur Pathologie und Bacteriologie der Grippe;—Corr.
    Blatt f. Schweizer Aerzte, 1919, 49, 554.

  59. Hewlett and Alberty: Influenza at a Navy Base Hospital in
    France;—J. A. M. A., 1918, 71, 1056.

  60. Hirsch and McKinney: Epidemic of Bronchopneumonia at Camp Grant,
    Prel. Bact. Rep.;—J. A. M. A., 1918, 71, 1735.

  61. Hirschbruch: Ueber die Ansteckende Lungenentzündung;—Deut. med.
    Wchnschr., 1918, 44, 935.

  62. Howard, S. E.: Bacteriological Findings in Epidemic
    Influenza;—Bull. Johns Hopk. Hosp., 1919, 30, 13.

  63. Howard, Wm. T.: Bull. Johns Hopk. Hosp., 1919, 30, 111.

  64. Hunt: Notes on Symptomatology and Morbid Anatomy of so-called
    Influenza with Special Reference to the Diagnosis;—Lancet, 1918,
    195, 419.

  65. Influenza Committee of the Advisory Board to the D. G. M. S.,
    France; The Influenza Epidemic in the British Armies in
    France;—Brit. Med. J., 1918, 2, 505.

  66. Jaffé: Zur pathologische Anatomie der Influenza 1918;—Wien. klin.
    Wchnschr., 1918, 31, 1203.

  67. Keegan: The Prevailing Pandemic of Influenza;—J. A. M. A., 1918,
    71, 1051.

  68. Kinsella: Bacteriology of Epidemic Influenza and Pneumonia;—J. A.
    M. A., 1919, 72, 717.

  69. Kline, B. S.: Experimental Study of Organization in Lobar
    Pneumonia;—J. Exp. Med., 1917, 26, 239.

  70. Kline, B. S., and Winternitz, M. C.: Studies upon Experimental
    Pneumonia in Rabbits;—J. Exp. Med., 1915, 21, 311.

  71. Knack: Das Verhalten der Nieren bei der Grippe;—Med. Klin., 1918,
    14, 902.

  72. Kosmak: Occurrence of Epidemic Influenza in Pregnancy;—Am. J.
    Obs., 1919, 79, 238.

  73. Krumbhaar, E. B.: The Bacteriology of the Prevailing
    Epidemic;—Lancet, 1918, 195, 123.

  74. Lacy: B. influenzæ in Sinusitis and Meningitis;—J. Lab. & Clin.
    Med., 1918, 4, 55.

  75. Lamar, R. V., and Meltzer, S. J.: Experimental Pneumonia by
    Intrabronchial Insufflation;—J. Exp. Med., 1912, 15, 133.

  76. Lamb: Primary and Post-Influenzal Pneumonia;—J. A. M. A., 1919,
    72, 1133.

  77. Lamb and Brannin: The Epidemic Respiratory Infection at Camp
    Cody;—J. A. M. A., 1919, 72, 1056.

  78. LeCount: The Pathologic Anatomy of Influenzal Bronchopneumonia;—J.
    A. M. A., 1919, 72, 650.

  79. LeCount: Disseminated Necrosis of the Pulmonary Capillaries in
    Influenzal Pneumonia;—J. A. M. A., 1919, 72, 1519.

  80. Leslie, R. M.: Discussion on Influenza;—Proc. Royal Soc. Med.,
    1919, 12, 67.

  81. Levy: Hämatologisches zur Grippe-Epidemie;—Deut. med. Wchnschr.,
    1918, 44, 972.

  82. Leichtenstern: Influenza;—Nothnagel’s Specielle Pathologie, 1896.

  83. Little, Garofalo, and Williams: Absence of B. influenzæ from the
    Upper Air Passages in the Present Epidemic;—Lancet, 1918, 2, 34.

  84. Locke, Rönne, and Lande: Clinical Aspects of the Recent Influenzal
    Epidemic;—Boston Med. & Surg. J., 1919, 180, 124.

  85. Lord: The Etiology of an Epidemic of Influenza;—J. Med. Res.,
    1908, 19, 295.

  86. Lord: Influenza;—Osler and McCrae, Modern Medicine, Vol. 1.

  87. Lord: Eleven Acute and Eighteen Chronic Cases of Influenza;—Boston
    Med. & Surg. J., 1902, 147, 662.

[Illustration:

  FIG. LVI. AUTOPSY NO. 135. ACUTE HEMORRHAGIC MYOSITIS (ZENKER’S
    NECROSIS).

  COMPARE FIG. LVII.

  HELIOTYPE CO. BOSTON
]

  88. Lord, Scott, and Nye: Relation of the Influenza Bacillus to the
    Recent Epidemic of Influenza;—J. A. M. A., 1919, 72, 188.

  89. Löwenfeld: Pathologisch-anatomische und bacteriologische Befund
    bei der Spanischer Grippe;—Wien. klin. Wchnschr., 1918, 31, 1274.

  90. Lyon: Gross Pathology of Epidemic Influenza at the Walter Reed
    General Hospital;—J. A. M. A., 1919, 72, 924.

  91. Lyon, I. P., Tenney, and Szerlip: Some Clinical Observations on
    the Influenza Epidemic at Camp Upton;—J. A. M. A., 1919, 72, 1726.

  92. MacCallum: Pathology of the Pneumonia following Influenza;—J. A.
    M. A., 1919, 72, 720.

  93. MacCallum: The Pathology of the Pneumonia in the United States
    Army Camps during the Winter of 1917–1918;—Monograph of the
    Rockefeller Institute, No. 10.

  94. MacKenzie: Influenza as Affecting the Respiratory
    System;—Practitioner, 1919, 102, 53.

  95. Malloch: Discussion on Influenza;—Proc. Roy. Soc. Med., 1919, 12,
    45.

  96. Manges, M.: Symptomatology of the Prevailing Epidemic
    “Influenza”;—N. Y. Med. J., 1918, 108, 722.

  97. Matthews: Preparing Medium for the Culture of Pfeiffer’s Influenza
    Bacillus;—Lancet, 1918, 195, 104.

  98. McIntosh: The Incidence of B. influenzæ in the Present Influenza
    Epidemic;—Lancet, 1918, 195, 695.

  99. McMeekin: The Present Epidemic of Influenza;—Med. J. Australia,
    1919, 1, 209.

  100. Medalia and Major: Influenza Epidemic at Camp McArthur: Etiol.,
    Bact., Path., and Sp. Ther.;—Boston Med. & Surg. J., 1919, 180, 323.

  101. Menetrier, M. P.: Bronchopneumonia à B. de Pfeiffer; Bull. de
    l’Acad. de Med., 1919, 81, 99.

  102. Mix, C. L.: Spanish Influenza in the Army;—N. Y. Med. J., 1918,
    108, 709.

  103. Moore, Sir John: Influenza from a Clinical
    Standpoint;—Practitioner, 1919, 102, 26.

  104. Nammack, C. E.: Clinical Features of the Recent Influenza
    Epidemic;—Med. Rec., 1918, 94, 1103.

  105. Netter, M. A: L’Epidemie d’Influenza de 1918;—Presse Med., 1918,
    26, 511.

  106. Nicolle and Lebailly: Le Microbe de la Grippe; Communication à
    l’Academie des Sciences par l’intermediare de M. le Professeur
    Roux;—Presse Med., 1918, 26, 537.

  107. Nuzum, Pilot, Stangl, and Bonar: Pandemic Influenza and Pneumonia
    in a Large Civil Hospital;—J. A. M. A., 1918, 71, 1562.

  108. Oberndorfer: Ueber die pathologische Anatomie der
    Influenza-artigen Epidemie;—Mün. med. Wchnschr., 1918, 65, 811.

  109. Opie, Freeman, Blake, Small, and Rivers: Pneumonia at Camp
    Funston:—J. A. M. A., 1919, 72, 108.

  110. Opie, Freeman, Blake, Small, and Rivers: Pneumonia following
    Influenza;—J. A. M. A., 1919, 72, 556.

  111. Orteconi, Barbie, et LeClerc: Contribution à l’Etude de la Flore
    Microbienne de la Grippe;—Presse Med., 1918, 26, 508.

  112. Orth: Thrombosen bei der Spanischen Krankheit;—Deut. med.
    Wchnschr., 1918, 44, 1298.

  113. Park, Wm. H.: Bacteriology and Possibility of Influenzal Vaccine
    as a Prophylactic;—N. Y. Med. J., 1918, 108, 621.

  114. Park, Wm. H., and Williams, A. W., et al: Studies on the Etiology
    of the Pandemic of 1918;—Am. J. Pub. Health, 1919, 9, 45.

  115. Parker, J.: A Filterable Poison Produced by B. influenzæ;—J. A.
    M. A., 1919, 72, 476.

  116. Peacock: Influenza;—Boston Med. & Surg. J., 1919, 180, 185.

  117. Peacock, T. B: Review of the Influenza or Epidemic Catarrhal
    Fever of 1847–1848;—The British and Foreign Medico Chirurgical
    Review, 1849, 7, 90.

  118. Pfeiffer, R.: Vorlaufige Mittheilungen über die Erreger der
    Influenza;—Deut. med. Wchnschr., 1892, 18, 28.

  119. Pfeiffer, R.: Die Aetiologie der Influenza;—Zeit. f. Hyg., 1893,
    13, 357.

  120. Pfeiffer, R., and Beck, M.: Weitere Mittheilungen über den
    Erreger der Influenza;—Deut. med. Wchnschr., 1892, 18, 465.

  121. Pritchett and Stillman: Occurrence of B. influenzæ in Throats and
    Saliva;—J. Exp. Med., 1919, 29, 259.

  122. Rapoport: The Complement Fixation Test in Influenzal
    Pneumonia;—J. A. M. A., 1919, 72, 633.

  123. Review of War Surgery and Medicine, Washington;—2, No. 1, 49.

  124. Robertson and Elkins: Report on an Epidemic of Influenza
    Occurring at the Royal Asylum, Morningside, Edinburgh;—Brit. Med.
    J., 1890, 1, 228.

  125. Rosenow: Prophylactic Inoculation against Respiratory
    Infection;—J. A. M. A., 1919, 72, 31.

  126. Rosenow: Studies in Influenza and Pneumonia;—J. A. M. A., 1919,
    72, 1604.

  127. Schinz: Die Influenza Epidemie bei der Guiden-Abteilung 5;—Corr.
    Blatt f. Schweizer Aerzte, 1918, 48, 1329.

  128. Schmorl: Pathologische-anatomische Beobachtungen bei der jetzt
    herrschenden Influenza Epidemie;—Deut. med. Wchnschr., 1918, 44,
    937.

  129. Schorer, E. H.: Influenza at the Port of Embarkation
    (Bacteriology);—N. Y. Med. J., 1918, 108, 641.

  130. Shera: Influenza Epidemic of Spring of 1915;—Lancet, 1917, 192,
    450.

  131. Simmonds, M.: Zur Pathologie der diesjährigen Grippe;—Mün. med.
    Wchnschr., 1918, 65, 873.

  132. Slye, Holmes, and Wells: Primary Spontaneous Tumors of the Lung
    in Mice;—J. Med. Res., 1914, 30, 417.

  133. Smith: Influenzal Intra-abdominal Catastrophies;—Lancet, 1919,
    196, 421.

  134. Soper: Pandemic in the Army Camps;—J. A. M. A., 1918, 71, 1899.

  135. Speares: Influenza;—Boston Med. & Surg. J., 1919, 180, 212.

  136. Spooner, Scott, and Heath: Bacteriological Study of the Influenza
    Epidemic at Camp Devens;—J. A. M. A., 1919, 72, 155.

  137. Spooner, Sellards, and Wyman: Serum Treatment of Type I
    Pneumonia;—J. A. M. A., 1918, 71, 1310.

  138. Stone and Swift: Influenza and Bronchopneumonia at Fort Riley;—J.
    A. M. A., 1919, 72, 487.

  139. Strouse and Bloch: Notes on Present Epidemic of Respiratory
    Disease;—J. A. M. A., 1918, 71, 1568.

  140. Symmers: A Note on the Pathology of the Prevailing Pandemic
    Influenza;—N. Y. Med. J., 1918, 108, 621.

  141. Symmers: Pathologic Similarity between Pneumonia of Bubonic
    Plague and of Pandemic Influenza;—J. A. M. A., 1918, 71, 1482.

  142. Symmonds, C. P.: Nephritis in Relation to the Recent Epidemic of
    Influenza;—Lancet, 1918, 195, 664.

  143. Synnot and Clark: The Influenza Epidemic at Camp Dix;—J. A. M.
    A., 1918, 71, 1816.

  144. Talbot: Influenza among Children;—Boston Med. & Surg. J., 1918,
    179, 779.

  145. Thayer: Discussion on Influenza;—Proc. Roy. Soc. Med., 1919, 12,
    28 & 61.

  146. Thomas, H. M., Jr.: Rupture of Encapsulated Empyema into Pleural
    Cavity;—J. A. M. A., 1919, 72, 29.

  147. Thompson: Influenza as it Affects the Air Passages;—Practitioner,
    1919, 102, 12.

  148. Titus and Jamison: Pregnancy Complicated by Epidemic
    Influenza;—J. A. M. A., 1919, 72, 1665.

[Illustration:

  FIG. LVII. AUTOPSY NO. 150. ORGANIZATION OF THE INFLAMMATORY EXUDATE
    AND REGENERATION OF THE MUSCLE FIBERS AFTER AN ACUTE HEMORRHAGIC
    MYOSITIS. COMPARE FIGURE LVI.

  HELIOTYPE CO. BOSTON
]

  149. Torry and Grosch: Acute Pulmonary Emphysema Observed during the
    Epidemic of Influenzal Pneumonia at Camp Hancock;—Am. J. Med. Sci.,
    1919, 157, 170.

  150. Uhlenhuth: Zur Bacteriologie der Influenza;—Med. Klin., 1918, 14,
    777.

  151. U. S. Pub. Health Reports, 1919, 34, 1.

  152. Valentine: Study of Agglutination Reactions of B.
    influenzæ;—Bureau of Lab., N. Y. Board of Health Report, 1918.

  153. Vaughan: The Bacteriology of Influenza (Editorial);—J. Lab. &
    Clin. Med., 1918, 4, 83.

  154. Wadsworth, A. B.: A Study of Experimental Organizing
    Pneumonia;—J. Med. Res., 1918, 39, 147.

  155. Wanner, F.: La Grippe à l’Hôpital d’isolement de Vevey en
    Juillet-Août, 1918;—Corr. Blatt f. Schweizer Aerzte, 1918, 48, 1729.

  156. Wegelin: Pathologische-anatomische Beobachtungen bei der Grippe
    Epidemie von 1918;—Corr. Blatt f. Schweizer Aerzte, 1919, 49, 65.

  157. Whittingham and Sims: Bacteriology and Pathology of
    Influenza;—Lancet, 1918, 195, 865.

  158. Winternitz, M. C.: Anatomical Changes in the Respiratory Tract
    Initiated by the Inhalation of Irritating Gases;—Military Surg.,
    1919, 44, 476.

  159. Winternitz, M. C.: Collected Studies in the Pathology of War Gas
    Poisoning;—Yale University Press, 1919.

  160. Winternitz, M. C., and Hirschfelder, A. D.: Studies upon
    Experimental Pneumonia in Rabbits;—J. Exp. Med., 1913, 17, 657.

  161. Winternitz, M. C., and Smith, G. H.: Intrapulmonary
    Irrigation;—Proceed. Soc. Exp. Biology & Med., 1919, 16, 55.

  162. Wolbach, S. B.: Comments on the Pathology and Bacteriology of
    Fatal Influenza Cases Observed at Camp Devens, Massachusetts;—Bull.
    Johns Hopk. Hosp., 1919, 30, 104.

  163. Wollstein, Martha: An Immunological Study of Bacillus
    influenzæ;—J. Exp. Med., 1915, 22, 445.

  164. Wollstein and Goldbloom: Epidemic Influenza in Infants;—Am. J.
    Dis. Children, 1919, 17, 165.

  165. Woolston and Conley: Epidemic Pneumonia (Spanish Influenza) in
    Pregnancy;—J. A. M. A., 1918, 71, 1898.

  166. Yanagisawa: Experimental Study on the Mixed Injection of Bacillus
    influenzæ and Various Species of Cocci;—Kitasato Arch. Exp. Med.,
    1919, 3, 85.

[Illustration:

  FIG. LV. AUTOPSY NO. 146. ACUTE HEMORRHAGIC ENTERITIS ASSOCIATED WITH
    MULTIPLE BACTERIAL EMBOLI IN THE CAPILLARIES OF THE INTESTINAL
    MUCOSA.
]


                PRINTED IN THE UNITED STATES OF AMERICA

-----

Footnote 1:

  The history of the epidemics of influenza cannot but impress one with
  the difficulties of medical progress. Beyond the fact that the
  descriptions of the epidemics are such that the disease is
  recognizable as being the same, there is little of real value in the
  literature until the beginning of the 19th century.

  In the 18th century the infectious nature of the malady had been
  recognized. The results of study in the first half of the 19th century
  are shown in the literature of the epidemic of 1847–49. In it,
  exceptionally good clinical descriptions and epidemilogical studies
  are published. In the next forty years great strides were made in
  Pathology and in the essentially new science of Bacteriology. With
  those two aids in the study of infectious disease, it is only
  reasonable to expect an increase in knowledge of influenza after the
  epidemic of 1889–90. Such is the fact and a comprehensive review of
  both the Bacteriology and Pathology of this disease is offered in
  Nothnagel’s Specielle Pathologie, 1896, Bd. IV, by O. Leichtenstern.

Footnote 2:

  Early in the epidemic, Nicolle (106) and his co-workers described a
  filterable virus as the probable etiological agent in influenza.
  Several investigators have corroborated this work. Chief of these are:
  Gibson, Bowman, and Connor (46); Bradford, Bashford, and Wilson (16).
  The latter investigators independently isolated a filterable virus
  which may be cultivated by the Noguchi method and which, when
  inoculated into monkeys, produces a general reaction with specific
  respiratory lesions which, they think, are comparable to those of man
  in influenza. While these results must be confirmed, they offer
  greater promise than any other.

Footnote 3:

  A marked fibrinous exudate in the lower trachea with the formation of
  a pseudomembrane was noted by Oberndorfer (108), Lubarsch (19), Coray
  (28), Borst (15), and Schmorl (128). Schmorl studied the bacteria from
  the trachea and found in sections streptococci, pneumococci, and
  staphylococci, but not B. influenzæ or B. diphtheriæ.

Footnote 4:

  Simmonds (131), Bernhardt and Meyer (19) note that perichondritis may
  be present, but do not give a detailed description of the lesion.
  Gruber and Schädel (50) found this perichondritis to be associated
  with abscess formation.

Footnote 5:

  Two examples of fresh endocarditis are reported by Malloch (95) and
  one by Dietrich (34), all of which were due to B. influenzæ. Acute
  myocarditis was observed by Blanton and Irons (12) and Gruber and
  Schädel (50). Glaus and Fritzsche (47) report a case with multiple
  hemorrhages, necrosis, and leucocytic infiltration of the heart muscle
  and also one of Zenker’s degeneration of the myocardium. Cases of both
  myocarditis and endocarditis are included by Leichtenstern (82) in a
  review of the epidemic of 1889–1890.

Footnote 6:

  The picture is not unlike that of the interstitial pneumonia after
  measles as described by MacCallum (93).

Footnote 7:

  Pneumothorax as a complication following influenzal pneumonia is
  mentioned in association with marked emphysema in the epidemic of
  1889–90 by Leichtenstern (82). It has been found by X-ray examination
  in two cases of interstitial emphysema by Berkley and Coffen (8) and
  also has occurred at Camp Dix according to the report of Synnot and
  Clark (143).

Footnote 8:

  The rarity of empyema has been commented upon by LeCount (78) and
  Torry and Grosch (149). The condition was found in a small number of
  cases by Wegelin (156), Malloch (95), Lyon (90), Chickering (25), and
  Thomas (146), while Goodpasture (48) described it in eleven out of
  sixteen cases of streptococcus hemolyticus pneumonia.

Footnote 9:

  Fibrinopurulent pericarditis has been described by Simmonds (131),
  Stone and Swift (138), Lyon (90), Fildes et al (40), Jaffé (66), Glaus
  and Fritzsche (47).

Footnote 10:

  The types of consolidation described as having been encountered at the
  post-mortem table apparently vary somewhat with the locality and the
  interpretation of the observers. The lobar type has been frequently
  found by Opie et al (110), Wollstein and Goldbloom (164), Stone and
  Swift (138), and others. The pseudolobar pneumonia has been mentioned
  by Abrahams et al (2), Keegan (67), and Speares (135), while the
  peribronchial type has been well described by Hubschman, Glaus and
  Fritzsche (47), and MacCallum (92). Lobular pneumonia has been noted
  by all observers. The type of consolidation in this series has been
  tabulated in relation to the inflammatory reaction.

               Acute Fulminating Pneumonia Necrotization Organization Total
 Lobar                                   0             2            3     5
 Pseudolobar                             2             4            3     9
 Peribronchial                           0             1            4     5
 Lobular                                42            32            2    76
                                      ————          ————         ————  ————
     Total                              44            39           12    95

Footnote 11:

  No particular search was made for such lesions until the epidemic was
  nearly half over. At that time word was received from Camp Devens that
  hemorrhagic lesions in the rectus muscle were being found. Thereafter,
  the recti were examined with care.

Footnote 12:

  Abscesses supervening upon the rectus hemorrhages are reported by
  Beals, Blanton and Eisendrath (7), and by Glaus and Fritzsche (47).
  Generalized abscesses are reported by the latter and by Dietrich (34).
  Abrahams, Hallows and French (2) report subcutaneous abscesses; Beals,
  Blanton and Eisendrath, abscesses of the kidneys.

Footnote 13:

  The sinuses of the head and middle ears were examined in a number of
  cases with negative findings. Suppuration of these areas is, however,
  reported by others.

  Stone and Swift (138) found pus in the sphenoidal sinus in 68 per cent
  of their cases with pneumococci, streptococci and B. influenzæ
  present. Wolbach (162) found twenty cases of infection of the sphenoid
  sinus from twelve of which B. influenzæ alone or combined with
  pneumococci or streptococci were isolated. Lacy (74) reports four
  cases of influenzal sinusitis.

Footnote 14:

  Acute nephritis has been reported by many observers, but the
  histological descriptions have been so meager that judgment regarding
  it must be suspended.

Footnote 15:

  This condition has been met with more frequently in other localities.
  Stone and Swift (138) report it in a high percentage of their cases.
  Lamb and Brannin (77) encountered it seven times, and Blanton and
  Irons (12) report two cases. Borst (15) and Jaffé (66) also have found
  this complication.

Footnote 16:

  Cheesman and Meltzer (24) demonstrated as early as 1898 the importance
  of primary injury for the localization and development of secondary
  infecting bacteria.

------------------------------------------------------------------------




                          TRANSCRIBER’S NOTES


 1. The illustrations are not numbered in the order they appear.
 2. Silently corrected typographical errors and variations in spelling.
 3. Retained anachronistic, non-standard, and uncertain spellings as
      printed.
 4. Footnotes have been re-indexed using numbers and collected together
      at the end.
 5. Enclosed italics font in _underscores_.