DISTRIBUTION OF PNEUMONIC LESIONS AND GRADES OF SEVERITY

═════════════════════════════════════

DEGREE OF INVOLVEMENT + ++ +++ Total

Left upper lobe 10 6 7 23

Left lower lobe 4 10 17 31

Right upper lobe 12 8 9 29

Right middle lobe 10 9 4 23

Right lower lobe 5 9 18 3

─────────────────────────────────────

All lobes were simultaneously

involved in some grade of pneumonia

in 18 cases—56 per cent.

at times quite remarkable. It may appear very early in disease. We have

not met with a single case where the emphysema of the lung led to a

rupture of the air sacs and an interstitial infiltration of air through

lung, mediastinum, neck and subcutaneous tissues. Some very remarkable

cases are reported by different authors where this emphysema was of

astounding grade leading to a crepitating infiltration throughout the

mediastinum, neck and the subcutaneous tissues over the thorax and

abdomen as low as the pubis. The milder grade of emphysema consisted

mainly of an abnormal expansion of the air sacs which were not

infiltrated by exudate and which probably had some effect in preventing

the diffusion of the inflammatory fluid from entering certain regions.

These emphysematous areas could be readily recognized by the naked eye

along the anterior borders of the lung as well as between the involved

pneumonic patches within the lung.

These lungs, involved in this early serous and hemorrhagic exudate

varied considerably in their appearance according to the regional and

quantitative involvement. As is seen from Table viii, the lower lobes

were more commonly occupied by massive exudate than the upper, and the

involvement of multiple lobes was the usual. Still more remarkable is

the fact that all lobes were simultaneously involved in some grade of

reaction (pneumonia) in 56 per cent. of cases. In complicated

influenza-pneumonia Goodpasture and Burnett found the inflammatory

reaction in both lungs and involving to a greater or less degree the

lobes on each side. Most commonly this involvement consisted of a lobar

distribution in one or two lobes with a lobular or patchy disposition of

exudate in one or more of the remaining lobes. Where the distribution

was lobar the involved lobe was distended to its fullest and the pleura

tightly stretched over the lung tissue which, heavy with fluid, was not

solid but flabby. The lung could be moulded under the finger and could

be compressed into various shapes. At first sight this flabby, heavy

lung tissue suggested the appearance of the waterlogged lung which one

encounters in renal disease or failing circulation. A closer analysis,

and particularly when the lung was sliced, showed an entirely different

character.

Where the inflammatory œdema was accompanied by much focal hemorrhage

the distribution was nodular and suggested the appearance of the

hemorrhagic lung of plague pneumonia. It was this appearance which led

to the suggestion that the pandemic was not one of influenza but

possibly of an infection related to the eastern plague. The nodular

masses of hemorrhage at times occupied areas varying from the size of a

walnut to that of a golf ball and were localized amidst a relatively

mildly involved lung tissue making a sharp contrast between the involved

and relatively normal tissue. With the removal of the lung from the body

and the partial collapse of the aerated tissues these nodules became

still more prominent. The greater the amount of hemorrhage within these

areas the more solid became the occupied tissue. Such sporadic

distribution of hemorrhagic lesions occurred in the two most intense and

rapidly fatal cases. Both of these individuals died within 48 hours of

the time of onset of the lung conditions. In these two cases we do not

believe that the pulmonary lesions had been prolonged over a time even

as long as 36 hours but with the difficulty of estimating the onset of

the lung involvement we are giving a liberal estimate of this time.

Besides meeting with the stages of congestion, œdema and hemorrhage

during the earliest days of the pulmonary lesions we have found that

they are to be encountered virtually through all the stages of the fatal

cases either as remnants of the original reactions which had not been

entirely obliterated by the succeeding purulent process or as was so

commonly found, new reactions occurred in other regions of the lung so

that, in the same individual, inflammatory reactions of different stages

of development could be defined. I do not recollect a single autopsy of

a case dying during the acute period which did not show evidence of some

areas in the stages of this early acute reaction. Naturally where

resolution is well advanced within the lung all trace of inflammatory

exudate of various kinds is removed and where such individuals with

their resolved pneumonia are brought to death through succeeding

complications the above finding will not be borne out. We limit,

however, our statement to the findings in the acute deaths.

We have previously intimated that the œdema present in the early stages

of the reaction is to be looked upon as an inflammatory œdema or better

as a true serous exudate, and must not be confused with the transudation

of fluids in non-inflammatory conditions. We have on several occasions

collected the fluid expressed from the soggy lungs and have made some

determinations of their chemical qualities. The difficulty immediately

arises in separating the materials arising from cellular degeneration

from the natural constituents of the serous exudate. We were unable to

obtain specimens in which laked blood was not present, so that even

though the cellular constituents and fibrin were removed, decomposition

products could not be separated. The analyses, however, gave a

differentiation from the transudate seen in renal and cardiac

conditions.

During the period of the accumulation of this inflammatory fluid the

clinician could often recognize a profuse watery exudate within the lung

or even observed an abundant serous discharge arising in bronchi and

trachea. At times the quantity of expectoration was great. Frothy serous

fluid accumulated in the air passages and would periodically be

expectorated. At other times the hemorrhage was of quite serious extent

and the patient would suddenly bring up several mouthfuls or more of

bright blood. This pulmonary hemorrhage was without manifestations

different from the acute illness with cyanosis of other individuals. The

two most acute cases, which we have referred to above, were of this

kind, both of them having marked hæmoptysis with the loss of upwards of

a pint of blood at a time.

The early pulmonary lesion which we have described, we have called acute

serous pneumonia and acute hemorrhagic pneumonia (or we might speak of

it as an acute sero-hemorrhagic pneumonia) and is one which is

distinctive for epidemic influenza. The cut surface of a lobe involved

in this reaction is wet, glassy, meaty and oozes much blood-stained

fluid. It contains no visible fibrin and presents no characters of a

“cellular consolidation.” As a serous inflammation of the lung it is

unique. The further remarkable character to the pulmonary lesion is that

in advancing through the other stages, it never passes through a stage

of “red hepatization.” Here again we have a distinctive difference from

the pneumococcus-pneumonia. From what we have previously said about the

nature of this early acute inflammation of the lung in this disease it

is apparent that red hepatization has no place in its process. The stage

of red hepatization is attained only when the inflammatory reaction is

accompanied by certain constituents in the exudate, which upon

coagulation (separation out of the fibrin) renders the lobe dry and

solid, while there is a sufficient abundance of red blood cells and

congestion to maintain a dark red color. The hepatized lung on section

is dry, more or less granular, containing fibrin, red cells and

leucocytes within the alveoli. Extensive œdema is unusual except in the

cases of hypostatic pneumonia, which in well marked cases bears some

resemblance to the gross appearance of the early influenza pneumonia. We

have not encountered a single case of the red meaty lung of influenza

which showed evidence of true red hepatization in the gross.

The _microscopical_ examination of the lung tissue confirmed the

observations which were made in the gross. In the early stages of

congestion the reaction was much more extensive than what could be

spoken of as a broncho-pneumonia. The capillary dilatation in the

alveolar walls occupied diffuse areas varying from multiple lobules and

areas several cm. in size to the common diffuse congestion of an entire

lobe. Capillaries were distended to their full capacity and often this

engorgement was associated with the leakage of blood or a serous fluid.

Not uncommonly a clear serous fluid was exuded into the interstitial

tissues of the alveolar wall and collected within the air sacs. The high

albuminous content of this fluid was seen in the homogeneous coagulation

which occurred when the tissues were placed in fixatives. The

microscopical sections of such parts demonstrated the coagulum occupying

the alveoli as a clear homogeneous substance containing relatively few

cells and looking not unlike the colloid deposit of the thyroid. The

alveolar walls, themselves, were infiltrated with fluid so that the

distended tissues and vessels made these structures thick and bulky. In

our own observations we were impressed by the differences of the early

inflammatory reaction from those ordinarily seen in pneumonia. Amongst

these differences was the quantity of fluid extruded into the lung with

a relative absence of fibrin. In some instances fibrin was completely

wanting, although small quantities could be demonstrated in isolated

areas. This observation upon the quantity of fibrin can be made only

during the early stage of the disease in as much as after secondary

infection of various kinds has become implanted the presence of fibrin

has become a variable quantity often exceeding that seen in the early

stages. This is one of the points upon which the older authors have laid

stress in differentiating influenza pneumonia from others. In this we

fully concur. Whether this lack of fibrin in the inflammatory exudate is

a characteristic to be associated with the infection by the B. influenzæ

alone is hard to say, but in as much as it was such a prominent finding

we are led to lay some stress upon it. It is, of course, to be realized,

as with all other micro-organisms that under certain conditions fibrin

will form an important part of the exudate even when the B. influenzæ is

present. This is true in the inflammatory reactions of the meninges

present in infections due to this bacillus. Under the conditions of

epidemic influenza where the lung lesion is the prominent and unique

reaction this micro-organism fails by itself to bring out this quality

in the exudate.

Not uncommonly this stage of inflammatory œdema was accompanied by

various grades of hemorrhage, varying from the presence of small

aggregations of red cells to a complete flooding of the lung tissue

making it look not unlike a red infarct of lung, save that the alveolar

walls still showed an active circulation and living cells. It was

remarkable that even though there was such an intense reaction taking

place in the lung tissue there was little or no evidence of a cellular

exudate during this stage of the process. Where much blood was extruded

into the alveoli occasional fibrin threads were found in the coagulum.

In these early cases the bronchicles and small bronchi were found to

contain an exudate similar to that in the alveoli. Not uncommonly the

vessels from which the red blood was escaping, could be demonstrated in

sections. The appearance of the vascular wall suggested that a definite

opening had occurred in the side of the capillary from which the blood

escaped. We were not able to demonstrate a fatty or other type of

degeneration in the cells of the capillary walls. It is probable that

the process of injury was much too acute to permit of the demonstration

of the products of degeneration within the surviving cells.

The hemorrhagic lesions which had existed for a longer period of time

gradually showed a varying infiltration by wandering cells. The earliest

cells not belonging to those of the hemorrhage or œdema appearing within

the alveoli were mononuclear elements partly arising from the alveolar

walls and partly coming from the circulation. Numerous mononuclear cells

of epithelial type desquamating from the inner surface of the alveoli

accumulated in the œdematous fluid and the hemorrhage within a short

time after their occurrence. These cells either appeared in clusters or

as single elements. Accompanying this were also large mononuclear cells

loaded with different quantities of pigment which had apparently escaped

from the lymphatic channels within the alveolar walls. These latter

cells belong to the wandering endothelial type which are active in

phagocytosis for foreign material and which assist so largely in

inducing the deposit of carbon in the lungs and lymph glands. A third

mononuclear cell appearing early in the reaction was the lymphocyte. The

numbers and extent of distribution of this cell were not constant. We

have seen it in some of the reactions where very few leucocytes were to

be seen, and where it constituted the main infiltrating cell of the

alveolar wall or the air sacs. We have previously mentioned its presence

in the inflammatory reactions of the bronchi. Here we find it in the

early response within the lung tissue and appearing amidst a reaction

which is intensely acute. It is not long after the finding of these

various cell elements that the polymorphonuclear leucocyte wanders in

large droves to numerically overshadow the mononuclear cells.

Nevertheless, the three types above mentioned can be recognized in the

exudate through the succeeding stages of reactions in the lung. The

large macrophage shows its phagocytic properties in taking up numerous

red blood cells, lymphocytes and occasional leucocytes.

It is not difficult to demonstrate that the inflammatory reaction within

the bronchi and bronchioles precedes the responses within the alveoli.

Quite often one may find an acute bronchiolitis with desquamation of the

lining epithelium and the early serous exudate lying amidst the lung

parenchyma unaffected by any irritant and reaction. There is every

evidence that the bacteria reach the lung tissue by extending along the

walls of the respiratory tubes and eventually reaching the air sacs

either in the distant extremities of the bronchioles or when they have

arrived at the thin-walled structures extend through them into the

neighboring air sacs.

It is during this early period that we are able to observe the

characteristics of the initial inflammatory exudate as we have described

it above. The serous exudate and the infiltration by mononuclear cells

appear early while the absence of fibrin also attracts attention. In

place of fibrin there appeared in a certain number of cases a peculiar

material of a hyaline nature which becomes plastered against the borders

of the air sacs forming a fairly thick laminated structure and within

which thread-formation is not to be seen. Occasionally a few cells lie

within this hyaline substance. Some have referred to this as a type of

fibrin. We have found, however, that it does not give the staining

reactions for fibrin and does not appear to be of the same composition.

These masses are tightly welded to the alveolar walls and the borders

are often indistinguishable. In part this material appeared to be made

up of necrotic cells of the septum which previously had suffered œdema

and circulatory interference. We have found in a number of cases hyaline

thromboses of the fine capillaries with more or less necrosis of the

alveolar septum. At times the septum was entirely destroyed so that a

thick hyaline mass alone separated neighboring air sacs. This hyaline

necrosis resembles in part the superficial necrosis which was observed

along the borders of the denuded bronchi. There is, however, more than

necrosis of cells constituting this deposit for the bulk of material

eventually deposited is much greater than could arise from tissue cells

alone. These hyaline masses have never been found to lie upon the

alveolar wall with an intact lining, but it is always accompanied by a

loss of the lining cells and more or less destruction of the wall

itself. As to the nature of the hyaline deposit which is laid down in

lamellae we do not know. Fibrin threads occasionally appear to arise

from these hyaline deposits and extend amidst the exudate in the air

sac. One cannot assume, however, that the fibrin and the hyaline

material have any relation to each other as their chemical

characteristics (and mode of deposition) appear to be quite different.

It has been suggested by some that this hyaline material represents an

imperfectly formed fibrin which has formed a jelly-like clot, not having

the property of developing the usual threads.

It is of importance to appreciate that the deposition of these hyaline

structures indicates a severe injury of the alveolar walls not commonly

observed in ordinary pneumonias.

In different areas of the same lung these constituents of the early

exudate may be observed in all proportions of admixture. Each one of the

elements of the exudate may largely overshadow the others and

prominently modify the appearance of the lesions. Broadly speaking,

however, the inflammatory œdema and hemorrhage occupying the greatest

part of the exudate in the lungs and the absence of marked leucocytic

response as well as the absence of the characteristic fibrinous meshwork

in the alveoli give to the early influenza-pneumonia a character

different from those which we ordinarily see.

It is during this early phase of the reaction that the influenza bacilli

can be shown within the lung structures. The distribution of bacteria is

not uniform. Clusters of these minute bacilli are found in the alveoli

at irregular intervals, many of the air sacs containing much exudate

being quite free from organisms. When present the bacteria appeared in

tightly aggregated schools lying free amongst cells of the exudate, but

also certain numbers being incorporated within the large mononuclear

cells. In some regions organisms of the type of the influenza bacilli

were alone seen, while elsewhere again, and particularly where the

exudate was assuming purulent characters other bacteria of the nature of

streptococci, staphylococci and micrococcus catarrhalis, were also

found.

_Lung—Secondary Stage_

Following upon the primary reaction in the lung as above described, a

secondary reaction makes its appearance at variable periods. This

reaction is one in which the inflammatory exudate resembles more closely

but is not identical with the responses which are observed in ordinary

lobar, lobular and pneumococcus-pneumonia. Whereas in the earlier

period, the reaction is largely one of a serous and hemorrhagic exudate

accompanied by peculiar hyaline deposits along the inner borders of the

alveoli, later there is seen a change in the quality of the exudate with

the accumulation of more cellular elements and some fibrin. The naked

eye appearance of the involved tissue changes considerably. The lung

tissue loses in weight but becomes more solid. The lung contains less

fluid and the cut surfaces are drier and the color of the reaction

changes from the dark congested appearance to one showing all varieties

of red and gray. This change from the flabby and soggy pneumonia to the

more definite type of consolidation occurs in the regions which have

been previously involved and is not to be found in the lung areas which

have escaped the early reaction. The gray consolidation appears to be

either a stage of the influenza-pneumonia or is a new reaction

superadded to those pulmonary lesions induced by the primary infection.

It is sometimes difficult to recognize the beginning of this pneumonic

stage inasmuch as the gray color does not make its appearance even with

the presence of fairly large quantities of cellular exudate. The amount

of hemorrhage that originally lay in the affected areas for a long time

overshadows the presence of the color of the cellular exudate. This is

also true of the characters that may be impressed by the presence of

fibrin. Small quantities of fibrin scattered through the congested and

œdematous lung are not readily recognized and the beginning of this

secondary reaction is also easily overlooked if one relies upon evidence

of consolidation. More or less solid exudate may occupy a flabby lung

without permitting one to appreciate its presence in the gross specimen.

When, however, the deposit is of sufficient quantity to change the color

of the involved lobe and to alter its consistency, one has little

difficulty in recognizing the changes now taking place. The earliest

development of this change in the inflammatory reaction was on the

fourth day. In the majority of instances the gray color and the

consolidation made its appearance about the sixth day. We have, however,

on several occasions observed hemorrhagic lesions as late as the seventh

and eighth day, at which time it was impossible to recognize a gray hue

to the exudate or the character of granular consolidation to the

involved lung.

The reaction naturally suggests the stage of gray hepatization as we so

well appreciate it in ordinary pneumococcus-pneumonia and from the

standpoint of its color and the greater solidification of the lung

tissue we might speak of it as such. Here, however, it must be clearly

distinguished from the gray hepatization of ordinary pneumonia. This

secondary lesion of influenza-pneumonia has but little in common other

than its color and the development of a consolidation with true lobar

pneumonia. It is never as clear cut as we see it in the latter and the

degree of the “gray hepatization” is not uniformly distributed through

the involved lobe. One portion of the lobe will show a diffuse gray hue

while in other parts more decided lobular or patchy areas are picked out

in the advanced reaction. There is not the uniformity of lobar

involvement nor is the distribution as regular as one obtains it in

broncho-pneumonia. Furthermore, the character of the consolidation

differs very decidedly in showing such a variety of hues in reds and

grays and the cut surface is not the picture of the dry granular

consolidation of our endemic disease. The gray areas are in all states

of wetness and ooze a slimy fluid on the cut surface. In the later

stages this exudate is most profuse resembling a sticky pus. In its

appearance we were reminded of the character seen in unresolved

pneumonia as well as in the pneumonias produced by the pneumococcus

mucosus, and the B. mucosus capsulatus. We would, therefore, avoid the

use of the term gray hepatization and in place of it, as the evidence

with the microscope confirms, use the term _purulent pneumonia_.

There are three other characters which differentiate this gray stage

from those of ordinary pneumonias—(1) the irregular distribution, (2)

the friability of the involved tissue and (3) the interstitial reaction.

We have never observed such an irregularity in the distribution of a

gray stage of pneumonia as we have seen it develop in acute

influenza-pneumonia. All types of involvement of the lobes are found in

different cases and even sometimes in the same case. The least frequent

type has been the broncho-pneumonia in its true form. Broncho-pneumonia

as we see it in children and the cases following measles is usually

fairly uniformly seeded through several lobes and the size of the

individual patches is about that of a split pea. The small bronchus can

be recognized about the center of the involvement. In those instances

one has studded through the lung tissue numerous small swollen areas

which are granular, dry and gray. Differing from this the patchy

distribution of the gray stage of influenza-pneumonia had no regularity

either in the size of the areas nor the distribution. A lobe may show

one or more patches. The patches may be distributed toward one portion

of the lobe more than another. Furthermore the areas do not always

encircle the small bronchi but involve the terminal portion so that an

entire lobule is more commonly affected. The lobular type rather than

the peribronchial type is most commonly seen and it is often remarkable

how sharply the gray lobule is demarcated from the surrounding congested

lung tissue. On several occasions we observed a single lobule in the

gray stage while the remaining portion of the lobe was in the serous and

hemorrhagic condition. However, multiple lobules are commonly seen

closely associated in the advancing inflammatory process. Such lobules

show peculiar geographical patches or leaflet-like configuration.

Varying with the number of lobules involved the extent of the gray

change in the lobes assumed more or less a lobar distribution. There was

no uniform position to this pneumonic state sometimes appearing in the

peripheral tissues of the lung, at other times lying centrally with less

involved or less advanced inflammatory reactions surrounding it.

Nevertheless, the gray stage made its appearance more rapidly in the

lower lobe than the upper and it was not uncommon to find this condition

appearing quite early in the upper posterior portion of the lower lobes.

This latter position is the one which is recognized during life by the

clinician as one of the earliest localizations of the demonstrable

pneumonia. It is reported by many that the first physical signs of

consolidation are to be obtained close to the lower angles of the

scapulae.

There is no doubt that the character of the pneumonic process in the

epidemic influenza was not the same in all localities. There have been

not a few who have reported a large proportion of their pulmonary

lesions as a definite broncho-pneumonia with an interstitial purulent

involvement. The prominent reaction was a small circumscribed yellow

focus about the bronchioles from which a bead of pus could be expressed.

These pea-sized foci were scattered through several or all lobes. It is

this type of reaction which appears to develop by a direct extension

through the bronchial walls and to remain quite localized in the alveoli

about these tubes. This reaction seems to be purulent from its very

beginning and does not pass through the stages as we have described them

above. There is more or less fibrin present in the exudate, but usually

not in the quantity observed in lobar pneumonia. These lesions closely

resemble those observed in the post-measles pneumonia, and it is claimed

are the result of the same agent; the hemolytic streptococcus. In only

one case did we observe a lesion of this kind. The small areas of

broncho-pneumonia were confined to the left lower lobe and in the lower

portion of the upper lobe. Each area was about the size of a split pea,

was quite yellow and in fairly sharp contrast to the background of an

acute sero-hemorrhagic pneumonia. The subsequent history of these

interstitial purulent broncho-pneumonias is like that in measles, where

the tendency toward an organizing pneumonia has been shown. The

importance of the hemolytic streptococcus in inducing purulent

interstitial lesions of the lung (and also of other organs) cannot be

over-impressed. It is not so much the type of the reaction during its

acute stage which attracts our attention, but the manner of the healing

process. It is more than probable that the organizing pneumonias of

influenza, not only of this distinct bronchial type, but also the

lobular, confluent and lobar variety have had an associated

streptococcus infection. The more intimate discussion of this type of

pneumonia has been given by MacCallum.

Our autopsy experience has led us to believe that the definite clinical

signs of pneumonia are associated with the development of this gray

consolidation of the lung. The lung tissue develops characters which

permit the physical signs to be recognized. The tissue is more solid and

more readily transmits the bronchial sounds. This is not true of the

earlier stages where the inflammatory process is contained within a lung

tissue which still is partially crepitant and when the so-called

consolidation is due to an inflammatory œdema and not to the more solid

fibrinous and cellular exudate. With the protean distribution of the

gray lesion one does not wonder at the clinical difficulties in mapping

out or even finding the consolidated tissues.

As soon as the lobes show this gray character and with the progressive

development of an acute interstitial purulent pneumonia, the lung tissue

becomes friable. All gradations of flabbiness may still be obtained and

in the early stages while the cellular exudate is accumulating to change

the color of the lung, little variation from the tough character of the

pulmonary tissues can be recognized. When, however, a true gray

character is assumed by a portion of the lobe, the tissue becomes so

soft that it is handled with difficulty without rupture. The thumb can

be pressed into the gray mass and pus will well up around the invading

phalanx. The consistency in the late stages reminds one of the pulpy

tissues in acute splenitis. In cutting such lobes it is almost

impossible to obtain slices of the tissues, their own weight often

breaking such a segment. When allowed to rest on the table for a few

moments, the cut surface becomes coated with a dirty yellow slime

representing pus and products of disintegration arising from the lung.

The stroma and alveolar tissues are themselves involved in the

inflammatory process and many of them have suffered complete or partial

destruction so that they offer but little resistance to pressure and

serve as a poor supporting stroma to the pulmonary tissues. The reaction

which has taken place within the lung producing both the gray color and

the destruction of the tissues is, indeed, an active suppurative one.

One would not be surprised to obtain not only a purulent lesion wherein

the cellular exudate occupies the air sacs and their walls but also a

further stage leading to a destruction of the tissues to the extent that

abscess cavities are produced. These we have met with in several

instances, some of them being small while others were several

centimeters in diameter. An abscess of larger extent and having a

destructive process which involved the surrounding tissues so that one

would speak of it as a process of gangrene, was observed by Dr. McMeans

in one of his cases. A lobar distribution of the purulent lesion takes

place where multiple involved lobules have fused in their periphery or

where a suppurative flooding of the tissues in this violent late

reaction has taken place.

The question at once comes to mind whether this gray stage is but the

late event of what we have previously spoken of as influenza-pneumonia

or whether this condition is superadded to what may begin as an

influenza-pneumonia but end in a pulmonary inflammation with a mixed

infection. Dr. Holman was not able to demonstrate a sufficient

difference in the bacteriology of the lobes in the gray stages from

those in the early acute stage to be able to say that the flora changes

at a certain time during the progress of the disease in the individuals.

It is possible, and there is some evidence in support of this, that the

earlier stages of the pneumonic process represent the reaction to the

influenza bacillus and that during this period the response is fairly

uniform and similar owing to the fact that this infection has but a

short incubation period and a high pathogenicity. In such an event the

particular micro-organism may bring about a peculiar response of its own

before the other organisms with which it is associated have the

opportunity of producing damage. Subsequently, however, these secondary

organisms impose their peculiar reactions upon an altered lung, thus

inducing an inflammatory lesion which differs from the preceding

reaction and also differs from the reaction usually induced by those

organisms upon relatively healthy tissues. It is difficult to account

for the very irregular distribution of the gray lesions by an

explanation concerning the influenza bacillus alone, or by the

characters peculiar to the secondary infection. There is an entire want

of character to these gray lesions which makes them differ from other

types of pneumonia known to us.

It is well to lay particular stress upon this peculiarity in the

distribution and extent of the lesions within the lobes; and it is also

important to appreciate the difference in the appearance of these gray

areas from those of true lobar or broncho-pneumonia.

Finally there is another point in which this stage of the pneumonic

process differs from that of pneumococcus lobar pneumonia. In frank

lobar pneumonia the reactions taking place in the involved portion of

the lung are fairly uniform in all its parts. The stage of red

hepatization occupies about that amount of lung which subsequently shows

itself in the state of gray hepatization. In other words, all of those

areas which appear gray are preceded by this peculiar red consolidation,

and all of the area occupied by the red hepatization will pass through

the phases of gray hepatization before entering upon the final stage of

resolution.

In influenza-pneumonia, on the other hand, the events taking place in a

given lobe are not uniform and various stages and grades of the

inflammatory reaction may be recognized at the same time, some appearing

red, some congested, some flooded with blood in hemorrhage and others

showing the purulent infiltration by the appearance of gray patches upon

the background of red. Not only do the various reactions within the same

lobe fail to show similar grades of intensity and similar stages or time

of involvement, but we find that all of the red and hemorrhagic areas

are not destined to pass through the gray stages. At times it is true an

entire lung will enter into the purulent phase and if this becomes

extreme abscess and gangrene are almost certain to develop. But often

the purulent infiltration occupies only a few or scattered lobules and

resolution may take place in a lung where the greater part of the lobes

is occupied by the inflammatory œdema and hemorrhage and has never

become truly consolidated by cellular and fibrinous exudate. This

feature that the involved lung tissues need not pass through the

sequence of events which is usually observed in frank lobar pneumonia is

so distinctive that it differentiates the character of the inflammatory

reaction very clearly. It may be that this is an indication of the

unequal distribution of the micro-organism and that the first infection

presumably by the _bacillus influenzæ_ has been much more diffuse and of

wider extent than the secondary invading bacteria which being

distributed through the bronchial tree are more or less localized to

those lobules most severely involved. It is impossible to claim for

influenza-pneumonia as clear and sharp-cut stages as we obtain them in

the pneumococcus lobar pneumonia.

During the period of the intense purulent reaction in certain portions

of the lung, the intrinsic structures within the area also partake in

the damage and response. The suppurative infiltration not only occupies

the alveolar walls but also extends through the tissues of the

bronchioles, the arteries and the veins. The polymorphonuclear

leucocytes seem to migrate into all of the parenchyma indicating some

damage by bacterial invasion. On more than one occasion have we observed

partial or incomplete thrombosis of arterioles and capillaries whose

walls showed an acute suppurative reaction. Some of these thromboses are

of importance, being associated with the interference with a blood

supply not compensated by adequate anastomosis. Necrosis and small areas

of gangrene and abscess are to be found in the region of the circulatory

disturbances. It is also during this period of the disease when the

bronchi and their ramifications contain pus or muco-pus, that the

exudate from the alveoli readily finds its way into the air passages and

becoming mixed with the mucus from these tracts forms a tenacious

discharge.

The presence of large amounts of exudate within the bronchi brought

these structures into unusual prominence. This was particularly true in

the purulent stage of the reaction when beads of sticky pus would well

up from the cut bronchioles. We were tempted on a number of occasions to

speak of this in terms of bronchiectasis but with the intense

inflammatory reaction occupying the bronchial wall and modifying its

contour on this account we avoided this diagnosis. In one instance,

however, the lesion was unmistakable. This was a case of purulent

pneumonia (764) dying on the ninth day of the disease. The distribution

of his pulmonary lesions was distinctly lobular, apparently following

the course of the bronchial distribution. The bronchi were followed

longitudinally and irregular pouchings of the lumen were very apparent.

The bronchi had suffered marked inflammatory reaction which had also

infiltrated the muscular tissues of the tubes. Goodpasture and Burnett

report finding two cases of acute bronchiectasis associated with abscess

and ulceration of the bronchi. In our case the bronchiectasis was found

bilateral but was more marked in the lower lobes than the upper.

The lymphatic channels within the lung tissue are found active in

establishing an internal drainage to the neighboring thoracic glands.

The lymph vessels were often found filled with leucocytes and variable

amounts of serum. During this late stage only a few of the endothelial

leucocytes were observed wandering to or from the lung with a load of

pigment or cell debris. These wandering endothelial cells, however,

appeared to become loosened from their normal situations and in the

vicinity of lymphatic nodes or communicating channels where these cells

are prone to localize with their carbon pigment, again assumed their

spherical form and took on migratory properties entering into the nearby

tissues and scattering themselves in the looser structures. It is an

interesting point to note that these pigment carrying cells, ordinarily

assuming a latent existence when their cytoplasm has been crowded with

foreign particles will assume all the activities of migrating cells when

the œdema of the tissues alters the physical properties not conducive to

a stationary existence. These cells will then be found to enter the lung

alveoli, often appearing as cells which have only recently picked up

their carbon load. When, however, the conditions of the experiment, that

is, the production of an inflammatory œdema in the lung, are produced in

the tissues of an individual with much anthracosis, he will, during the

period of his pneumonia and for some time during convalescence, bring up

a greater number of these cells in his sputum than are ever obtained

during the times when the lung is not involved. We are convinced that

inflammatory conditions of the lung tend to reduce the total number of

latent pigment bearing cells present in the involved tissues, and in

this way somewhat reduce the grade of anthracosis.

A considerable discussion has arisen concerning the proper nomenclature

for the pneumonia or pneumonias found in epidemic influenza. From some

quarters have come the reports of a true lobar pneumonia, from others a

lobular or broncho-pneumonia and others again claim that the reaction is

an interstitial pneumonia of varying distribution. It appeared to us

that the gross distribution of the lesions is not alone the criterion

for a proper appreciation of the inflammatory states which may arise

within the lung. I believe it has been amply demonstrated that the

pneumonic reactions appearing in different regions of the United States

as well as in different countries are not of a constant kind when viewed

alone in the light of the gross picture nor are they constant from the

standpoint of their bacteriology. We are of the opinion that the earlier

phases of the pulmonary reaction are fairly constant in different places

and that this constancy is dependent upon the common virus which

initiates the respiratory lesion and which then permits a variety of

micro-organisms invading as secondary agents. The secondary agents vary

with the community and depending upon their nature the character of the

reaction differs from that in other places. It has been well

demonstrated that in some regions the hemolytic streptococcus is the

important organism following the primary injury by the initial virus. In

other places the pneumococcus or the staphylococcus or the M.

catarrhalis is found to be of primary importance. Up to the present it

has not been shown that the influenza bacillus is not the important

organism causing the initial reaction and being responsible for the

opportunity of secondary invaders leading to such diverse reactions in

the lung. In our series we have met with lobar, lobular, interstitial

and broncho-pneumonic types. We have not observed a case of the miliary

bronchial reaction as described and illustrated by Goodpasture and

Burnett and fully investigated by MacCallum. Moreover we have not met

with the type of purulent bronchitis as a characteristic lesion

preceding pulmonary involvement. The occurrence of pus within the

bronchi occurred not early in the pulmonary lesion but later after the

bronchi and bronchioles had passed through their stages of acute, serous

and hemorrhagic pneumonia and were entering upon their secondary stage

with pus production. The pulmonary lesion had long preceded the

appearance of pus in the bronchi. We do not hold, however, that such

relations between the pulmonary lesion and the purulent bronchitis do

not exist for there is evidence that in particular regions this sequence

of events was closely observed.

We cannot, however, correlate our findings with the classification of

pneumonias as given by MacCallum. His claim for specific types of

pneumonia as a sequel to influenza is based upon his statement that “no

satisfactory evidence has been brought forward to show that the epidemic

influenza is a bacterial infection. It is evidently a general or

systematic infection not especially affecting the respiratory tract and

analogous in many respects, as Bloomfield has pointed out, to the acute

exanthematic diseases.” Thus we are confronted by two schools concerning

the nature of influenza. The one claiming that epidemic influenza is

essentially a disease of the respiratory system and the other completely

denying this.

I am unable to understand the claims which are put forward to

substantiate the second view.

The classification of the pneumonias as suggested by MacCallum would be

valuable if it could be applied in a practical manner. We find, however,

that his description for the pneumococcus-pneumonia hardly coincides

with common observations on endemic pneumonia and if the description is

to apply only to the pneumonias associated with influenza wherein

pneumococcus alone is isolated we find that our own observations do not

coincide with this. The picture offered by MacCallum under this heading

was reproduced when the bacteriological findings illustrated the

presence of organisms other than the pneumococcus or combinations of

these. The most characteristic of his description is the one for the

streptococcus-pneumonia which when present alone gives quite a unique

picture. The picture, however, is to a certain degree modified by the

reactions which precede the streptococcus in the lung. Furthermore to

offer as a characteristic picture for the influenza infection of the

bronchi the presence of a thick yellow pus is hardly complete inasmuch

as this exudate appeared only as a stage in the inflammatory process.

The intense serous and hemorrhagic response observed early in this type

of infection is more unique than the presence of pus which appears

somewhat later and which may occur with infections other than the B.

influenzæ. It has long been the hope in pathology to be able to

establish by the character of the tissue reaction, the nature of the

infecting agent. Up to the present this has been possible only with a

very few types of bacteria.

_Lung—Stage of Resolution_

The removal of the infection and the inflammatory exudate from the lung

tissue is accomplished slowly. Clinically the pulmonary process clears

up by lysis, and it is quite unusual to have a crisis with the rapid

disappearance of the serious manifestations. It is difficult to obtain a

clear conception of what takes place in any individual case recovering

from an influenza-pneumonia, but if we have an understanding of what may

occur in the inflamed lung tissue in any one of the stages or varieties

of kind, we may visualize the changing character of the lung condition

tending toward the final restoration.

We have previously pointed out that the early stage of

influenza-pneumonia is one of congestion, œdema, hemorrhage and more or

less leucocytic infiltration, and that this reaction differs materially

from that observed in pneumococcus lobar pneumonia. There being no stage

of true red hepatization, it has also become apparent that this peculiar

primary reaction need not pass into the stage of gray consolidation.

Scattered areas in the lung pass from the condition of acute serous and

hemorrhagic pneumonia to a type of purulent pneumonia while much of the

remaining tissue continues in the state as seen in the early reaction. A

certain amount of cellular exudate makes its appearance but not

sufficient to lead to a true consolidation. This variety of reaction is

present from the fifth day of the pneumonia onwards and may continue

with all of its varieties through until the tenth or twelfth day or even

longer when recovery from the infection is beginning. Thus the stage of

resolution makes its appearance before the inflammatory reaction in the

involved lobes has assumed a common character and where we are able to

recognize different grades of severity and different stages of

inflammation within the same lobe. Resolution taking place in such a

lobe has responses occurring in the different parts determined by the

nature of the antecedent reaction. We have found that those portions

which have not advanced beyond the stage of œdema and hemorrhage may

clear up with the disappearance of this early exudate and its infection.

In a neighboring portion the purulent inflammation passes through phases

differing somewhat from the preceding but also tending toward the

restoration of the parenchyma and the disappearance of the inflammation.

It would be incorrect to consider the resolution of the early type of

inflammatory reaction as an abortive process inasmuch as it is not yet

clear whether this serous and hemorrhagic process is not the

characteristic inflammation of a peculiar micro-organism or organisms

and that when acting alone these bacteria do not in themselves stimulate

a further inflammatory response. Hence if it is true that there is a

peculiar inflammatory reaction of a non-suppurative and non-fibrinous

kind the manner of resolution will differ somewhat from that where these

other constituents of the exudate are present. It becomes clear,

therefore, that in influenza-pneumonia all of the lung involved in the

early peculiar inflammatory reaction need not pass through those stages

and reactions as we recognize them in pneumococcus lobar pneumonia.

The resolution taking place in the areas of serous and hemorrhagic

pneumonia is accomplished largely by a reabsorption of the fluid,

autolytic disintegration of the red blood cells and a certain amount of

phagocytosis of red blood cells and their debris. This resolution is

quite rapidly accomplished, and the clearing up of such an area may take

place in a remarkably short period of time. The leucocytes and

endothelial cells which are present with every such reaction become

active in phagocytosis of bacteria, and we have repeatedly observed them

crowded with small Gram negative bacilli, whose morphology is similar to

that of the B. influenzæ. These areas contain but few bacteria of other

kinds. The exudate in the alveolar walls is also simple in character and

is readily removed. Slight suffusion of blood, serous fluid, and

migrating cells may occupy portions of the alveolar walls during the

acute reaction, but these, too, are easily removed and the tissue

rapidly resumes its normal character. The vascular and lymphatic

congestion again disappear and the tissues which once were soggy return

to a normal state without leaving behind evidence of the pulmonary

incapacity. The lining epithelium of trachea, bronchi and alveoli is

restored by proliferation from the neighboring less injured parts.

If this early stage in influenza-pneumonia is to be compared with the

early reactions of endemic pneumonia, it is interesting to note with

what ease the resolution may be accomplished in the former, whereas in

the latter a further sequence of stages must apparently be passed

through before the lung is cleared of its inflammatory products. As we

have intimated before, the early exudate in these two types of pneumonia

differs very essentially, the one being accompanied by much fibrin and

leucocytes which are present only in small quantities in the pulmonary

lesion of influenza.

Resolution of the other portions of the involved lobes in influenza is

not so easily accomplished. Where a progressive lesion with its

development of pus occupying both the air sacs and the tissue of the

lung, the outcome of attempts at repair are uncertain. Complete

resolution with complete disappearance of the purulent exudate may take

place as we see it in many other regions occupied by a similar reaction;

and where the purulent response is not accompanied by material damage to

the tissue the restoration of the lung is so complete that upon its

recovery no evidence is left behind of the former injury, but in as much

as the presence of a purulent reaction in the lung is often of more

severe grade than this, a certain amount of tissue destruction having

been accomplished, the repair does not completely restore the tissue to

its former normal state. The purulent lesion, however, is not uncommonly

accompanied by minute capillary thromboses, tissue derangement, organic

destruction, with even tissue alteration amounting to abscess or

gangrene, and it is too much to hope that the lung may be completely

restored. Minute abscesses varying from microscopic size to large

cavities, several centimeters in diameter, were not unusual in the

tissues severely involved in the purulent reaction. Thus in these areas,

resolution can be accomplished only by a process of slow organization of

the damaged parts with the final production of fibrosis. These fibroses

are of variable extent depending upon the initial damage. We have been

very much struck with the speed with which this process of organization

may take place and the extent of the lung tissue which may become

involved in this late lesion. In one of our cases we have evidence of

marked fibrosis present on the twenty-third day of his illness. Patches

of organization varying from one to four centimeters in diameter

occupied the different lobes of the lung. The new fibrous tissue was

well developed and the purulent reaction had largely disappeared. The

fibrosis obliterated the normal architecture of alveoli and bronchioles,

leaving only irregular islands of epithelium which assumed grotesque

glandular shapes and looked not unlike a new growth. One of the

interesting features of these late fibroses which come to occupy various

extents of the lung and bronchial tissues is that the individual after

recovering from his acute influenzal lesions again passes, in about his

third week, into a stage of dyspnœa with manifestations out of

proportion to the physical signs or constitutional derangements which

can be determined. The dyspnœa is often the outstanding sign and the

patient may die in a state of asphyxia.

We have observed evidence of organization in its earlier reactions

taking place in the patches of gray consolidation. This organization of

the lung tissue takes place as an interstitial fibrosis and as an

alveolar organization. Masses of granulation tissue grow out into and

come to occupy the lumen of the air sacs, while in other instances the

new growth of tissue takes place mainly in the alveolar walls converting

them from thin partitions to thickened and tough structures. In the

cases in which a purulent pneumonia was present for some time, and where

some of these tended towards repair, this type of restoration with the

new development of connective tissue was found. The amount of fibrosis

varied very much, and in many instances there was no evidence that

obstruction to the bronchioles occurred to a material degree. Hence,

although we believe that more or less organization occurs in all of

those cases which have passed through a purulent pneumonia, and that a

permanent mark is left upon the lung tissue, it is not probable that the

amount of involvement and final damage by fibrosis is sufficient to

seriously influence the pulmonary respiration. There is, however, a

certain percentage of cases in which this organization and fibrosis does

involve sufficient of the lung parenchyma and bronchioles to interfere

with the pulmonary ventilation.

Where the purulent pneumonia has markedly involved the parenchyma, and

particularly where vascular channels both large and small have suffered,

some of them by thrombosis, others by a sclerotic thickening, the

circulatory disturbance may be sufficiently interfered with to infarct

the area. The infarction usually occupies the purulent area itself, and

with the complete occlusion of the circulation the resulting necrosis

gives rise to an appearance different from that usually seen in

pulmonary infarcts. The area may lie in the peripheral portion of the

lobe or may occupy deeper parts. The infarct is of a cream-white color,

quite homogeneous, and resembles the appearance of a local area of

caseous pneumonia. This appearance is brought about through the local

purulent consolidation undergoing necrosis. Some of these areas rapidly

develop a cavity through liquefaction of the exudate.

The localization of the inflammatory products not only upon the surface

of the air sacs but also in the stroma of the alveoli; the interlobular

trabeculæ, and about the vascular channels indicates the intense effect

of the virus of this disease. The exudate is largely an indication of

the point of action of the irritant upon the tissues, and in influenza

with its variety of bacteria in the lung this is not limited to the

surface membrane of the air sacs. During this second stage of the

reaction the purulent exudate was found occupying all structures of the

involved area. Damage upon the component tissues was to be seen in the

endothelium of the capillaries, the muscle tissue of the bronchioles and

arterioles, the connective tissues and the epithelium. It was seldom

that bacteria were demonstrated in the interstitial parts, and it would

appear that the damage was the result of their toxins.

Hence, broadly speaking, the end result of the pneumonic process in

influenza is far more complex and indefinite than that in lobar

pneumonia. Resolution may take place early with the clearing up of the

first products of the exudate; or it may be delayed in association with

the secondary purulent process which not uncommonly occupies multiple

lobes. Where the resolution begins in purulent regions the final outcome

is most variable, depending upon the amount of damage which has been

imposed upon the lung tissue during the suppurative inflammation, ending

either in complete restoration or slight fibrosis of the lung, or

passing on to focal scarring of various degrees, sufficient to alter the

pulmonary capacity. In other instances the resolution is delayed by the

development of abscess, infarct and gangrene. Here the final outcome is

determined by the amount of tissue involved in the destructive process,

and the persistency with which the infecting micro-organisms attack the

local tissues and the constitutional resistance of the individual. Those

individuals in whom resolution begins before there is much purulent

pneumonia stand the best chance of having the lung return to its normal

characteristics.

_Pleura_

Inflammation of the pleura was a complication which varied in its extent

and appearance. It appeared to us that a definite interval lapsed

between the development of the lesions in the lung and the appearance of

an inflammatory reaction upon the pleural surfaces. Although we have

recorded evidence of a pleural reaction in 27 cases, this does not

indicate that we have met with that number of pleurisies of clinical

severity. In this group we include all gradations of pleural reaction

from the merest evidence of irritation and slight dulling of the surface

to the cases in which definite and marked inflammatory exudate

accumulated within the cavity. In many cases we observed a slight

increase in the amount of the fluid present in one or other pleural

cavity, while there was little or no macroscopic evidence of a cellular

or fibrinous exudate. An examination of the fluid showed the presence of

lymphocytes and endothelial cells in small numbers, and sections of the

pleural surface at points where a slight dulling of the serous membrane

was seen at autopsy showed the presence of a very thin layer of a

hyaline fibrin. By taking these reactions as indicative of pleurisy we

have recorded 6 cases of acute fibrinous pleurisy, 20 of acute

serofibrinous pleurisy, and 1 of acute fibrino-purulent pleurisy.

An increase in the quantity of fluid in the pleural sacs was the most

common indication of pleural irritation. The quantity varied from 50 to

500 c.c. of a clear or slightly turbid fluid. Not uncommonly this fluid

was blood stained and evidence of superficial extravasation of blood

could be recognized directly beneath the pleural membrane. These serous

reactions accompanied the early acute stage, while hemorrhage was the

accompaniment of the early period of the influenzal pneumonia when

similar hemorrhages were found in the lung substance. The pleural

reactions were almost entirely confined to the visceral pleura, and only

in the very severe responses did we obtain a marked inflammatory

reaction with hemorrhage upon the chest wall. Goodpasture and Burnett

state that “there is commonly a moderate serous effusion in one or both

pleural cavities amounting to 50 or 250 cubic centimeters. The fluid is

clear and has the color of blood-stained serum. The pleural surfaces are

smooth, shiny and wet, though occasionally a thin, granular fibrinous

exudate may be seen by reflected light over limited areas. Often

numerous small, red, discrete, or confluent pleural hemorrhages are

present over consolidated portions, especially posteriorly on the

surface of the lower lobes.” Where organisms other than the influenza

bacillus had invaded the pleural sac and had been present for a

sufficient time to obtain a reaction, the serous type of exudate

observed in the early lesions changed to the turbid type of fluid

accompanied by more or less fibrin deposit. There was one case where the

intense reaction with fibrin and leucocytes gave rise to a new character

to the pleural exudate, a fibrino-purulent pleurisy or empyema.

As we have subsequently learned the pleurisies developing late in the

course of the influenza and those which persist after the pulmonary

inflammation has passed are prone to be of a purulent kind. There have

been a fair number of cases of empyema brought to our attention by the

surgical department in the bacteriological laboratory of the hospital,

subsequent to the wave of epidemic influenza. If one were to base his

finding alone upon observations obtained in the operating room, he would

be impressed by the fact that the pleurisy accompanying the epidemic of

influenza is of a purulent type. On the other hand, if one were alone to

consider the findings at the autopsy table during the five weeks of the

epidemic, one would be of the opinion that the pleurisy is of very minor

consequence and of a serous type. It is this changing picture which is

particularly to be kept in mind. And our experience indicates that

during the height of the influenzal lesions of the lung when the

pulmonary lesions develop so rapidly that we obtain a pleural reaction

closely resembling the inflammatory conditions in the lung and also

containing bacteria not unlike the pulmonary flora. Dr. Holman has

obtained the influenza bacillus and other varieties from the pleura

during these early periods of the pulmonary inflammation. It is more

than probable that just as in the infection of the lung tissue where

there is a change in the type of the bacteria present, so, too, the

flora of the pleura alters in the succeeding stages of the pulmonary

reaction. In the late event of empyema we have not observed the

influenza bacillus. The majority of the empyemas possess hemolytic

streptococci and occasionally pneumococci.

_Heart_

During the acute epidemic and while the disease was at its height it was

remarkable how few cases showed involvement of the heart. It was the

common observation that even during intense illness the heart action

remained fairly stable and did not indicate an effect by intoxication as

might be expected from the severity of the illness. In as much as the

majority of deaths occurred within relatively few days of the onset of

the severe infection, the type of lesion that would be looked for in the

heart would be either bacterial inflammatory products within the

pericardium, myocardium or endocardium or toxic lesions of musculature

alone.

In our series we have encountered no cases of pericarditis. This lesion

in the experience of others has also been unusual, and it would appear

that bacterial invasion of this sac is accomplished mainly in the

presence of secondary infections localizing in the neighboring pleura.

It was not uncommon to find a slight increase in the serous fluid in the

sac, but this on no occasion amounted to a hydropericardium. The fluid

was always clear and with no evidence of fibrin or cellular exudate.

Petechial hemorrhages scattered over the epicardium were noted in seven

cases. In the majority of instances these minute hemorrhages were

scattered in small numbers over the ventricular walls. In one instance

these petechial hemorrhages were also present through the myocardium,

suggesting the influence of an intoxication not upon the tissues of the

heart as much as upon the finer structures of the vascular channels.

This is furthermore borne out in the presence of petechial hemorrhages

confined not to one organ, but to various tissues and structures in the

body.

More or less cloudy swelling or granular degeneration of the muscle

elements of the heart was not uncommon. It was sufficiently pronounced

in 12 cases to be readily detected by the naked eye. A lesser amount was

also observed in other cases on microscopical examination. In only one

instances was the myocardial degeneration of such extent to lead to a

definite and recognizable weakening of the musculature. In this instance

the autopsy showed a flabby myocardium which was relatively soft and

easily broken and in which all the chambers of the heart were decidedly

dilated. This was the only case in which we were convinced of a

sufficient influence of the toxic effects upon the musculature to permit

a stretching of the walls, with failure of function.

In a number of other instances, however, in which there was more or less

granular degeneration and cloudy swelling we found that the right

ventricle ceased in diastole without, however, the capacity of the

chamber being enlarged. We would make this differentiation in speaking

of dilatation of the heart. We have met with 11 cases in which the right

heart died in diastole, but in which there was no evidence that the

right ventricle had been unduly expanded. In four cases there was

evidence of an old compensatory hypertrophy of the left ventricle in

which the cavity of this chamber was also slightly larger than normal.

The lesions in these four cases, however, bore no direct relation to the

results from the influenza infection. The appearance of the musculature

with moderate grade of cloudy swelling suggested some œdema of the

tissues. In the myocardium, œdema is difficult to recognize, and we

would not place great stress upon its presence in mild degree.

The microscopic examination of the myocardium showing cloudy swelling

gave the usual picture as is seen with a variety of infections. The

muscle fibers showed a fine granular deposit in their cytoplasm and the

staining quality of the tissue was somewhat altered. The transverse

striæ were less distinct than normal, while not uncommonly the

longitudinal fibrils became more evident. Fatty degeneration was not

encountered.

In the single case showing a definite and acute dilatation of the

ventricles the cause of the myocardial lesion could not be placed at the

door of the influenzal infection. This was the case suffering from a

secondary streptococcal bacteriæmia arising in the middle ear. It is

more than probable that the streptococcus was the immediate cause of the

acute muscle change and weakening. In a number of cases we have studied

the tissues of the bundle of His, but we were unable to note any

definite change.

It is interesting that the intoxication associated with acute influenza

is selective in localizing in certain muscle tissues. We have previously

indicated the intensity of muscle degenerations occurring in the

abdominal recti. Even in these cases where these striped voluntary

muscles were markedly affected the myocardium showed nothing more than a

mild or moderate grade of cloudy swelling. We can only account for this

in a difference in the constitution of these muscular structures, some

being of such composition permitting of the localizing and damage by the

unknown intoxicant. It does not appear that the reason for localization

in certain tissues is in any way related to the character of the blood

supply, nor is it related to the activity of the part.

In three cases we have found an inflammatory lesion of the endocardial

tissues. In all of them this consisted of a slight acute verrucose

mitral endocarditis. The lesions were very small, consisting only of a

fine granular deposit looking like grains of sand localized along the

border of the mitral leaflets. In no instance was the leaflet injured or

incapacitated. Unfortunately the lesion not being suspected was

encountered after the heart had been removed and opened and when it was

too late to make bacteriological analyses. This point is greatly to be

regretted, in as much as it is of great importance to know whether some

distant lesions are induced through the influenza bacillus or its

symbiotic flora.

The majority of authors report but little upon the heart lesions in

influenza. Many deny that a heart involvement is to be found, a few

report an occasional endocarditis. Wallis and Kuskow found more or less

myocardial change similar to what is usually described as cloudy

swelling. This reaction they point out differs in no way from the

degenerations arising from other types of intoxications. Keegan in a

series of about 23 autopsies found only a single case with acute

dilatation.

Abrahams, Hallows and French had an opportunity of observing over 400

autopsies upon the influenza patients, and they comment upon the

infrequency of cardiac dilatation. A slight dilatation of the right

ventricle was seen in a few cases, and in no instance did they find

pericarditis or endocarditis. They comment upon the heart condition as

follows: “The most remarkable feature about the heart is the general

absence of dilatation. In quite a large proportion of cases there has

been no trace of dilatation; in a fair number of others there has been

some dilatation of the right side, but this has seldom been extreme,

perhaps enough to cause the apex of the heart to be formed about equally

by right and left ventricles. Most often the heart has appeared of

normal dimensions and the apex has been formed entirely by the left

ventricle. This absence of dilatation accounts for the clinical absence

of orthopnœa.” In direct contradiction to the above findings, the

Advisory Board to the D. G. M. S., France, report the findings in 30

autopsies of clinical influenza. Twenty-nine of these 30 cases showed

dilatation of the heart, chiefly of the right side, but very commonly of

the left side as well. Twenty-one showed myocarditis and two

endocarditis. In this report it is stated that these patients showed

evidence of obsolete tuberculosis. It is possible that the condition of

the patients and the presence of an unusual complicating infection led

to the high incidence of cardiac involvement. The figures in this last

series are much too high when compared with the frequency of heart

involvement as found by the majority of other investigators.

A number of heart lesions not resulting from influenza were observed.

For none of them was there an antecedent history, but in some cases the

condition may have had an influence in causing accessory cardiac

embarrassment. One case had a chronic interstitial myocarditis of the

rheumatic type, three had mild grades of chronic sclerotic mitral

endocarditis, one a bicuspid pulmonary valve and three showed old

pericardial adhesions, one of them having a complete obliteration of the

sac. The foramen ovale was patent in six of the hearts.

_Arteries_

The arteries in these young adults were remarkably healthy, and in none

of them did we observe the characters of arteriosclerosis or leutic

lesions. On the other hand, evidence of superficial fatty streaks lying

in the intima of the aorta and some of its large branches were not

uncommon and are believed to have had a relation to the acute infection

of which they died. In only four cases in the series of 32 autopsies was

evidence of these fatty streaks wanting. In about one-half of the

remaining number these fatty streaks were only slight or moderate in

extent, while in the rest of them these lesions were particularly

prominent and striking. They formed linear markings on the posterior

wall of the aorta, aggregating with particular prominence about the

intercostal arteries. The anterior wall was quite free from them. The

greater extent of these lesions lay in the descending thoracic and was

less marked in the arch and the abdominal aorta. At times these fatty

streaks were found to extend into the large vessels of the neck and into

the intercostal arteries, and they were also found in the coronaries of

the heart. It was uncommon to observe their presence in the arteries of

the abdominal viscera.

This type of lesion has been discussed from the standpoint of its

etiology and its possible bearing upon true arteriosclerosis. Some

believe that the frequency of its finding in autopsy material suggests

the non-importance of its presence. This we can hardly agree with. It is

true that the presence of these lesions does not materially incapacitate

the aorta in acting as the main channel for the distribution of blood.

The lesions are quite superficial in the intima and cause but little

elevation on the surface. The amount of roughening which the intima

presents to the blood is not great. Nevertheless, the presence of these

fatty streaks is an index of the disturbed metabolism of the cholesterin

products of the body. Under certain conditions they make their

appearance when there is a true hypercholesterinemia such as is readily

produced in the animal experiments by feeding cholesterin. Under these

circumstances the various tissues of the body, including the adrenal,

the corpus luteum, the spleen, liver and arteries, all participate in

localizing cholesterin in the form of cholesterin-ester in peculiar

cells which have been termed cholesterin-ester phagocytes. It has been

shown that cholesterin metabolism is quite readily altered in the human

and that the blood content will vary from the normal. In chronic kidney

disease, pregnancy, diabetes, chronic heart disease and arteriosclerosis

the blood cholesterin rises, while in many of the acute infectious

diseases the cholesterin in the blood is materially diminished. It is

particularly in these latter cases where fatty streaks of the intima are

prone to occur. Hence in human pathology we more often meet with the

development of fatty streaks of the intima associated with a

hypocholesterinemia than with a hypercholesterinemia.

The fatty streaks of the intima of the aorta to which we are referring

are lesions quite aside from true endarteritis as well as atheroma. In

naked eye appearance the lesion is of a fatty nature and suggests

atheroma, but it differs from this well-known lesion in the fact that

the fatty materials, cholesterin-esters, are contained within cells

which are of uniform type and have no reaction in their immediate

vicinity. True atheroma may occur in definite levels of the intima, most

commonly in the deepest portion, and is characterized by the fact that

we are dealing with a variety of fatty materials, neutral fat, fatty

acids, soap, cholesterin-ester and free cholesterin which lie between

the tissue cells forming a detritus following a process of true

degeneration. It is possible that some of the superficial fatty streaks

do give rise to a small atheromatous area by death of the cells which

primarily contain the fatty substances. Most commonly, however, the

fatty streaks do not progress directly to atheroma but may entirely

disappear, as we have seen it occur in our experimental animals. At

other times these fatty streaks are followed by a slight thickening of

the surface of the intima so that the resemblance to early endarteritis

is obtained. We do not believe that these fatty streaks in themselves

lead to the chronic nodular thickening of the aorta, but that other

factors giving rise to a low grade inflammatory reaction must be

present.

There appears to be a relation between the development of these fatty

streaks and the altered cholesterin metabolism, brought about by

pathological change in the blood, adrenal cortex and it may be in the

liver. It is under these conditions where these tissues are altered

particularly by bacterial toxins in a process of marked cloudy swelling

that these intimal fatty streaks arise. Analyses in other diseases have

shown that such organic changes lead to a diminution in the cholesterin

content of the blood, while at the same time there is neither an

increased intake nor an excessive output. It would appear that certain

types of tissues and cells are stimulated into activity to become depots

for the cholesterin which is not being properly handled by the adrenal

and other organs. These cells in the intima which become active in

taking up cholesterin-esters are types of endothelial cells whose origin

is not entirely clear. In these lesions it is observed that the most

superficial cells of the intima do not show an overloading with the

fatty compound, but that the cells active in absorption lie at a level

slightly beneath the endothelial lining and form colonies as if arising

through active division of cells which are present in these parts.

Active migration on the part of these cells is not to be observed. They

do not appear to wander far from the location where they are found

during the acute process. The plaque may enlarge by proliferation and

thus enlarge the extent of the involved area. We have failed to find,

however, that these cells migrate into the lowermost portion of the

intima or into the media. The possibility that these cells do arise from

the endothelium lining the blood vessels has, up to the present, not

been excluded. If such is the case, the cells appear to adopt a function

which is not commonly observed in normal arteries nor present in the

endothelial cells lying immediately above the fatty plaque.

We have searched various arterial systems in the cases of acute epidemic

influenza for inflammatory lesions lying in the adventitia and media.

These, up to the present, we have not discovered. Some years ago a

number of French authors reported the development of acute

non-suppurative influenza lesions in the outer coats of arteries which

at times had aneurysm as the outcome. These cases, however, occurred

during non-epidemic periods, when the type of influenza of which the

patient suffered was quite different from that seen in pandemics. As far

as we know none of the reported cases of arteritis and aneurysm

occurring under these conditions has shown the presence of the influenza

bacilli in the arterial lesion. It is possible that sporadic influenza

has complicating secondary infections which are of importance in

localizing in the arterial wall.

Occasional reports have been made upon the occurrence of thrombosis

immediately following an attack of influenza. These thromboses have

occurred in diverse regions, the brachial, femoral, the mesenteric, and

other arteries. It is possible that the development of the deep

hemorrhagic lesions of muscles in the extremities are associated with

thrombosis. It is impossible, however, to demonstrate within such blood

masses the presence of thrombosed vessels which had preceded the

hemorrhagic state. It was, however, possible to demonstrate capillary

thromboses through the lung and in the submucosa of bronchi and trachea.

In these instances the damage to the vascular walls was brought about by

the action of the infection immediately surrounding them, and was not

associated with a process beginning within the lumen of the channel. The

type of thrombosis within the lung to which we have referred in a

previous discussion is interesting in that it does not show the usual

type of fibrin clotting, but in place of fibrin threads a gummy

homogeneous material is deposited upon the vessel walls within which the

red blood cells soon undergo dissolution. It would appear that these

thromboses within the lung are dependent upon a toxic action on the

vessel wall and its plasma content.

Thromboses within venous channels are met with more often than in

arteries. The veins of the lower extremities are most frequently

affected, and yet amidst the many cases of influenza it is an unusual

occurrence. The various thromboses of larger vessels usually occur as

post-influenzal complications rather than as accompaniments of the acute

disease. It is possible that factors other than those present during the

acute stage play an important part, and that the virus of influenza is

not directly the cause of the thrombosis.

_Lymphatics of Lung and Mediastinum_

One of the prominent reactions which was almost constantly present as

the inflammatory reaction involving the lymphatic system of the chest.

The lymph glands within the chest responded to a marked degree in

hyperplasia and commonly showed enlargement quite out of proportion to

what is usually observed in lobar pneumonia. These reactions were in

direct relation to the inflammatory processes of the lung and appeared

to be involved in proportion to the inflammation occupying the tissues

drained by them. Elsewhere in the body the lymph glands responded but

slightly, and often no change was observed in the lymphatics of the

abdomen, axilla and lower extremities. The systemic intoxication thus

had no effect upon distant lymph glands, and even the presence of

micro-organisms in the circulation did not appear to cause responses in

these tissues other than in the neighborhood of the chest. Within the

chest the lymphatic system became involved through the presence of the

various bacteria migrating along the lymphatic channels as well as

through its activity in removing products of inflammation.

The response of the thoracic lymphatics, including those within the lung

and mediastinum, is observed in all stages of pneumonia. But in epidemic

influenza the reaction was much more prompt, appearing in the early

stages and rapidly developing tissue changes along the channels and in

the lymph nodes. The lymph channels during the period of the early

serous pneumonia became dilated and filled with fluid with relatively

few cells. The stroma immediately surrounding became œdematous, so that

in the gross specimen the connective tissue between the lobules of lung

were sometimes easily seen as gray strands. At this time this tissue was

not increased in quantity and did not project above the level of the cut

lung. The fibrous tissue remained soft and pliable, but formed quite

wide strands. When the pulmonary reaction became hemorrhagic, red blood

cells, leucocytes and large mononuclears were found mixed with the fluid

in the lymphatics. We had no way of determining the direction of the

lymph flow from the pulmonary tissues, but it was assumed that as there

was no excessive loss of serous fluid from the lung and the lymphatics

beneath pleura into the chest cavities that the fluid was draining

through the channels lying about the bronchi and vessels. The further

evidence of the direction of flow was seen in the rapid and comparable

responses which occurred in the lymph glands along these routes. The

glands about the bronchi and at the hilus became enlarged, red and

succulent. The glands were often two and one-half centimeters in

diameter. Their capsule was thin and stretched and the gland was quite

soft. Many of them when cut open were almost diffluent.

This acute lymph hyperplasia occurred in 30 of our cases. It is

impossible to indicate any particular type of infection as being

responsible for these lymphatic lesions. The nature of the bacteria

present in these 30 cases differed quite considerably: 25 showed

influenza bacilli, 15 pneumococci, 18 streptococci, 8 M. catarrhalis and

17 staphylococci. In as much as the pulmonary reaction was fairly

constant in certain characteristics in all of our cases, and as we

believe that the influenza bacilli were the very important factor in

these reactions, it would appear that the lymphatic responses are only a

part of the general inflammation of the respiratory organs. Comparison

can also be made of the character of the lymphatic changes with that

occurring within the pulmonary tissues. The lymphatics were filled with

fluid which dilated all the available sinuses; the lymph nodes were

œdematous and within them the reaction often had numerous small

hemorrhages.

The lesion within the lymph nodes following the early serous

inflammation was of a non-suppurative kind. The lymph follicles lost

their outline, and the lymphocytes were diffused through the stroma so

that no recognition of the germinal centers could be found. The dilated

sinuses within the lymph nodes were filled with large mononuclear cells,

of the type of endothelial cells, along with some lymphocytes and

leucocytes. Subsequently the leucocytes increased very materially so

that the lymphatic fluid became purulent. Smears obtained from larger

lymphatics showed leucocytes and varieties of bacteria. This was

particularly true in those cases where the pulmonary lesion had itself

become purulent either localized in a patchy pneumonia or with lobar

involvement. Under these circumstances focal areas of purulent

infiltration were found within the tissues of the gland occupying the

regions of the former follicles and leading to necrosis or abscess.

Where such purulent reaction and abscess formation were found within the

lymph nodes there was remarkably little reaction in the tissues of the

immediate vicinity. No attempt at the development of a pyogenic membrane

or granulation tissue was observed, though this probably does take place

in the cases recovering.

In only one instance did we observe the development of the peculiar

fibrosis along the lymphatic channels where the freshly cut section of

lung reveals prominent and raised demarcation between the lobules. This

response has been described by MacCallum as unique for the streptococcus

inflammation of the lung. The character of the exudate within the

lymphatics with many mononuclear cells and blood is not to be considered

singular for the influenza pneumonia. It has been found that in ordinary

lobar pneumonia, as well as in the pneumonia following measles, the

early pulmonary reaction is accompanied by the dilatation of the

lymphatic channels along the bronchi, containing serous fluid,

mononuclear cells, blood and leucocytes, while occasionally thrombosis

entangling bacteria is also encountered. It would seem, however, that

the lymphatics in epidemic influenza can more readily recover their

normal character when a streptococcus infection is wanting.

In the late purulent lesions of the lung we have encountered dilated

lymphatic channels whose yellow contents could be recognized by the

naked eye. At times this could be followed for short distances along the

bronchi as narrow yellow cords, or when cut transversely appeared as

small dots close to the bronchi or vessels. On pressure small droplets

of pus may be evacuated, or again where fibrin has led to a coagulation

of the exudate a yellow plug can be withdrawn from the channel. These

small plugs resembled the thick exudate seen within the bronchi and

often were misleading when first viewed. The distribution of the

purulent lymphatic masses was most irregular occupying only local or

patchy fields in the lung, particularly associated with the purulent

confluent pneumonia. In one instance such a lymphatic appeared to be

associated with the development of a small abscess lying close to the

bronchus.

Too much stress cannot be placed upon the importance of the lymphatics

in all forms of pneumonia. They play an important role in the drainage

of the lung during inflammation. In the normal lung we hardly appreciate

the lymphatic distribution except in our observations upon anthracosis.

But even under these conditions when much carbon is deposited in

conjunction with the lymphatic system we do not gain a true appreciation

of the activity of the lymph channels and nodes during an acute process.

Bacteria may be demonstrated in acute infections of the lung within the

fluid and cells of the lymph channels. Less easily may we demonstrate

bacteria in the lymph nodes under similar conditions, although when

abscess has occurred their presence is readily recognized. The transport

of bacteria is accomplished not only by a passive migration of

micro-organisms in the fluid as it drains from the lung, but organisms

are also found within the leucocytes as they travel with the current.

Only occasionally have we demonstrated bacteria within the wandering

large mononuclear cells, although we have observed them in a few

instances within the cells lining the sinuses of the nodes.

Whether the inflammation of the pleura is directly related to the

involvement of the pleural lymphatics we have not been able to

determine. In our series of cases pleurisy has not been a prominent

feature of the disease, and in many instances the grade of involvement

was so slight that it was not easily recognized by the naked eye and

showed only a slight reaction microscopically. That the presence of

bacteria within the intricate plexus of lymphatics beneath the pleura

may be responsible for the development of an inflammation of this

membrane may well be the case, and in this way simulate the mode of

transmission of the infection as seen in lobar pneumococcus pneumonia

and in the streptococcus type of infection.

_Abdominal Viscera_

The lesions occurring in the abdominal viscera were of less importance

than those within the thorax. In none of the cases of the epidemic was

the intestinal type of the disease, described in previous years,

encountered. The changes found in the various viscera were concomitant

with evidences of intoxication as observed clinically or at autopsy in

other regions of the body. We found no evidence that the bacteria of the

disease localized in the tissues of the abdominal viscera, and we were

led to believe that the alterations in morphology and function were the

result of diffusible toxins. The action of these toxins was either upon

the parenchymatous cells of the organs, as in the liver and kidney,

resulting in granular degeneration, or upon the capillaries with the

development of petechial or diffuse hemorrhage as was encountered in the

stomach, intestines and bladder. The absence of definite localized

inflammatory processes in these distant tissues, including the abdominal

lymphatics, speaks against the probability of a bacteriæmia playing an

important role in the disease. That transient bacteriæmias by the

influenza bacillus do occur has been repeatedly demonstrated, and that

the organisms associated with this bacillus may also enter the blood

stream has likewise been found. But these states are accessory to the

disease, and must be viewed as complications rather than the rule. Hence

the occasional observations by some, of bacterial inflammatory reactions

in liver and kidney must not be considered a part of epidemic influenza,

for in many cases it is wanting. The majority of lesions of the

abdominal viscera probably arise through the action of the unknown toxin

in the blood.

In the _stomach_ and _intestines_ the lesions were of two kinds, (1)

hemorrhage and (2) erosions. Petechial hemorrhages were present in the

stomach 15 times, in the intestines 4 times. These small dots of blood

extravasation, lying in the mucosa and submucosa, differ in no way from

those observed in other acute infections and intoxications, save that

the tendency for the leakage of blood into the lumen of the viscera was

more pronounced. Often we could observe the presence of free and more or

less altered blood in the stomach and intestines, and in 12 cases the

amount was considerable, sufficient to be spoken of as melena. It is

probable that the oozing of blood takes place not only from the areas

visible to the eye as petechial hemorrhages, but also from the more

normal-looking mucosa of stomach and bowel. The tendency to hemorrhage

was not necessarily accompanied by visible alterations in the epithelial

layer of the mucosa, though at times erosions were found. When

hemorrhage could be observed, the extravasation of blood occupied the

superficial layers of stroma, causing a separation of the tissues

beneath the epithelial layer. At times the submucosa was also

infiltrated, and in one instance the musculature. The lesions were

isolated and sporadic, but always about small capillary loops. It

appeared to us that the damage was primarily upon the vascular tissues

and particularly upon the endothelial walls of the fine channels.

Inflammation was not present, and the hemorrhage was more or less

passive—that is, a slow oozing rather than acute hemorrhage by rhexis.

The second type of lesion of the gastro-intestinal canal was erosion.

This was of the nature of a defect in the mucosa, usually multiple,

small and well circumscribed. The tissue loss was superficial. In their

appearance these lesions were similar to those encountered in these

parts in other infections, and also as described by McMeans in

experimental infections of animals. The erosions appear to arise in a

process of bland necrosis, limited in the periphery by healthy tissue

and not tending to enlarge. It is probable that these erosions are

associated in their development with the petechial hemorrhages, being a

sequel to the vascular disturbance of the mucosa and subsequent

digestion of the injured tissue. Multiple lesions of the stomach were

found 10 times and twice in the intestine. The largest was 1.25 cm. in

diameter. They are more common on the posterior than anterior wall, and

usually toward the lesser curvature. It is probable that these defects

are limited in their progress and heal readily.

The changes occurring in the _liver_ were not of striking account.

Cloudy swelling was observed 13 times, usually of moderate grade. The

usual appearances with enlargement of the organ, bulging of the

parenchyma on section and a dull gray cut surface were all that could be

found. The one case with icterus was the only one in which the natural

discharge of bile from the liver was interfered with through the

swelling. Even in this case the obstruction to the outflow of bile in

the small channels was not demonstrable in the microscopic sections, nor

was there evidence of unusual bile staining of the liver-points

suggesting the possible origin of the icterus in an unusual hemolysis.

On no occasion did we meet with recent inflammatory reactions in the

gall bladder or bile ducts, and we have no evidence that the organisms

of the infection are discharged from the body by these routes. The

cloudy swelling of the liver was accompanied by slight œdema of these

tissues in seven cases; and in six instances focal necroses were

observed. These focal necroses were similar in appearance to those seen

in typhoid fever, but were much less frequent in the tissue. Only

careful search revealed isolated pinhead gray dots with depressed

centers. They were most commonly in the mid-zone of the lobule, and in

the early stage were without inflammatory reaction. Subsequently,

leucocytes infiltrated the area, but not in an amount to form pus.

Bacteria were never demonstrated in the areas of focal necrosis. Four

cases showed old adhesions about the gall bladder and in one a gall

stone was present.

Lesions of the _pancreas_ were not encountered. In a few cases the lymph

glands about the head of the pancreas were slightly enlarged.

The _spleen_ showed relatively little reaction and in only two cases was

it enlarged. Fourteen times a diagnosis of acute splenitis was made on

examination of the gross specimen. This diagnosis rested upon the

finding of a swollen spleen with tense capsule and with a dark bulging

pulp. The Malpighian bodies were usually in part or completely

obliterated, though in a few instances these grayish nodules seemed even

larger than normal. These spleens contained an excess of blood within

the pulp. In one case several isolated areas appeared hemorrhagic as if

a local rupture of the tissues had occurred. The microscopic examination

of these specimens showed mainly a marked congestion of the sinusoids, a

diminution in the size of the lymphoid corpuscles and some increase in

the number of leucocytes within the blood spaces and reticulum. Only

occasionally did we observe a proliferative reaction of the large

mononuclear cells lying in the reticulum. This proliferation was not

sufficiently marked nor uniformly present to be considered as

characteristic. We did not find abnormal deposition of blood pigment

indicating an unusual destruction of red blood cells within the spleen.

It is interesting to note that 5 of the 32 cases showed obsolete miliary

tubercles in the spleen.

Our analysis of the changes occurring in the _kidney_ bore out the

clinical findings observed in the wards. Like in so many acute

infectious diseases urinary changes were commonly present. These are in

part dependent upon systemic changes in the metabolism of tissues and

not entirely the result of renal lesions. In acute epidemic influenza

there was no common characteristic in the urinary output. The amount

excreted in 24 hours was usually diminished to a small extent, the color

was darker, the specific gravity slightly increased, as well as the

total solids. There was no marked change in the total quantity of output

of any one of the constituents as far as they were analyzed by us.

Albumin was present in the urine in variable amounts and in the more

severe cases casts were also present. There was only one case in which

the quantitative output was much diminished and where some fear was

entertained of development of acute uremic manifestations. This

individual, however, died before these made their appearance and before

there was any evidence that the retention of waste products was causing

definite clinical symptoms.

In 30 cases coming to autopsy more or less cloudy swelling was to be

observed in the kidney. This reaction varied from a very mild swelling

and granular degeneration of the tubules of the cortex to a decided

parenchymatous degeneration with loss of nuclear structure and erosion

of some of the cells lining the tubules. The convoluted tubules were

always most markedly involved. Occasionally this tubular degeneration

was accompanied by a desquamation of the lining cells of the glomerular

capsules. We were, however, unable to recognize an acute inflammatory

reaction in the interstitial tissue or in the glomeruli in any of the

cases, except the one which had developed a streptococcus bacteriæmia as

a sequel to an otitis media. The kidney lesion reminded one very much of

the toxic lesion which is observed in the kidney in typhoid fever.

Differing, however, from the latter there was a variable congestion of

the fine vessels associated with the cyanosis which was present in a

certain percentage of these cases. At times the kidneys were quite wet

with blood from the venous engorgement.

The lesions in the kidney were of a toxic type and did not resemble

reactions following the presence of the bacteria in the stroma of the

organ. In the majority of instances in other diseases where bacteria

themselves locate in tissues we are able to recognize focal lesions of

acute necrosis or inflammation. In epidemic influenza where a variety of

micro-organisms within the lung are able to reach distant structures in

a bacteriæmia, we would, because of their type, expect to find

inflammatory reactions of a definite kind. The absence of such reactions

is very suggestive that the bacteria do not commonly localize in the

kidney, but that their toxins alone affect it during its elimination. We

have also entirely missed the finding of any vascular lesions in the

renal system. Neither degeneration nor inflammatory reactions of any of

the coats of the blood vessels could be distinguished.

The partial incapacity on the part of the kidneys must, therefore, be

viewed as a complication resulting from the effect of a diffusible toxin

reaching them by the blood stream. The damage performed in this manner

may be quite extensive upon the secreting tissues of the tubules leading

to an increased or decreased output of the urinary constituents. Because

of the nature of the lesion, it is probable that the kidney damage

incurred during the acute epidemic influenza is only temporary and not

permanent. Tubular degeneration is readily repaired, and in the absence

of an inflammatory reaction in the interstitial tissue or the glomeruli

avoids the development of a permanent mark or derangement in the system.

This is as we find it in typhoid fever.

In two cases we observed very interesting lesions in the _bladder_.

These two individuals during life had been excreting markedly

blood-stained urine for some days preceding death. In the one case the

hemorrhage was so marked that on standing, about one-tenth of the urine

was composed of sedimented red blood cells. It was assumed that the

hemorrhage was of kidney origin until the autopsy revealed a simple

cloudy swelling of the kidney associated with a hemorrhagic state of the

submucosa of the bladder. In both cases the posterior wall of the

bladder was heavily infiltrated with blood so that the mucosa was raised

from the surface and the prominent folds showed a superficial erosion

with small points of greenish necrosis. This bladder hemorrhage was

concomitant with hemorrhagic foci elsewhere in the body, pericardium,

pleura, stomach and intestine. Alone in the bladder however, the

hemorrhage formed a distinct mass and allowed a considerable escape from

the lesions on the surface. These areas of hemorrhage were not infected

and showed no local inflammatory reaction. They also appeared to be

toxic in origin and resembled the hemorrhages occurring in the muscles

of the abdomen.

Changes in the _adrenal_ gland were noted in 14 instances. In all of

these there was the picture of what is commonly known as cloudy swelling

of the cortex and, in addition to this, in three cases small petechial

hemorrhages were observed. The so-called cloudy swelling of the adrenal

consists largely in a loss of the bright golden appearance of the

cortical tissues accompanied by soft œdematous swelling. The tissues

change color to a brown or clay color, and it is not uncommon to observe

that the inner zone of pigmentation is more diffuse. There is no sharp

demarcation between the layers of the cortex. With this alteration in

the outer structure of the adrenal, the medulla not uncommonly appears

smaller. This change is more apparent than real, and we have not been

able to observe any definite lesion in the nervous portion. At times we

believed that the inner tissue appeared more cellular, but it was not

possible to determine any specific alteration in the cells.

The changes in the adrenal cortex are comparable to those observed in

typhoid fever. The analyses of these tissues showed that the cells were

almost devoid of cholesterin bodies and few doubly refractile globules

could be demonstrated. This change in the adrenal is by no means

specific for any acute disease, it being found in many of the severe

infections. We regret that systematic analysis of the blood serum in

these cases was not made to determine the cholesterin content. If the

comparison bears out with typhoid fever, we would expect to find that

the quantitative cholesterin of the blood is diminished. Some importance

attaches itself to the study of the cholesterin metabolism, particularly

in regard to the development of the peculiar fatty streaks which develop

in the aorta and other arteries during these acute infections. It has

been claimed that in the human these streaks bear an analogy to those

produced in the experimental animals and that the arterial lesions are

associated with an altered activity on the part of the adrenal cortex in

handling the cholesterin compounds. In influenza there is evidence that

the adrenal does not function in a normal fashion and that the storage

of cholesterin-esters does not take place. From this, however, we cannot

conclude that the blood content is increased, and, in fact, it is more

than probable in comparing the other reactions of the disease that it

follows the changes as seen in typhoid fever where the blood content of

cholesterin is lowered. In this way comparison with the experimentally

produced arterial lesions in animals is not clear, in as much as in the

experimental work a true hypercholesterinemia was induced. Nevertheless

it is possible that with the abnormal function on the part of the

adrenal the cholesterin materials are made more available for absorption

by other tissues and that a true hypercholesterinemia is not necessarily

a constant factor, even with the abnormal accumulation of these

substances in the intima. It may well be that the normal activity of the

adrenal is related to the presence of toxins in the circulation and an

attempt by mobilizing cholesterin to diminish the activity of these

harmful substances.