CHAPTER II
CLINICAL FEATURES AND BACTERIOLOGY OF INFLUENZA AND ITS ASSOCIATED PURULENT BRONCHITIS AND PNEUMONIA
FRANCIS G. BLAKE, M.D., AND THOMAS M. RIVERS, M.D.
The material presented in this section of the report consists of clinical and bacteriologic observations made during the course of an investigation of influenza and its associated bronchitis and pneumonia at Camp Pike, Ark., between September 6 and December 15, 1918, comprising part of a correlated study of the epidemiology, bacteriology, pathology, and clinical features of these diseases. The bacteriologic studies are in the main limited to those made during life, those made at necropsy being reported in another section of this report.
=Methods.=—All cases upon which the clinical and bacteriologic data presented are based, were examined by the authors and our own clinical histories and physical examinations were recorded. This was considered of special importance, since in studying a group of diseases in which secondary infection of the respiratory tract might supervene at any time, it was essential to determine as far as possible the exact clinical condition of the patient at the time when bacteriologic examinations were made. The bacteriologic methods employed were the direct culture of nose and throat swabbings and of selected and washed specimens of sputum on the surface of 5 per cent defibrinated horse blood agar plates, the intraperitoneal inoculation of white mice with specimens of sputum according to the method described by Blake[28] for the determination of pneumococcus types, and in some cases the method of Avery.[29] B. influenzæ pneumococci and hemolytic streptococci were identified by the methods described elsewhere. Note was made in most instances of the presence of other organisms such as members of the Gram-negative diplococcus group, staphylococci, diphtheroids, and members of the streptococcus viridans group, but no attempt was made to further isolate or identify them since they played no significant part in the cases studied except in rare instances.
Influenza
The fall epidemic of influenza at Camp Pike began about September 1, 1918, and reached epidemic proportions on September 23 when 214 cases were admitted to the base hospital. The epidemic was at its height from September 27 to October 3, during which period there were in the neighborhood of 1,000 new cases daily. From this date until October 31 the number of new cases occurring daily steadily decreased and by the latter date the epidemic was over. Scattered cases continued to occur, however, throughout November, and during the last week of this month and the first week of December a second epidemic wave of relatively mild character occurred. From September 1 to October 31 the total number of cases of influenza reporting sick was 12,393. During the same period there were 1,499 cases of pneumonia with 466 deaths.
Influenza as observed at Camp Pike differed in no essential respects from that occurring elsewhere. In brief, it presented itself as a highly contagious, self-limited infectious disease of relatively short duration in most instances, the principal manifestations of which were sudden onset with high fever, profound prostration, severe aching pains in back and extremities, conjunctival injection, flushing of the face, neck, and upper thorax often amounting to a true erythema, and a rapidly progressing attack upon the mucous membranes of the respiratory tract as manifested by coryza, pharyngitis, tracheitis and bronchitis with a marked tendency to hemorrhage; in itself it is rarely serious, but in reality serious because of the large number of individuals attacked and temporarily incapacitated and because it predisposed to widespread and highly fatal secondary infection of the lungs.
=Clinical Features.=—A clinical study of 100 consecutive cases of influenza admitted during the height of the epidemic was made.
The onset was sudden, in most instances being initiated with marked sensations of chilliness in 82 cases. Although a severe chill was probably relatively uncommon, 44 of these patients considered the symptom of sufficient severity to describe it as such. This was accompanied by extreme general malaise with severe aching pains throughout the whole body. Intense backache was complained of in 40 cases, headache in 54 cases. A varying degree of prostration, sometimes leading to complete collapse, was almost universal; 5 patients complained of extreme asthenia and 2 of marked dizziness. At time of admission to the hospital the face, neck and upper chest exhibited a uniform erythematous flush, never macular in appearance. The conjunctivæ were deeply injected, but lacrimation was not noticeable and a true exudative conjunctivitis was not encountered. Onset was accompanied by a sharp elevation of temperature ranging from 100° F. to 106° F., in most cases being between 102° F. and 105° F., at the time of admission. No constant type of temperature curve was maintained. Excluding the 15 cases in this group that developed pneumonia, the temperature was well sustained throughout the course of the disease in 46, irregular in 33, and definitely remittent in 6. The duration of the fever varied between one and seven days, the temperature having returned to normal in all but 19 of the 85 cases by the end of four days. The duration of fever was one day in 18 cases, two days in 12, three days in 19, four days in 17, five days in 10, six days in 4, and seven days in 5. Of the 4 cases with fever for six days, 2 had a fairly extensive bronchitis, 1 a laryngitis. Of the 5 cases with fever of seven days’ duration, 3 had signs of an extensive bronchitis, 2 of only a mild bronchitis.
The pulse was relatively slow in rate as compared with the degree of temperature elevation, running between 90 and 100 beats per minute in the large majority of cases. At the height of the disease it was full and easily compressed. No irregularities were noticed. With recovery it fell promptly to normal. The respiratory rate showed only moderate elevation, being between 20 and 26 in most cases. In a few instances a rate as high as 32 was recorded at time of admission to the hospital, but this promptly fell with rest in bed. A respiratory rate rising above 26 after the third or fourth day of the disease nearly always indicated a beginning pneumonia. With recovery the rate promptly fell to normal. Cyanosis did not occur in the absence of pneumonia.
Aside from the manifestations of a profound toxemia, influenza was preeminently characterized by symptoms of respiratory tract infection. The appearance of respiratory symptoms occurred at varying intervals after the onset of the disease, being well developed by the end of twenty-four hours in most cases. A progressive attack upon the mucous membranes of the respiratory tract was universal, beginning with coryza and pharyngitis and progressing to tracheitis or _vice versa_. Further extension of the infection to the bronchi, however, was by no means universal, 49 cases in the group studied recovering without developing evidence of bronchitis. Sore throat was rarely complained of, and laryngitis, possibly due to secondary infection, occurred only once. The progress of the infection was marked subjectively by sensations of irritation, stinging, and a feeling of tightness. A profuse, thin, mucoid exudate appeared; the pharyngeal walls and the soft palate showed a characteristic deep red granular appearance. The onset of tracheitis began with a sense of burning and tightness beneath the sternum accompanied by a harassing cough, at first nonproductive, later with the outpouring of an exudate becoming productive. The sputum varied in character between a scanty, thin, mucoid sputum and a profuse, frankly purulent sputum in cases subsequently developing an extensive bronchitis. Hemorrhage from the mucous membranes was common. Epistaxis occurred in 12 per cent of the cases and was often profuse. The sputum contained fresh blood in varying amounts in 24 per cent of the cases; 51 per cent of the cases developed signs of bronchitis. In 15 of these the bronchitis was mild, probably limited to the larger bronchi, physical examination showing only inconstant sibilant and musical râles. The sputum in these cases was neither profuse nor frankly purulent; 36 cases developed a fairly extensive purulent bronchitis as manifested by more or less diffusely scattered moist râles and by moderately copious mucopurulent or frankly purulent sputum. This bronchitis was not accompanied by an increase in the respiratory rate or by cyanosis unless pneumonia subsequently developed.
Gastrointestinal symptoms were insignificant: 8 patients complained of nausea early in the disease and 6 of them vomited. Diarrhea occurred in only 1 case, constipation being the rule. The spleen was palpable in 21 cases, but this is of doubtful significance, since nearly all the patients came from malarial regions. Jaundice was not noted. Aside from the profound depression, sometimes amounting to stupor, mental symptoms were not noted except in 1 case which showed a mild delirium.
Influenza, although _per se_ a self-limited disease of short duration, frequently leads to the development of serious complications, the most important of which are pneumonia and purulent bronchitis with a varying degree of bronchiectasis. In the group of 100 cases of influenza studied, purulent bronchitis developed in 36 instances, pneumonia in 15; in 3 cases there was lobar pneumonia, in 12 bronchopneumonia. Further discussion of these complications is reserved for the sections dealing with them in detail. Other complications were relatively rare. Otitis media occurred in one case and frontal sinusitis in one. No fatalities were observed among cases of uncomplicated influenza, the deaths that occurred being invariably associated with a secondary pneumonia due in nearly all instances to secondary infection with pneumococci or hemolytic streptococci.
Purulent Bronchitis
It has been stated that a considerable number of cases of influenza developed a more or less extensive purulent bronchitis. This term is used as descriptive of a group of cases showing clinically evidence of a diffuse bronchitis as manifested by numerous medium and fine moist râles scattered throughout the chest and evidence of a definitely purulent inflammatory reaction as indicated by the expectoration of fairly copious amounts of mucopurulent or frankly purulent sputum. This condition is regarded as quite distinct, on the one hand, from the common type of mucoid bronchitis frequently associated with “common colds” and a fairly common feature of uncomplicated cases of influenza, in which physical examination of the chest reveals only transient sibilant and musical râles without evidence of extension to finer bronchi, and, on the other hand, from bronchopneumonia.
=Bacteriology.=—Thirteen cases of purulent bronchitis following influenza in none of which was there any evidence of pneumonia at the time cultures of the sputum were made nor later were subjected to careful bacteriologic study. Specimens of bronchial sputum were collected in sterile Petri dishes and selected portions thoroughly washed to remove surface contaminations before bacteriologic examinations were made. The results are shown in Table XIII.
TABLE XIII
BACTERIOLOGY OF THE SPUTUM IN CASES OF PURULENT BRONCHITIS FOLLOWING INFLUENZA
════╤══════════════════════════╤═════════════════════╤═════════════════ CASE│ STAINED FILM OF SPUTUM │ DIRECT CULTURE ON │MOUSE INOCULATION │ │ BLOOD AGAR PLATE │ │ │ │ ────┼──────────────────────────┼─────────────────────┼───────────────── GJ │B. influenzæ + + + │B. influenzæ + + + + │B. influenzæ │ │ │Pneumococcus │Gram + diplococci + │Pneumococcus + │(type │ │ │undetermined) WAL │B. influenzæ + + │B. influenzæ + + + │ │Gram + diplococci + + │Pneumococcus IV + + │ TH │B. influenzæ + + + │B. influenzæ + + + + │ │Gram + diplococci + + + │Pneumococcus IV + + │ LH │B. influenzæ + │B. influenzæ + + │ │Gram + diplococci + │Pneumococcus IV + + │ FBD │Gram + diplococci + + + + │Pneumococcus IV + + +│Pneumococcus IV │ │B. influenzæ + │B. influenzæ Wa │B. influenzæ + + │B. influenzæ + + │ │Gram + diplococci + + │Pneumococcus IV + + │ Sh │B. influenzæ + + + │B. influenzæ + + │ │Gram + diplococci + + │Pneumococcus IV + + +│ Wal │Gram + diplostrep + + + │S. viridans + + │ │B. influenzæ + │B. influenzæ + + │ CLF │B. influenzæ + + + + + │ │B. influenzæ │Gram + diplococci + │ │Pneumococcus IV NCC │B. influenzæ + + │B. influenzæ + + + │B. influenzæ │Gram − micrococcus + │M. catarrhalis + + │M. catarrhalis │Gram + diplostrep. + │S. viridans + + │ JCM │B. influenzæ + + + │B. influenzæ + + + + │B. influenzæ │Gram + streptococcus + │S. hemolyticus + │S. hemolyticus │Gram − micrococcus + │M. catarrhalis + │Pneumococcus IV │Gram + diplococcus + │ │ Bl │B. influenzæ + │ │B. influenzæ │Gram + diplococcus + │ │Pneumococcus IIa Bu │B. influenzæ + + + + │B. influenzæ + + + │B. influenzæ │Gram + diplococcus + + + +│Pneumococcus IV + + +│Pneumococcus IV ────┴──────────────────────────┴─────────────────────┴─────────────────
From the data presented in Table XIII it is evident that a mixed infection existed in all cases. The results obtained by stained sputum films and by direct culture on blood agar plates are of special significance. B. influenzæ was present in all cases, being the predominant organism in 6 cases, abundantly present in others, and few in number in 2. Of other organisms the pneumococcus was most frequently found, occurring in 11 of the 13 cases, in all but 2 instances being present in considerable numbers. S. viridans was encountered twice, once in association with a Gram-negative micrococcus resembling M. catarrhalis culturally. S. hemolyticus was found once, together with M. catarrhalis and a few pneumococci, Type IV, coming through in the mouse only and of doubtful significance. The stained sputum films and direct cultures always showed these organisms present in sufficient abundance to indicate that they were present in the bronchial sputum and were not merely contaminants from the buccal mucosa.
It seems quite probable from these results that purulent bronchitis following influenza is, in most cases at least, due to mixed infection of the bronchi and should be looked upon as a complication of influenza. Whether the condition may be caused by infection with B. influenzæ alone is difficult to say. No evidence that it may be caused by B. influenzæ alone was obtained in the cases studied. It is not intended to enter here into a discussion as to whether B. influenzæ should be regarded as a secondary invader or not; the other organisms encountered certainly are. It would seem most probable that purulent bronchitis is caused by the mixed infection of B. influenzæ and various other organisms, commonly the pneumococcus, but that the condition is initiated by the invasion of the bronchi by these other organisms in the presence of a preceding infection with B. influenzæ.
=Clinical Features.=—Purulent bronchitis following influenza began insidiously without any prominent symptoms to mark its onset. About the third or fourth day of influenza, when recovery from the primary disease might be looked for, the patient would begin to cough more frequently, raising increasing amounts of mucopurulent sputum. This sputum was yellowish green in color, copious in amount, and often somewhat nummular in character, sometimes streaked with blood. These symptoms were accompanied by the appearance of coarse, medium and fine moist râles more or less diffusely scattered throughout the chest and usually most numerous over the lower lobes. The percussion note, breath and voice sounds, and vocal and tactile fremitus remained normal. There was no increase in the respiratory rate or pulse rate, and cyanosis did not develop in the absence of a beginning pneumonia. Many such cases, of course, developed bronchopneumonia; in this event areas showing diminished resonance, suppressed breath sounds, and fine crepitant râles with the “close to the ear” quality would appear, the respiratory rate would become increased and cyanosis would become evident. In those cases of purulent bronchitis not developing pneumonia, a moderate elevation of temperature, rarely above 101° F., and irregular in character usually occurred and persisted for a few days or a week.
Many cases maintained a persistent cough, raising considerable amounts of sputum throughout the period of their convalescence in the hospital, which was often considerably prolonged when this complication of influenza occurred. Although no clinical data are available on such cases over a prolonged period of observation, it seems probable that some of them, at least, had developed some degree of bronchiectasis. This would seem all the more probable, since many cases of pneumonia following influenza showed at autopsy extensive purulent bronchitis with well-developed bronchiectasis. Bronchiectasis will be discussed in greater detail in another section of this report. It is this group of cases with more or less permanent damage to the bronchial tree that makes this type of bronchitis following influenza a serious complication of the disease.
Pneumonia
The opportunity presented for a correlated study of the clinical features, bacteriology, and pathology of pneumonia following influenza throughout the period of the epidemic at Camp Pike from September 6, 1918, to December 15, 1918, made it evident that this pneumonia could be regarded as an entity in only one respect, namely, that influenza was the predisposing cause. Clinically, bacteriologically, and pathologically it presented a very diversified picture ranging all the way from pneumococcus lobar pneumonia to hemolytic streptococcus interstitial and suppurative pneumonia with the picture modified to a varying extent by the preceding or concomitant influenzal infection.
One hundred and eleven consecutive cases in which careful clinical and bacteriologic studies were made form the basis of the material presented. Of these cases, 38 came to necropsy so that ample opportunity was presented to correlate the clinical and bacteriologic studies made during life with the pathology and bacteriology at necropsy. It has seemed advisable to group the cases primarily on an etiologic basis with secondary division according to clinical features in so far as this can be done. Bacteriologic studies showed that at the time of onset these pneumonias were either pneumococcus pneumonias or mixed pneumococcus and influenza bacillus pneumonias in nearly all instances. Certain of these cases later became complicated by a superimposed hemolytic streptococcus or a staphylococcus infection. In a few instances hemolytic streptococcus pneumonia directly followed influenza without an intervening pneumococcus infection. B. influenzæ was present in varying numbers in nearly all cases. In only 2 instances however, was it found unassociated with pneumococci or hemolytic streptococci, once alone and once with S. viridans.
Clinically the cases fell into four main groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia (pneumococcus); (4) bronchopneumonia (streptococcus). It should be borne in mind, however, that the picture was a complex one and that correct clinical interpretation was not always possible, since many cases did not conform sharply to any one type and superimposed infections during the course of the disease often modified the picture.
=Pneumococcus Pneumonia Following Influenza.=—Bacteriologic examination of selected and washed specimens of sputum coughed from the lungs at time of onset of pneumonia showed the various immunologic types of pneumococcus to be present in 105 cases. The incidence of the different types is shown in Table XIV.
TABLE XIV
TYPES OF PNEUMOCOCCUS IN 105 CASES OF PNEUMOCOCCUS PNEUMONIA FOLLOWING INFLUENZA
═══════════════════════╤═════════╤═════════════════╤═════════╤═════════ │ LOBAR │BRONCHOPNEUMONIA │ TOTAL │PER CENT │PNEUMONIA│ │ │ ───────────────────────┼─────────┼─────────────────┼─────────┼───────── Pneumococcus, Type I │ 8│ 0│ 8│ 7.6 Pneumococcus, Type II │ 3│ 1│ 4│ 3.8 Pneumococcus, II atyp. │ 12│ 7│ 9│ 18.1 Pneumococcus, Type III │ 3│ 3│ 6│ 5.7 Pneumococcus, Group IV │ 32│ 36│ 68│ 64.8 ───────────────────────┴─────────┴─────────────────┴─────────┴─────────
The most noteworthy feature of the figures in Table XIV is the high proportion of pneumonias due to types of pneumococci found in the mouths of normal individuals, 93 cases or 88.6 per cent, being caused by Pneumococcus Types II atypical, III, and IV. This is in harmony with the results generally reported and is in all probability due to the fact that in patients with influenza pneumococci, which under normal conditions would fail to cause pneumonia, readily gain access to the respiratory tract and produce the disease. It is also of interest that with one exception the highly parasitic pneumococci of Types I and II were associated with pneumonias clinically lobar in type.
Superimposed infection of the lungs with other types of pneumococci than those primarily responsible for the development of pneumonia occurred not infrequently in this group of cases either during the course of the disease or shortly after recovery from the first attack of pneumonia. Pneumococcus Type II infection was superimposed upon or shortly followed pneumonia caused by Group IV pneumococci in 4 instances, by Pneumococcus II atypical in 1 instance. In 1 case pneumonia due to Pneumococcus II atypical occurred three days after recovery from a Pneumococcus Type I pneumonia, in another case Pneumococcus Type III infection was superimposed upon a pneumonia originally due to a pneumococcus of Group IV. These cases are presented in detail in another section of this report, and in several instances were shown to be directly due to contact infection from patients in neighboring beds.
In a similar manner, superimposed infection with S. hemolyticus at some time during the course of the pneumonia occurred in 13 cases in this group, with fatal result in all but one. Streptococcus infection occurred in pneumonia due to Pneumococcus II atypical once, to Pneumococcus Type III once, and to pneumococci of Group IV eleven times. Nine of these cases were free from hemolytic streptococci at the time of onset of the pneumonia, 4 showed a very few colonies of hemolytic streptococci in the first sputum culture made.
B. influenzæ was found in the sputum coughed from the deeper air passages in the majority of cases, being present in 80, or 76.2 per cent, of the 105 cases. In the 58 cases of lobar pneumonia it was found 41 times, or 70.7 per cent, in the 47 cases of bronchopneumonia 39 times, or 82.9 per cent. The abundance of B. influenzæ in the sputum varied greatly in different cases. Microscopic examination of stained sputum films and direct culture of the sputum on blood agar plates showed that in general it was more abundant in the mucopurulent sputum from cases of bronchopneumonia than in the mucoid rusty sputum from cases of lobar pneumonia. This was by no means an invariable rule, however, since in the former the bacilli were sometimes very few in number, in the latter quite abundant. Whether B. influenzæ shared in the production of the actual pneumonia in these cases is difficult to decide and cannot be stated on the basis of the bacteriologic and clinical observations which have been made.
=Clinical Features.=—One of the most striking aspects of pneumococcus pneumonia following influenza was the diversity of clinical pictures presented. These varied all the way from the classical picture of lobar pneumonia to that of bronchopneumonia of all grades of severity from the rapidly fatal coalescing type to that of very mild character with very slight signs of consolidation. For this reason it is questioned whether there is any real justification for speaking of a typical influenzal pneumonia, an opinion that seems well supported by the diversified picture found at the necropsy table.
For purposes of presentation, pneumococcus pneumonia following influenza may be divided into three clinical groups: (1) Lobar pneumonia; (2) lobar pneumonia with purulent bronchitis; (3) bronchopneumonia. No accurate data are available as to the relative frequency with which these three types occurred at Camp Pike. In the group of 105 cases studied there were 58 cases of lobar pneumonia, 11 of which had purulent bronchitis, and 47 cases of bronchopneumonia. The majority of these cases, however, occurred during the early days of the epidemic of influenza and probably show a considerably higher proportion of lobar pneumonias than actually occurred in the total number of pneumonias throughout the epidemic. This is indicated by the fact that of 100 consecutive cases of influenza selected for observation at the height of the epidemic, 3 developed clinical evidence of lobar pneumonia and 12 of bronchopneumonia.
(1) Lobar pneumonia presenting the typical clinical picture with sudden onset, tenacious rusty sputum, sustained temperature, and physical signs of complete consolidation of one or more lobes occurred in 47 cases; 36 cases in this group definitely followed influenza. In 11 cases no certain clinical evidence of a preceding influenza was obtained, and it is probable that some of these represent cases of pneumonia occurring independently of the epidemic of influenza.
The onset of pneumonia in this group of cases occurred from four to nine days after the onset of influenza and with few exceptions was ushered in by a chill and pain in the chest. In several instances the patient had apparently recovered from influenza as evidenced by fall of temperature to normal. After twenty-four to seventy-two hours of normal temperature the patient would have a chill and develop lobar pneumonia. In the majority of cases, however, lobar pneumonia developed while the patient was still sick with influenza. The course of the disease, symptomatology and physical signs were quite characteristic of lobar pneumonia and require no special comment. Recovery by crisis occurred in 21 cases, by lysis in 8. Pneumococcus empyema developed in 3 cases, fibrinopurulent pericarditis in 3 and all but 1 of these 6 cases terminating fatally.
In Table XV 5 fatal cases of lobar pneumonia, which illustrate some of the unusual features of the disease when it follows influenza, have been summarized. The first 2 cases represent examples of recurring attacks of pneumonia which developed shortly after recovery from the first attack, in both instances being due to types of pneumococci different from those causing the first attack. The third case represents an example of superimposed infection of the lungs with hemolytic streptococci and staphylococci during the course of a pneumonia due to Pneumococcus IV and disappearance of the latter organism from the tissues so that it was not found at time of necropsy. The last 2 cases are examples of fulminating rapidly fatal cases of lobar pneumonia associated with mixed infections of pneumococci and hemolytic streptococci, the streptococci probably being secondary in both cases. Cases like the few examples cited above, which occurred not infrequently throughout the epidemic of influenza, serve to illustrate the difficulties which may be met in attempting to correlate the clinical, bacteriologic and pathologic features of pneumonia following influenza unless careful bacteriologic examinations are made both during life and at the necropsy table in the same group of cases.
TABLE XV
CASES OF LOBAR PNEUMONIA FOLLOWING INFLUENZA
════╤═════════╤══════════╤══════════════════╤════════════════════════════════ CASE│ONSET OF │ ONSET OF │SPUTUM EXAMINATION│ COURSE OF PNEUMONIA │INFLUENZA│PNEUMONIA │ │ ────┼─────────┼──────────┼─────┬────────────┼──────────────────────────────── │ │ │DATE │BACTERIOLOGY│ ────┼─────────┼──────────┼─────┼────────────┼──────────────────────────────── Pul │Sept. 7 │Sept. 9 │Sept.│Pn. IV ++++ │Recovery by crisis on Sept. 14. │ │1st attack│10 │B. inf. +++ │On Sept. 21 developed lobar │ │bronchopn.│ │ │pneumonia. Died Sept. 30 │ │ │ │ │ ────┼─────────┼──────────┼─────┼────────────┼──────────────────────────────── Lew │Sept. 16 │Sept. 20 │Sept.│Pn. I +++ │Lobar pn., recovery by crisis │ │chill │22 │B. inf. + │Sept. 29. Developed 2nd attack │ │ │ │ │lobar pn. on Oct. 2. Died Oct. 8 │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ ────┼─────────┼──────────┼─────┼────────────┼──────────────────────────────── Col │Sept. 20 │Sept. 24 │Sept.│Pn. IV ++ │Severe lobar pneumonia. Died on │ │ │27 │ │Sept. 30 │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ ────┼─────────┼──────────┼─────┼────────────┼──────────────────────────────── Gar │Sept. 23 │Sept. 28 │Sept.│Pn. IV ++ │Fulminating rapidly fatal lobar │ │ │30 │S. hem. + │pneumonia. Died Sept. 30 │ │ │ │B. inf. + │ │ │ │ │ │ ────┼─────────┼──────────┼─────┼────────────┼──────────────────────────────── Hol │Sept. 25 │Sept. 30 │Sept.│Pn. III ++ │Fulminating rapidly fatal lobar │ │ │30 │B. inf. ++ │pneumonia. Died Oct. 1. │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ │ ────┴─────────┴──────────┴─────┴────────────┴────────────────────────────────
════╤══════════════════════════════════════════════════ CASE│ NECROPSY │ ────┼────────────────────────────────┬───────────────── │ DIAGNOSIS │ BACTERIOLOGY ────┼────────────────────────────────┼───────────────── Pul │Lobar pneumonia. Gray │H.B. Pn. II │hepatization L.L, L.U, R.L. │Br. Pn. II ++++ │ │B. inf. +++ │ │R.L. Pn. II + + ────┼────────────────────────────────┼───────────────── Lew │Lobar pneumonia. Gray │H.B. Pn. II atyp. │hepatization R.U. │Br. B. inf. ++++ │Fibrinopurulent pleurisy │Pn. IIa +++ │ │S. hem. + │ │Staph. + │ │R.U. Pn. IIa ++++ ────┼────────────────────────────────┼───────────────── Col │Lobar pneumonia. Red │H.B. S. hem. │hepatization all lobes. │Br. S. hem. ++++ │Serofibrinous pl., rt. 125 c.c. │Staph. + │ │L.L. S. hem. ++++ │ │Staph. + ────┼────────────────────────────────┼───────────────── Gar │Lobar pneumonia. Engorgement and│H.B. S. hem. │red hepatization L.U., R.U. │Br. S. hem. ++++ │ │B. inf. +++ │ │L.U. S. hem. ++++ ────┼────────────────────────────────┼───────────────── Hol │Lobar pneumonia. Engorgement all│H.B. sterile │lobes │Br. B. inf. ++++ │ │Pn. III ++ │ │S. hem. + │ │R.L. Pn. III ++++ │ │B. inf. ++ │ │S. hem. + ────┴────────────────────────────────┴─────────────────
L.L. R.L., etc., indicates lobes involved. H. B. = Heart’s blood. Br. = bronchus.
(2) There were 11 cases of lobar pneumonia with purulent bronchitis in the group studied. Clinically, they closely resembled the cases in the preceding group except in so far as the picture was modified by the presence of the purulent bronchitis. All directly followed influenza. The sputum, instead of being rusty and tenacious, was profuse and mucopurulent, usually streaked with blood. Stained films and direct culture on blood agar plates showed pneumococci in abundance and B. influenzæ in varying numbers, in only two instances the predominant organism. The physical signs were those of lobar pneumonia with, in addition, those of a diffuse bronchitis as manifested by medium and coarse moist râles throughout both chests. Five cases recovered by crisis; 6 terminated fatally and in all of them the clinical diagnosis of lobar pneumonia with purulent bronchitis was confirmed at necropsy.
(3) Forty-seven cases in the group studied presented the clinical picture of bronchopneumonia. The onset of pneumonia in these cases was in most instances insidious and appeared to occur as a continuation of the preceding influenza. The temperature, instead of falling to normal after from three to four days, remained elevated or rose higher, the respiratory rate began to rise, a moderate cyanosis appeared, the cough increased, and the sputum became more profuse, usually being mucopurulent and blood streaked, sometimes mucoid with fresh blood. The pulse showed little change at first, being only moderately accelerated. Pleural pain, so characteristic of the onset of lobar pneumonia, was rarely complained of, but a certain amount of substernal pain was common, probably due to the severe tracheobronchitis. Physical examination at this time revealed small areas showing relative dullness, diminished or nearly absent breath sounds, and fine crepitant râles. These areas usually appeared first posteriorly over the lower lobes.
The subsequent course of the disease showed the widest variation from mild cases with limited pulmonary involvement going on to prompt recovery in four or five days with defervescence by lysis or crisis to those presenting the picture of a rapidly progressive and coalescing pneumonia with fatal outcome. In the milder cases the diagnosis of pneumonia depended in considerable part upon the general symptoms of continued fever, increased respiratory rate, and slight cyanosis. Definite pulmonary signs were always present if carefully looked for, though sometimes not outspoken. Areas of bronchial breathing and bronchophony often appeared late, sometimes not until the patient was apparently recovering. In the severe cases cyanosis became intense and an extreme toxemia dominated the picture. In certain of these cases there was an intense pulmonary edema. The respiratory rate showed wide variation, the breathing in some cases being rapid and gasping, in others comparatively quiet. Progressive involvement of the lungs occurred with the development of marked dullness, loud bronchial breathing and bronchophony. Abundant medium and coarse moist râles were heard throughout the chest, probably due in considerable part to the extensive bronchitis almost universally present. An active delirium was not uncommon. Signs of pleural involvement, even in the most severe and extensive cases, rarely occurred, except in those cases in which a hemolytic streptococcus infection supervened.
Of the 47 cases in this group, 29 recovered; 14 by crisis, 15 by lysis. The average duration of illness from the onset of influenza until recovery from the pneumonia was ten days, the majority of these cases being relatively mild in character with pneumonia of three to six days’ duration. Empyema with ultimate recovery occurred in 1 of these cases, Pneumococcus Type II being the causative organism.
There were 18 fatal cases in the group. Nine of these are summarized in Table XVI as illustrative of the frequently complex character of bronchopneumonia following influenza and because of the interest attaching to the bacteriologic examinations made during life and at necropsy. Case 70 is a typical instance of the rapidly progressive type of confluent lobular pneumonia with extensive purulent bronchitis, intense cyanosis, and appearance of suffocation, with which pneumococci, in this case Pneumococcus IV, and B. influenzæ are commonly associated. Case 59 is illustrative of the small group of bronchopneumonias following influenza which die, often unexpectedly, after a long drawn out course, in this instance three weeks after onset. Examination of the sputum at the time the pneumonia began, showed Pneumococcus Type IV and B. influenzæ. At necropsy there was a lobular pneumonia with clustered small abscesses, probably due to a superimposed infection with S. aureus. There was a well-developed bronchiectasis in the left lower lobe. Cultures taken at autopsy showed a sterile heart’s blood, which is not infrequently the case in cases of pneumococcus lobular pneumonia after influenza. Cultures from the consolidated portions of the lung showed no growth, the pneumococcus having disappeared as might be expected from the duration of the case. B. influenzæ together with staphylococci were found in the bronchi. In Cases 50 and 56 a second attack of pneumonia caused by a different type of pneumococcus from that responsible for the first attack occurred, the second attack in both instances being due to contact infection with Pneumococcus Type II from a patient in a neighboring bed suffering with Pneumococcus Type II pneumonia. Both cases showed at necropsy the type of confluent lobular pneumonia so commonly found in pneumococcus pneumonias following influenza. Case 107 illustrates well the extent to which mixed infections may occur, especially when cases are treated in crowded hospital wards. The sputum at time of onset showed Pneumococcus IV in abundance and a few staphylococci. At necropsy there was a confluent lobular pneumonia with clustered abscesses, purulent bronchitis, and bronchiectasis in the left lower lobe. The heart’s blood was sterile, the lungs showed Pneumococcus Type III and staphylococci. B. influenzæ was not found, but through oversight, no cultures were taken from the bronchi. Cases 92, 99, 102, and 104 are all examples of superimposed hemolytic streptococcus infection occurring in the presence of a Pneumococcus Type IV pneumonia, with the picture of interstitial suppuration, abscess formation, and empyema due to S. hemolyticus on the background of a pneumococcus lobular pneumonia found at necropsy. All showed abundant pneumococci and B. influenzæ in the sputum and were free from hemolytic streptococci at time of onset of pneumonia, except Case 92 which showed 2 colonies of S. hemolyticus in the first sputum culture made. At time of death the pneumococci had disappeared in all cases and were replaced by hemolytic streptococci.
TABLE XVI
CASES OF BRONCHOPNEUMONIA FOLLOWING INFLUENZA
════╤═════════╤═════════╤══════════════════╤═══════════════════════════ CASE│ONSET OF │ONSET OF │SPUTUM EXAMINATION│ COURSE OF PNEUMONIA │INFLUENZA│PNEUMONIA│ │ ────┼─────────┼─────────┼─────┬────────────┼─────────────────────────── │ │ │DATE │BACTERIOLOGY│ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 70│Sept. 18 │Sept. 21 │Sept.│B. inf. ++++│Diffuse bronchitis with │ │ │22 │Pn. IV ++ │rapidly progressive │ │ │ │ │confluent bronchopneumonia. │ │ │ │ │Died Sept. 24 │ │ │ │ │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 59│Sept. 13 │Sept. 18 │Sept.│Pn. IV +++ │Bronchopneumonia with long │ │ │19 │B. inf. + │drawn out course. Died Oct. │ │ │ │ │4 │ │ │ │ │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 50│Sept. 14 │Sept. 17 │Sept.│Pn. IV +++ │Mild bronchopneumonia │ │ │18 │ │improving on Sept. 24. On │ │ │ │ │Sept. 26 became suddenly │ │ │ │ │worse and died on Sept. 30 │ │ │ │ │ │ │ │ │ │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 56│Sept. 10 │Sept. 17 │Sept.│Pn. IIa +++ │Bronchopneumonia with │ │ │18 │ │recovery by crisis on Sept. │ │ │ │ │19. Developed a second │ │ │ │ │attack of pneumonia and │ │ │ │ │died Sept. 29 ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 107│Sept. 27 │Sept. 29 │Oct. │Pn. IV +++ │Diffuse bronchitis and │ │ │1 │B. inf. + │severe bronchopneumonia. │ │ │ │Staph. + │Died Oct. 5 │ │ │ │ │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 92│Sept. 23 │Sept. 28 │Oct. │B. inf. │Severe bronchopneumonia │ │ │1 │+++++ │with empyema. Died Oct. 5 │ │ │ │Pn. IV +++ │ │ │ │ │S. hem. 2 │ │ │ │ │col. │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 99│Sept. 24 │Sept. 29 │Oct. │B. inf. ++++│Diffuse purulent bronchitis │ │ │1 │Pn. IV ++ │with bronchopneumonia. Died │ │ │ │S. vir. + │Oct. 7 ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 102│Sept. 24 │Sept. 28 │Oct. │Pn. IIa +++ │Severe bronchopneumonia │ │ │1 │B. inf. ++ │with empyema. Died Oct. 4 │ │ │ │ │ │ │ │ │ │ ────┼─────────┼─────────┼─────┼────────────┼─────────────────────────── 104│Sept. 26 │Oct. 1 │Oct. │B. inf. ++++│Diffuse purulent bronchitis │ │ │1 │Pn. IV +++ │with severe │ │ │ │ │bronchopneumonia. Developed │ │ │ │ │streptococcus empyema. Died │ │ │ │ │Oct. 11 ────┴─────────┴─────────┴─────┴────────────┴───────────────────────────
════╤══════════════════════════════════════════════════════════════════ CASE│ NECROPSY │ ────┼─────────────────────────────────┬──────────────────────────────── │ DIAGNOSIS │ BACTERIOLOGY ────┼─────────────────────────────────┼──────────────────────────────── 70│Nodular and diffuse confluent │H.B. sterile │lobular pneumonia. Purulent │Br. B. inf. ++++ │bronchitis. Bronchiectasis │Pn. IV ++ │ │Lun. B.inf. +++ │ │Pn. IV +++ ────┼─────────────────────────────────┼──────────────────────────────── 59│Lobular pneumonia, with clustered│H.B. sterile │abscesses. Bronchiectasis │Br. B.inf. +++ │ │Staph. ++ │ │R.L. no growth. ────┼─────────────────────────────────┼──────────────────────────────── 50│Nodular and confluent lobular │H.B. sterile │pneumonia. Purulent bronchitis │Br. B.inf. +++ │ │Staph + │ │R.L. Pn. II +++ │ │B.inf. + │ │L.U. Pn. II +++ ────┼─────────────────────────────────┼──────────────────────────────── 56│Confluent lobular pneumonia │H.B. Pn. II │ │Br. Pn. II +++ │ │B.inf. ++ │ │L.L. Pn. II +++ │ │B.inf. + ────┼─────────────────────────────────┼──────────────────────────────── 107│Confluent lobular pneumonia with │H.B. sterile │clustered abscesses. Pur. │R.L. Pn. III ++ │bronchitis and bronchiectasis │Staph. ++ │ │L.L. Staph. ++ ────┼─────────────────────────────────┼──────────────────────────────── 92│Lobular pneumonia. Empyema. │H.B. S.hem. │Purulent bronchitis │Br. B.inf. +++ │ │S.hem. +++ │ │R.L. S.hem. +++ │ │B.inf. ++ Emp. S.hem. ────┼─────────────────────────────────┼──────────────────────────────── 99│Bronchopneumonia. Purulent │H.B. S.hem. │bronchitis │Br. B.inf. +++ Lun. S.hem. +++ │ │S.hem. ++ B. inf. + ────┼─────────────────────────────────┼──────────────────────────────── 102│Lobular pneumonia with │H.B. S.hem. │interstitial suppuration. Pur. │Br. B.inf. +++ │bronchitis. Empyema │S.hem. +++ │ │R.L. S.hem. +++ ────┼─────────────────────────────────┼──────────────────────────────── 104│Nodular bronchopneumonia with │H.B. S.hem. │interstitial suppuration. Pur. │R.L. S.hem. ++++ │bronchitis and bronchiectasis. │Emp S.hem. │Empyema. │ │ │ ────┴─────────────────────────────────┴────────────────────────────────
The cases cited in the preceding paragraph are illustrative examples from a series of over 250 necropsies which are described in another section of this report. They serve to indicate clearly the extent to which mixed and superimposed infections of the lungs may occur in pneumonia following influenza and leave little doubt that a considerable proportion of the deaths from influenzal pneumonia are due to this circumstance.
Hemolytic Streptococcus Pneumonia Following Influenza
But 4 cases of hemolytic streptococcus pneumonia directly following influenza without an intervening pneumococcus infection of the lungs occurred in the group of cases studied clinically. Superimposed infection with S. hemolyticus, however, occurred not infrequently during the course of pneumococcus pneumonia following influenza, as has been stated above. This occurred 3 times in lobar pneumonia and 10 times in bronchopneumonia, with fatal outcome in all but 1 case.
=Bacteriology.=—Bacteriologic examination of the sputum in the 4 cases of streptococcus pneumonia directly following influenza showed S. hemolyticus present in abundance. B. influenzæ was also present in large numbers in 3 cases, but was not found in the fourth. In 1 case a Gram-negative micrococcus resembling M. catarrhalis was also present in large numbers in the sputum. Pneumococci were not found either by direct culture on blood agar plates or by inoculation of the sputum intraperitoneally in white mice.
In the 13 cases of superimposed hemolytic streptococcus infection occurring during the course of pneumococcus pneumonia, bacteriologic examination of the sputum by direct culture and by mouse inoculation shortly after onset of the pneumonia showed Pneumococci (atypical II once, Type III once, Group IV eleven times) B. influenzæ present in large numbers, and no hemolytic streptococci except in 4 instances in which a very few organisms were present. Subsequent invasion of the lower respiratory tract by S. hemolyticus was shown to occur by means of cultures of empyema fluids or by cultures made at necropsy.
=Clinical Features.=—The 4 cases of hemolytic streptococcus pneumonia following influenza that occurred in this series resembled in all respects the secondary streptococcus pneumonias of the winter and spring of 1918 and presented no features requiring special comment. The onset resembled that of pneumococcus bronchopneumonia, the disease appearing to develop as a continuation of the preceding influenza. The sputum was profuse and mucopurulent in 3 cases, mucoid and bloody in the other. Two cases ran a severe and rapid course with the development of empyema early in the disease and fatal outcome. The other 2 cases ran only moderately severe courses without developing empyema and recovered by lysis in twenty and fifteen days, respectively, after the onset of influenza. Clinical differentiation between streptococcus and pneumococcus bronchopneumonia following influenza did not seem possible without bacteriologic examination of the sputum except in those cases of the streptococcus group which developed an extensive pleural effusion early in the disease.
The advent of superimposed hemolytic streptococcus infection of the lower respiratory tract during the course of pneumococcus pneumonia following influenza presented no clinical features that made diagnosis certain without bacteriologic examination. The sudden occurrence of a pleural exudate during the course of the disease seemed of particular significance, especially since empyema in the bronchopneumonias following influenza was exceedingly rare in the absence of hemolytic streptococcus infection. Other suggestive symptoms were a chill during the course of the disease, a sudden turn for the worse in cases apparently doing well, or the development of a cherry red cyanosis. None of these features, however, was sufficiently constant or distinctive of streptococcus invasion to be depended upon and when they occurred, were merely indications for further bacteriologic examination.
Bacillus Influenzæ Pneumonia Following Influenza
Bacteriologic evidence that cases of pneumonia following influenza might be due to B. influenzæ alone was very meager in the group of cases studied clinically at Camp Pike; in fact, no convincing evidence was obtained that such cases occurred. In one case B. influenzæ alone was found in the sputum coughed from the deeper air passages, and in another case B. influenzæ with a few colonies of S. viridans was found. Both were cases of bronchopneumonia, mild in character, and recovered promptly. They presented no clinical features by which they could be distinguished from cases of pneumococcus bronchopneumonia.
It has been previously stated that B. influenzæ was found in all early uncomplicated cases of influenza somewhere in the respiratory tract; that it was present together with other organisms, notably pneumococcus in the sputum from cases of purulent bronchitis following influenza; and that it was found in the sputum coughed from the lung in approximately 80 per cent of cases of pneumonia complicating influenza. In 35 cases it was very abundant, often being the predominating organism. In all these cases, however, pneumococci or hemolytic streptococci were also present in considerable numbers at the time of onset of the pneumonia. It is impossible to say merely from the clinical and bacteriologic data under consideration what part B. influenzæ played in the development of the actual pneumonia in these cases. Discussion of this subject is therefore reserved for the section of this report dealing with the pathology and bacteriology of pneumonia following influenza.
Summary
Influenza as observed at Camp Pike presented itself as a highly contagious infectious disease, the principal clinical manifestations of which were, sudden onset with high fever, profound prostration with severe aching pains in the head, back and extremities, erythema of the face, neck and upper chest with injection of the conjunctivæ, and a rapidly progressive attack upon the mucous membranes of the respiratory tract as evidenced by coryza, pharyngitis, tracheitis and bronchitis with their accompanying symptoms. In the majority of cases it ran a short self-limited course, rarely of more than four days’ duration, and was never fatal in the absence of a complicating pneumonia.
Bacteriologic examination in early uncomplicated cases of the disease showed the B. influenzæ of Pfeiffer to be present in all cases, often in predominating numbers. It was found more abundantly present during the acute stage of the disease than during convalescence in uncomplicated cases. No other organisms of significance were encountered by the methods employed.
Purulent bronchitis of varying extent developed in approximately 35 per cent of the cases and often prolonged the course of the illness to a considerable extent. Bacteriologic studies showed that it was invariably associated with a mixed infection of the bronchi with B. influenzæ and other bacteria, in most instances the pneumococcus, and indicated that it should be regarded as a complication rather than as an essential part of influenza. Its clinical features consisted of a mild febrile reaction, frequent cough with the raising of considerable amounts of purulent sputum, and the physical signs of a more or less diffuse bronchitis. It led to a varying degree of bronchiectasis in at least some instances.
Pneumonia complicating influenza presented a very diversified picture and appeared to have only one constant character, namely, that influenza was the predisposing cause. It may be best classified on an etiologic basis since the clinical features to some extent and the pathology to a much greater extent depended upon the infecting bacteria in a given case.
Bacteriologic examination showed that a very large proportion of the cases was due to infection with the different immunologic types of pneumococci or to a mixed infection with B. influenzæ and pneumococci. The types of pneumococci commonly found in normal mouths, namely, II atypical, III, and IV, comprised approximately 88 per cent of these, the highly parasitic Pneumococci Types I and II, but 12 per cent. A small number of cases were due to hemolytic streptococci or to mixed infection with B. influenzæ and S. hemolyticus. No certain evidence was obtained that pneumonia was due to B. influenzæ alone. This organism was present in varying numbers, however, in approximately 80 per cent of the sputums examined, and it seems fairly certain that it must have played at least a part in the development of the pneumonia in many of the cases in which it was found. Superimposed infections with other types of pneumococci than those primarily responsible for the development of pneumonia, with hemolytic streptococci and with Staphylococcus aureus occurred frequently in cases of pneumococcus or mixed pneumococcus and B. influenzæ pneumonia and undoubtedly contributed to a considerable extent in increasing the number of deaths.
Three clinical types of pneumococcus pneumonia following influenza occurred: lobar pneumonia, lobar pneumonia with purulent bronchitis, and bronchopneumonia. Lobar pneumonia was usually sudden in onset and ran the characteristic course of the primary disease. Lobar pneumonia with purulent bronchitis similarly ran the characteristic course of the primary disease but presented the unusual picture of lobar pneumonia with mucopurulent rather than rusty, tenacious sputum and numerous moist râles throughout the unconsolidated portions of the lungs. The cases of bronchopneumonia ran a very variable course from mild cases of a few days’ duration and meager signs of consolidation to rapidly progressive cases with signs of extensive pulmonary involvement. Purulent bronchitis was very frequently associated with bronchopneumonia.
Hemolytic streptococcus pneumonia following influenza presented the clinical picture of bronchopneumonia and was not readily distinguished on clinical grounds from pneumococcus bronchopneumonia except in those cases which developed a pleural exudate early in the disease. The advent of tertiary infection of the lower respiratory tract with hemolytic streptococci in cases of secondary pneumococcus pneumonia presented no symptoms sufficiently constant or certain to make clinical diagnosis easy. The development of empyema in pneumococcus bronchopneumonia usually meant streptococcus infection.
Pure B. influenzæ pneumonia, if such cases existed, presented no diagnostic features by which it could be distinguished from pneumococcus bronchopneumonia following influenza. It was impossible to determine on clinical and bacteriologic grounds alone what part the prevalent influenza bacilli played in the causation of the actual pneumonia.
Discussion
That wide variations in the conception of influenza have arisen during the recent pandemic, even a hasty review of the literature makes clear. In its essence this divergence of opinion seems to depend upon whether pneumonia is considered an essential part of influenza or a complication due either to the primary cause of influenza or to secondary infection. One extreme is expressed by Dunn[30] who says “the so-called complication is the disease,” the other by Fantus[31] who finds influenza a relatively mild disease with pneumonia a relatively infrequent and largely preventable complication.
A similar divergence of opinion prevails with respect to the bacteriology of influenza. There is fairly general agreement that the members of the pneumococcus and streptococcus groups and to a less extent other organisms are responsible for a large proportion of the secondary pneumonias, and but few observers hold that they possess any etiologic relationship to influenza. No such uniformity of opinion exists, however, with respect to the relation of B. influenzæ to influenza and to the complicating pneumonia. By some it is considered the primary cause of influenza, by others it is regarded as a secondary invader responsible for a certain proportion of the secondary pneumonias, and by still others it is not considered to bear any relation either to influenza or its complications.
A limited number of references to the extensive literature of the recent pandemic will amply serve to illustrate the various points of view that have developed.
Keegan[32] regards pneumonia as a complication and considers that B. influenzæ, the probable cause of influenza, is the primary cause of the pneumonia which may or may not be still further complicated by pneumococcus or streptococcus infection as a terminal event. Christian[33] states that epidemic influenza causes a clinically demonstrable bronchitis and bronchopneumonia in the larger proportion of cases, and lays particular emphasis upon the fact that it is quite incorrect to consider fatalities in the epidemic as due to influenza uncomplicated by bronchopneumonia. Blanton and Irons[34] speak of influenza as an “antecedent respiratory infection” of undetermined etiology, and believe that pneumonia when it occurs is due to autogenous infection by a variety of secondary invaders, principally of the pneumococcus and streptococcus groups. Hall, Stone, and Simpson[35] regard pneumonia strictly as a complication and quite distinct from influenza itself. Synnott and Clark[36] believe that the infection is characterized by a progressive intense exudative inflammation of the respiratory tract often terminating in an aspiration pneumonia with a variety of conditions found at autopsy and a multiplicity of secondary organisms responsible for the fatal termination. B. influenzæ was usually found but always with other organisms. Friedlander and his collaborators[37] speak of a fulminating fatal type of influenza with acute inflammatory pulmonary edema, but regard true bronchopneumonia as secondary, due to infection with pneumococcus or S. hemolyticus. B. influenzæ was not found more frequently than under normal conditions. Brem[38] and his collaborators present a clear cut clinical picture both of influenza and the secondary pneumonia to which it predisposes, regarding the latter as definitely due to secondary infection with pneumococcus, streptococcus or B. influenzæ, the virus of influenza being unknown. Ely[39] and his collaborators make no distinction between influenza and pneumonia, and apparently consider the epidemic due to a hemolytic streptococcus of indefinite and inconstant characters. The Camp Lewis Pneumonia Unit[40] states “the process [influenza], whether mild or severe, is etiologically and pathologically the same; * * *.” B. influenzæ was not found. In a report of The American Public Health Association[41] it is stated that deaths resulting from influenza are commonly due to pneumonias resulting from an invasion of the lungs by one or more forms of streptococci, by one or more forms of pneumococci, or by the so-called influenza bacillus. This invasion is apparently secondary to the initial attack. Wolbach[42] found B. influenzæ in a high proportion of cases, not infrequently in pure culture in the lung, and believes that there is a true influenzal pneumonia whether B. influenzæ is the cause of the primary disease or not. Spooner, Scott and Heath[43] isolated B. influenzæ in a high percentage of cases and consider it reasonable to suppose that it was the prime factor in the epidemic. Kinsella[44] found B. influenzæ infrequently and regards it as a secondary invader. MacCallum[45] regards B. influenzæ as a secondary invader and believes that it is responsible for a form of purulent bronchitis and bronchopneumonia following certain cases of influenza. Pritchett and Stillman[46] found B. influenzæ in 93 per cent of cases of influenza and bronchopneumonia. Hirsch and McKinney[47] state that B. influenzæ played no rôle in the epidemic at Camp Grant and apparently consider it due to a specially virulent pneumococcus.
No further references to the extensive literature of the recent pandemic seem necessary, since those cited above serve to illustrate the various points of view that exist. A similar diversity of opinion may be found in the reports from foreign sources.
It would appear that much of the divergence of opinion that has been formed has depended to a considerable extent upon the conditions under which cases have been observed. This is clearly brought out by contrasting the experience of Fantus[39] dealing with private cases in civilian practice, where pneumonia was relatively uncommon, with that of others dealing only with cases in large hospitals, where those admitted have been in large part selected seriously ill patients with a high incidence of pneumonia, the milder cases comprising from 60 to 90 per cent of those attacked by influenza never reaching the hospital. Variations in opinion with respect to the bacteriology of the epidemic, especially in regard to B. influenzæ, would appear to be due for the most part to differences in bacteriologic technic, in some degree to differences in interpretation. Accumulating evidence can leave little doubt that B. influenzæ was at least extraordinarily and universally prevalent throughout the period of the epidemic and thereafter, and that earlier reports of failure to find it were due to the use of methods unsuitable for its detection and isolation.
The opportunity afforded the commission at Camp Pike to devote their full time to a systematic and correlated group study of the epidemic simultaneously from many aspects throughout its whole course made it apparent that influenza _per se_ is in the large majority of instances, in spite of the initial picture of profound prostration, a relatively mild disease which tends to rapid spontaneous recovery. This opinion is supported by the fact that the disease during the first waves of the epidemic in this country, which it is now recognized occurred pretty generally in the army camps during the spring of 1918, was so mild that it attracted only passing attention, since the disease at that time was not sufficiently virulent to predispose to any alarming amount of pneumonia. With the return of the epidemic in the late summer and early fall, however, the disease had attained such a high degree of virulence that it predisposed to an appalling amount of severe and often rapidly fatal pneumonia, which often detracted attention from the real nature of the preceding disease. Yet even during the fall epidemic from 60 to 90 per cent of the cases of influenza proceeded to rapid recovery without developing complications. On this ground alone it would seem only logical to regard pneumonia strictly as a complication of influenza rather than as an essential part of the disease, irrespective of whether the pneumonia may be caused by the primary cause of influenza or not. The complexity of the clinical features, the bacteriology and pathology of the pneumonias following influenza lend further support to this opinion.
It seems better, therefore, to consider influenza first as a disease by itself and subsequently to take up the question of pneumonia and the relation of influenza to it.
The most striking clinical features of influenza are its epidemic character, its involvement of the respiratory tract, its extremely prostrating effect, and the often surprising rapidity with which the individual cures himself. These features strongly suggest that the etiologic agent of the disease is an organism subject to rapid changes in virulence; that it is confined to the respiratory tract where it produces a superficial inflammatory reaction giving rise to the characteristic symptoms of coryza, pharyngitis and tracheitis; that it elaborates a poison, possibly a true toxin, readily absorbed by the lymphatics, the effect of which is manifested in the profound prostration, severe aching pains, erythema, and leucopenia; and that it may either disappear promptly from the respiratory mucous membrane at time of recovery or may persist, leading a relatively saprophytic existence for an indefinite period of time, being no longer harmful to the individual, at least more than locally, because of an acquired immunity. Furthermore, in our opinion, the very brief incubation period suggests that the disease is bacterial in origin, rather than that it is analogous to the exanthemata, the majority of which present a comparatively long, fairly constant, incubation period.
B. influenzæ has characteristics in accord with the clinical features of influenza. It is an organism of very labile virulence; it is always present in our experience on the mucous membranes of the respiratory tract in early uncomplicated cases of influenza, often in overwhelming numbers; in only very exceptional instances, in adults at least, does it invade the body producing a general infection, as the numerous reports of negative blood cultures testify; recent investigations by Parker[48] and others indicate that it is capable of producing a toxin quickly fatal for rabbits; it is predominantly present in the respiratory tract during the active stage of the disease and disappears in a considerable proportion of cases at time of recovery, while in others, more particularly those that develop an extensive secondary bronchitis and bronchiectasis it may persist for an indefinite period of time.
It is, of course, fully appreciated that the foregoing is in the main merely argumentative reasoning and it is put forth only to suggest that B. influenzæ merits a much closer scrutiny with respect to its etiologic relationship to influenza than the trend of present opinion has awarded it.
Although there remains some difference of opinion as to the relation of influenza to pneumonia, the majority of observers concur in regarding pneumonia as a complication and this would seem to be the only logical interpretation of the facts available. The same may be said with respect to purulent bronchitis and bronchiectasis. It is of considerable significance in this connection that pneumonia following influenza presents no uniform clinical picture, no uniform bacteriology and no uniform pathology. Whether the predisposition of patients with influenza to contract pneumonia is preponderantly due to lowering of general resistance to infection by the extremely prostrating effect of the disease and the inhibition of leucocytic defense, or to a destruction of local resistance against bacterial invasion by reason of profound injury to the bronchial mucosa, or to a combination of both factors, is difficult to say. It seems most probable that both are concerned. At any rate it seems clear that in the presence of influenza a considerable variety of organisms which under ordinary conditions do not find lodgement in the lungs are able to gain access to the lower respiratory tract and produce pneumonia.