This is a special session convened on November 19, 1957, by the New York Academy of Medicine, moderated by Columbia University's Harry M. Rose and including the following:
Morris Greenberg, Director of Bureau Preventable diseases NYC DOH
Milton Helpern, New York City's Chief Medical Examiner
George K Hirst, Director of the Public Health Research Institute
Shirley C[arter] Fisk, Columbia Presbyterian Medical Center
David E Rogers, Weill Cornell Medical Center
Edwin D Kilbourne, Weill Cornell Medical Center
With introductory and closing remarks delivered by New York Academy of Medicine President Dr. Robert L. Levy.
The proceedings were presumably broadcast over the Municipal Radio Station, WNYC.
For more information, see the following CDC reports:
Rundown: Intro remarks by Dr Levy, who calls the special meeting on a “very timely topic” (0:29)
Dr Rose introduces panel
Dr Hirst - “most publicized epidemic we’ve ever had” (4:23)
Historical overview “now entering another phase” (7:25), very distantly related to current so very few people have antibodies, strains very different from any previously known. [Sounds scary]
Dr Rose “one of the astonishing things indeed is that the epidemic proportions were not even larger” in October (10:41)
Dr Greenberg ”“ current NY situation. First from exchange students from Europe and Asia. Then in late September “the thing came down with a bang” (12:40). So many calls for ambulances “police was unable to keep up” (12:52) Starts slides. Absenteeism up to 1/3 of student population; since come back to normal, same with reported cases. Children more affected than adults. 51% of all excess deaths among those older than 50; also high for pregnant women and those with heart disease; but (unexpectedly) normal rate for infants. Low vaccine until end of October. “We did not know a great deal; nobody knew very much because this was a new virus” (23:40) Incidence and mortality lower in NYC than elsewhere.
Dr Rose: Do antibiotics work for secondary infection which often causes the actual death? “There are situations in which influenza occurs without super infection in which we are currently quite helpless” (27:10)
Dr Helpern ”“ on death. Unusually high numbers of fairly rapid onset with at first not alarming symptoms. Some exchange students aboard ship Arosa Sky (later Bianca C, the “Titanic of the Caribbean”) from Rotterdam. A boy jumped from a window after going “berserk” in the care of a relative. 20-25 deaths due to influenzal bronchial pneumonia. Slides showing symptoms of some specific cases, not too different from cases in the past
Dr Rogers and Dr Kilbourne ”“ Gives up on slides. 2 types of patients: One with pneumonia similar to the cases of Dr Helpern’s, another with no additional bacterial infection but dying from the virus itself; most of these have died in the hospital. “This is somewhat terrifying because it indicates that this is clearly a situation where antimicrobial therapy cannot be expected to avail us, and indeed it has not” (53:41)
Dr Rose ”“ Confirms Kilbourne findings. “We are confronted with a situation where in a certain proportion of cases we have a disease which we are in no ways able to control” after a certain point (55:55). “It is a little bit frightening to think what might happen if we had a recurrence of the disease as we have seen it so far this year and had a larger or a greater incidence of cases of this sort.” (56:12) “Let us hope and pray that nothing of that sort actually happens and that in the meanwhile we can come up with some ways and means to deal with the problem, should it arise” (56:24)
Dr Fisk ”“ clinical aspects, advice to physicians. Most are mild infections treatable at home. Small percentages are fulminating, as well as other infections. If Aspirin does not help, assume pulmonary infection. In hospitals antibiotics generally work, first penicillin and streptomycin, then more general antibiotics.
Dr Rose ”“ immunization. Manufacturing issues: vaccine had to be monovalent, and less than ideal quantity, slowly available. How good is the vaccine? Mentions Fort Dix study in August, then an “extraordinarily high” peak in October. One with 200 CCA (chick-cell agglutinating) units, one with 750 units, and a control group. Vaccine has “somewhat” of a protective effect at 200 units, but “it leaves a good deal to be desired” (1:11:05) ”“ needs greater potency. Due to Public Health Service recommendations a higher (400 cca) vaccine became “official” Nov 1.
Dr Kilbourne ”“ multiple doses better although study is small.
Dr Hirst ”“ how immunization works in general; we do not know how it works with new viruses
Q&A ”“ Dr Fisk - cannot clinically distinguish common colds, adenovirus (a-p-c) infection and Asian flu; Dr Rogers thinks they can (rapid onset, headache); Dr Fisk disagrees. Dr Rose talks about possible tests to identify presence of virus, Dr Hirst points difficulties
Dr Greenberg ”“ 2nd wave in Japan same? Will there be a 2nd outbreak in US? Probably not because it has already been all over the world. Infant/children vaccination? Not advisable; bad reaction and low infant mortality. Advise: elder, heart disease, pregnant women
Dr Hirst ”“ Contracting and vaccinating same rate of protection
Dr Kilbourne ”“ Unlike (reportedly) 1918, no neurologic complications. Need more study, better techniques.
Dr Helpern ”“ No brain lesions. One point about earlier slides: bacterial presence does not mean pathology was their result.
Dr Fisk ”“ good idea to give antibiotics to flu patients with chronic pulmonary disease.
Dr Hirst ”“ no antigenic variation
Dr Rose ”“ Vaccine is efficacious
Drs Kilbourne and Hirst ”“ Spacing of double dosage is important, and not settled
Dr Levy ”“ one case with striking periocarditis.
WNYC archives id: 67585
HARRY M. ROSE . . . Moderator
John E. Borne Professor of Medical and Surgical Research; Chairman, Department of Microbiology, College of Physicians and Surgeons, Columbia University; Attending Microbiologist and Associate Attending Physician, Columbia-Presbyterian Medical Center
Panel Members MORRIS GREENBERG
Director, Bureau of Preventable Diseases, Department of Health, City of New York
Chief Medical Examiner, City of New York
GEORGE K. HIRST
Director, Public Health Research Institute, City of New York
EDWIN D. KILBOURNE
Associate Professor and Director, Division of Virus Research, Department of Public Health and Preventive Medicine, Cornell University Medical College; Associate Attending Physician, The New York Hospital
SHIRLEY G FISK
Assistant Professor of Clinical Medicine, College of Physicians and Surgeons, Columbia University; Assistant Attending Physician, Presbyterian Hospital
DAVID E. ROGERS
Associate Professor of Medicine, Head of the Section of Infectious Disease, Cornell University Medical College; Associate Attending Physician, The New York Hospital
MODERATOR HARRY M. ROSE: We thought that the topic could best be presented this evening by having three or four of the panel members first present short introductory discussions. We shall then have a period for general discussion and questions, trying to answer written questions as they are submitted from the floor and reserving some right to ask questions ourselves of the panel members.
I should like first to ask Dr. Hirst to speak about the background of epidemic influenza as it has currently been seen in our community, and to say a few words about the responsible strains of virus.
DR. GEORGE K. HIRST: These will probably be the most obvious reÂ¬marks of the evening, since this is the most publicized epidemic that we have ever had and anyone who has read the newspapers at all will know pretty much what to expect.
The modern history of influenza dates from 1933 which was the first time the virus was isolated in human beings. There are roughly three divisions of our experience with influenza A epidemics. The first of these ran from 1933 to 1947. During that time there were a number of epidemics of influenza A occurring roughly at intervals of two years and the viruses responsible for these epidemics were similar, just how similar we don't know because we did not have good methods of han-dling and comparing these strains at that time.
In 1943 a vaccine was prepared against several of these strains which was effective in the epidemic of that year. In 1947 this type A strain, which had been widely prevalent, widely seeded in the population and had caused repeated epidemics, disappeared and in this country was replaced rather suddenly in the summer of 1947 by a new strain which was very distantly related and was called Ai. The name has no special significance but we did see at that time a new type of episode in the history of epidemic influenza in that a new, relatively unrelated type of strain could crop up, one with which the population had had little or no experience. This type of strain then, was prevalent for the next ten years, changing a little from year to year, causing epidemics of moderate severity, sometimes of world-wide spread. The predictability of the spread was not very high. Those who were students of the situation never knew from year to year exactly when a new outbreak might occur. Last spring, when a note appeared in The Neiv York Times that there was an epidemic of influenza in the Far East, the strain was obtained through Army facilities. From the cases studied it was found that we were entering the third phase of influenza A epidemiology. The antigenic type of this strain, while it was an A strain, was so distantly related to all other A strains as to make it difficult to determine whether it actually was an A strain. Very few people in the general population had antibodies against it. This promised, therefore, to be a repetition of the 1947 experience with a world-wide spread of the disease because the population had no antibodies against the new strain. You have all seen how it spread,””rapidly first in the Far East, Russia, and then in our hemisphere south of us. During the summer months there was liberal seeding of this country without any definite outbreak and then finally blossoming into a full blown epidemic shortly after the schools opened here in the fall.
Throughout this epidemic the virus has been uniform, as far as we know. Definitive studies on this have yet to be done but all strains isolated so far appear to be the same and are very different from any which had previously been isolated. In the laboratory they displayed no particularly distinctive behavior. The main concern, I should say, lay in the fact that the population had had no experience with the strains of this variety.
MODERATOR ROSE: I shall now call upon Dr. Greenberg to tell us how the disease has affected our metropolitan community so far this year (1957).
As Dr. Hirst has already pointed out to you, the strains of virus which are responsible for currently prevalent influenza seem to be closely related to one another. They are causing disease in a population which is largely devoid of antibodies and therefore relatively susceptible. It is not surprising that under these circumstances the disease has as-sumed epidemic proportions in this area. One of the astonishing things, indeed, is that these proportions were not even larger.
Perhaps Dr. Greenberg can shed some light on this point.
DR. MORRIS GREENBERG: The epidemic of the present type of inÂ¬fluenza started in China, apparently at the beginning of the year. As Dr. Hirst told you, a strain of the virus was obtained here around April and the tests confirmed the information from the Far East that it was a new strain of influenza A virus.
In New York City our acquaintance with influenza caused by the new strain began in August, when a number of exchange students arÂ¬rived from abroad by airplane and by boat. They came from various parts of Europe and some from Asia and were sponsored by families in this country. There were about 50 students who were quite ill in one of the first boats that came here. About 200 of them had been ill en route, but had recovered. As other boats came from Europe, they began to bring in occasional cases, and we felt certain that the population was being seeded fairly heavily. We did not get any clinical cases in our indigenous population during August, nor during September. A few cases of respiratory disease, suspected of being influenza, did occur. Actually, we recovered the virus from only three individuals who had been living in New York City. Then suddenly, in the last weekend in September, the epidemic of influenza hit the city. We were conscious of it because the municipal hospitals received so many calls for ambulances that they were unable to keep up with the telephone calls and we had to send some to sanitarians to help them out.
(Slide) We tried several ways to determine how intensive the epidemic was. This obviously was not too easy. One could not depend entirely upon reports from physicians because the clinical diagnosis of influenza is not easily made. One thing we did try to do was to find the rate of absenteeism in the schools. This is shown in the lower curve which is rather sharp because we had only 3 points of reference. On October 4th, absenteeism in the schools was about 100,000-150,000. Normally there is a daily absenteeism of between 60,000 and 80,000 individuals. By October 7 th, there were some 300,000 absent, a third of the school population. Then the curve began to decline and by the end of October, the number of absentees had fallen to about 150,000. It has since reached normal. The second curve shows the number of cases of influenza reported by physicians. The number kept on rising until about the middle of October when there were approximately 300 cases reported per day. After that there was a gradual decline. This curve is only for the month of October. By now the curve is way down. At present about 25 cases a day are being reported. The top curve indiÂ¬cates the cases of upper respiratory infection that were reported from the municipal hospitals. These were cases that walked into the emerÂ¬gency rooms, cases that were brought in by ambulance, cases that were in the hospitals and cases among hospital employees. Here, too, the peak was reached about the second week in October, about 5,000, and since then the numbers have been gradually coming down. At the present time they are fairly normal.
(Slide) It is interesting that most of the cases occurred in children, children in the elementary and high schools. After that, influenza at-tacked others in the families of those children. To find out what the situation was among adults, we canvassed a number of industrial con-cerns. You notice that absenteeism in industry was never very great. Here is R. H. Macy & Co. The peak of the curve was reached about two weeks after the children had their peak and about 12 per cent were absent. The normal rate of absenteeism is about 5 per cent. The Met-ropolitan Life Insurance Company had a similar peak, about 12 per cent absent as against a normal rate of about 5 per cent. Consolidated Edison Company never had more than about 7 or 8 per cent absenteeism and that also held true for the New York Telephone Company and for the New York Transit Authority. There were very few absences among policemen or firemen and there were few absences among the personnel of our own Health Department.
(Slide) This curve is taken from Collins' paper which shows that we have had many epidemics of influenza in this country, as Dr. Hirst has said. We have had some 21 epidemics of influenza since 1918, which is that first curve. These were measured by the excess deaths from in-fluenza and pneumonia. It is a very good measure. It is much easier to measure deaths than it is to gauge the number of people who are sick. Note the many peaks in 1921 and 1922 and so on. Notice that these peaks gradually get lower and lower, demonstrating that the more recent epidemics were not as severe as the earlier ones.
(Slide) In this city we also measure the mortality from pneumonia. The thin, solid line is the normal curve, the expected trend. Notice that in the epidemic of 1953 there was an excess number of deaths from pneumonia. The big curve represents the excess number of deaths from pneumonia this year, beginning toward the end of September and con-tinuing into mid-October. By now that curve has come way down.
(Slide) You can also measure the extent of an epidemic by total mortality. Here is the expected curve, the solid line; the broken line represents the actual death rates and the other line is the infant death rate. This is an ordinary year, not an epidemic year, and the three curves are close to each other.
(Slide) In 1943-1944 when we had an epidemic year, you notice there was a rise in total mortality. The infant deaths, however, did not rise. They remained within the normal range. I stress that because we had been told at the beginning of the epidemic that most deaths occur in very young infants and in old people. That isn't so. They occur in old people but not in very young infants.
(Slide) Here is the curve for this year and you notice that the total mortality went way up and that this is true also for old people over 65. But the infant mortality stayed within the hatched area, which is within the expected limits. These curves, by the way, have come down mark-edly at this date (November 7th).
(Slide) During the month of October we had 151 deaths associated with influenza and the majority of those were in the old age group. Those over 50 years of age accounted for 51 per cent of the deaths. There were comparatively few in those under 10 years of age. We had no death in a child under one year in the month of October. If you sepÂ¬arate male and female deaths, the death rate in the older group is much higher in males than in females. That was largely due to the fact that most of these deaths occurred in people with chronic heart disease, atherosclerotic heart disease and coronary thrombosis, diseases which occur more frequently in males than females. On the other hand, in the age group 20-29, deaths in females made up 29.5 per cent of the total, while in males they accounted for only 6 per cent. This was due to excess deaths associated with pregnancy. In pregnant women there were two and one-third to two and one-half times as many deaths in the month of October this year (1957) as last year.
If the death certificates are examined and the secondary or asso-ciated conditions are classified, it is found that arteriosclerotic heart disease was present in about 3 3 per cent of the cases, pneumonia in 31 per cent, pregnancy in 10 per cent and 6.5 per cent had rheumatic heart disease. This last group is actually larger because there were three deaths from rheumatic heart disease in pregnant women which were not inÂ¬cluded in the rheumatic heart disease group. About 5 per cent each had cancer and diabetes, about 3 per cent asthma, and other miscel-laneous conditions made up the rest.
In August we ordered some vaccine with the expectation that it would be given to city employees engaged in essential city services. However, we received only a limited supply of vaccine. By the end of September some of our supply was turned over to the Department of Hospitals to immunize doctors and nurses and then we began to im-munize firemen and policemen. The bulk of vaccine was not received
until the end of October when the epidemic was nearly over.
During the height of the epidemic when the municipal hospitals were being overwhelmed with patients, we opened several of our District Health Centers to take the overflow. These centers were open day and night, Saturdays, Sundays and holidays, and patients were treated there.
Conferences with the Department of Hospitals were held daily. Because the ambulances could not take care of all the cases, arrange-ments were made for interns to go out in police cars and see patients in their homes and treat them there; only those patients with pneumonia or other complications were removed to hospitals.
We also informed all the doctors and hospitals in the city that our laboratory was equipped and able to process any specimens sent to us. We received quite a number. We received a great many specimens of lungs obtained at postmortem. From 25 of these, influenza virus was recovered. Incidentally, from 20 of those 25 we also recovered the staphylococcus in fairly concentrated culture. We also tried, to the best of our ability, to keep the public informed of what we knew. It is quite true that we did not know a great deal about this new strain. In fact, nobody knew very much about it because it was new and very little work had been done with it. However, we did have some information about the natural history of this type of influenza which we shared with the public.
I shall not go into a discussion of vaccination nor of pathology nor treatment since these matters will be discussed by other members of the panel.
MODERATOR ROSE: Would you care to hazard a guess as to why the epidemic, which was proceeding merrily on its way in the early part of October, suddenly began to decline?
DR. GREENBERG: Reports indicate that in the Far East, in the very thickly populated areas, the incidence was about 20 per cent, over-all. In some areas, of course, in small groups, incidence rose as high as 50-60 or even 80 per cent, but on an over-all basis it was about 20 per cent. On the other hand, in Australia where the population is less con-centrated, the percentage was about 10 per cent. I judge that in this city it was about 5 to 8 per cent. It is difficult to give an exact figure.
It is also interesting that the mortality, which was about 0.1 to 0.2 per cent in the Far East, was only about 0.02 to 0.03 per cent here; about 0.1 of what it was in the Far East.
MODERATOR ROSE: In other words, Dr. Greenberg, you feel that the decline in incidence of the disease does not actually reflect the fact that we are approaching saturation so far as the population of the community is concerned?
DR. GREENBERG: I am sure that a great part of the population has been infected without showing symptoms but I have no doubt that there is a fair percentage of the population which has not been infected. That of course bears on the question whether we should continue the vac-cination.
MODERATOR ROSE: That is why I asked the question and that is the answer I wanted to get from you. We shall come back to it a little later.
I shall now ask Dr. Helpern to discuss some of the findings in the fatal cases of influenza.
One of the considerations that has interested a great many of us is the mechanism which actually causes death. It has been known for many years that animals to which influenza virus has become adapted may die as the result of the virus infection alone. On the other hand, it has been generally believed in the majority of fatal cases in man that superinfec-tion with some bacterial agent, generally staphylococcus, has been responsible for death, at least in the cases that have been seen during the last 20 years or so. On this account it has usually been said that we have effective means, in the form of antibiotics, which will enable us to control secondary bacterial infections and to prevent death in the majority of instances. However, I think I can assure the audience that there are situations when influenza occurs without superinfection, in which we are currently quite helpless. Dr. Helpern, would you comÂ¬ment on that point?
DR. MILTON HELPERN: Yes. The Medical Examiner's Office is inÂ¬volved in this particular study because all sudden and unexpected and medically unattended deaths in New York City are referred to this agency for investigation. When such deaths occur in young people it has been the policy of the Medical Examiner's Office to perform an autopsy as part of the postmortem examination to determine the cause of death. Such a situation presented itself this year in which deaths from epidemic influenza were encountered. The fatalities from this cause began to appear sporadically about the middle of August and then became increasingly more frequent toward the end of September and continued all through the month of October, our incidence corÂ¬responding very closely to that which Dr. Greenberg has already given. An unusual number of unattended deaths in the home were reported to the Aiedical Examiner's Office of persons who had been in apparent health and concerning whom a history was obtained of a fairly rapid onset and progression of a respiratory illness which, initially, did not suggest anything serious enough to warrant calling a physician.
I might say that from year to year the Medical Examiner's Office has had an occasional similar case referred to it.
Rare deaths from influenza and its complications have been en-countered by the Medical Examiner in non-epidemic years and have been verified only by the means at hand, chiefly the pathological appearÂ¬ance of the lungs. Prior to this year we did not have the opportunity of checking the pathological findings with viral studies and in this conÂ¬nection I should like to acknowledge the great help we received from the New York City Health Department Virus Laboratory by their determination of the presence of influenza virus in most of the cases that we encountered and in which the lungs were submitted to them for viral studies. The check was a very close one indeed.
The first case brought to our attention occurred in the middle of August and was that of a 17 year old boy, one of a group of exchange students who came over on the steamship Arosa Sky. He was one of many others who had been mildly ill with influenza on the boat but his symptoms suddenly became worse after debarkation. He was hos-pitalized promptly but developed very severe toxic symptoms with fever and died about 24 hours after admission to the hospital. The death was reported to the Medical Examiner's Office and an autopsy was performed by Dr. Vance, Deputy Chief Medical Examiner, who had autopsied a good many of these cases during the 1918 influenza epidemic, and other similar cases occasionally from year to year. His experience led him to diagnose this as a death from influenzal broncho-pneumonia. Subsequent studies by the Health Department revealed the presence of the Asian strain of influenza virus which was the etiological infective agent in all the cases here reported.
Our next case did not occur until the latter part of September and from then on, and through the month of October, we had a fair number of them. I should like to point out that in our series of cases the subjects were not debilitated. They did not have other diseases and most of them were adolescents and young adults. In all the cases, there was gross and microscopic evidence of an influenzal type of bronchopneumonia. In this connection, I should like to point out that the Medical Examiner's Office encounters many cases of death from unsuspected lobar pneuÂ¬monia. I think we see more lobar pneumonia in our autopsy material than do the hospitals. Lobar pneumonia is now rarely fatal in hospital practice but it is not uncommonly encountered as an unsuspected cause of natural death in the Medical Examiner's material. In recent years it has been the second most common cause of sudden natural death disclosed by our autopsies, ranking second only to occlusive coronary artery disease. Lobar pneumonia is readily distinguished at autopsy from influenzal pneumonia, which is the subject of tonight's discussion.
(Slide) This represents the incidence of influenzal deaths in Man-hattan and Brooklyn autopsied by the Medical Examiner's Office. Most of these occurred during October, only one in September and one in August. The ages were 17, 17, 14, 9, 13, 12, 30, 6l/2, 42, 41, 22, 35, 37, 23, 46; there were 10 Negro and 5 white persons, 10 females and 5 males. The influenza virus was cultured from most of the cases. The case of the 14 year old boy in Brooklyn was very interesting. The virus was recovered from the lungs on culture. This boy had a respiraÂ¬tory infection and the family, because of their knowledge of what they had read in the newspapers, that the disease was epidemic, correctly assumed that the boy had influenza. While at home in the care of a relaÂ¬tive who was old and somewhat helpless, he went berserk and leaped from the window and died of his injuries; the autopsy revealed that death had resulted from injuries but that he also had an influenzal type of bronchopneumonia from which influenza virus was recovered.
One of the cases is that of an eight months pregnant, 20 year old Negro woman who had a fulminating infection with fairly characteristic findings in the lungs from which the virus was recovered. Out of curios-ity the placenta was also submitted for culture. However, Dr. Widlock, who carried out the viral studies, reported that there was no virus in the placenta.
Four of the cases, two adults from Brooklyn and two from Man-hattan, revealed pathological findings recognizable as those of influenzal pneumonia. Material from these cases was not submitted for culture. As for the incidence of fatal cases investigated by this office, in the other boroughs, there were five cases in Queens, two in the Bronx and one in Richmond. So that in all there were 23 cases of fairly rapid acute fatal illness referred to the Medical Examiner's Office during the short period of time mentioned, in which death was primarily the result of influenzal bronchopneumonia.
I should like to show illustrations of the pulmonary lesions which I think are very typical of the disease and yet, while it is the most strik-ingly severe case in our present experience, it does not quite match in severity the lesions that were encountered and described in the 1918 epi-demic in which the lungs revealed the very remarkable and bizarre changes described and illustrated in The Pathology of Influenza *
The case I am now illustrating has the most severe pulmonary lesions in this series and most of the others have comparable findings. (Slide) This is a colored photograph of the lungs of a 13 year old girl, who was ill at home for about 24 hours in all. She came down abruptly with a respiratory infection with fever and cough. Within a few hours she began to expectorate blood, became cyanotic, went into shock and col-lapsed and died without medical attention. The lungs in this case are quite characteristic. There are large areas of confluent hemorrhagic bronchopneumonia of the right upper and lower lobes with similar large elevated hemorrhagic areas and a dull red discoloration of the pleura of the left lower lobe. (Slide) Another photograph reveals similar changes on the posterior surfaces of the lungs. The mucosa of the trachea and bronchi appears swollen, intensely congested and in places hemorrhagic and covered with a gray pseudomembrane, the mucosa having a necrotic appearance in places. The primary lesion of this disÂ¬ease is this acute necrotizing pseudomembranous tracheobronchitis and the inflammation spreads into the parenchyma and interstitium of the lung. The smaller bronchi and bronchioles are surrounded by gross and microscopic zones of bronchopneumonia with larger areas of confluent hemorrhagic bronchopneumonia. Intrabronchial plugging by secretion and exudate occurs and a conspicuous feature is the edema and hemorÂ¬rhage of the parenchyma. Subpleural collections of serosanguinous exudate are found in the inflamed bronchi. A photomicrograph of a large bronchus reveals necrosis and sloughing of the mucosa. The partly sloughed off necrotic mucosa is covered with fibrin enmeshed with red blood cells and some leukocytes. Dilated mucosal vessels contain fibrin thrombi. There is considerable edema, congestion and some interstitial hemorrhage. Other sections of lung reveal incompletely consolidated
* Winternitz, Wason and McNamara, Yale University Press, 1920.
parenchyma with over-distention of some of the alveoli. There are patchy areas of acute bronchiolitis and bronchopneumonia. In some secÂ¬tions, many colonies of bacteria, probably staphylococci, were found in the involved parenchyma. Considerable edema and not very much leukocytic exudate although some, both mononuclear and polymor-phonuclear leukocytic in type, were seen. An area of the same lung under slightly higher magnification reveals a small bronchiole with its mucosa sloughed off and very intense inflammation of the surrounding parenchyma in which there are colonies of bacteria representing sec-ondary invaders with resulting distortion and over-distention and rup-ture of air vesicles. The alveolar and bronchiolar effect is partly inflam-matory and partly mechanical as the result of the obstruction of the smaller bronchi. Other sections of the same lung reveal considerable interstitial inflammatory edema, and areas of hemorrhagic bronchopneuÂ¬monia.
The pneumonic areas are almost solid and filled with blood which is partly hemolyzed and confluent due to rupture of interalveolar septa, with considerable over-all damage to the lung. Small areas of hemor-rhagic pneumonia surround inflamed bronchioles. In some areas of hemorrhagic pneumonia, colonies of bacteria, representing secondary invaders, are conspicuous and the blood here is partly hemolyzed.
In another case, that of the 20 year old pregnant woman, that was not cultured for the presence of virus, the necrotizing bronchiolitis is conspicuous. In this section the inflammatory exudate lies partly on the mucosa and penetrates and partly destroys it, infiltrating the interstitium. Sections of the first case reveal very characteristic intense lesions in the lining and wall of a fairly large bronchus.
(Slide) The sections reveal necrosis of the bronchial epithelium, mononuclear and slight polymorphonuclear leukocytic infiltration and infection with secondary bacterial invaders. The pathological lesions in all the cases studied are those of influenzal tracheobronchitis and bronchopneumonia.
MODERATOR ROSE: Dr. Rogers and Dr. Kilbourne have been much interested in these cases of fatal influenzal pneumonia and have studied them bacteriologically and for virus, as well as noting the histologic changes. I should like to ask Dr. Rogers to comment briefly on the findings.
DR. DAVID E. ROGERS: It might be helpful for me to outline certain clinical syndromes that we have seen arising during the current influenza epidemic.
When the epidemic first reached New York it was decided that we would admit to the hospital only patients who had lower pulmonary tract complications of influenza. Consequently my remarks are confined to this very small segment of the population who were admitted with pneumonia secondary to influenza. We have become impressed with two very different syndrome groups.
One group of patients have had clinical illnesses which have re-sembled those that Dr. Helpern has just discussed. These individuals have developed influenza, followed by a period of declining sympto-matology. They have then become worse precipitously and have been admitted with symptoms that we associate with any type of bacterial pneumonia. These patients have had pleural pain, typical signs of local consolidation, and sputa which reveal many bacteria on smear. They have had x-ray changes compatible with local bacterial consolidation and they have responded rather promptly to antibacterial therapy. The majority of these pneumonias have been caused by pneumococci. We have also had cases of secondary staphylococcal pneumonia similar to those Dr. Helpern has discussed, though to date we have not lost any patient with what we believe to be the pure secondary bacterial pneu-monias in association with influenza.
We have, on the other hand, seen another group of patients who present quite a different clinical syndrome. These patients, usually rheumatics with a mitral lesion, have uniformly had preceding cardiac disease. They have had typical influenza which has been followed with-out any remittive period by increasing respiratory distress and cyanosis. On examination these patients have been acutely ill. They have had striking tachypnea and dyspnea. They have had no signs of local con-solidation. On physical examination, the principal findings have been those of diffusely suppressed breath sounds, rather prominent expiratory wheezing, and as the disease has progressed, fine diffuse rales over all lung fields. Chest x-rays have revealed massive bilateral infiltrates””a picture which has been indistinguishable from that seen in cardiogenic pulmonary edema. Nevertheless these patients have had no signs of right-sided failure. Venous pressures have been normal and no peripheral edema has developed. These patients have had high sustained fevers. We have been unable to culture significant bacteria in their sputa or from their lungs at autopsy. The clinical course has been characterized by progressive increasing dyspnea, cyanosis and profound oxygen un- saturation. Five of the seven patients with this syndrome have died of their disease.
Perhaps Dr. Kilbourne might indicate his findings in the laboratory on this group. We have found no bacteria on rather carefully titered cultures.
MODERATOR ROSE: Dr. Kilbourne, would you tell us what you have found?
DR. EDWIN D. KILBOURNE: First of all, I would like to indicate that Dr. Rogers is so intimately familiar with his material that he slipped a gear tonight and failed to mention that these patients, the latter group, are indeed distinguishable from patients with pulmonary edema in that they have in addition to the findings of pulmonary edema, bronchial and bronchiolar necrosis which would characterize them as being probÂ¬ably influenzal in origin. Even at the pathological level of our studies there is considerable evidence that they are different from rheumatic heart disease patients who are dying of pulmonary edema. We have been surprised to find how easy it is to isolate virus from these patients. The virus is present in the lung in fairly high concentration. We have thus far titrated two of the lung specimens in detail and this would indicate that it is probable that the virus is just there as a contaminant from tracheal secretions. The titers of virus in the lungs have been appreciably higher than we find with titrations of virus concentrations in the throat washings.
If Dr. Rose will permit, it might be helpful to give some background concerning what we believe to be the importance of observations of this kind which are far from limited to our group. I have heard that similar cases have occurred in Cleveland and Denver. This may prove to be a universal phenomenon, when further cases have been careÂ¬fully studied.
The people who dealt with the 1918 phenomenon have been debatÂ¬ing for years just what caused the deaths in 1918, and I think some of this debate has given rise to the feeling and the predictions that we have seen in the press that the deaths were due mainly to secondary bacterial infection. I am sure that many of them were. There was a great con-troversy about what sort of secondary bacterial infection caused the deaths, depending upon the part of the country in which one lived.
If one died in an Army camp, he died of streptococcal or pneumococcal, or hemophilus influenzae, bacterial pneumonia.
In addition to these cases there has always been evidence””well re-ported -which would indicate that some of the deaths were so extremely rapid that it was doubtful that they could be explained solely on the basis of secondary bacterial infection.
I think that with the modern virus isolation techniques now available in this epidemic it is interesting to find some verification of the fact that people can die of influenza virus infection alone. This is somewhat terriÂ¬fying because it is clearly indicative of a situation in which we cannot anticipate assistance from antimicrobial therapy. As Dr. Rogers indiÂ¬cated, the cases we have lost have not been those which have been primarily influenza virus pneumonia.
MODERATOR ROSE: We can certainly confirm in all details what Dr. Kilbourne has said about the etiologic factors and the importance of influenzal pneumonia per se as the cause of death. Thus far there have been seven deaths from acute fulminating pneumonia at Presbyterian Hospital which could be ascribed in all likelihood to influenza or in-fluenza aided by secondary bacterial infection. In three of these seven cases it was possible to demonstrate in the lungs large numbers of staphyÂ¬lococci that presumably played a role in the death of the patient. In all seven of these cases it was easily possible to isolate the virus from the lung, so there was no question about the diagnosis; moreover, the hisÂ¬topathologic findings were those that have been described. I would certainly agree that tracheobronchitis is one of the outstanding and most characteristic features.
As I indicated a moment ago, three of these seven cases apparently had complicating staphylococcal infection. In the other four there was no evidence that any bacterial agent contributed to the patient's death, which must be ascribed to pneumonia caused solely by the virus. So, in a certain proportion of the cases we were unable to control events by any of our current therapeutic methods. It is somewhat frightening to think what might happen if the disease recurred and if there were a greater incidence of cases of this sort. Let us hope that nothing of this sort actually happens and that meanwhile we can find a way of dealing adequately with the problem.
I should now like to call on Dr. Fisk, who is here this evening as a substitute for Dr. Kneeland who unfortunately was unable to be with us because of illness. I wonder, Dr. Fisk, if you will comment on the clinical aspects of the disease as it may be seen by the practicing physi-cian and say what you wish about therapeutic measures.
DR. SHIRLEY c. FISK: As indicated by the other members of the panel, influenza as seen by the practicing physicians here in this city is a mild infection and can generally be treated at home with supportive measures. However, a very small percentage of patients has fulminating pneuÂ¬monia with secondary invaders which may conceivably play a role in the fatalities. For this reason I think we must be extraordinarily careful in following cases to determine whether they are mild and self-limited or complicated by pneumonic involvement, either of primary or secondary origin.
In the cases seen in hospital, the procedure is relatively simple, at least therapeutically. One uses antibiotics in an attempt to suppress or control the bacterial aspect of the disease and in the instances that we have seen at Presbyterian Hospital the staphylococcus was our major problem. Most of these organisms were susceptible to most antibiotics, unlike the resistant staphylococci seen in hospital infections. It is our belief that adequate results are achieved in these cases only if treatment is initiated before culture sensitivity studies are done and reported. To begin treatment it is best to use the bacteriocidal drugs, penicillin and streptomycin; and, if the sensitivity studies show the staphylococci to be resistant to these, more appropriate broad-spectrum drugs such as chloramphenicol should be used.
Fortunately these cases with pneumonic involvement represent a small minority of the general group. We believed that the cases present-ing themselves at the clinic without evidence of pulmonary infection should not be treated with an antibiotic but should be treated conserva-tively with aspirin and bed rest at home. MODERATOR ROSE: Thank you, Dr. Fisk.
I think we should now speak about immunization. We shall first present some relevant data and then get on to the questions””there are a lot of them and many are extremely interesting.
Some of the speakers have already covered some of the points which were raised in your questions. When it became apparent, as Dr. Hirst said in his introductory remarks, that we were confronted with a viral agent to which the population at large had no demonstrable antibodies, it seemed only prudent to consider the use of an immunizing agent which might conceivably induce sufficient protection in the population to reduce at least the severity and incidence of the disease, if not to prevent it altogether.
We had as a precedent the results of studies which were started a number of years ago and have since been continued by the Commission on Influenza and the United States Public Health Service. These in-dicated that a properly constituted influenza virus vaccine, i.e., a killed vaccine containing enough antigen similar to the strain or strains pre-valent in the community, would have at least some immunizing effect.
Very early in the manufacture of the vaccine it became apparent that production of a polyvalent vaccine was virtually impossible. A monovalent vaccine containing one of the prevalent strains was there-fore considered. Difficulties were encountered in the manufacture of this product because these strains are somewhat peculiar compared with others so far as the amount of virus produced in the developing hen's egg is concerned, particularly the amount of hemagglutinin. Since hemagglutinin is one of the indexes determining the amount of antigen in vaccine, it was obvious””I won't go into the reasons””that the amount of virus acceptable in the vaccine would have to be somewhat less than the optimum. It was on this account that a vaccine containing 200 chick cell agglutinating units per milliliter was decided upon. More than 40,000,000 milliliters of this vaccine were released by November 9, 1957, of which the majority had been distributed to civilian agencies. This represents a considerable achievement by the manufacturers if one realizes that the vaccine was in short supply until recently. In any event, with the vaccine in production, a number of questions arose: Is it any good? Will it protect against influenza? If so, how much should be given, by what route, how often, etc.?
As mentioned earlier, studies concerning experimental immunization against influenza have been going on for some years under the auspices of the Commission on Influenza. One of these studies has been under way at Fort Dix, another at Lowry Air Force Base and another at Fort Ord. In addition, the Navy has conducted similar work at Great Lakes Naval Training Station, and another study has been done in Wilming-ton, Delaware, by the Public Health Service. In each of these places an experimental program was laid out during the summer to ascertain as quickly as possible the effectiveness of the vaccine.
At Fort Dix, vaccine was received on July 28. The immunization
program was begun on August i, and the supply of vaccine was exhausted by September 6. There were two vaccines available, one of the sort that has been distributed to the general public, containing 200 CCA units per ml., and the other an experimental vaccine containing 750 CCA units per ml. These vaccines were given in single doses of 1.0 ml. subcutaneously to recruits, distributed by companies so that one-third of the men in each company received the 200 CCA unit material, one-third got the 750 material and one-third remained as conÂ¬trols. Altogether, by September 6, there were 1869 men in the 200 CCA unit group and 1665 in the 750 CCA unit group, as you will see in a moment on the slide.
As Dr. Greenberg has indicated, influenza became very prevalent toward the end of September and on the first slide we shall see what the respiratory disease picture was at Fort Dix at that time.
(Slide) (Table 1.) This slide is a graph of the total rate of respiraÂ¬tory disease by hospital admissions. On the vertical axis the hospital ad-mission rate per 1,000 per annum is plotted. On the horizontal axis are date lines for the months of August, September, October and November, up to the week ending December 4. The solid line indicates the hospital admission rate for acute non-bacterial respiratory infections. This, of
TABLE II””EFFECT OF IMMUNIZATION WITH MONOVALENT VACCINES ON HOSPITAL ADMISSION RATES DURING EPIDEMIC PERIOD OF ASIAN TYPE INFLUENZA
Week 200 CCA U 750 CCAU Controls
Ending (1869) (1665) (1655)
2 October 7 5 30
9 October 20 8 36
16 October 22 11 51
23 October 9 7 9
Total 58 31 126
Rate/1000 31.0 18.6 76.1
% Reduction 59 76 ””
Ratio 1/2.4 1/4.0 ””
course, would include both cases of influenza and cases of respiratory disÂ¬ease caused by other viruses, so it is a crude way of showing the picture with respect to influenza. Back in August it can be seen that for the week ending on the 7th, about 70 per cent of the men who entered the hosÂ¬pital had serologic evidence of influenza. The rate climbed to about 75 per cent by the middle of August but had fallen off considerably by early September. Subsequently you will see that there is an extraÂ¬ordinarily high peak reaching its height on October 9, at which time the rate for influenza during this time was approximately 85 per cent.
(Slide) (Table II.) Let us look at the next slide and see what hap-pened to the study groups. These are the data for the weeks ending October 2nd through October 23rd, during the period when the big peak in incidence occurred. There are three columns indicating the number of cases from each of the groups admitted to the hospital in these periods, for those vaccinated with the 200 unit material, the 750 unit material and the controls; the numbers in parentheses, 1869, 1665 and 1655 are the actual numbers of men in each of these groups. There was a total of 126 cases admitted from the controls, only 31 from the 750 unit group and 58 from the 200 unit group. You can see that the reduction was 59 per cent in those given the 200 unit vaccine and 76 per cent in those given the 750 unit vaccine. The protection ratio was i: 2.4 for the first group and 114.0 for the second. These data clearly indi-cate that the 200 CCA unit vaccine had some protective effect, although it left a good deal to be desired. Also, that a vaccine of greater antigenic potency exerted a better protective effect.
You may be interested to know that the results obtained by Dr. Gordon Meiklejohn at Lowry Air Force Base with the 200 unit vaccine showed a reduction of 60 per cent as compared with our 59 per cent. He used 400 unit CCA vaccine as an alternate, instead of the 750 unit material which we employed. His reduction with the latter vaccine was 75 per cent as compared with our 76 per cent, clearly indiÂ¬cating that the results are probably significant and that the 200 unit vaccine is actually not a completely satisfactory product although it will afford considerable protection.
On the basis of studies of this kind, the Public Health Service rec-ommended that the amount of virus in the vaccine be increased and that the potency be raised from 200 CCA units per ml. to 400 CCA units per ml. The 400 unit vaccine became official on November first and on that date production of the 200 unit vaccine was discontinued. It was recommended that 1.0 ml. of the 400 CCA unit vaccine be given sub- cutaneously for immunization.
It was also found in the course of these studies that inoculation of o. 1 ml. intradermally in adults is not an adequate immunizing procedure, although this amount of vaccine followed by another similar dose may be effective in children.
Dr. Kilbourne, you have had experience with these matters, would you like to make some comment?
DR. KILBOURNE: Our experience was predicated on the necessity of vaccinating people at New York Hospital and we were aware of the background of a great deal of this military experience and the extensive work with immunizing agents containing influenza virus in the past. However, recognizing that we were using doses which were less than optimal, we were forced, as were, I think, a great many practicing physicians, into the necessity of trying to immunize 100 people instead of 10. There was evidence in the literature to indicate that intradermal injection or perhaps more specifically double injections, or multiple injections of antigen””intradermal or not””would give a far better im-munizing stimulus than the same quantity of vaccine in a single injec-tion. Perhaps Dr. Rose will comment on this later, but I think for rea-sons of the technical details of administration of vaccine and the like, the military has never been enamored of the idea of giving multiple injections or giving it by the intradermal route. So, actually there was not a great deal of practical information on this point. Therefore, we thought that in the course of immunizing our personnel we would acquire information more germane to civilian practice.
(Slide) This represents a small experiment compared with the mili-tary experience””with the Fort Dix experience””but it indicated to us that intradermal immunization had some worth. Inadequate as it may be, if you look at the first schedule, which is i ml. subcutaneously, it comÂ¬pares with the administration of I/IO of this amount, twice, in spaced injections one week apart. Most interesting to us is the fact that if you split the i ml. and give it in two injections, a week apart, you do conÂ¬siderably better. This particular technique of antibody measurement produces from 14 per cent to 49 per cent demonstrable antibody.
Comparable with this experience and this study of antibody, Dr. Rogers and I observed an epidemic in the hospital involving patients who were not immunized and involving some other personnel who had been immunized. They had been immunized with the two "inadequate" schedules of 200 CCA units in one injection of old vaccine or in some cases with only 1/10 of a milliliter intradermally, and there was definite evidence of protection against clinical disease in both these groups.
MODERATOR ROSE: Dr. Hirst, would you care to discuss the relation-ship of antibody titers, as determined by hemagglutination-inhibition tests, to protection?
DR. HIRST: I think it is fairly clear now that the antigen in the virus which induces an antibody responsible for protection, is an antigen which is able to make red cells agglutinate. This has been shown by fluorescence antibody technique, not only for influenza but for fowl plague virus, which falls in this same general group. There is a general correlation between hemagglutination antiÂ¬body and protective antibody as measured in the laboratory and there is the negative correlation for certain other antibodies. As far as field studies go, there have been some fairly good correlations of protection with circulating antibody level. What we don't know is the answer to the question raised here””about the protective level when we encounter a new virus giving antibody responses which on the whole are relatively low compared to those we are accustomed to getting with other strains. Where the level of protection lies is hard to say. It is possible that these low antibody levels are as protective as the higher levels against other strains.
MODERATOR ROSE: Very good. If we wish to get out of here before morning I presume that we had better get on with the questions. A whole series of questions along similar lines are written on the papers which lie before me. Some of them we can answer, at least in part.
Dr. Fisk, here is one for you: What would be a working clinical method to distinguish between adenovirus infections and Asian influ-enza?
DR. FISK: Short of viral studies, these cases would be difficult to differentiate clinically. Let us classify them all as respiratory and say they are all self-limited and subside spontaneously without any specific therapy.
MODERATOR ROSE: In other words, you feel that even when influenza is prevalent in the community, the fact that a patient has an acute respiratory infection with some fever does not necessarily mean he has influenza?
DR. FISK: Yes.
MODERATOR ROSE: We arrive then at the unhappy conclusion that the clinician is stuck for an etiologic diagnosis.
DR. ROGERS: I would like to take issue with that. MODERATOR ROSE: I wish you would.
DR. ROGERS: Dr. Kilbourne and I have been commenting on this recently. I think we agree that one can make a fairly reasonable etiologic guess at the clinical level regarding the specific virus producing a clinical syndrome. Therefore this appears to be a very reasonable question. The vast majority of cases of influenza can be distinguished at a clinical level from the great majority of adenovirus infections or the common cold. Let me give just a short example. In our experience, influenza has been an illness in which the patient goes from relatively good health to fairly striking illness within a short period of time. He is well in the morning, sick in the evening. He has a prominent cough, which is not an early feature of a cold. He has a striking headache; he has very few nasal symptoms. I am oversimplifying this, nevertheless I think you can make a sound case for differentiating viral illnesses at the clinical level and be right 60 to 75 per cent of the time.
DR. FISK: I don't like to argue the point.
DR. ROGERS: Please do.
DR. FISK: I think if you see the cases in the home or if you see them particularly in your own home where you can observe the early pro- dromata you will be struck by the fact that there is a period of 12 to 24 hours during which the patient will have vague myalgias, slight head-ache, mild congestion of the nose, slight sore throat before the acute onset, mentioned by Dr. Rogers, of severe headache, fever to 104Â° F., prostration and cough.
DR. KILBOURNE: That is not a common cold.
DR. FISK: I would at this point agree it is not a common cold. I still think that as a clinical entity it is difficult to distinguish. I think we assume most of these respiratory infections are influenza but in a non- influenza year one would see this same picture reproduced””call it then la grippe.
DR. ROGERS: I feel that la grippe presents quite a different clinical picture than influenza. I would like to debate this further but I think we probably should go on.
MODERATOR ROSE: We can stay here for quite a long time to debate this interesting point, which is of real moment to the practicing physician who is responsible to his patient and has to make up his mind. He has to deliver an important message to the family concerning the diagnosis. I think I would be inclined to agree with you to a certain extent, Dr. Rogers. I have seen so many cases of influenza that were difficult to distinguish, even in a season when influenza was prevalent, that I would not want to stick my neck out and do anything more than bet the percentages. As far as diagnosis is concerned, I think we are approachÂ¬ing the time when the clinician may have more accurate diagnostic methods at his disposal, but I don't know exactly how accurate some of the new techniques are.
Consider, for example, the problem presented when a known agent, such as type A influenza, suddenly becomes prevalent in the community. Realizing that a large proportion of respiratory disease may be caused by this virus, it is possible, by means of recent techniques employing tagged antibodies, to investigate nasal smears taken from the patient and to see whether specific antigens can be demonstrated by flooding the smear with tagged antibody, washing and examining it with the fluorÂ¬escence microscope. This is not the sort of equipment that every pracÂ¬ticing physician has in his office, but it is certainly available on a fairly wide scale in health centers, teaching institutions, and commercial labÂ¬oratories. This technique is actually under investigation at the present time. Perhaps Dr. Hirst is in a position to say something about it.
DR. HIRST: As a matter of fact, I was going to look up the data on the fluorescence technique for virus in sputum. It can be done if you have the reagents and it permits a quick bedside etiologic diagnosis.
MODERATOR ROSE: In any event, it is along these lines, I suppose, that the physician will be given methods which eventually will eliminate some of the uncertainty that he now experiences when confronted by problems of this sort.
Kindly unwrap your crystal ball, Dr. Greenberg. Here is a question for you: Is the second wave of influenza in Japan caused by the same strain of virus and do you think that there is going to be a second out-break of influenza in the United States?
DR. GREENBERG: I suppose that the questioner means, are we going to have a second very severe outbreak which is much more severe than the present outbreak, with a great deal of mortality. I am inclined to doubt that. My reason is that here we had a virus which started to attack people in January in China and which has since affected millions and millions of people all over the globe. It has gone through any number of individuals and has arrived in the United States not any more virulent than it was in Hong Kong back in April or in China back in January. It is hard for me to believe that this virus will suddenly change its character in a few weeks and become extremely severe. That we may have more influenza or a slight rise in influenza in the next few months is possible. They have had it in Japan, another small wave, which is not as big as the wave before. We have had that experience in this country in at least two years. We had a wave of influenza and then a few months later another little wave. I don't think we shall have anything comÂ¬parable to the severity of the epidemics of 1918, 1919 or 1920.
MODERATOR ROSE: Here is a series of questions, all of which bear on the same topic. Immunization is recommended for "everybody". Would it be advisable to give vaccine to very young infants? At what age would you start? What is the present policy in immunizing children under one year? If a second wave is anticipated, is it advisable to immunize young children?
DR. GREENBERG: At the beginning of the program of immunization when there was only a small amount of vaccine available, many pedia-tricians who had small amounts on hand gave this to infants of only two or three months of age and to children of older age. We questioned quite a number of these physicians and we found that the reactions in the small infants were very severe. One physician had immunized 30 infants and had 50 per cent reaction. When I say "reaction" I mean that these children had temperatures of 103, 104, 105. There were at least five infants who had convulsions. One of these was the child of a doctor, who had had only 0.05 ml. intradermally. In the older children there were not many reactions.
DR. KILBOURNE: All intradermal injections?
DR. GREENBERG: All intradermal. In view of the fact that the morÂ¬tality from the disease in the young infant must be very low””as I indiÂ¬cated to you, in our 157 deaths in October we did not have a single one under one year””and the fact that there were very few in children under five years of age, I question the advisability of giving vaccine to young infants. The mortality in the children, even up to 10 and 15, is not high. My own preference would be to give the vaccine primarily to old people, particularly those with chronic heart disease, to pregnant women, to individuals with rheumatic heart disease and perhaps to other adults. I question its value for young children and whether it is worth the risk of giving it to small infants.
The American Academy of Pediatrics has recommended that vaccine be given to infants from three months to five years of age, 0.1 ml. intra-dermally repeated in two weeks; from 5 years to 13 years of age, 0.5 ml. repeated in two weeks; for older children, 1 ml. in a single dose, subcutaneously.
MODERATOR ROSE: Dr. Hirst, does vaccine confer a greater immunity than an actual attack of influenza?
DR. HIRST: As far as we can judge it must be about the same. The antibody rise one gets with infection and vaccination can be roughly the same. It depends upon how much vaccine is given. One can readily induce a circulating rise of about the same magnitude. This is the only measure we have of the immunity. It may not be the complete answer.
MODERATOR ROSE: What was the cause of the difficulty in distributÂ¬ing the vaccine? I think we must qualify this question. Actually, conÂ¬sidering the problems that were encountered in manufacture and disÂ¬tribution, a fairly good job was done.
Here is an interesting question, Dr. Kilbourne: What neurologic complications are being seen in the present epidemic? What is the prog-nosis when they occur?
DR. KILBOURNE: Thanks a lot, iMr. Chairman! You know as much or more about this than I do, because I think both of our experiences are derived from the same recent talks in Chicago. We have seen locally”” and Dr. Rogers can tell us more about it if he wishes””only one case where we felt that there were any real neurotoxic complications during a syndrome of clinical influenza. It has been a purported problem of the 1918 outbreak which was never established as being solidly related to influenza. There have been associations of various neurologic syndromes with clinical influenza, which apparently have been well documented, that is, the influenza has been well documented. I think all of the cases are as yet inadequately studied with respect to trying to exclude known neurotropic viruses; with so many known neurotropic viruses, that is a formidable problem. With modern techniques it will be of great interest to determine whether neurologic sequelae are really related to influenza.
As Dr. Hirst can tell better than I, there is evidence that some strains of influenza in the laboratory can undergo a mutation to the neurotoxic form. It is conceivable that the virus actually is related to some of these complications.
MODERATOR ROSE: This is along the same line. Dr. Helpern, did any of the patients who died of influenza have evidence of encephalitis?
DR. HELPERN: In one of these cases there were a few petechial hemor-rhages in the floor of the fourth ventricle. There were not any diffuse lesions, in the cases we saw, to suggest later development of sequelae in the event of survival.
MODERATOR ROSE: Like the referee at the football game, I shall now inform the team that the two minute mark has been reached. After that period of time this session will be brought to a close. Meanwhile, we shall cover as many questions as we can. There are a number which deal with the use of antibiotics in the management of uncomplicated influenza. I think that Dr. Fisk has covered that fairly well. Here is one question, however, which has to do with the use of antibiotics in the management of uncomplicated influenza in patients with chronic pul-monary disease, and this presents a special problem.
DR. FISK: Because of the fact that individuals with chronic pulmonary disease harbor many bacteria in their lungs which may be activated by an attack of influenza, it is felt that these individuals should be treated with a broad-spectrum antibiotic to tide them over their period of infection.
MODERATOR ROSE: Dr. Hirst, is there any evidence of antigenic varia-tion among strains of virus during the current epidemic?
DR. HIRST: Not so far. I believe if you will look carefully you will find it, though.
MODERATOR ROSE: We have at least ten questions concerning the efficacy of vaccine given intradermally in a dose of 0.1 ml. to adults. This point has been discussed by Dr. Kilbourne. I believe I said someÂ¬thing about it myself. Dr. Kilbourne has evidence that the antibody responses as measured by hemagglutinin inhibition following administraÂ¬tion of two doses of 0.1 ml. subcutaneously are equivalent to the reÂ¬sponses of 0.5 or 1.0 ml. subcutaneously. However, so far as we can determine from studies in the field, there is evidence that adults get rather better protection from the larger dose of vaccine. This is hardly surprising, because it is a well-known immunologic fact that antibody response is usually related to antigenic mass; also, the character of antiÂ¬genic response may be related to the periodicity and route of administraÂ¬tion of antigen, although the route is generally least important. It is of interest in this connection, as I have already pointed out, that the vaccine has been increased in potency to 400 CCA units per ml., which fact of itself indirectly answers the question about intradermal inoculation.
DR. KILBOURNE: I think it might be re-emphasized that, in my opinion, studies of the intradermal situation itself would suggest that the im-portance is not the route but the spacing of multiple injections.
DR. HIRST: It is easy to get some very confusing information on that point. Was your increased response obtained with the spacing of one week with the doses?
DR. KILBOURNE: That is right.
DR. HIRST: I have seen data where inoculation repeated in three to four weeks was without any added response from the second one. Then in a study done by Meikeljohn, where the spacing was six weeks, there was a distinct added effect. So the whole question of double dosage in the absence of any antibody in the population is one which is more or less wide open at the moment and is perhaps more complicated than we might be led to believe from seeing one or two isolated results.
DR. KILBOURNE: I would agree, Dr. Hirst. The only point I was makÂ¬ing was that o. 1 ml. given twice subcutaneously, is apparently as good as the same amount given by the intradermal route. From the limited reports published regarding results of injection via the intradermal route, it would appear that the appropriate control of giving the same dose of virus twice by the subcutaneous route was not followed; where it was followed, indications are that it proved as effective as injection into the skin.
MODERATOR ROSE: I think we have come to the end of our proceed-ings. I am sorry that we have not been able to answer all the questions which were submitted. For the most part they have been extremely interesting questions and I wish to thank the audience for its participa-tion.