CHAPTER IV
Influenza
Thomas Francis, Jr., M. D.
EPIDEMIOLOGY
Influenza as a Military Problem
The long history of influenza does not indicate a close association between its epidemic occurrences and major military undertakings. Because of the frequency of both phenomena, however, it is to be expected that they may at times coincide. The appalling pandemic of 1918 in the last months of the exhausting conflict of World War I, with massive mobilization of armies and upheaval of civilian populations, has irrevocably linked those two catastrophes. It demonstrated that virulent influenza may be more devastating of human life than war itself. Jordan2 has estimated that, in a few months, 20 million people perished; 548,000 in the United States alone; the number attacked was 50 times as great. Among the military personnel of the United States there was "an estimated total of 24,853 deaths from influenza as recorded, 469 from bronchitis, 10,341 from brochopneumonia, and 11,329 from lobar pneumonia, a grand total of 46,992. This is nearly as large a total as that of the battle deaths, American Expeditionary Forces--- 50,385." These deaths occurred among approximately "797,993 cases of influenza, 272,735 of bronchitis, 37,334 of bronchopneumonia, and 51,115 of lobar pneumonia, a total of 1,159,177 cases of respiratory diseases." 3 About 1 out of every 5 men contracted influenza in the service.???
Many students of the disease have sought to explain the factors responsible for the enormity of that devastation. The clinical, pathologic, epidemiologic, and bacteriologic data have been voluminously recorded.4 It has in many quarters been accepted as the prototype of pandemic influenza, an unwarrantable conclusion since this most exceptional episode in the history of the disease
1 The author is greatly indebted to Col. John D. Morley, MC, USA (Ret.), Resident Lecturer, Department of Epidemiology, School of Public Health, University of Michigan, who gave extensive assistance in reviewing material and in the preparation of the graphs and tables dealing with incidence.
2 Jordan, E. O.: Epidemic Influenza: A Survey. Chicago: American Medical Association, 1927.
3 The Medical Department of the United States Army in the World War. Washington: U. S. Government Printing office, 1928, vol. IX, pp. 67-68.
4 (1) Thomson,D., and Thomson, R.: Influenza, With Special Reference to the PartPlayed by Pfeiffer's Bacillus,Streptococci, Pneumococci, etc., and the Virus Theory. Monograph 16,pt. II. Ann. Pickett-Thomson Research Lab. 9: 1-640, November 1933. (2)Thomson, D., and Thomson, R.: Influenza, With Special Reference to theComplications and Sequelae, Bacteriology of Influenzal Pneumonia,Pathology, Epidemiological Data, Preventionand Treatment. Monograph 16, pt.II. Ann. Pickett-Thomson Research Lab. 10: 641-1477, May 1934.
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cannot be considered typical. Among other criteria suggested as beingcharacteristic ofpandemic influenza in contrast to that of interpandemic years are (1) acycle of approximately 30years; (2) the tendency for there to be three waves, the first a mildwidespread disease, thesecond a severe autumnal epidemic with high fatality, the third oflower incidence but highfatality and less constant in occurrence; (3) a greater independence ofseason; (4) greater andmore rapid dispersion; (5) a greater influence upon general mortality;and (6) a different agedistribution so that the incidence in old people is less than that inthe younger, especially middleage, groups. In many respects, these epidemiological generalizationshave few supporting dataother than those of 1918, and most of the other criteria appear tomeasure severity of the disease.Confronted with this vast occurrence and the lack of adequateinformation as to the nature of thecausative agent, interpretations of the conditions responsible for the1918 pandemic haveinevitably considered the dislocations and crowding of populations bywartime conditions to beessential elements in the development irrespective of the biologiccharacteristics of the microbialagent involved.???
In the latter case, the various bacterial pathogens of the respiratory tract were extensively studied and Hemophilus influenzae, while considered an important contributor to severe disease, was not believed to meet the requirements of the specific inciting agent of the, epidemic. Realization of the role of beta hemolytic streptococci and of staphylococci in severe pulmonary disease. was heightened. But beyond these was a progressive development of the idea that a highly virulent virus was involved, and a number of studies were made in efforts to demonstrate its presence. No conclusive or consistent results were obtained, even from the intensive efforts of Rosenau and others,5 to transmit the disease to human volunteers. It is interesting and surprising that apparently no material from patients was kept which could be subjected to later study for virus. Nevertheless, it seems probable that the autumnal epidemic of 1918 was initiated by a virus of high virulence in association with a high prevalence of potent bacterial pathogens. It is unlikely that this inciting agent was one with which the general population was completely inexperienced because all evidence emphasizes that the greatest proportion of the population did not take sick, indicating a resistance acquired earlier. Moreover, the fundamental characteristics of the disease clearly suggest that it was of similar behavior to influenza known before and since that time. As later data will make clear, the etiologic identity of the "waves" cannot be unreservedly assumed. Thomson and Thomson indicated that units affected in the spring prevalence were relatively resistant in the fall, although "seasoning" as such did not prevent infection since veterans and recruits were attacked in the autumn in organizations which had escaped the spring experience.
5 Rosenau, M. J., Keegan, w. J., Goldberger, J., and Lake, G. C.: Experiments Upon Volunteers to Determine the Cause and Mode of Spread of Influenza, Boston, November and December 1918. U. S. Pub. Health Serv. Hyg. Lab. Bull. 123: 5- 41, February 1921.
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The relativehelplessness with which prevention or treatment could be approached isapparent.Apart from the possible use of antipneumococcal serum in a limitedfashion for treatment ofspecific cases, treatment was essentially palliative. A few studieswere concerned with the useof convalescent serum. In the main, however, prompt bed rest, quiet,and simplified diet wererelied upon. The handling of empyemas was revolutionized. In someinstances, an intelligenteffort was made to limit the opportunity for transmission of pathogensby segregating, forexample, those with streptococcal infections from others. Along withthese went efforts toprevent or reduce crowding by increasing space per man in barracks andin transportation and byavoiding congregations. The hygiene of housing and of person, togetherwith isolation andquarantine, were the armamentarium of prevention.
Experience during World War I
During the period of World War I and the pandemic ofinfluenza, one of the important agenciesutilized in the campaign against respiratory diseases was the PneumoniaBoard, appointed in1918, at the request of The Surgeon General, by War DepartmentSpecial Order No. 118, 20May 1918. Composed of civilian and military experts in the field ofrespiratory and otherinfectious diseases, this board rendered advisory services andorganized and directedinvestigations at posts, camps, and hospitals. The Pneumonia Board wasa forerunner of theBoard for the Investigation and Control of Influenza and Other EpidemicDiseases in the Armywhich was established in 1941 through the initiative of the PreventiveMedicine Service, Officeof the Surgeon General.6 The latterbecame known as the Army Epidemiological Board (p.94).
Influenza is notespecially a disease of wartime. However, conditions of mobilization,masstransportation, and crowding furnished a medium for the rapid spreadand accentuation inseverity of the disease. Because the microbial agents may be prevalenton a post or may becomewidely disseminated by transfer of personnel, influenza is a disease ofgreat hazard to militaryeffectiveness. Under these conditions, it appears that the militaryforces may sufferdisproportionately iii comparison with civilian populations.
With this perspective, the onset of another war inevitably recalled the specter of 1918 and the possibility that the development of similar or greater concentrations of population would again result in epidemiologic conditions which would heighten the severity of influenza to a catastrophic level. Influenza after 1918 had reverted to its normal behavior of recurrent epidemics at intervals of a few years, varying in distribution and severity but commonly mild. This increased the tendency to conclude that interpandemic influenza was a different disease and that influenza was in fact a clinical syndrome rather than a disease entity.
6Bayne-Jones, S.: Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army. Army M. Bull. 64: 1-22, October 1942.
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Experiencein 1919-39
Between 1919 and1939, 12 epidemics of influenza were recorded 7 by theUnited States PublicHealth Service on the basis of excessive mortality accompanying sharpepidemic waves of acuterespiratory disease. The most prominent were those of 1919-20, 1922-23,1925-26, 1928-29,1932-33, and 1936-37, but others such as 1935-36 were widespread. Thatthey were notinconsiderable is indicated by the fact that the estimated excessmortality from influenza andpneumonia in the 1919-20 epidemic was 100,000 and, in 1928-29, 50,000.Most of theremainder exhibited sharp peaks but were less widely distributed. Adefinite decline inpneumonia mortality began about 1929 and continued except for a rise inthe epidemic period of1935-37. Consequently, the scope of epidemics based upon excessmortality is less clearlydemonstrated after 1930. A second interpretation for this alterationcould be offered; namely,that the agent or agents of 1918 continued in prevalence through the1928-29 epidemic and werereplaced by milder strains thereafter. Nevertheless, the 1937 periodhad a sharp increase inmortality.
The experience of the Army during the interval between the two World Wars was not significantly different from that of the civilian population, and the mortality rates were extremely low. The small strength, furthermore, would give little meaning to an organizational rate except as it reflected general experience. In the annual reports of The Surgeon General, United States Army, for 1929 and 1930, it was pointed out that since 1920 there had been only the mild epidemic of influenza in 1926 until 1928 when "there occurred a more serious and generally distributed epidemic * * *. A comparatively large percentage of the strength of the Army was affected * * *. "In December of 1928, a rate was reached of 523 per 1,000 white enlisted men in the United States; in January 1929, the rate was 336. The annual admission rates are less informative, since they bisect the epidemic, but that of 81.7 per 1,000 for 1928 is the highest of the decade 1920-29. The rates for pneumonia and common respiratory disease during these years were also among the highest for the decade. The death rate from pneumonia and influenza was, however, not proportionately elevated.
Special attentionis called to a year such as 1936 when, in certain regions among thecivilianpopulation, influenza reached the level of sharp epidemics during theearly months; then inDecember the peak of the 1936-37 pandemic spread was rapidlyapproached. The first wasinfluenza B, the second influenza A.8The latter was worldwide and typically influenzal.Moreover, it was
7 (1) Collins, S. D.: Influenza-Pneumonia Mortality in a Group of About 95 Cities in the United States, 1920-29.Pub.Health Rep. 45:361-406, 21 Feb. 1930. (2) Collins, S. D., and Gover, M.: Influenza and Pneumonia Mortality in a Group of About 95 Cities in the United States During Four Minor Epidemics, 1930-35, With a Summary for 1920-35.Pub. Health Rep. 50:1.668-1689, 29 Nov. 1935. (3) Gover, M.: Influenza and Pneumonia Mortality in a Group of 90 Cities in the United States, August 1935-March 1943. With a Summary for August 1920-March 1943. Pub. Health Rep. 58. 1033-1061, 9 July 1943. (4) Collins, S. D.: Age and Sex Incidence of Influenza in the Epidemic of 1943-44, With Comparative Data for Preceding Outbreaks.Pub. Health Rep. 59: 1483-1503, 17 Nov. 1944. (5) Collins, S. D.: Influenza and Pneumonia Excess Mortality at Specific Ages in the Epidemic 1943-44, With Comparative Data for Preceding Epidemics. Pub. Health Rep. 60: 821-835, 20 July; 853-863, 27 July 1945.
8 Francis, T.,Jr.: Epidemiological Studies in Influenza. Am. J. Pub.Health 27: 211-225, March 1937.
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identified etiologically in manyparts of the world. Among white enlisted men in the Army in theUnited States, the admission rate for 1937 rose to 50.1 per 1,000average strength, but seasonaldata are not available. There is evidence, nevertheless, that the1936-37 epidemic was sharplyexpressed in the Army, although no significant increase in mortalityoccurred. In 1938-39, a mildprevalence of a spotty nature was present (charts 12 and 13).
Influenza, then,in the 20 years since 1919 had returned to its former status ofrecurrentepidemics at short intervals, often so mild as to be unnoticed but withcertain episodes ofpandemic distribution and of sufficient severity to cause considerablealarm and disturbance inthe general population. That it was a disease of potential severity wasclearly apparent since eventhe mild prevalences tended to cause a heightened mortality fromrespiratory disease. The excessmortality remained a valuable index of the spread and severity ofepidemics and even of theirrecognition. Reports based upon clinical diagnosis were, as always,unreliable since manyfactors, including publicity or special instructions, had a largeinfluence in this respect. Armydata show this effect clearly, as will be illustrated later, in thelack of reports of influenza fromsome areas when an epidemic was known to be occurring, or high reportsof influenza inprevalences of acute respiratory disease known not to be identifiableas influenza. However, inmost instances, the character of the epidemic curve and thedistribution among troops of abruptrapid epidemics of nonbacterial acute respiratory disease readilysuggest its nature. Theoccurrence of the disease and the factors which govern it remainedessentially unaffected at theonset of World War II.
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EpidemicInfluenza, 1940-45
Experiencein 1940
The Army began itsexpansion program in 1940, and the draft was adopted. The increase instrength began slowly in June, then rapidly in October, November, andDecember. This and theindustrial program brought together a large number of individuals fromdiversified areas underconditions furnishing ready opportunity for the rapid spread ofrespiratory infections. However,in general, the health of the Army and the United States during thisperiod was excellent.
Early in 1940, a limited epidemic of mild influenza occurred, first in the Southeastern States and shortly afterward in New York. This was the out break from which influenza virus, type B, was first isolated.9 In the civilian population, it was said to be limited to the eastern part of the United States, but serologic data demonstrated it to be more widely dispersed.10 The admission rates for influenza in the Army show a moderate rise in the Third, Fourth, and Fifth Corps Areas during the months of January and February. In general, the United States Army within the continental limits had a low incidence of influenza for the first half of the year as compared with the previous
9 Francis, T., Jr.: A New Type of Virus From Epidemic Influenza .Science 92: 405-408, 1 Nov. 1940.
10 Seefootnote 7 (3), p. 88.
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5-year average. The admission ratefor common respiratory diseases for the same period,however, was in general higher than the 5-year average. Influenza B wasrecognized in southernEngland,11 and, in the summer of 1940, itwas prevalent in Cuba.12 Therecognition of this diseaseand means for identification were extremely important for properunderstanding of the problem.
In June and July1940, well-marked epidemics of influenza A occurred in Cuba and PuertoRico.There was a sharp rise in the admission rate to 126.4 for influenzaamong the Puerto Ricantroops in June followed by a moderate rise to 93.9 in July among thecontinental troops stationedon the island, but in August no cases were reported.
At this same time, an epidemic of mild influenza was reported from Argentina.13 This outbreak reached its peak in the Argentine Navy in the week ending 21 July 1940, in the Army during the following week, and in the civilian population in the week ending 4 August.
In August, theadmission rates for influenza showed a sudden rise in the PhilippineIslands. Theincidence during the month was twice as high among Filipino troops asthat reported for UnitedStates troops stationed there. Unfortunately, the data for admissionsin the overseas departmentsare not available for the remaining months of 1940 (September toDecember).
During 1940 in Australia, especially in military camps, extensive epidemics of pharyngitis and tracheitis occurred. Influenza was not isolated until September when more typical cases occurred in a military camp and in a small hospital outbreak.14
Influenza wasnoted in Hawaii in themiddle of September 1940 and declared epidemic on 26September. Reporting was then made mandatory until 31 December.Approximately 16,500cases were reported. The majority of these were from the island ofOahu, including Honolulu. The epidemic peaked sharply during the middleof October. Doolittle 15 stated theimpressionthat the disease came from the West and suggested that it wasintroduced by a Japanese trainingship from the Japanese Mandated Islands where an epidemic wasprevalent. The influenzaincidence among white enlisted troops stationed in Hawaii during 1940was 65.3 per 1,000average strength per year. The highest incidence for white enlistedmelt for the year wasreported in the United States (77.6) with Hawaii in second place.
In November 1940, the admission rates for influenza in the Ninth Corps Area showed a sharp rise which reached its peak in the 4-week period of
11 Andrewes, C. H., Glover, R. E-, Lush, D., Hudson, N. P., and Stuart-Harris, C. H.: Influenza in England in 1940-41.Lancet 2: 387-389, 4 Oct. 1941.
12 Lennette,E. H., Rickard, E. R., Hirst, G. K., and Horsfall, F. L.: The DiverseEtiology of Epidemic Influenza.Pub. Health Rep. 56: 1777-1788, 5 Sept. 1941.
13 Sordelli,A., Taylor, R. M., and Parodi, A. S.: Estudio de los virus de laepidemia de influenzao currida on laArgeninga durante el a?o 1940. Rev. d. Inst. bact, Buenos Aires 10:265-274, December 1941.
14 (1) Rudd, G. V.: Influenza Epidemic atPuckapunyal. M. J. Australia 1: 7-9, 4 Jan. 1941. (2) Burnet, F.M., andFoley, M.: Two Methods for the Detection of Influenza Virus in HumanThroat Washings Without the Use ofFerrets. M. J. Australia 1: 68-72, 18 Jan. 1941.
15 Doolittle, S. E.:Clinical Observations During the 1940 Epidemic ofInfluenza in Honolulu. Proc. Staff Meet.Clin., Honolulu 7: 1-8, March 1941.
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December. During this same period,the Fifth Corps Area had a very high incidence (1,444 per1,000 per annum based on the 4-week period). The Eighth Corps Area alsorecorded its highestrates during December. The other six corps areas reached their highestincidence during the 5-week period of January 1941. The First, Second,and Sixth Corps Areas lead a relatively lownumber of cases of diagnosed influenza (below 200 cases per 1,000 perannum in the highestperiod), although definite epidemic peaks were attained. The rate ofadmissions in white enlistedmen in the United States was 77.6 for 1940, which was approximatelyfour times that for 1939,20.3. Admissions for common respiratory disease in each corps area,except the Fifth CorpsArea, showed a sharp rise coincident with the rise in influenza. Theincidence of these diseasesremained generally high until March in contrast with the much morerapid subsidence ofinfluenza. The combined annual rate for common respiratory diseases andinfluenza was nearly1,200 for the entire Army in the United States for 1940-41 (chart 14).
A widespread epidemic of influenza occurred in the civilian population at the same time.16 The notable feature of this outbreak was the rapidity of spread from the Pacific Coast eastward throughout the United States and Canada. The peak of incidence in the Pacific Coast States was reached in mid-December. The West South Central and Mountain States reached their peak in late December or the first week in January, the East South Central and South Atlantic States the second week in January, and the East North Central and Middle Atlantic States during the third week of January. However, the New England States reached their peak during the second week in January. The spread of the disease as shown in the Metropolitan Life Insurance Company survey 17 seemed to follow three main paths: (1) The southernmost route across the Southern and Gulf States spread most rapidly and showed the most ordered progress; (2) the path across the middle of the country was not quite as rapid; (3) the northernmost route showed the slowest rate. The peak of the incidence in South Dakota was in early February and in Iowa and Wisconsin in mid-February. As the admission rates for the Army are given for 4- or 5-week periods, no such orderly progress of the disease was discernible.
Clinically thedisease was a mild acute febrile illness with abrupt onset associatedwith mildmyalgia, some lassitude, but little prostration. Complications wererare. Of 19,609 casesoccurring among Army personnel in the United States, 57 developedpneumonia. Only 1 deathfrom influenza was reported in the Army for 1940 and only 3 deaths fromacute primarypneumonia.
16(1) See footnote 7 (4) and (5),p. 88. (2) Brown, J. W., Eaton, M. D., Meiklejohn, 0..;Lagen, J. B., and Kerr, W.J.: An Epidemic of Influenza. Results of Prophylactic Inoculation of aComplex Influenza A-Distemper Vaccine. J.Clin. Investigation 20: 663-669, November 1941. (3) Sulkin, S.E., Bredeck, J. F., and Douglass, D. D.: EpidemicInfluenza: Epidemiological, Clinical, and Laboratory Aspects of the1940-41 Outbreak in St. Louis. Am. J. Pub.Health 32: 374-380, April 1942.(4) Pearson, H. E., Eppinger, E. C.,Dingle, J. H., and Enders. J. F.: A Study ofInfluenza in Boston During the Winter of 1940-41. New England J. Med.225: 763-770, 13 Nov. 1941.
17 TheCourse of the Recent Influenza Epidemic Statist. Bull. Metrop. LifeInsur. Co. 22 (No. 4): 3-6, April 1941.
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The excessmortality recorded in thecivilian population was slight, but, according to therecorded rates of the Army in the continental United States, this wasthe highest epidemic of thewar period.
It was during this explosive outbreak of influenza that the planning and guidance exercised by the reorganized Preventive Medicine Service, Office of the Surgeon General, under the immediate direction of Lt. Col. (later Brig. Gen.) James S. Simmons, MC, resulted in the development of a new and powerful means for combating infectious diseases in the Army. Since the start of World War II in Europe in 1939, followed by the expansion of the Army, the Preventive Medicine Service had seen the necessity for preparing in advance for dealing with new and large problems. It was foreseen that there would be urgent need for the services of the best civilian specialists in the field of infectious diseases. The Pneumonia Board of 1918, previously mentioned, was recalled as an example of the kind of organization that would be needed. Proceeding along these lines, Colonel Simmons drew up a plan for a greatly enlarged and strengthened civilian body of this type and, on 27 December 1940, recommended to The Surgeon General that the plan be forwarded to The Adjutant General for approval. This was done the same day by Maj. Gen. James C. Magee, The Surgeon General, and, on 11 January 1941 by order of the Secretary of War, the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army was established. Within a a few months, a number of civilian commissions on various infectious diseases were formed, and the Commission on Influenza was one of the first to be established. The Board and its commissions were attached to, and administered by, the Preventive Medicine Service, Office of the Surgeon General.
Experience in 1941-42
During theremainder of the year 1941, the admissions for influenza and the commonrespiratorydiseases followed the usual seasonal pattern and fell to the lowestlevel in July. However, theincidence of acute respiratory disease during the summer seasonremained higher than theaverage for the preceding decade.
With the onset of open hostilities in December 1941, the mobilization for war was tremendously increased. The very rapid induction of men when housing facilities were inadequate caused definite overcrowding. It was necessary to reduce the floor space per man in barracks from 50 to 40 square feet, and a considerable proportion of troops were housed in tents. Such Housing conditions undoubtedly contributed to the moderately high admission rates for acute respiratory disease in the winter of 1941-42, but no epidemic of influenza was encountered.
Experience in 1942-43
In the summer of 1942, the military forces were still increasing rapidly. New groups of recruits were constantly entering camp, troop movements were
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continuous, and the expansionfrequently resulted in overcrowding on trains and in barracks,especially in induction and training centers. There was at the sametime a migration of civiliansinto overcrowded industrial centers. In keeping with the recurrence ofinfluenza A every otheryear since 1932, 1942-43 was scheduled for an epidemic with conditionsin the populationapparently favorable to the disease. Studies of vaccination were linkedto this premise, and closeobservation was maintained. Influenza A was epidemic in Australia inMay 1942, 18 butelsewhere the disease did not appear in significant amount, and in theUnited States it was notfound.
On the other hand, noninfluenzal acute respiratory diseases and atypical pneumonia rose to epidemic heights and maintained a high level throughout the season when respiratory diseases were expected to occur. In the continental United States, a peak of 530 per 1,000 per annum for January 1943 slowly receded over several months. The disease was particularly prominent in recruits and in other epidemiologic characteristics differed from the usual epidemics or influenza.
Experience in 1943-44
Although influenzawas inconspicuous during the preceding winter, each succeeding seasoncarried the possibility of a severe epidemic which, with crucialoperations mounting in manyparts of the world, might be critical. Advance information wasdesirable. The virus laboratoriesof the Commission oil Influenza of the Army Epidemiological Board werestill alert in variousareas, and the continued high incidence of respiratory disease held theattention of all medicalagencies. Commission investigators identified influenza B widely butlargely subclinically intwo institutions in Michigan during March and April; two cases of typeA were also found.Sporadic cases of type B were also detected at Fort Custer, Mich., andamong students at theUniversity of Michigan.19 A smallamount of influenza B was identified in Australia .20
In May, threesporadic cases of influenza A were identified at Fort Custer, and viruswasisolated.21 Serologic examination demonstrated that alimited outbreak inApril among interns in aNew York hospital was influenza A and Eaton detected five cases ofinfluenza A among studentsat the University of California in April and isolated a strain ofvirus. Here were strikingevidences of a scattered low-grade circulation of influenza withoutepidemic conditions. Epidemic influenza in July was reported in Hawaiibut not iden-
18 Burnet, F. M., Beveridge, W.I.B., Bull, D. R., and Clark, E.; Investigations of an Influenza Epidemic in Military Camps in Victoria, May 1942. M. J. Australia 2: 371-376, 24 Oct. 1942.
19 Salk, J. E.,Pearson, H. E., Brown, P. N., Smyth, C. J., and Francis,T., Jr.: Immunization Against Influenza WithObservations During an Epidemic of Influenza A One Year AfterVaccination. Am. J. Hyg. 42: ;107-322, November1945.
20 Beveridge, W.I.B.,and Williams, S. E.: Sporadic Occurrence of Influenza in VictoriaDuring 1943. M. J.Australia 2: 77-80, 22 July 1944.
21 Francis, T., Jr.: TheDevelopment of the 1943 Vaccination Study of the Commission onInfluenza. Am. J. Hyg.42: 1-11, July 1945,
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tified by type. Scattered flurries inmilitary camps were observed in Canada.22 In the late springand summer, limited scattered bursts of influenza A were identified inBritish civilians; 23 inAugust a localized unidentified epidemic occurred among United Statestroops in Southern BaseSection. Much of the foreign information was only known throughsubsequent publication orthrough informal channels.
The possibility was recognized that these episodes might be the forerunner, or first wave, of a serious autumnal experience. With plans for evaluation of vaccine by the Commission on Influenza actively proceeding, the new strain of virus was incorporated in the vaccine; the continuous lookout for influenza was enlarged to include a greater number of listening posts maintained by Commission members throughout the nine service commands; and a formal arrangement for reporting was concluded. Samplings of throat washings and blood were obtained at intervals from patients with upper respiratory disease even though the diseases did not resemble influenza clinically. The results from each observation post were communicated to each of the others and to the Preventive Medicine Service, Office of the Surgeon General, at biweekly intervals.
On 17 and 18November 1943, several patients presenting a picture which resembledinfluenzawere observed in the ASTP (Army Specialized Training Program) unit atthe University ofMichigan. Throat washings given to ferrets elicited a typical reaction,and transfer of ferretmaterial to eggs permitted identification of influenza virus, type A.On 22 November, Dr. E. R.Rickard in St. Louis, Mo., reported that between 11 and 18 Novemberwhat appeared to be anepidemic of influenza had occurred in the ASTP unit at St. LouisUniversity, involving 100 outof 550 men. He also reported that in one of the groups underobservation at the University ofMinnesota at Minneapolis, a sudden outburst of 20 cases had occurred on21 November. Type Ainfluenza virus was identified by direct inoculation of throat washingsinto the allantoic sac ofeggs. All other investigating groups were notified that influenza A hadbeen identified in boththe Sixth and Seventh Service Commands.
Word was received from Lt. Col. F. B. Lusk, MC, Chief, Medical Service, Station Hospital, Fort Custer, on 15 November 1943, that a sharp increase of febrile respiratory disease had taken place. Material obtained from patients becoming ill there during the next week demonstrated that almost all of these patients had influenza A. After this time the spread of the disease was rapid, and subsequent reports from Commission members indicated that, within 7 to 10 days, cases had begun to appear over a great part of the United States.
From July 1943 to the week ending 6 November 1943, the weekly rates for influenza and common cold for the entire Army in the continental United
22 Hare, R., Hamilton, J., andFeasby, W. R.: Influenza and Similar Respiratory Infections in aMilitary Camp over aPeriod of Three Years. Canad. J. Pub. Health 34: 453-464, October 1943.
23Andrewes, C. H.,and Glover, R. E.: The Influenza "A" Outbreak of October-December 1943.Lancet 2: 104-105, 22 July 1944.
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States had remained at a level ofapproximately 100 per 1,000 per annum and up to 30 Octoberin none of the service commands had rates reached 150.
In the week ending 6 November 1943, the first rises to levels greater than 150 were noted in the Sixth and Seventh Service Commands, to greater than 200 in the weeks ending 13 and 20 November, respectively; the two areas proceeded rapidly to reach their respective peaks of 1,279 and 1,050 the week ending 4 December (table 19). The first sharp increase recorded at posts in these commands was at Fort Custer where rates rose from 113 in the week ending 30 October to 441, 1,075, and 1,212 in the weeks of 6, 13, and 20 November, respectively. It was here, too, that influenza A was identified in May 1943. The First, Second, Third, and Fifth Service Commands reached heights of greater than 200 during the week ending 27 November and attained their peaks the week of 11 December. Rates in the Fourth, Eighth, and Ninth Service Commands, although giving evidence of increased prevalence of influenza, did not exceed 200 until the week of 4 December. The peaks in these three commands were considerably lower and later in their occurrence than elsewhere.
It is of interestto note that on 24 November, at which time the recorded figures givelittleindication of influenza in the Eighth Service Command, patients withinfluenza A wereidentified in the station hospital at Fort Custer. These men hadentrained 48 hours earlier inTexas (located in the Eighth
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Service Command) and lead remained in the troop train but became illbefore arrival at FortCuster.
The highest rates for the entire Army in the continental United States were 631 and 593 in the weeks of 11 and 18 December. By 7 January 1944, the epidemic period had practically ended in all areas, and the rate for the entire Army fell below that for the previous year but, due to the seasonal increase in upper respiratory infection of other etiology, in no command did the rate return to the level which had existed in early November. That the continued incidence was not due to influenza A is seen in the reports of the different investigators who, with the exception of those in California, considered the epidemic prevalence of cases to have ended before 1 January. Further support for this conclusion is found in the results of studies made in the respiratory wards at Fort Custer on 28 January 1944 when serologic tests in recent febrile respiratory admissions were all negative for influenza A although similar studies on 20 November and 27 December were almost uniformly positive. Precise information of the epidemic is largely derived from the Commission studies.24
In an analysis ofthe reported cases of influenza during the 1943-44 epidemic among thecivilianpopulation, Holland and Collies 25 found that the maximalincidence ofthe disease for thecountry as a whole occurred between 25 December 1943 and 4 January1944, 2 to 3 weeks laterthan that noted in the Army. They conclude that the 1943-44 epidemicwas larger than any since the period 1918-20" For a group of 90large cities, the excess mortality during the 11 weeks from 21 November1943 to 5 February 1944 was 50 per 100,00 population incomparison with 65 per 100,00 for the epideic of 1928-29 and 598 forthe pandemic of 1918-19. Comparable data are not available forthe 1936-37 epidemic, but a statement has been made that it wa smallerthan earlier outbreaks.
Collins 26 comparedthe results of house-to-house canvasses in Baltimore during the 1943-44epidemic with those in other communities during 12 other epidemicssince the beginning of 1918. He states, "considering actcualrates, the recorded incidence for all ages in the 1943-44 outbreak washigher than in any other epidemic since that of 1918-19; the incidenceamong children under 10 years of age approximated that in 1918-19, andthe incidence above 40
24 (1) Rickard, E.R., Thigpen, M., and Crowley, J.H.: Vaccination Against Influenzaat the University of Minnesota- Am. J. Hyg. 42: 12-20, July1945. (2) Hale, W. M., and McKee, A. P.: The Value ofInfluenza Vaccination When Done at the Beginning of an Epidemic.Am. J. Hyg. 42: 21-27, July 1945. (3) Eaton,M. D. , and Meiklejohn, G.: Vaccination Against Influenza:A Study in California During the Epidemic of 1943-44. Am. J. Hyg.42: 28-44, July 1945. (4) Hirst, G. K., Plummer, N., andFriedewald, W. F.: Human
ImmunityFollowing Vaccination With Formalinized Influenza Virus. Am. J.Hyg. 42: 45-56, July 1945. (5) Salk, J. E. Menke, W.J., Jr., and Francis T., Jr.: A Clinical Epidemiological andImmunological Evaluation of Vaccination Against Epidemi Influenza.Am. J. Hyg. 42: 57-93, July 1945. (6) Magill, T. P.Plummer, N., Smillie, W. G., and Sugg, J. Y.: An Evaluation ofVaccination Against Influenza. Am. J. Hyg. 42: 94-105, July 1945.
25 Holland,D. F., and Collins, S. D., TheInfluenza Epidemic of the Winter of 1943-44 in theUnited States: A Preliminary Summary. Pub. Health Rep.59. 1131-111, 1 Sept. 1944.
26 See footnote 7 (4), p. 88.
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years was greater than in 1918-19. The percentage of the total casesthat were complicatd bypneumonia in the 1943-44 epidemic was far below the figure for anyother epidemic for whichdata are available.' Nevertheless, the pneumonia rates among personsover 25 years of agecorrespond closely to those recorded in this age group during theepidemic of 1928-29.
The data from all sources indicate, then, an epidemic of high incidence making its earliest prominent appearance in the North Central States in the first half of November 1943, spreading rapidly to a peak in December, and then promptly declining to the seasonal level of respiratory disease, thereby occupying a total of approximately 6 weeks for the evident epidemic period. It is of interest that, in the Gulf, Southwestern and Pacific States, the onset was slower and the peak lower and later than in other parts of the country. The data indicated that in terms of incidence the outbreak was of major proportions but the complications and case fatality rates were low, although its effect on total mortality by virtue of the high incidence was greater than the case fatality rate would indicate.
In the entireArmy, only 8 deaths occurred among influenza patients and 290 deathsamongadmissions for pneumonia oter than primary atypical. Even a roughestimate of case fatalityrates is unreliable since reported and summarized data are inconsitent.Of the total 89,764 casesrecorded for the total Army in 1943, 69,840 were in the United Stateswith 5 deaths and a casefatality rate of 0.01 percent. In the European theater, 4,717 cases arerecorded with 1 death(table 20).
European Theater of Operations.-American troops in the European theater experienced an epidemic of influenza A in the fall of 1943, which reached its peak about 2 weeks earlier than in the United States. 27 After a suggestive rise in reported cases of acute respiratory disease in the last week of October and the first week of November, there was an extremely rapid incrase to maximum annual admission rates of 1,079 per 1,000 strength for the week 26 November 1943. The decline of the epidemic was as sharply marked as its rise. By the end of December, the rate was 387. Virus A was demonstrated to be present in each of the principal base sections by serologic studies. Influenza B was not found. The disease was described as mild and uncomplicated with an acute onset and lasting only a few days. Constitutional rather than local symptoms predominated. The outbreak was almost completely unassociated with an increase prevalence of primary and secondary penumonia. There were no death.
According to Gordon, admission rates for common respiratory diseases, including influenza, among Negro troops were much less than for white troops in the theater. The maximum rate for the two groups occurred during the week of 26 November 1943. The rate for white troops was 1, 129 and for Negro troops, 477.
27 Gordon, John E.: A Historyof Preventive Medicine in the European Theater of Operations, U.S.Army, 1941-45,vol. I. (Official record.)
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TABLE20.-Incidence ofinfluenzain the U.S. Army, by area and year, 1942-45
The civilianpopulation of the United Kingdom had a similary epidemic atapproximately thesame time.28 It differed from that of theUnited States Army principally in respect to mortality. The maximumnumber of 1,148 deaths from influenza was reported during the week of11December 1943. This was 2 weeks later than the peak for themilitary cases. The deaths werelargely among the older age group.
Other overseas theaters. -Alaska reported an explosive epidemic suggestive of influenza among military and civilian populations in the first 2 weeks of April 1943, and, again beginning on 21 December 1943, there was a sudden increase in the incidence of acute respiratory disease at Fort Greely, Alaska, which quickly reached a peak and subsided within 1 month. Small outposts were not involved. A total of 535 cases were admitted to hospital and 1,043 to quarters. Average duration of hospital and quarters stay was 5 and 4 days, respectively. The clinical description was 'typcal' of influenza. There was no recurrence and no deaths.
Dr. J. H. Dingle, a member of the Commission on Acute Respiratory Diseases, investigated a mild epidemic of influenza that occurred in Puerto
28 See footnote 23, p. 96.
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Rico in July 1943. It wasestimated that 500 cases occurred among the civilian population ofSan Juan. There was no pulmonary involvement. Troops in Saint Thomashad a small outbreakof approximately 50 cases.
During July and August, an epidemic of acute respiratory disease, probably influenza, occurred in the 65th Infantry Division (Puerto Rican Regiment) with 441 admissions. There were 452 cases among employees of the Panama Engineer Division. Cases were also reported in Camps Sabanita and Coiner, Canal Zone.
Hawaii reported anepidemic of mild influenza in late June and July.
In the Southwest Pacific and China-Burma-India theater no influenza outbreak were reported.
In the North African theater, especially in Italy, no evidence of influenza in significant amount was discerned.
Variations in behavior. -The commission on Influenza reported that differences in the behavior of the epidemic in adjacent units were clearly observed. For example, at the University of Minnesota, the incidence among the total study population was 5.9 percent, while in another group it was 38 percent. At the University of Michigan, a wide variation in involvement of different companies of the ASTP unit was observed, two companies having but a single hospitalized case each, while from another company not in the study 20 percent were hospitalized. The commission on Acute Respiratory Diseases had recorded a number of significant features. At Camp Mackall, N.C., the troops were all seasoned men with 6 months or more of training. The epidemic appeared in all parts of the camp in an explosive fashion with 64 percent of the admissions occurring in a period of 5 days. Approximately half the admissions in the 11th Airborne Division occurred among the artillerymen with a rate of 8.8 percent, which comprised less than one-fifth the total strength. Very low admission rates, approximately 1.0 percent, were observed among 2 of the 3 infantry regiments. It was thought that 'the explosiveness and short duration of the epidemic at Camp Mackall appear to be related to the environment and activities of the troops. There was marked crowding in the barracks; the inhabited area of the post was small; and all groops shared common transportation facilities.' At this camp, 29 cases of pneumococcal pneumonia, most of which were type I, occurred during the epidemic period with a rather prompt disappearance thereafter.
At Pope Field, Fort Bragg, N.C., a detachment of glider mechanics had sick men with them on arrival at the post. They were put into quarantine under crowded conditions and in 7 days had a total admission rate of 35 percent. The remainder of the units in adjacent barracks had no contact with the affected unit. Cases occurred over a month's time with a total admission rate of 5 percent. A contrasting episode was that of the 326th Glider infantry Regiment which arrived by train from the Midwest; a large number of admissions occurred in the first 2 days, but then the incidence dropped and remained low as they were moved into uncrowded barracks and field activities. No explosive outbreaks were seen at Fort Bragg in troops engaged in continuous
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field training. These reports emphasized, too, that at Fort Braggthe virus was repeatedlyintroduced by men who had acquired their infection in widely separatedareas of the country. This was also noted at Fort Custer where troopsarriving promptly from Texas were sickalthough the disease had not been recognized there.
Gordon refers to the unified experience of the 358th and 360th Engineer (GS) Regiments, old units which constituted a single military population. The epidemic began 8 November and reached the extremely high level of 6,111 per 1,000 per annum during the week of 26 November. The disease declined rapidly without fatality. This represents again the abrupt rapid involvement of seasoned troops with a mild disease. The apparent spread from unit to unit and the irregularity in incidence of adjacent units is illustrated in the following example from the European theater.
General Depot G-18of the Western Base Section had a strength of 5,737 men divided intoeight camps. The firstfive were situated near Sudbury, England, and Nos. 6, 7, and 8 were atEggerton, several miles away. On 3November, the first probable patient with influenza from C Company,131stQuartermaster Regiment (TRK), CampNo. 2, reported to the dispensary with headache, backache, prostration,and an elevated temperature. Within 12hours, the medical officer developed the same symptoms. The followingday 21 men of C Company were ill. On5 November cases began to develop in the 445th Engineer Base Company,on 7 November in 608th Engineer Light Equipment Company and on 8Novemberin the 887th Ordinance AmmunitionCompany. Altogether, Camp No. 2 with 837 men had 121 patients inhospital with influenza, practically all ofwhom developed the infection between the 4th and 11 of November andbelonged to one or other of the fourcompanies noted.
Camp No. 1 was located in the same vicinity as Comp No. 2, and shared the same dispensary. The outbreak in this camp extended over the same period. Of 849 men, 72 were admitted to hospital with influenza.
Camp No. 3,housing the 534th Quartermaster Service Battalion, a colored laborunit, had no known association withany other camp except for an exchange of labor with the 2d platoon of DCompany located at Camp No. 8. Theoutbreak of influenza began at Camp No. 3 on 14 November with thehospitalization of six men. The following dayso many new cases appeared that two empty barracks were converted intoa camp infirmary. During the period 14 to24 November, this unit had 111 cases of respiratory disease. Theinfection spread to 2d platoon, D Company atCamp No. 8 and 26 cases were reported between the 22d and 25th ofNovember. With the exception of this platoonthere were few cases of respiratory infection at Camp No. 8.
Camp 4, with 689 men, sent 15 to the hospital between 17 November and 25 November, and the daily sick call averaged about 15 which was only slightly higher than had held in October.
Camp 5, an Air Corps Depot having little association with other camps, had no cases of influenza.
Camps 6 and 7, located several miles from the other camps, likewise had very few cases of respiratory disease.
It is clearly demonstrated that respiratory disease spread rapidly from one group to another within an incubation period of about 24 to 48 hours. Association of groups was a much more important factor than kind of work or type of quarters.
It was recognized from the start that the epidemic disease affected recruits and seasoned men alike. In fact, at many posts this feature was
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emphasized to differentiate betweeninfluenza and the acute respiratory disease which waspreponderant in recruits. At Fort Bragg, it was precisely observed thatthe incidence of influenzaA was not different among the two classes of men living undercomparable conditions. Thismay well be indicative of the fact that infection with influenza is nota year-in, year-out processbut one which takes place primarily in epidemic periods; alternativelyit may also be interpretedto demonstrate that immunity is not durable or that strain variation isinvolved.
As previously mentioned, in the European theater the peak incidence of influenza in Negro troops was less than half that in white troops. No other data of this nature are available.
In reviewing thevariations that were encountered, it becomes increasingly convincingthat, apartfrom the need for exposure of susceptibles to disease, the mostimportant factor in determiningthe behavior of epidemic influenza within limited units is that ofcrowding, particularly when ahigh rate of change in the population exists.
A few instances are recorded of the epidemic moving into units in which beta hemolytic streptococcal infection was prevalent.29 The incidence of respiratory diseases was highest thoughout the epidemic in the Seventh Service Command, where streptococcal disease was highly prevalent. There was in these areas, however, no evidence that the bacterial invasion was accentuated by influenza as was clearly the case in 1918. Coburn 30 has indicated that influenza had a definite influence upon the behavior of streptococcal infection in naval units, and, at the United States Naval Training Center at Farragut, Idaho, the occurrence of influenza was clearly related to an exaggeration in spread and severity of streptococcal disease. There are also numerous studies indicating that pneumococcal penumonia was more prevalent during the epidemic, but in other instances as at Sioux Falls, S. Dak., where pneumonia was epidemic, Hodges and MacLeod 31 conclude that influenza was not unduly prominent as a participating factor.
Special concernwas attached to the transport of troops during the epidemic. Serioustrouble wasnot encountered in overseas movements although a convoy of 63,750troops had 7,529 (12percent) sick calls for respiratory disease while en route to GreatBritain inDecember; 962 menwere hospitalized and 86 were evacuated to hospital on debarkation.32In another instance, 23percent of a contingent were sick aboard ship. Official recommendationwas made that at allports of embarkation a minimum of 60 square feet housing space be re-
29 See footnote 24 (2) and (3), p. 98.
30Coburn, A.F.: MassChemoprophylasix. Th U.S. Navy's Six Months' Program for the Control ofStreptococcalInfections. In United States Navy Department, Bureau ofMedicine and Surgery: The Prevention of RespiratoryTract Bacterial Infections by Sulfadiazine Prophylaxis in the UnitedStates Navy. Washington: U.S. GovernmentPrinting Office, 1944, pp. 149-162.
31 Hodges,R.G., and MacLeod, C. M.: Epidemic Pneumococcal Pneumonia, IV. TheRelationship of NonbacterialRespiratory Disease to Pneumococcal Pneumonia. Am. J. Hyg. 44; 231-236,September 1946.
32 Informalmemorandum, Lieutenant Cree for Colonel Gordon, 20 Dec. 1943, subject:Respiratory Disease onTransports on Shipment UT 5.
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quired; this was an effort to avoidcrowding and illness at the time of embarkation. 33
Control measures. - The general control measures were those designed to prevent or retard the spread of infection from person to person. Emphasis was placed on the avoidance of overcrowding by increasing the floor space per man in barracks and reducing the number of troops per car on trains. Troop movements were kept at a minimum during the outbreak. Personal hygiene and proper sterilization of messgear were stressed. During the epidemic, fatigue and exposure to cold and wetness were minimized. In high-priority units, medical inspection of troops and the hospitalization of patients with incipient disease were advocated.
The action takenby the Preventive Medicine Service of the Surgeon General's Office tomaintain close touch with the epidemic situation and to gain theadvantage of environmentalcontrol measure is summarized as follows: 34
1. The first definite information that epidemic influenza was occurring came on 21 November 1943. The isolation of virus A from such an outbreak was first reported on 25 November.
2. On 3December, the Medical Statistics Division was requested to furnish thenumber of casesof influenza separate from common respiratory diseases.
3. All service commands, the Air Surgeon, and the Chief of Transportation were requested on 6 December to notify all stations under their jurisdiction to report by telegram all influenza outbreaks then occurring, as well as future outbreaks, to The Surgeon General. This action was taken at the request of General Simmons, and the reports were rendered under previously granted Control Approval Symbol MCE-64.
4. On 16December, all posts over 5,000 strength were asked to telegraph weeklyreports of thenumber of cases of common respiratory disease, including influenza andpneumonia, to servicecommand headquarters, which was in turn, to forward a consolidatedreport by wire to TheSurgeon General. This action followed a staff conference at which itwas indicated that TheSurgeon General was expected to know the current situation with respectto influenza. Thereporting system thus set up reduced by a week the delay in compilationof rates, although therates computed were, of course, estimates based on a sample only.Experience showed theestimated rates to be fairly accurate in comparison with the finalreturns on the monthlysummary reports from all posts.
5. A report based on the telegraphic rates was made by The Surgeon General to the Secretary of War, Chief of Staff, and Commanding General,
33 (1) Coded message (routine), Chief ofTransporation to all Ports of Embarkation, 19 Dec. 1943, subject:Instructions in Control Measures to Be Put Into Effect. (2) Memorandum,Chief of Staff for Commanding General,Army Service Forces, 30 Dec. 1943, subject: Considerations of InfluenzaPrecautions With Respect to OverseasTroop Movements. (This was accompanied by a list of 15 stationsdesignated to provide overflow capacity forregular port staging areas in an emergency.) (3) Momorandum, CommandingGeneral, Army Service Forces, forChief of Transportation, 6 Jan. 1944, subject: Measures to PreventEpidemics During Troop Movements.
34 Memorandumfor file, 24 Feb. 1944, subject: Summary of Developments and ActionTaken During 1943 InfluenzaEpidemic.
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ASF (Army ServiceForces),on 21 December, and similar reports were rendered
at theend of themonth and againon 7 January 1944.
6. On 28
December, a request was made tothe Control Division, ASF, for approval of the weekly telegraphicreport;it had previously been understood that such approval was unnecessary.This request was disapproved, and TheSurgeon General was instructed to advise service commands immediatelythat the
weekly telegraphic report was nolonger required. The Preventive Medicine Service, Office of the SurgeonGeneral, informed the CommandingGeneral, ASF, that his instructions had been carried out but indicatedthat this office did not concur in the objectionsto the report.
7. All service commands, the Air Surgeon, and the Chief of Transportation were notified by wire on 7 January
1944 that the telegraphic reports of respiratory diseases were discontinued.
8. On 15December 1943, the Deputy Chief of Staff sent a radiogram to all majorcommands in the United Statescalling attention to control measures and authorizing hospitalization
of civilians in military hospitals whennecessary. Reference was made to the maintenance of productionschedules in industrial plants. Reports of influenzaoutbreaks in units soon to go overseas were to be telegraphed to TheSurgeon General.
9. On 19 December, the Transportation Corps telegraphed all ports, giving instructions in control measures. These instructions were prepared in consultation with the Epidemiology Branch, Preventive Medicine Division, Office of the Surgeon General.
10. On30 December 1943, the Chief of Staff sent the Commanding General, ASF,a memorandum, entitled"Consideration of Influenza Precautions With Respect to Overseas TroopMovements," accompanied by a list of 15stations designated to provide overflow capacity for regular portstaging areas in an emergency.
11. The Commanding General, ASF, in his memorandum for the Chief of Transportation, dated 6 January 1944, entitled "Measures to Prevent Epidemics During Troop Movements," forwarded a copy of the memorandum from the Chief of Staff, previously referred to.
12. The Commanding General, ASF, also sent The Surgeon General amemorandum, same subject, on 6 January,including a copy of the memorandum from the Chief of Staff and attachedlist of stations. The Surgeon General wasdirected to issue necessary technical instructions and reportrecommendations for the modification of presentprocedures. The Surgeon General's endorsement on 20 January stated thatan article on influenza would be publishedshortly in a medical technical bulletin and recommended that directivesbe published requiring a minimum of 60square feet of space per man in barracks.???
13. The Chief, Preventive Medicine Service, Office of the Surgeon General, sent a draft of medical technical bulletin entitled "Influenza," to the Executive Officer on 28 January.
14. On29 January, a directive entitled "Measures to Prevent Epidemics ofRespiratory Diseases," was sent to alldefense commands, service commands,
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ports, and technicalservices. This was substantially the same as the letter recommended byThe Surgeon General.
Cooperationwith civilian groups.-Because of the potentialities of a severeoutbreak of influenza similar to the1918-19 epidemic, plans were made by the Preventive Medicine Service,Office of the Surgeon General, for theArmy to give assistance in the medical care of civilians in cases ofemergency. Medical Department personnel,supplies, hospitalization, and transportation were to be made availableto the maximum extent after the first andsecond echelon facilities consisting of the local and Statephysicians and facilities, American Red Cross, UnitedStates Public Health Service, and Office of Civilian Defense, wereexhausted. Hospitalization of civilian personnelwas authorized, and each service command and post surgeon made plans tobe put into effect if indicated. As theepidemic remained generally mild, these procedures were not used.
Experiencein 1944
With theabrupt subsidence of the epidemic of influenza A in the winter of1943-44, the admission rates forrespiratory diseases within the continental limits of the United Statescontinued to decline rapidly and remainedbelow the average level of Army experience for the decade 1930-39(chart 13). After January, they also readied alevel well below that of the three preceding winters. The Army at thistime was composed largely of seasonedtroops since the rate of induction was low as compared with the 3preceding years.
Experience in 1945
A smallseasonal rise in rates occurred during the winter months 1944-45 butthat for troops in the United Statesremained under 200 admissions per 1,000 per annum. The overseastheaters had similar low rates for acuterespiratory disease. No outbreaks of influenza occurred. However, theCommission on Influenza continued a moreextended alert for detection by investigating unusual rises inadmissions for acute respiratory disease and samplingcases in respiratory, wards of various Army hospitals. Investigation ofan outbreak of illness in the AntillesDepartment reported to be influenza revealed it to be infectiousmononucleosis; nevertheless, an opportunity wasprovided for setting up a center for the identification of influenza inthe area.35
Beginning in March 1945, small localized outbreaks of influenza B occurred in many parts of the United States and overseas theaters. Detailed investigations of a number of these outbreaks are described in special reports from members of the Commission on Influenza to The Surgeon General, United States Army. However, it is of interest and importance to indicate the time, location, and extreme variability of these widely scattered upsurges of the disease which were identified by virus isolation or by serologic evidence.
35 EssentialTechnical Medical Data, Caribbean Defense Command, 20 Feb. 1945.
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The earliest outbreak occurred in March atSioux Falls, although the serologic evidence of influenza B was notobtained until after the virus had been identified by Dr. J. E. Salk insharp outbreaks at Buckley and Lowry Fields,Colo., in May. Streptococcal infection was also high. Evidence pointedto the fact that influenza was present, too, inthe neighboring civilian population of Colorado as a very mild illness,not recognized clinically as influenza.Serologic. studies at this same time in a hospital ward for respiratoryillnesses at Sheppard Field, Tex., demonstratedthat influenza B was present although its nature had not been suspectedclinically. In April, a flurry was identifiedserologically at Fort Lewis, Wash., by the Ninth Service CommandLaboratory. A sharp civilian outbreak in thetown of Kasson, Minn., was recognized only in the school children, 80percent of whom were affected; the peak wasin the middle of May. Tests with sera from patients convalescent froman outbreak in Alaska in May demonstratedinfluenza B.
In June and July, sharp outbreaks occurred in the prisoner-of-war camps at Camp Edwards, Mass., and Camp Atterbury, Ind. The Fifth Service Command Laboratory identified the Camp Atterbury outbreak. The outbreaks seemed to be limited entirely to the prisoner-of-war compounds with prevalence of 10 to 12 percent, but Dr. 'I'. P. Magill demonstrated by serologic studies that infection had been widely distributed in United States military personnel at Camp Edwards. He suggested that the Americans were being largely immunized by subclinical infection and that the prisoner groups became more prominently affected
if they were not closely associated with United States troops. The Antilles Department laboratory reported an epidemic in San Juan beginning 8 June and reaching a peak about 22 June. In Jamaica, an estimated 50 percent of the population of Kingston were attacked in an epidemic. The disease was also identified in United States Army troops in Panama and in civilian employees in the Canal Zone. It is well to point out that Army laboratories were at this time actively engaged in the detection of the disease both by virus isolation and serologic tests.
Influenza was widely disseminated over a great part of the Pacific area. In Honolulu, a sharp civilian epidemic of 7,000 to 8,000 cases was reported by the Board of Health from 1 June to 15 July. Army admissions at this same time increased sharply with a peak on 27 June. The author and Capt. G. K. Hirst, MC, undertook an investigation at this time in the Pacific Ocean Area. Sampling of cases showed virus B was widespread. In this instance, too, streptococcal infection was prevalent without serious complications. Vaccination of essential personnel was carried out. The disease was demonstrated in naval forces at the same time, and vaccination was extended to certain specific personnel. At Tarawa in June, 83 percent of the Gilbert-Ellice labor troops were affected in an epidemic that followed the arrival of two Army ships. Caucasians in the area had little illness. Judged by admissions, little respiratory infection
occurred at Saipan and Guam, but serologic samplings showed influenza B to be prevalent. On Okinawa, serologic studies of a denguelike
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disease that was prevalent among the troops showed somesignificant rises in titer for influenza B from 23 July to aslate as 27 August.
In July,evidence accumulated of localized outbreaksin Australia 36 and British Guiana. 37 In California, influenza Bwas identified by Dr. M. D. Eaton in troops who became ill aboardtransports from the Pacific, and, at the same time,a local outbreak was seen at Stockton Ordnance Depot.
From late August through October, influenza B was encountered at Fort Bragg, Fort Dix, Fort Lewis, and at Fort Benjamin Harrison, Ind. In October, Burnet reported both influenza A and B in Australia with a concentration of cases in young people or in country districts while troops and adult city dwellers escaped almost completely. He reported two patients with influenza from whom virus B was isolated; 10 to 12 days later, during a second attack, virus A was also isolated from those individuals.
The disease was mild during the summer of 1945 but varied from typical febrile illness of 3 to 4 days' duration, with an occasional instance of pulmonary involvement, to transient indisposition and subclinical infection. It is quite likely that in the civilian population much more of the disease was unrecognized and ignored. However, the accumulated information identified clearly a continued but shifting prevalence of influenza B during a period of 8 months. The alerted interest was thus very effective in demonstrating a peculiar, irregular blustering occurrence, rising here or there for many months. Some of the minor episodes were of considerable size but localized, yet they recurred in the same posts at intervals of months in a typical endemic-epidemic manner.
The extensive distribution of the disease was considered to indicate that a definite epidemic wave was likely in the latter part of the year. On this basis, the Commission on Influenza recommended to General Simmons, on 21 June 1945, that vaccination with influenza A and B be carried out in the entire United States Army during the month of October 1945. War Department Circular No. 267, dated 5 September 1945, instructed that the forces in all Army commands be vaccinated in October and November.
Theanticipated epidemic of influenza B occurred in November and December1945. A definite increase inrespiratory admissions in the Army in the United States began in theweek ending 23 November when the rate rosefrom 88 to 103. It rose to 148 the following week and continued to apeak of 170 in the week ending 14 December. This rise was strikinglysimilar in time to the onset of the 1943 epidemic of influenza A.However, the increase wasnot nearly so great or abrupt.
The civilian population of the United States experienced an epidemic at the same time. Reported cases rose abruptly beginning the last week in November and reached a sharp peak of 148,688 cases during the second week
36 Burnet,F. M., Stone, J. D., and Anderson, S. G.: An Epidemic ofInfluenza Bin Australia. Lancet 1: 807-811,1June 1946.
37 Letter, Maj. H.G. Grady, MC, Commanding Officer, Medical Laboratory,to Brig. Gen. S. Bayne-Jones, 24 Sept.1945, subject: Study of Influenza-Like illness in British Guiana.
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in December.38They fellrapidly in the next 3 weeks to less than 50,000 cases per week. Theareas most severelyaffected were the South Atlantic, South Central, East North Central,and Mountain States. The Pacific and NewEngland areas, which were not affected severely, reached peaks late inDecember or in the first 2 weeks ofJanuary.In comparison with the 1943-44 epidemic of influenza A, the1945-46 epidemic of type B in the generalpopulation reached a higher level for the peak week, but in total casesit was less. For the period 18 November 1945to 26 January 1946, a total of 454,833 cases were reported ill theStates where influenza is a reportable disease. Forthe corresponding period in 1943-44, there were 587,193cases and in the nonepidemic year 1944-45 only 32,620cases. In the peak week of December 1945, the State of Kentuckycontributed 60 percent of the total cases whilethis same State contributed 18 percent in the 1943-44 peak. This reportis apparently made on the basis of estimatesrather than actual reported cases. If the estimates for this State wereexcluded for comparison purposes, the civilianincidence in 1945-46 was at least half of the 1943-44 epidemic.39
In the Army, the increase as measured by admission rates for respiratory diseases, after correction of strengths due to the number of troops on furlough during this period, remained less than 25 percent of the 1943-44 epidemic; the actual increase over the preepidemic level was so small as to give evidence of only a minor increase. The Navy admission rates were 55 percent of those in 1943-44. In attempting to evaluate the efficacy of the vaccine, a detailed study of the incidence in the Army and Navy was made. The evidence available indicated that vaccination played a considerable role in the reduction of influenza in the Army (luring the winter 1945-46. More specific studies in the comparison of ASTP units with naval and civilian students at universities are given under the vaccination studies.
In England and Western Europe, the possibility of a widespread influenza epidemic appeared as a serious threat in the fall of 1945. The shortage of fuel, the nutritional status of the population, and the continued shifting and crowding of displaced persons on the Continent appeared to set the stage for such an occurrence. In order to establish listening posts and to organize laboratories for the detection of influenza, a mission consisting of Dr. Salk, Maj. G. J. Dammin, MC, and Lt. V. Sprague, MC, was dispatched to the European theater in November 1945.40 Countrywide epidemics of mild influenza B were reported in December in Belgium and Holland.41 Sporadic cases of influenza A and B were identified in United States troops and civilians in Germany, but no general epidemic occurred. A continuous survey center for the area was established in the Fourth Medical General Laboratory. In
38Prevalence of Disease in the United States. Pub. Health Reps. 60 and61, July-December 1945 and January-June1946, respectively.
39 MonthlyProgress Report, ASF, War Department, 31 Dec. 1945 and 31 Mar. 1946,Section 7: Health.
40 InfluenzaMission in Europe.Bull. U. S. Army M. Dept. 5: 495-496, May 1946.
41 (1) Letter, Dr.J. E. Salk and Lt. Col. G. J. Dammin, MC, to Surgeon General, 1 May1946, subject: Report ofSpecial Group Assigned to the Office of the Chief Surgeon, EuropeanTheater, to Assist in the Problem of InfluenzaDuring the Winter of 1945-46. (2) Dudgeon, J. A., Stuart-Harris, C. H.,Andrewes, C. H., Glover, R. E., andBradley, W. H.: Influenza B in 1945-46. Lancet 2: 627-631, 2 Nov. 1946.
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England, there were few sharpoutbreaks recognized, but influenza B was identified in most areas withthe height ofthe prevalence in January 1946. As measured by an increasein deaths, the epidemic was considered moderatelysevere.
The Army had essentially completed its year long experience with influenza B by the end of 1945, although some extension into 1946 was noted in Europe. It is of interest, however, to note that troops, mostly from the 13th Replacement Depot in Hawaii, had a sharp increase of respiratory disease about 1 February 1946, which was identified serologically as influenza A.42 In the remainder of the Army, respiratory disease reached a point comparable to the same period of 1945, the lowest recorded level for the season (chart 13). The Army was being demobilized, and the threat of influenza which had hung over the entire period of World War II was dispelled. The experience of 1918 was not renewed, and influenza again behaved as a disease not primarily related to military conditions.
Thetremendous dislocations of populations, the destruction of housing, andthe rapid intermingling of people frommany areas under crowded conditions was a milieu in which epidemics oftyphoid fever, diphtheria, and tuberculosisrapidly gathered momentum. Circumstances were such that influenzacomparable in severity to that of 1918 wouldbe insusceptible to control. No other conclusion seems possible butthat the biology of the infectious agents was thedecisive factor in avoiding such an event. The studies of the diseaseand its prevention contributed greatly to a betterunderstanding of its epidemiology and were responsible in a significantfashion for heightened efforts to identify andcontrol respiratory disease of all types. There was, as always, asomewhat fatalistic attitude toward prevention orcontrol measures, but in many situations a true effort was made to gainwhat benefit could be had by early institutionof measures to limit crowding, to control transport of infected men,and at times to use sulfonamidesprophylactically in the hope of reducing complications.
Circumstances were favorable. The periods of greatest effort were largely free from influenza or the disease was of sufficiently mild character to avoid serious disturbance. The widespread epidemic of 1943 was not prevalent in the major combat area at that time, Italy. In 1945, the European theater was essentially free from influenza B. Reports from the Pacific theater contained no significant references to influenza until 1945, with the exception of Hawaii which appears to have become a major crossroads for the transfer of influenza. Other theaters in the Far East made no reference to the disease. There is little doubt that the mild character of influenza in busy areas attracted little attention, and many were concerned with a diagnosis of influenza only if it were rapidly fatal or overwhelming. In many instances, epidemics clearly shown to be influenza, with classical clinical and epidemiologic
42 Essential TechnicalMedical Data, U. S. Army Forces, Pacific, February1946.
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characteristics, were callednasopharyngitis. This practice sometimes avoided additionalrequirements imposed bythe diagnosis of influenza. The constant insistence of the
PreventiveMedicine Service, Office of the SurgeonGeneral, and its expert consultants on prompt investigation ofoutbreaks had left little doubt that the earlydistribution of information was an important factor in maintaining thealertness and interest of all commands.
RESEARCHWITH INFLUENZAVIRUS
Developmentof Knowledge
The lack ofdecisive information regarding the etiology of the pandemic disease of1918 led to numerous efforts toestablish the nature of the inciting agent of influenza. Variousbacterial agents were isolated, heralded, anddismissed. Shope, in 1931,43 however,described and established the evidence that swine influenza is causedby acombined infection of virus and Hemophilus influenzae suis,with the former serving as the effective agency indissemination and immunity. The parallelism between the characteristicsof this disease in swine and influenza inmen, together with an etiologic complex to mollify thebacterial and viral schools of thought, promptly opened thefield to further work. At the same time, viral studies of the commoncold and psittacosis were enhancing interest inrespiratory diseases.
Type A virus.- In 1933, Smith, Andrewes, and Laidlaw44 isolated a virus from human cases of influenza A, which produced in ferrets, inoculated in the nose with garglings of the patients, a simple febrile upper respiratory disease of 3 to 4 days' duration involving the turbinate tissues. After recovery they were resistant
and developed in their blood antibodies which would neutralize the virus so as to prevent infection when a mixture of convalescent serum and virus was inoculated into normal ferrets. In 1934-35, the author45 Confirmed and extended those results with recovery of virus from influenza patients in many communities of the Western Hemisphere, and also in showing that, with repeated passages of these human strains in ferrets by intranasal route, the animals developed extensive, fatal viral pneumonia. Virus was established by intranasal inoculation in mice so as to produce fatal viral pneumonia. Through their use, neutralization tests for antibody were readily possible. Complement fixation tests were developed. Virus was cultivated ill tissue culture and in chick embryos.46 Subsequently, the observation by
43Shope, R.E.: Swine Influenza: III. Filtration Experiments and Etiology. J.Exper. Med. 54: 373-385, September1931.
44Smith, W., Andrewes, C. H., and Laidlaw, P. P.: A Virus Obtained From Influenza Patients.Lancet 2: 66-68, 8 July 1933.
45Francis,T., Jr.- Transmission of Influenza by a Filterable Virus.Science 80:457-459, 16 Nov. 1934.
46 (1)Francis, T., Jr., Magill, T. P., Rickard, E. R., and Beck, M. D.:Etiological and Serological Studies inEpidemic Influenza. Am. J. Pub. Health 27: 1141-1160, November1937. (2) Friedewald, W. F.: The ImmunologicalResponse to Influenza Virus Infection as Measured by the ComplementFixation Test. Relation of the ComplementFixing Antigen to the Virus Particle. J. Exper. Med. 78: 347-366,November 1943.
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Hirst,47 and McClelland and Hare,48 that avian erythrocytes were agglutinated by influenzavirus in infectedallantoic fluid, added another important technique for identificationof virus and serologic diagnosis. The applicationof these procedures to the problem of epidemic influenza becameprogressively established in a few years.49
It was found that, after the first years of life, a large proportion of the human population had antibodies to influenza A virus. Hence, at the onset of illness, a patient might well possess demonstrable antibodies from earlier infection, but, with recovery, a sharp rise in the level took place. It was necessary, therefore, for specific diagnosis to compare the titers of antibody in the acute phase of illness with that reached in convalescence. The specificity of the reaction was also clearly established. The serologic test thus became a procedure applicable to clinical diagnosis and to broader epidemiologic investigation in conjunction with the, isolation and identification of virus.50
Employingthese procedures, it was shown that outbreaks associated with type Avirus lead recurred at intervals of 2years between 1932 and 1940-41.51They varied widely in extent and severity; the 1936-37 epidemic wasworldwide and that of 1938-39 extremely spotty and of low order, butthey were both influenza A. That not all thestrains of influenza A are identical was established in 1936; 52 whilemost strains from the same epidemic areclosely similar, those from different epidemics may showdistinct differences. That they are of the same type can bedemonstrated by complement fixation or by hyperimmunization of animalswhich bring out the common typeantigenicity. Under the latter circumstances, the swine strains werealso seen to be related to type A strains fromman. Nevertheless, another feature arose to be considered inrecurrences of influenza.
Type B virus.- From the epidemic in the early months of 1940, another influenza virus, type B, (p.90) was established, and it was then possible to demonstrate that the widespread epidemic of 1935-36 was also influenza B. This virus was shown to be immunologically distinct from type A, thereby introducing a second disease, clinically and epidemiologically influenza, to be considered in the analysis of recurrences and of immunity to influenza.
Noregular bacterial accompaniment
of the virus was found inthe epidemic
47 Hirst, G.K.: The Agglutination of Red Cells by Allantoic Fluid of Chick EmbryosInfected With Influenza Virus. Science 94: 22-23, 4 July 1941.
48 McClelland, L.,and Hare, R.: The Adsorption of Influenza Virus by RedCells and a New In Vitro Method ofMeasuring Antibodies for Influenza Virus. Canad. .J. Pub. Health 32:530-538, October 1941.
49(1)Andrewes, C. H., Laidlaw, P. P., and Smith, W.: Influenza: Observationson the Recovery of Virus From Manand on the Antibody Content of Human Sera. Brit. J. Exper. Path. 16:566-582, December 1935. (2) Francis, T., Jr.,and Magill, T. P.: The Incidence of Neutralizing Antibodies for HumanInfluenza Virus in the Serum of HumanIndividuals of Different Ages. J. Exper. Med. 63: 655-668, May 1936.
50 Salk,J. E.: Laboratory Methods Used for the Recognition of Influenza. Bull.U. S. Army M. Dept. 5: 32-37,January 1946.
51 Francis, T., Jr.: Factors Conditioning Resistance to Epidemic Influenza. Harvey Lect. 37: 69-99, 1941-42. 52 (1) Magill, T. P., and Francis, T., Jr.: Antigenic Differences in Strains of Epidemic Influenza Virus: I. Cross Neutralization Tests in Mice. Brit. J. Exper. Path. 19: 273-284, October 1938.
11. Cross-Immunization Tests in Mice. Ibid.: 284-293. (2) Smith, W., and Andrewes, C. H.- Serological Races of Influenza Virus. Brit. J. Exper. Path. 19: 293-314, October 1938.
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disease of man.53Hemophilus influenzae was uncommon, but, in occasional,rapidly fatal cases with extensivedestruction of the respiratory epithelium, hemolytic Staphylococcusaureus had been encountered. Thus, theevidence firmly established influenza virus as the essential infectiousagent in characteristic epidemic influenza.
Antibody formation. Influenza virus produces all infection essentially limited to the respiratory tract. It has a highly selective, destructive action upon the ciliated respiratory epithelium of the nasal mucosa and upon that of the trachea and bronchi. After large doses given intraperitoneally to mice,
virus can be recovered from the lungs and, if well adapted to that species, may produce extensive pulmonary lesions. The WS strain of type A can be established ill the central nervous system of mice by the intracerebral route. Generally, however, the influenza virus can be considered rather strictly pneumotropic since, under most circumstances, inoculation of various species with active virus by other than the respiratory route elicits no evidence of infection but, circulating antibodies and resistance may ensue.
Ferrets andmice recovering from infection are commonly immune to reinoculation ofthe same strain of virus andalso to others of the same type. This effect is not permanent for, aswell demonstrated in the ferret, after a fewmonths, even though antibodies are present in the blood, reinoculationmay again cause febrile illness, withdestruction of the respiratory epithelium although pulmonary lesions donot ordinarily develop. The general clinicaland epidemiologic experience of man with influenza has resulted in theconclusion that immunity to the disease is ofa transient nature; the evidence has always been clouded, however, bylack of knowledge of the agent involved.Nevertheless, the experimental data in man and lower animals are inaccord. The fact that many of the humanpatients have antibodies to virus of the same type before, or at thetime of, onset of influenza is clear evidence ofprevious experience with the agent. This knowledge, together with the,realization that there are two or more distincttypes of virus and many variations of strains within the types,presents a formidable array of problems.
On the other hand, mice can be readily immunized by intraperitoneal vaccination of active or inactive virus and less readily by subcutaneous inoculation; they become resistant even after infection with virus not sufficiently well adapted to cause severe disease. Ferrets, too, can be vaccinated but usually less effectively than mice. In 1935, Francis and Magill 54 demonstrated that, virus cultivated in tissue culture can be given to man subcutaneously or
53 (1)Shope, R. E.: The Influenzas of Swine and Man. Harvey Lect. 31:183-213, 1935-36.(2) Shope, R. E.: SwineInfluenza. In Rockefeller Institute for Medical Research. VirusDiseases. Ithaca: Cornell University Press, 1943, pp.83-109. (3) Andrewes, C. H : Immunity in Influenza. The Bearingof Recent Research Work. Proc. Roy. Soc. Med.32: 145-152, 1939. (4) Stuart-Harris, C. H.: Influenza Epidemicsand the Influenza Viruses. Brit. M. J. 1: 209-216.251-257, February 1945. (5) Francis, T., Jr.: Influenza: Methodsof Study and Control.Bull. New York Acad. Med.21: 337-355, July 1945. (6) Burnet, F. M., and Clark, E.:Influenza.A Survey of the Last Fifty Years in the Light ofModern Work on the Virus of Epidemic Influenza.Monographs from theWalter and Eliza Hall Institute of Researchin Pathology and Medicine, No. 4. Melbourne: Macmillan, 1942, pp. 1-118.
54 Francis,T , .Jr., and Magill, T. P.: Cultivation of Human Influenza Virus inArtificial Medium. Science 82: 353-354, 11 Oct. 1935.
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intracutaneously withouteliciting signs of infection but resulting in the development ofantibodies which reach apeak in about, 14 days and are maintained for months. The levelsattained, the curve of development, and thepersistence are quite parallel to those observed in subjects undergoingthe actual disease; hence, if immunity in manis correlated with antibodies as it is in other animals, the results ofvaccination strongly suggest that resistance inman could be similarly effected. In this background of information laya basis for efforts toward prophylacticimmunization. Before the advent of the Commission on Influenza,different investigators had undertaken furtherstudies of vaccination with preparations of virus from tissue culture,mouse lung, and chick embryo.55 Ineachinstance, vaccination had resulted in antibody formation, but theprotective value against the disease had not beenclearly established; nevertheless, some of the results had suggested abeneficial effect.
Organization for ResearchinWar Period
The onset of war in Europe met in the United States a firm commitment of neutrality. However, with the progressive victories of the German armies, it became apparent that American democracy must be prepared for its own defense. Preparation meant more than the induction of men and the manufacture of materials. It meant the creation of forces trained in advance and maintained in a state of effectiveness. No longer did events await the arrival and the preparation of volunteers in the numbers now required. Manpower was important.
It is commonly said that the medical knowledge of one war has usually been forgotten and bitterly relearned in the next. The microbial enemy has often been more destructive than lead and steel. Certainly it is true that personal courage and indifference to risk have frequently been the substitute for sanitary and other preventive measures. But preparedness is medical too. In this instance, the history of respiratory disease in World War I in a nastily mobilized army without adequate provision for mass phenomena of disease had left its memory. The improvised efforts to meet a terrible situation had been splendid, but they emphasized the need to view the possible problems in ad-
55 (1) Stokes, J., Jr., McGuinness, A. C., Langner, P. H., Jr., and Shaw, D. R.: Vaccination Against Epidemic Influenza With Active Virus of Human Influenza. Am. J. M. Sc. 194: 757-768, December 1937. (2) Smorodintseff, A. A., Tushinsky, M. D., Drobyshevskaya, A. I., Korovin, A. A., and Osetroff, A. I.: Investigation on Volunteers Infected With the Influenza Virus. Am. J. M. Sc. 194: 159-170, August 1937. (3) Martin, W. P., and Eaton, M. D.: Experiments on Immunization of Human Beings Against Influenza A. Proc. Soc. Exper. Biol. & Med. 47: 405-409, May June 1941. (4) Horsfall, F. L., Jr., Lennette, E. H., Rickard, E. R., and Hirst, G. K.: Studies on the Efficacy of a Complex Vaccine Against Influenza A. Pub. Health Rep. 56: 1863-1875, 19 Sept. 1941. (5) Dalldorf, G., Whitney, E., and Ruskin, A.: A Controlled Clinical Test of Influenza A Vaccine. J. A. M. A. 116: 2574-2577, 7 June 1941. (6) Brown, J. W., Eaton, M. D., Meiklejobn, G., Lagen, J. B., and Kerr, W. J.: An Epidemic of Influenza.Results of Prophylactic Inoculation of a Complex Influenza A-Distemper Vaccine. J. Clin. Investigation 20:663-669, November 1941. (7) Stuart Harris, C. H., Smith. W., and Andrewes, C. H.: The Influenza Epidemic of January-March, 1939.Lancet 1: 205-211, 3 Feb. 1940. (8) Taylor, R. M., and Dreguss, M.: An Experiment in Immunization Against Influenza With a Formalde hyde-Inactivated Virus. Am. J. Hyg. 31: 31-35 (see. B), January 1940. (9) Siegel, M., Muckenfuss, R. S., Schaeffer, M., Wilcox, H. L., and Leider, A. G.: A Study in Active Immunization Against Epidemic Influenza and Pneumococcus Pneumonia at Letchworth Village. IV. Results in an Epidemic of Influenza A in 1940-41. Am. J. Hyg. 35: 186-230, March 1942.
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vance, to watch for signs of their development, and to seek control methods for early and extended application. Moreover, much greater scientific knowledge of specific approaches toward the prevention or treatment of epidemic infection had developed. The interest of many capable investigators was already moving in these directions. In addition, many problems could, because of special circumstances, be adequately studied only under military conditions. The Surgeon General's Office was not only aware of these facts but acutely interested in applying the concepts to the profit of the actively growing military forces. Under these influences, the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army was initiated by the Preventive Medicine Division (fig.2), and the Commission on Influenza was organized under the Board. Much of the research and observations relating to influenza was conducted by the Commission, but its functioning was at each step dependent upon the financial aid from the Board and the strong and imaginative support furnished by General Simmons, Brig. Gen. Stanhope Bayne-Jones, and others of the staff, and the splendid cooperation of the personnel of many organizations in which work was undertaken.
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From the start, emphasis was placed on a broad program of study of epidemics and of control measures as shown by the initial outline presented by the Commission on Influenza to the Board on 27 and 28 February 1941:
I. Study of Control Measures.
I. Hygienic and Environmental Controls.
a. Influence of housing, size of cantonments, troop movements.
b. Isolation of individual or post; the use of masks.
c. Disinfection-sterilization of dishes, sterilization of air with aerosols or ultraviolet light.
2. Specific Control.
a. The efficacy of vaccination against influenza virus infection in man.
b. Prophylactic use of immune serum.
II. Study of Epidemics.
1. Clinical.
a. Attempts to establish clinical criteria for differentiation of disease caused by different types of influenza virus or by other agents.
b. Possible study of chemoprophylaxis of bacterial complications.
2. Epidemiological.
a. To ascertain incidence of immunes, subclinical and clinical cases in correlation with laboratory studies.
b. The method of introduction, the factors influencing spread, and the pattern of epidemics.
3. Bacteriological.
a. To determine whether any particular bacterium constantly accompanies influenza virus infection.
b. Concentrated study of H. influenzae.
c. Significance of bacteria in the course of the disease.
4. Virus.
a. To identify virus in epidemics, especially in recurrent waves, and the relation of illness to the immunologic state.
b. To evaluate importance of factors other than circulating antibody in resistance.
c. To institute prophylactic measures.
d. To ascertain complications caused by virus alone. .
5. Pathological
a. To correlate the picture in fatal cases with etiological studies.
b. To search for diagnostic criteria when illness was not caused by known virus.
6. Cooperative studies with other Commissions, especially in the field of complications and chemotherapeutics.
In order to meet these objectives, a more detailed pattern of organization and plan of operation was designed by which the United States was divided geographically into eastern, midwestern, and far western areas, and the members of the Commission were largely divided in the same manner. It was proposed that, in the event of a severe epidemic, an equipped, highly qualified team of investigators comprising a clinician, a pathologist, an epidemiologist, a bacteriologist, and a virologist would enter the field in each area and function as an investigative unit to gain a rounded picture of the epidemic disease and special knowledge of the different aspects of the problem.
Interim studies would deal largely with practical approaches to the improvement of control procedures. At the meeting of the Board, 19 to 21 June
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1941, specific authorization was given for the following interim investigations: (1) Experimental trial of influenza vaccine should a promising vaccine be available and suitable opportunity arise; (2) studies of the efficacy of respiratory masks; and (3) laboratory studies of materials and samples collected in the field bearing on the etiology, epidemiology, and immunology of influenza and its complications. The problems of air sterilization were referred to a newly formed Commission on Cross-infections in Hospitals. An appropriation of $25,000 for interim and $30,600 for field studies was voted. The original estimate was sharply reduced by the offer of the Rockefeller Foundation to provide, without cost, the facilities and participation of their laboratories in New York and San Francisco. Mobile laboratories were considered unnecessary because of the availability of corps area laboratories.
Here was provided a coordinated alert in which all members of the Commission would report immediately any outbreaks of respiratory diseases so that investigations could be rapidly instituted and in which civilian personnel with special interests were prepared to study influenza from a variety of approaches in their own laboratories or, in the field, to assist the Army during epidemics as ordered by The Surgeon General. A statement summarizing the current status of influenza and its control was prepared and published in Circular Letter No. 124, Office of the Surgeon General, on 23 December 1941.
Studies of Vaccination
Although a great deal of the subsequent discussion is concerned with the problem of vaccination against influenza, many of the major problems presented in the original plan were integrated into this broad concept in which research in the problems of the disease and the virus constitute the basis for studies in vaccination.
Intranasal vaccination.-Two major concepts of vaccination were considered. The one was intranasal introduction of active virus so attenuated as to give mild or subclinical infection with the expectancy that satisfactory resistance would develop. This would simulate natural conditions and should contribute any advantage, including possible alterations in tissue susceptibility, which accompanied actual infection. Preliminary observations had indicated that virus which had been maintained for long periods in tissue culture could be used without eliciting symptoms but the serologic response was quite irregular. The pathogenic balance was, therefore, of importance. Moreover, the objection was raised that within military forces active virus might be enhanced by passage and give rise to outbreaks of the disease. Nevertheless, in an approach to the problem, 3 series of 10 human subjects each were sprayed with different doses of type B virus from allantoic fluid. 56 After incubation periods of 18 to 24 hours, 27 of 30 men developed clinical influenza and with recovery showed significant rises in circulating antibody. But when retested
56 Francis, T., Jr., Pearson, H. E., Salk, J. E., and Brown, P. N.: Immunity in Human Subjects Artificially Infected With Influenza Virus, Type B. Am. J. Pub. Health 34:317-334, April 1944.
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4 months later with the same virus, one-third again developed acute illness comparable to the first, while others had milder illness. Inactivated virus caused no reaction. There was thus no uniform, firm immunity acquired under the condition of the study.
Subcutaneous vaccination.-The second approach to which greatest attention was given was that of subcutaneous vaccination. The various studies previously carried out (p.113) had shown that virus administered in this manner could stimulate good levels of antibody, and some indications of resistance had been observed in man under epidemic conditions. Although active virus could be given, the problems of stability of virus, bacterial sterility and possible viral contaminants, and storage and distribution were practical objections. Finally, attention was centered upon the preparation of vaccine containing type A and type B viruses from the allantoic fluid of infected chick embryos. High titers of virus were available, and the problem here became one of developing procedures and production. For the latter purpose, the interest of commercial biologic firms was enlisted. The development of the program is given in detail in the history of the Commission oil Influenza, and this discussion will present only summaries of the actual trials. The principles at all times were to provide for a supply of practicable vaccine; the selection of a homogeneous, stable vaccine; uniform procedure; close observation by highly competent investigators; confirmation of diagnosis by etiologic and serologic methods; and adequate controls at all steps.
Studies in 1941-42
Authorization was given for a study, under the immediate supervision of Dr. Eaton, in troops in California if the opportunity for a satisfactorily controlled experiment arose. Two thousand doses of a vaccine prepared from chick embryos were made available by Drs. J. H. Bauer and G. K. Hirst of the laboratories of the International Health Division of the Rockefeller Foundation. This effort was abandoned in January 1942 because of change in conditions due to our entry into war.
Studies in 1942-43
In addition to evidence that inactivation of virus caused a reduction in antigenic potency, data of Hirst, Rickard, Whitman, and Horsfall 57 indicated that within limits higher antibody levels were reached in man with preparations of virus concentrated from allantoic fluid by centrifugation. Hirst, Rickard, and Whitman, 58 and Hare, McClelland, and Morgan 59 described the concentration of virus by collection on a precipitate which formed when previously frozen material was allowed to thaw.
57 Hirst, G. K.., Rickard, E. R., Whitman, L., and Horsfall, F. L., Jr.: Antibody Response of Human Beings Following Vaccination With Influenza Viruses. J. Exper. Med. 75: 495-511, May 1942.
58 Hirst, G. K., Rickard. E. R., and Whitman, L.: A New Method For Concentrating Influenza Virus, From Allantoic Fluid. Proc. Sec. Exper. Biol. & Med. 50: 129-133, May-June 1942.
59 Hare, R., McClelland, L., and Morgan, J.: A Method for the Concentration of Influenza Virus. Canad. J. Pub. Health 33: 325-331, July 1942.
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The probabilities of an epidemic in this period were high since it would be in keeping with the 2-year cycle of identified influenza A since 1932-33. A field trial of vaccine prepared by this method was then planned for the winter of 1942-43.
Cornell study.-Drs. Magill, N. Plummer, and W. G. Smillie and their associates undertook a study in the student body and faculty at Cornell University, Ithaca, N. Y. Recruitment into the study was on a voluntary basis with administration of vaccine or control material of normal allantoic fluid subcutaneously. Of a total of 2,885 persons, 1,672 received vaccine and 1,213 control material. Great difficulty was encountered by the firm which undertook the preparation of precipitated vaccine, and Dr. Hirst aided by providing 1,000 doses from the Rockefeller Foundation. Another lot of unconcentrated type A vaccine was also used. Careful clinical, viral, and serologic observation was maintained on respiratory illness in the population. No virus was isolated. No influenza was detected although serologic evidence suggested that a few infections with influenza B occurred. No difference in incidence, of any class of respiratory disease was noted among the vaccinated and control groups. Good antibody responses to vaccination were maintained during the 4 to 5 months' observation. Reactions with systemic symptoms of fever, aches, and other conditions were observed in approximately 10 percent of those receiving either concentrated or unconcentrated vaccine and in 2 percent of the controls.
Michigan study.-In two institutions, a study was arranged to test the, cold-precipitated type of vaccine. Owing to the difficulty mentioned in manufacture, attention was turned to vaccine prepared by concentration of virus from allantoic fluid by adsorption to, and elution from, erythrocytes of the infected embryo.60 In this manner, an eightfold to tenfold concentration of virus could be obtained in salt solution while leaving a large proportion of extraneous material behind. The virus was readily inactivated by 0.05 percent formalin, and sterility was relatively easy to control. Its potency was equal to that prepared by freezing and thawing. The greater ease of its production resulted in obtaining sufficiently large amounts of finished vaccine from the same commercial firm. Each 1.0 cc. contained the virus obtained from 5.0 cc. of type A fluid and from 5.0 cc. of type B fluid.
In late December and early January, 3,914 persons received 1.0 cc. vaccine and 3,909 alternately received control solution. The expected epidemic of influenza A did not occur, although in one institution influenza B at a subclinical level was detected (p.95). Antibodies to both viruses rose after vaccination and diminished slowly over a year's time but still remained above prevaccination levels. Data oil antibody levels of the same persons before, and at intervals after, vaccination with combined A and B vaccine are presented in table 21.
60 Francis, T., Jr., and Salk, J. E.: A Simplified Procedure for the Concentration and Purification of Influenza Virus Science 96: 499-500, 27 Nov. 1942.
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TABLE 21.-Average antibody titers at intervals after vaccination
The results of the year's endeavors had given information that concentrated vaccine was producible by two different methods of preparation and, in addition, that after eluate vaccine a high level of antibody was maintained for an extended period-a year at least. This observation was amply confirmed in later studies.
To gain information of the protective effect of vaccine by direct means, a test of immunity to induced influenza A and influenza B was undertaken by spraying with active virus groups of the vaccinated and control populations.61 The results demonstrated a high degree of protection against influenza B. There was an incidence of 10 percent in those vaccinated as long as 4 months earlier and in 40 percent of the controls, a greater resistance than had been obtained by actual experimental infection with the same virus. In the case of influenza A, vaccination 2 weeks before test reduced the incidence from 50 percent in the controls to 16 percent in the vaccinated, although vaccination 4 months earlier had a less definite effect. There was, therefore, definite information of immunizing influence of the vaccine produced by elution. Stokes and Henle 62 had also demonstrated in a similar fashion the protection of a group of children from experimentally induced influenza A after subcutaneous vaccination with vaccine prepared from allantoic fluid.
Other studies.-Dr. Hirst undertook a study involving 8,058 persons in institutions who received vaccine concentrated by freezing and thawing with a similar number of designated uninoculated controls. The absence of epidemic influenza thwarted an evaluation of effect.63 Another study by Dr. Eaton with alum-precipitated vaccine met the same situation, but he showed that the antibody titers were comparable to those obtained with the other preparations.
61 (1) Francis, T., Jr., Salk, J. E., Pearson, H. E., and Brown, P. N.: Protective Effect of Vaccination Against Induced Influenza A. J. Clin. Investigation 24: 536-546, July 1945. (2) Salk, J. E., Pearson, H. E., Brown, P. N., and Francis, T., Jr.: Protective Effect of Vaccination Against. Induced Influenza B. J. Clin. Investigation 24: 547-553, July 1945.
62 Henle, W., Henle, G., and Stokes, J.. Jr.: Demonstration of the Efficacy of Vaccination. Against Influenza Type A by Experimental Infection of Human Beings. J. Immunol. 46: 163-175, March 1943.
63 Hirst, G. K., Rickard, E. R., and Friedewald, W. F.: Studies in Human Immunization Against Influenza. Duration of Immunity Induced by Inactive Virus. J. Exper. Med. 80: 265-273, October 1944.
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Studies in 1943-44
The desirability of field studies of vaccination in military units was increasingly evident and for this reason authorization was obtained to conduct investigations in Army Specialized Training Program units. They were stable populations and subject to constant, uniform observations. It was possible to obtain participation of entire units so that vaccinated persons and controls could be properly designated rather than depending upon the less desirable and unpredictable basis of volunteers. Different members of the Commission were responsible for the work with units in different parts of the country; however, the same vaccine, the same record system, the same plan of observation, including clinical criteria, and viral and serologic studies were agreed upon. Alternate men in each unit were to receive vaccine and control material subcutaneously. The vaccine prepared by the elution method contained 50 percent type B (Lee) virus and 50 percent type A virus. Of the latter, half was the PR8 strain and half the Weiss strain, which had been isolated from a sporadic case in Mav 1943, and was employed because of the possibility that it might represent a forerunner of a subsequent strain.64
Six studies in nine ASTP groups constituting approximately 12,500 men were established with vaccination scheduled for October or November. Again, emphasis was placed upon a continuous, intensive watch for the occurrence of influenza. A coordinated system was arranged for sampling of respiratory illness in the selected units and throughout the different service commands with regular reporting of results. The epidemic of influenza A was promptly detected in the Sixth and Seventh Service Commands between 15 and 20 November at which time vaccination of the study groups was, with one exception, either completed or in progress. It spread rapidly through the service commands with sharp peaks during the early weeks of December, but in the Fourth, Eighth, and Ninth Service Commands the epidemic was more prolonged and at lower levels than in the others. It was essentially over by T January. The results of the study gave conclusive evidence, because of the carefully controlled procedures, that vaccination had exerted a sharply protective effect against epidemic influenza A (table 22).65
The final figures differ little from those of the preliminary summary. The total incidence based upon admissions was 7.3 percent among 6,198 controls and 2.2 percent among 6,253 vaccinated, a ratio of 3.3:1. No fatalities occurred in the study groups and there were few cases of pneumonia.
Other data of importance were also obtained. It was found that the epidemic was essentially a pure one in that 80 to 90 percent of cases were identifiable as influenza A. In addition to the incidence of 8 to 10 percent as measured by the admissions, it was shown that as high as 35 to 40 percent of the control population had undergone infection, much of it subclinical. This
64 See footnote 21, p. 95.
65 Commission on Influenza: A Clinical Evaluation of Vaccination Against Influenza. Preliminary Report. J. A. M. A. 124: 982-985, 1 Apr. 1944.
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TABLE 22.-Summary of clinical evaluation of vaccination against influenza, 1943 (combined totals of all results) is of importance in estimating the immunizing effect of either vaccine or of the natural infection. There was a definite trend indicating the tendency for the highest frequency of disease to occur in that portion of the vaccinated population with the lowest antibody titers; the same relation existed in the unvaccinated population. There were suggestions that this correlation was more distinct when antibodies were measured against strains from the epidemic rather than against the PR8 strain of the vaccine.
The vaccine induced localized erythema, edema, and heat in the majority of those inoculated; some systemic manifestations such as mild aching and chilliness occurred in as many as 25 to 30 percent, and 1 to 2 percent of some groups were sick enough to report to sick call. In the total vaccinated population, four instances of apparently allergic reactions were recorded.In two instances, the epidemic began while vaccination was being done; it was observed that the incidence curves began to separate in the vaccinated and controls 5 to 8 days after vaccination, indicating that after this interval the vaccine effect had begun. In two groups, streptococcal infection was prevalent, but no accentuation in severity of disease took place. The duration of protective effect was not demonstrable by these studies, but it was uniformly noted that, over several months only a mild fall in the postvaccination antibody titers to type A or type B virus took place. Two other groups which had been vaccinated the previous year were observed during this epidemic with results indicating that vaccine had exerted a protective influence even after that
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interval. 66 The suggestion was made that the California study had been less decisive than the others because of a longer interval between vaccination and the epidemic occurrence, but this does not appear to be valid.
The success of the study in evaluating the vaccine and in gaining a large amount of accessory information was the result of a carefully planned program by highly interested and qualified investigators who maintained a uniformity of procedure and observation while using adequate controls in each please of the study. The speed with which the epidemic developed, spread, and declined strongly demonstrates the difficulty to be encountered if the study is not established in advance of the epidemic; otherwise, it is probable that the opportunity will have passed before the work can be done.
With the termination of the 1943 epidemic, influenza apparently disappeared in the United States and, although the continuous alert for detection was maintained and expanded, no field studies were planned for 1944. The question of providing suitable vaccine for use throughout the Army was being studied. The problem of reactions was investigated, with a clear demonstration that this typhoidlike effect was strictly related to the amount of virus in the vaccine and that the amount contained in the eluate vaccines used in 1943 was about the limit tolerable.67 The increase in antibody titer was not directly proportionate to the amount of virus; 2.0 mg. of virus protein resulted only in a twofold increase in titer over that obtained with 0.2 mg. It was clear, nevertheless, that too small a dose did not elicit adequate response, and it was concluded that a range between 0.2 and 0.5 mg. of "estimated virus protein" was the most practicable from all considerations-alltibody response, percentage of reactions, and cost of production. The previous vaccines appeared to fall in this range. Concentration of vaccine by centrifugation was studied, standards for its production were devised, and it was accepted as an alternative procedure for Army vaccine.
Studies in 1945
In view of the increasing prevalence of influenza B noted in 1945, the recommendation was made through the Epidemiological Board that vaccination be carried out in the Army in October unless events warranted its earlier use. Final approval of The Surgeon General and of the Secretary of War was given in August. In some areas of the Pacific, vaccination had already been instituted because of higher incidence of the disease, but the program was carried out almost uniformly in all Army personnel in all theaters of operations during October and November 1945 with vaccine prepared by the elution method.
66 See footnotes 19, p. 95, and 63, p. 120.
67 (1) Salk, J. E.: Reactions to Concentrated Influenza Virus Vaccines. J. Immunol. 58: 369-395, April 1948. (2) McLean, I. W., Jr., Beard, D., Taylor, A. R., Sharp, D. G., and Beard, J. W.: The Relation of Antibody Response in Swine to Dose of the Swine Influenza Virus Inactivated With Formalin and With Ultraviolet Light. J. Immunol. 51: 65-99, August 1945.
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Because of the uniform regulation concerning vaccination throughout the Army, no controlled study could be established within that service. However, in two locations circumstances were such that an opportunity for evaluation arose. Naval personnel were not vaccinated, otherwise V-12 units were closely comparable to ASTP units, and the university agency for supervision of their health was usually the same. At the University of Michigan and at Yale University, the naval units and the ASTP units were under observation at the time the sharp epidemic of influenza B developed in November and December 1945. The opportunity was thereby provided for a comparison of the occurrence of influenza in the two organizations. 68 The results based upon admissions to the infirmaries were striking. As clearly demonstrated in table 23, vaccination had been highly protective against epidemic influenza B. The effect was even sharper than the results with the same vaccine against influenza A in 1943. Etiologic studies demonstrated that the epidemic was limited to type B virus. The strains of type B virus showed serologic characteristics which readily separated them from the vaccine strain (Lee) although the latter gave adequate cross-immunity. Two further indications were obtained. The first is in accord with earlier data that type B is a better immunizing agent than type A strains. The second is that vaccination of a total group gives better protection to the group than when, as in 1943, only half the group is vaccinated. Comparison of a completely vaccinated group with a completely unvaccinated unit might also yield a sharper differential possibility also suggested in 1943 when the incidence in certain unvaccinated companies was found to be strikingly higher than in the unvaccinated half of the study groups. Thus, vaccination of half a closely associated unit would have a limiting effect upon the risk to the unvaccinated portion so as to
TABLE 23.-Admissions for influenza in vaccinated Army units and unvaccinated Navy units at the University of Michigan and at Yale University over an 8-week period
68 (1) Francis, T., Jr., Salk, J. E., and Brace, W. M.: The Protective Effect of Vaccination Against Epidemic Influenza B. J. A. M. A. 131: 275-278, 25 May 1946. (2) Hirst, G. K., Vilches, A., Rogers, O., and Robbins, C. L.: The Effect of Vaccination on the Incidence of Influenza B. Am. J. Hyg. 45: 96-101, January 1947.
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reduce the incidence ill the latter below that of a totally untreated population. There is no indication in the tabulated data that resistance of the vaccinated unit was any different in the late stages of the epidemic than earlier. Moreover, the close, similarity of the results in the two institutions adds to their significance.
Further effort to gain information on the effect of vaccine upon the incidence of disease in the Army was presented in ASF monthly progress reports. Analysis was made of respiratory disease rates in Army and Navy personnel in the United States during the 1945 epidemic, when vaccine had been widely administered in the Army but the Navy remained unvaccinated, and compared them with the experience of the two services in 1943 when neither lead been vaccinated. Whereas, in 1943, the incidence of admissions for common respiratory disease and influenza in the Army was 117 percent of that of the Navy at the peak of the epidemic, in 1945 the Navy rate at the peak was 173 percent of that of the Army, or, conversely, the Army rate was only 57 percent of the Navy's. While the Army rate in 1945 was only 27 percent of that observed in 1943, the Navy rate was still 55 percent (chart 15).
The excess rate over the preepidemic level for common respiratory diseases in the Army in 1945 was only about 16 percent of that in 1943, while in the Navy it was still about 46 percent of the 1943 excess. The comparison with previous experience between the two services points out: "The increase in Army morbidity should have been just twice what was actually reported for November and December. A large part of the 50 percent increase not prevented may have consisted of common colds rather than influenza." The latter suggestion is further supported by the fact that the increased incidence in the Army did not abruptly subside as it did in the Navy, indicating that it might be largely the seasonal rise of common respiratory disease. It was not markedly different from that of 1944 when little influenza was observed. Moreover, the contrast, held when the incidence in naval districts and Army service commands was compared geographically. In the areas of the Fifth, Sixth, and Seventh Service Commands and the Ninth Naval District, where the ASTP study was convincing, the epidemic peak in the Navy was two and one-half times as high as in the Army (chart 16). The analysis indicates that vaccination was not complete in the Army and that most cases of confirmed influenza were in unvaccinated men. Further analysis emphasizes that the incidence curve in the Army did not differ strikingly from that of 1944, while the Navy experienced sharp epidemics. "In summary it may be said that all available evidence points to a considerable saving in morbidity. It seems entirely fair to judge the efficacy of the vaccination program on the basis of the period when the epidemic was in progress. One can only conclude that the epidemic of mild influenza B touches the Army only very lightly because of the protection afforded by the vaccine." 69
69 See footnote 39, p. 109.
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CHART 15.Incidence of common respiratory diseases and influenza in the Army 1 and the Navy in the United States for the winters of 1943-44, 1944-45, and 1945-46
The field studies of vaccination against influenza led to an application of the procedure in the entire Army. Their development was guided by evidence as it could be acquired and upon the pattern of the scientific experiment with proper control. Even when an ideal study could not be planned in advance, active investigators, continuously on the alert, could seize the unplanned opportunity to gain evidence.
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CHART 16.-Incidence of common respiratory diseases and influenza in the United States in the Fifth, Sixth, and Seventh Service Commands of the Army 1 and the Ninth District of the Navy for the writer of 1945-46
Other Research
Other pleases of research important to the problem of influenza were being carried on. A serious question was whether drugs effective in the treatment of bacterial pneumonia would be efficient when those pneumonias were as sociated with infection with influenza virus. Laboratory investigation lead shown that the virus was not affected by sulfonamides or penicillin, but studies by Drs. Barry Wood and Carl Harford 70 demonstrated that sulfonamides would control pneumococcal infection in rats and mice in which pneumonia was produced by combined virus and bacteria. The clinical experience first
70 Harford, C. G., Smith, M. R., and Wood, W. B., Jr.: Sulfonamide Cherotherapy of Combined Infection With Influenza Virus and Bacteria.J. Exper. Med. 83: 505-518, June 1946.
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recorded by Eaton and Meiklejohn 71 during the 1943 epidemic developed also to establish the fact that the bacterial pneumonias encountered in influenza patients could be effectively treated with sulfonamides. The subsequent availability of penicillin enhanced the treatment, and a major threat was thus subject to control.
There still persisted a great possibility that H. Influenzae might be seriously involved. For this reason, continuous studies were conducted on this organism, its prevalence, and its characteristics, by Dr. Hattie Alexander, and a diagnostic center was maintained. 72 No significant participation of that bacterium was encountered.
The idea that prophylaxis of influenza by use of intranasal spray with immune serum had developed. The concept was that antibody provided at the site of virus introduction might protect the susceptible epithelium of the respiratory tract. A series of studies in mice showed that it was possible; it was not effective in ferrets. Smorodintseff and his associates 73 had reported that influenza in mice could be prevented in this manner. In 1943, through the Commission on Influenza, a significant series of studies was conducted to determine whether human sera with high titers of antibody given by intranasal spray could prevent experimental infections with influenza virus. The studies were conclusive and indicated no prophylactic effect. The details are given in the history of the Commission on Influenza. The idea is, however, still of interest for further study.
The investigations of atypical pneumonia originally instituted through the Commission on Influenza gave rise to the Commission on Acute Respiratory Disease, and those on air sterilization were developed by the Commission on Air-Borne Infection. Details of other studies are also included in the histories of the respective Commissions.
71 See footnote 24 (3), p. 98.
72 Alexander, H. E., Leidy, G., and MacPherson, C.: Production cf Types A, B, C, D, E, and F H. influenzae Antibody for Diagnostic and Therapeutic Purposes.J. Immunol. 54: 207-211, October 1946.
73 Smorodintseff, A. A., Gulmow, A. G., and Tscbalkina, O. M.: ? ber die spezifische Propyhlaxe der epidemischen Grippe durch Inhalation antigripp?sen Serums. Ztschr. f. klin. Med. 138: 756-765, 1940.
