History

CHAPTER XVII

Viral Hepatitis

John R. Paul, M.D., and Horace T. Gardner, M.D.

EVOLUTION OF CONCEPTS OF HEPATITIS

The story of hepatitis in World War II will not soon be forgotten. The dramatic impact of this disease on U.S. troops was heightened by the fact that, at the outbreak of war, little of a specific nature was known in the United States about viral hepatitis, either as a military disease or as a common civilian disorder.

Until the year 1942, there was relatively little appreciation of the fact that there may be two forms of hepatitis, the so-called infectious hepatitis and serum hepatitis. Whether the differences in these two forms are due to two viruses or to varieties of the same virus is still a moot point in some circles, but the question is not discussed in this history. It is sufficient to state that considerable experimental evidence indicates that there is a difference in these two agents in the human host and that their modes of transmission may differ, however indistinguishable clinically these two diseases may be. Infectious hepatitis and serum hepatitis are discussed separately for this reason and also because they confronted the U.S. Army essentially in separate epidemics; namely, (1) the great epidemic of serum hepatitis of 1942, transmitted by the inoculation of infected serum incorporated in yellow fever vaccine and (2) extensive epidemics of infectious hepatitis in the Mediterranean and Middle East theaters during the years 1943-45 and in the European and Pacific theaters mainly in 1945.

Actually, the first of these epidemics, that of serum hepatitis, fell upon the troops like another unsuspected bombshell within 4 months of Pearl Harbor, and viral hepatitis proved to be a scourge to the Army throughout the remaining years of the war and long after the end of hostilities.

How did it happen that the impact of this disease on the Army was unexpected? The answer probably lies in the fact that hepatitis had not been a significant problem to U.S. troops during World War I and the overall plans laid in 1941 for dealing with infectious disease were modeled largely on experiences of the Medical Department in the previous war.

It should be pointed out, however, that early in 1941 the Preventive Medicine Service in the Office of the Surgeon General had established a planning and investigative board, designed to investigate and control both

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the known epidemic diseases and those which might eventuate. This board was originally known as the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army. It was approved by the Secretary of War in January 1941 and subsequently became known as the Army Epidemiological Board. It is not surprising that no separate commission on hepatitis (p. 411) was established, for at that time no one could have foretold the importance which this disease was to assume, and most physicians (both military and civilian) did not appreciate its potential military importance or, indeed, its seriousness as a common disorder among civilians. What then were the views current in 1940 about hepatitis in the United States?

It would be presumptuous for any one or two persons to attempt to state the general concept of the medical profession in the United States in 1940 in regard to hepatitis. However, one can either do this or offer no review of the prewar situation at all, and perhaps the former is the lesser of two evils. It is the authors' impression that during the 1930's most physicians in the United States recognized an epidemic form of mild jaundice, which was distinct from Weil's disease but was ill-defined, uncommon, and probably different from the common sporadic disease known as catarrhal jaundice. This idea was held despite the fact that there was good evidence in Europe, England, and, indeed, in the United States that epidemics of mild jaundice were not rare and that epidemic and sporadic (or catarrhal) jaundice might, on occasions, be the same disease. However, the latter assumption was not particularly acceptable, and understandably so, because in the 1920's and 1930's many physicians believed that epidemic jaundice was a diffuse hepatitis often due to a spirochete such as the causative agent of Weil's disease, and that catarrhal jaundice, the sporadic disease, was an obstructive jaundice, said to be the result of a primary inflammation of the bile ducts and quite different in its pathology, prognosis, and clinical picture.

This view was held despite the fact that there was also good clinical and epidemiological evidence in medical publications that it was incorrect. Blumer¹ had been among the first in this country to uphold the idea that catarrhal jaundice probably was the sporadic form of infectious hepatitis. His evidence, presented in 1923, was excellent, but his views were not generally accepted for some 20 years. Blumer had been preceded in turn by Cockayne in England, who had published (Quart. J. Med. 6: 18, October 1912) a historical review with a comprehensive title, "Catarrhal Jaundice, Sporadic and Epidemic, and Its Relation to Acute Yellow Atrophy of the Liver," in which the unity of these conditions was stated prophetically in no uncertain terms. Cockayne's views also received little attention for a generation. Apparently, the reason for considering catarrhal jaundice to be a distinct entity, despite its unknown etiology, was that its name implied that the pathogenesis of this type of jaundice was an inflammation and catarrh of the biliary tract, particularly the common duct, which at the height of the disease might be

¹Blumer, G.: Infectious Jaundice in the United States. J.A.M.A. 81 : 353-358, 4 Aug. 1923.

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blocked by a mucous plug. So strong was this view that one school championed the idea that a rational, direct, and effective method of therapy was the removal of this plug of inspissated mucus "corking" up the ampulla of Vater, by the introduction of magnesium sulfate into the duodenum. This concept, that is, that the pathology of catarrhal jaundice developed from an extension of a gastroduodenitis upward into the terminal portion of the bile ducts causing edematous swelling and congestion with an increased production of mucus in the common bile duct, was still widely accepted in 1940. This is not surprising, for the concept had had strong backing for some 60 or 70 years.

The great pathologist, Virchow² had ascribed one common form of jaundice to a mucus plug in the ampulla of Vater resulting from "catarrh" which could arise from a multiplicity of causes, the so-called katarrhalische Gelbsucht.³ This idea had been carried down through successive editions of many textbooks of medicine, including Osler's influential text, for almost two generations. But the concept of the plug as an etiological agent had been challenged since the early 1920's. Thus, Eppinger,⁴ in Vienna, was the first to suggest that the pathogenesis of catarrhal jaundice was due rather to a hepatocellular necrosis. Eppinger's views were later upheld by Rich⁵ who reported in 1930 that, in the records of 11,500 autopsies performed at the Johns Hopkins Hospital during 40 years, there was not a single case in which the diagnosis of catarrhal jaundice could be regarded as accurate. Thus, it seems that the concept of the pathogenesis of the clinical entity known then as catarrhal jaundice had been based, correctly perhaps, on the existence of a primary duodenitis but that it had gone beyond the facts in suggesting that the jaundice was obstructive. Actual firsthand observations of this obstruction are few because patients seldom die with the diagnosis of catarrhal jaundice or, at least, pathologists have seldom confirmed the diagnosis. That such an entity as catarrh of the bile ducts exists, few would deny, but that it is the cause of most cases of sporadic jaundice which have gone under the name "catarrhal jaundice" seems most unlikely. Therefore, it appears in retrospect that catarrhal jaundice was more of a clinical than a pathological concept and that the vast majority of cases so called in reality included examples of either sporadic infectious hepatitis or serum hepatitis.

Epidemic jaundice, so-called icterus epidemicus, is an old disease said to have been recognized even in Hippocratic times. It has had a long military history, and accounts of epidemics of this disease have been recorded in Germany and elsewhere in Europe since the middle of the 18th century. From a

²Virchow, R.: Ueber das Vorkommen und den Nachweis des Hepatogenen, Insbesondere des Katarrhalischen Icterus. Virchows Arch. f. path. Anat. 32 : 117-125, 1865.
³Virchow had been anticipated in this explanation by others beside Bamberger. Donald Monro (p. 415) in 1764, in his discussion of jaundice, stated : "This disorder (jaundice) * * * sometimes takes its rise from a viscid Mucus or Pituita obstructing these passages."
⁴Eppinger, H.: Die Pathogene des Ikterus. Verhandl. d. deutsch. Gesellsch. f. inn. Med. 34 : 15-39, 1922.
⁵Rich, A. R.: The Pathogenesis of the Forms of Jaundice. Bull. Johns Hopkins Hosp. 47 : 338-377, December 1930.

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historical standpoint it has not always been easy to recognize what disease is meant by the term "icterus epidemicus." The serious form of icterus epidemicus, subsequently designated as Weil's disease, was differentiated on clinical grounds in 1886, although the discovery by Japanese workers of the spirochetal etiology of Weil's disease was not made until 1914. This discovery left its mark. It so influenced Noguchi that he shortly announced his belief that yellow fever was due to a leptospira. In any event, the influence of this discovery was such that the term "infectious hepatitis," or "epidemic jaundice," became for the time being synonymous with Weil's disease, and for a period of about 20 years (during the 1920's and 1930's) most important American textbooks of medicine eliminated from their lists of diseases the term "infectious hepatitis," including it instead under the title, "Weil's disease" or "leptospirosis."

Indeed, an understandable tendency still exists to confuse the mild form of epidemic jaundice, now known as infectious hepatitis, with Weil's disease. Perhaps this confusion may be attributed in part to the fact that, during the period 1920-45, there were erroneous reports of finding leptospira in the blood of patients in a variety of types of clinical cases of jaundice. Laboratory workers in civilian and military hospitals may be easily led astray by the finding of artifacts in the blood which can bear an uncanny resemblance to a living spirochete. This was a common error in a number of military hospitals during the early years of the war. However, a differentiation of Weil's disease from the disease we now know as infectious hepatitis can be made when good laboratory facilities are available, though it may, of course, be difficult under other conditions. Recent reports indicate that clinical differentiation on the basis of leukocytosis and albuminuria are not always dependable and that the most reliable diagnosis of Weil's disease may be made by leptospiral agglutination to various strains of the organism, since variability in the susceptibility of guinea pigs makes animal inoculation and subsequent dark-field examination occasionally unreliable.

Today, it is realized that the two diseases, infectious hepatitis and leptospirosis (Weil's disease), are quite different, and it is of prime importance to differentiate them. Weil's disease is rare in some parts of the world where infectious hepatitis is common. During 1944-45, about 60 cases of Weil's disease were reported in the total Army; 10 in continental United States, 20 in Europe, 5 in the China-Burma-India theater, and 25 in the Pacific.

This, then, was the rather confused concept with which the authors believe infectious hepatitis was regarded by physicians in this country during the prewar period and the early years of World War II.

HISTORICAL NOTE

Epidemic hepatitis is an old and ugly camp follower. Over and over again, accounts of it appear, written by military surgeons attached to the armies which fought back and forth across Europe in the 18th and 19th cen‑

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turies. During the Seven Years' War, the disease occurred in armies in the field in Germany and in the Low Countries, where it was described by Pringle⁶ and Monro.⁷ The disease in a British garrison at Malta was described by Cleghorn.⁸ Hirsch⁹ lists a number of these epidemics in the 19th century among German as well as other European troops from 1842 to 1856, and they are thoroughly discussed by Fr?hlich¹⁰ who reported some 30 epidemics, 4 of which he had studied himself. So common was this disease in Germany among both garrison and field troops that it became known as Kriegsikterus, Kriegsgelbsucht, or Soldatengelbsucht, just as it had been known among the French from the time of the Napoleonic Wars as the jaunisse des camps. During Napoleon's Egyptian campaign, the French Army had a severe epidemic which was described by the Baron Larrey,¹¹ whose avuncular relationship to the organization of the U.S. Army system of evacuation in the field is well known because of his influence on Jonathan Letterman.

U.S. wars, 1840-66.-Among U.S. troops, the best known early record is that of the Civil War, and the story of jaundice (hepatitis) among Union troops in that war is familiar to many students of American medical history. However, before the Civil War (1861-66), there already was evidence that hepatitis had been a problem in the U.S. Army. The nomenclature used was far from specific, but, during the period between 1840 and 1859, which includes the years of the Mexican War, 350 cases of "Hepatitis acuta" and 8 deaths due to this disease had been recorded. During the same period, 7 deaths due to "icterus" had been recorded.¹²

During the Civil War, this troublesome question of nomenclature again appears. How many of the cases of jaundice described as occurring among the Union troops were actually due to infectious hepatitis and how many to other causes is unknown, and of this fact that medical officers recording the medical history of the Civil War were well aware.¹³ They state: "Jaundice occurred frequently in the progress of the malarial and other fevers as the result of morbid changes affecting the liver or the blood." They also observe: "There were, however, a large number of hepatitic and haematemic disorders in which the alteration of the color constituted so prominent a symptom that

⁶Pringle, John: Observations on the Diseases of the Army in Camp and Garrison. 6th ed. London: A. Millar and T. Cadell, 1768.
⁷Monro, Donald: An Account of the Diseases Which Were Most Frequent in the British Military Hospitals From January 1761 to the Return of the Troops to England in March 1763. London: Millar, Wilson, and Durham, 1764.
⁸Cleghorn, George: Observations on the Epidemical Diseases in Minorca, From the Year 1744 to 1749. London : D. Wilson, 1751, p. 281.
⁹Hirsch, August : Handbook of Geographical and Historical Pathology. London : The New Sydenham Society, 1886.
¹⁰Fr?hlich, C. : Ueber Icterusepidemien. Deutsche Arch. f. klin. Med. 24 : 394-406, 1879.
¹¹Larrey, D. J. : Relation Historique et Chirurgical de l'Expedition de l'Arm?e d'Orient en Egypte et en Syrie. Paris : Demonville et Soeurs, 1803.
¹²Statistical Report on the Sickness and Mortality in the Army of the United States, 1855?1860. Ex. Doc. No. 52, 36th Cong. 1st sess., p. 322.
¹³Medical and Surgical History of the War of the Rebellion. Medical History. Washington : Government Printing Office, 1888, pt. III, vol. 1, pp. 874-879.

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the disease was recorded under the heading of jaundice. No less than 71,691 cases of this kind were reported among the white troops."

Generally, these military cases of jaundice were sporadic, but sometimes a series occurred in a command, constituting a local epidemic which was frequently associated with an outbreak of continued fever, the jaundice sometimes preceding the appearance of fever and sometimes following its subsidence. The evidence that many, if not the great majority, of these cases of jaundice were, in all probability, infectious hepatitis can be inferred from the records of the variation in the seasonal prevalence of jaundice as recorded in the white and Negro troops in the Atlantic and Central regions for the Union Army during the period from July 1862 to June 1866. These rates, which range from less than 1 to over 13 per 1,000, recall the seasonal incidence of viral hepatitis in U.S. troops in Europe during World War II, some 80 years later, that is 1944-46, where there was a characteristic rise in the infectious hepatitis cases during the late summer and fall. The high rates during certain seasons recorded in the Union Army in the Civil War probably reflect the local epidemics mentioned above. Specifically, they were recorded for white and Negro troops in the Atlantic region for the autumn of 1863 and in both the Atlantic and Central regions for 1865; rates reached 13.25 per 1,000 in November 1863 and 7.75 per 1,000 in August 1865. Several autopsy records of fatal cases are described in the medical history of the Civil War, and the picture of acute atrophy of the liver given therein is indeed compatible with that of infectious hepatitis.

U.S. experience, World War I.-In considerable contrast is the story of infectious hepatitis during World War I. Epidemic or infectious hepatitis did not appear to be, or at least was not regarded as, a problem of any significance for the U.S. Army, although the same cannot be said of the British or the French armies, particularly of their troops at Gallipoli. In the medical history of the U.S. Army during World War I, infectious jaundice is dismissed with 13 lines. The term "infectious jaundice" was at that time a synonym for Weil's disease. The statement is made under the heading Infectious Jaundice that the cause is a spirochete. The U.S. Army reported 452 admissions for spirochetal jaundice and 15 deaths due to the disease during World War I. This total included 35 officers. The geographic distribution of the remaining 417 cases was as follows: The United States, 279; Europe, 108; the Philippine Islands, 15; Panama, 9; other countries, 5; and transports, 1. To the 452 original admissions must be added 80 instances in which the same malady occurred concurrently with other disease admissions among enlisted men in the United States and Europe making a grand total of 532 cases. It would seem at first thought that the U.S. Army had been remarkably fortunate in escaping outbreaks of infectious hepatitis in World War I, but, as a matter of fact, in retrospect one might question whether or not it really was good fortune. Had the Army had even a little more experience

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with this disease, it is possible that more extensive preparations would have been made for its occurrence in World War II.

British and French experiences, World War I.-During World War I, epidemic catarrhal jaundice or infective hepatitis broke out among British troops in Alexandria in July 1915 and rapidly spread to Gallipoli, Mo?dhros, Thessalon?ki, and Mesopotamia. As an example of its severity, from the 13th British Division at Anafarta Limani, 555 cases occurred in June alone in 1916. Spirochetal jaundice was definitely excluded. It was noted by the British that the peak of the jaundice outbreak occurred about 3 weeks after the summit of the dysentery curve was reached and that a recent history of diarrhea was common in the hepatitis cases. Willcox,¹⁴ who reported on the epidemics in the Dardanelles, made the following observations: "The epidemic jaundice of campaigns appears to start as a gastrointestinal infection, * * * and is almost certainly conveyed by the alimentary tract and contamination of food with infective dust probably plays a most important part in the causation. Flies also * * * may convey infection to food; but they are probably not the main cause of the spread of the disease." He also incriminated water as a possible source of infection. Even though his epidemiological evidence was based mainly on rather fragmentary data, a lesson is implicit here in regard to this disease and to others: That it is profitable to examine and investigate theories of transmission in infectious disease held by those with field experience even though the experimental evidence is scanty. It was not, of course, until World War II that Voegt,¹⁵ in Germany, and workers in England and the United States (p. 435) were able to establish that the disease could be transmitted by feeding infected stools, and the first experimental evidence of waterborne infectious hepatitis was reported by Neefe and Stokes in 1945.¹⁶

Epidemic jaundice also occurred among French troops in the Dardanelles where an attempt to associate it with salmonellal infections was made, a relationship which has not yet been completely clarified. There were very extensive epidemics of this disease among both German and Rumanian troops in Rumania in 1917.

In none of these epidemic areas such as the eastern Mediterranean, the Middle East, or the Balkans, were U.S. troops stationed during World War I. However, a mild epidemic of epidemic jaundice did occur among U.S. troops in 1918 in the Army of Occupation on the Rhine.

In brief, then, there was in World War I extensive British, French, German, and Rumanian experience with large epidemics of infectious hepatitis,

¹⁴Willcox, W. H.: The Epidemic Jaundice of Campaigns. Brit. M.J. 1 : 297-300, February 1916.
¹⁵Voegt, H. : Zur Aetiologie der Hepatitis Epidemica. M?nchen. med. Wchnschr. 89 : 76, 23 Jan. 1942.
¹⁶Neefe, J. R., and Stokes, J., Jr. : An Epidemic of Infectious Hepatitis Apparently Due To a Water Borne Agent. J.A.M.A. 128 : 1063-1075, 11 Aug. 1945.

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particularly in certain special areas such as Egypt, Mesopotamia, the Dardanelles, and the Balkans, an experience which the U.S. Army did not share.

There is little indication that serum hepatitis had ever played any part in military medical history before World War II, unless one counts the experiences in the 1920's and 1930's which the Germans encountered in their salvarsan clinics. "Salvarsangelbsucht" was particularly noted by Ruge¹⁷ in the German Navy, and received rather special and prolonged attention from him, as will be discussed later (p. 420) .

U.S. troops during period between world wars.-During the period between World War I and World War II, infectious hepatitis in the Army both within and without the continental United States probably occurred at about the same rate as it did in the civilian population of the United States. Because the disease was not reportable, the incidence in civilians is not known. That it was regarded as being of no great significance in the U.S. Army may be seen from the fact that before 1939 it was reportable not as an entity but under "spirochetal hemorrhagic jaundice," under "other protozoal diseases," or under "other disease of the gallbladder and biliary passages" and until 1943, when the first single code for infectious hepatitis was provided, was variously reported or coded as "spirochetal jaundice," "cholangitis," or "other disease of the gallbladder and biliary ducts." Table 44 shows the approximate admission data for hospitalized cases of cholangitis in the U.S. Army between 1931 and 1942.

TABLE 44.-Admissions and admission rates for cholangitis in the U.S. Army, by year, 1931-41¹

[Rate expressed as number of admissions per annum per 1,000 average strength]

Year	Admissions	Rate	Year	Admissions	Rate
1931	273	2.02	1937	263	1.50
1932	305	2.31	1938	318	1.74
1933	251	1.84	1939	370	1.93
1934	250	1.86	1940	549	1.63
1935	234	1.64	1941	1,611	1.20
1936	269	1.63

¹Data for the years 1931 through 1938 are for "Other diseases of gallbladder and biliary passage" which included, in addition to cholangitis, a very few cases of adhesions of gallbladder, stricture of gall ducts, and other diseases of gallbladder.

Summary.-In 1941, the likelihood of infectious hepatitis and serum hepatitis becoming epidemic diseases of potential danger to U.S. troops seemed extremely remote. Serum hepatitis was practically unknown as a military disease. Throughout the medical profession in this country the concept of infectious hepatitis had received scant attention, and there was not a little misinformation about it in widely used texts. On the other hand, in 1940 the

¹⁷Ruge, H.: Zehn Jahre Gelbsucht in der Marine (1919-1929), Beobachtungen an 2500 Fallen. Ergebn. d. inn. Med. u. Kinderh. 41 : 1-112, 1931.

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British troops had already begun to experience epidemics of hepatitis in their troops in North Africa, and there was actually, at the same time, a considerable amount of correct and important information about infectious and serum hepatitis available in medical literature which was not to be generally realized or perhaps appreciated in this country until early in 1942.

THE SERUM HEPATITIS EPIDEMIC OF 1942

It was only a few months after the declaration of war in December 1941 that the most extensive outbreak of serum hepatitis ever to be recorded in military history broke out among U.S. troops both in the United States and abroad. This outbreak of "jaundice" in the Army, which began in February 1942, was the cause of great concern to the Medical Department and particularly to the Preventive Medicine Service, Office of the Surgeon General. Not the least of its disconcerting features was the fact that it was so unexpected, and also that some 4 or 5 weeks elapsed before there was general acceptance of the fact that it was actually homologous serum jaundice following vaccination for yellow fever and perhaps not due to attenuated yellow fever virus.¹⁸

In brief, the events were as follows: In February 1942, an increased incidence of jaundice in the Army of the United States was reported to the Preventive Medicine Service of the Office of the Surgeon General. By March it was evident that a widespread epidemic was imminent, and it was soon apparent that the epidemic was not limited to the continental United States but was occurring simultaneously in troops in such widely separated regions as Hawaii, the Southwest Pacific, Alaska, Iceland, and England. For 4 or 5 weeks, the nature of this outbreak was in doubt, but data submitted by a team of the Army Epidemiological Board seemed conclusively to exclude toxic agents or contacts with infected civilians as causes and established statistically a causal relationship between the administration of certain lots of yellow fever vaccine which had been given 2 or 3 months previously. On the basis of this information and an analysis of reports from various affected units, The Surgeon General, on 15 April 1942, discontinued the administration of serum-containing yellow fever vaccine. At that time it seemed possible that an icterogenic agent, perhaps the unknown cause of infectious hepatitis, had been introduced into the vaccine by way of the human serum used in its preparation. Subsequently, this was abundantly proved. A serum-free vaccine was substituted in April 1942, and no jaundice that was proved to be associated with yellow fever vaccination, per se, developed subsequently in recipients of this vaccine.

Although hindsight is infinitely and prosaically clearer than foresight, it is perhaps not too hard today to understand why there was so much diffi‑

¹⁸For certain sections of this account, particularly those dealing with the facts which led to discontinuance of the icterogenic yellow fever vaccine, the authors are especially indebted to Brig. Gen. Stanhope Bayne-Jones and to Dr. Kenneth F. Maxcy.

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culty in determining the origin and nature of this outbreak of serum hepatitis. A review of the diagnostic problems is instructive. Serum hepatitis, or syringe hepatitis, had never occurred or been recognized before as a problem in the U.S. Army or in any army. Civilian outbreaks of postvaccinal or postinoculation hepatitis, although recorded, had not received much attention in the United States before 1942, because the literature on this subject had either been published largely in England and elsewhere abroad or at least had dealt with populations which had been inoculated abroad. The serum-containing menstruum of the yellow fever vaccine, which came under suspicion in February 1942, had been heated to 56?C. and was therefore considered free of contaminants. This led to a false sense of security because it was not generally appreciated then that the virus of serum hepatitis is more thermostable than most well-known viruses pathogenic for man.

Historical Background

It may be wise to review at this time the prewar history of serum hepatitis. Probably the first example of postvaccinal, or needle, hepatitis was the epidemic observed by L?rman¹⁹ in Bremen from October 1883 to April 1884. Among 1,200 to 1,500 workmen employed in a shipyard during this period, there were approximately 200 cases of jaundice, while in Bremen itself during the same period there were very few sporadic cases of jaundice. L?rman found that during a period of 19 days, 1,289 workmen had been vaccinated with human glycerinized lymph. Within a few weeks, 191 of these men became jaundiced while none of 500 men vaccinated with a different lymph at the same time acquired jaundice. After concluding it was due to "bad lymph," L?rman remarked on the rather unusual fact that the incubation period was prolonged from several weeks to even a couple of months. Here is perhaps the first description of the artificial inoculation of hepatitis.

This was followed in the same year by a report by Jehn²⁰ of another such outbreak in Germany occurring in Merzig. Here, five different groups were vaccinated by four different doctors using lymphs from five different sources. In one group, more than 25 percent of those vaccinated contracted hepatitis; in others, the percentage was much lower. The incubation period was from 2 to 8 months, which is suggestive of the long incubation period of serum hepatitis. The episodes in Germany were apparently regarded as curiosities, and their significance was forgotten for many years. In fact, it was not until 36 years later that Dr. John H. Stokes,²¹ at the Mayo Clinic, Rochester, Minn., regarded the jaundice which had occurred in a group of patients undergoing antisyphilitic treatment as being due to infectious jaundice. Dr. Stokes believed, as did Ruge in Germany 5 years later, that catarrhal jaundice and

¹⁹L?rman, A.: II. Eine Icterusepidemic. Berl. klin. Wchnschr. 22: 20-23, January 1855.
²⁰Jehn -.: Eine Icterusepidemie in wahrscheinlichem Zusammenhang mit vorausgegangener Revaccination. Deutsche med. Wchnschr. 11 : 339-340, 354-356, May 1885.
²¹Stokes, J. H., Ruedemann, R., Jr., and Lemon, W. S.: Epidemic Infectious Jaundice and Its Relation to the Therapy of Syphilis. Arch. Int. Med. 26: 521-543, November 1920.

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salvarsan icterus represented the same entity. Both syphilologists presumed that either the luetic infection or its treatment were factors predisposing to the acquisition of the hepatitis that followed the type of intravenous therapy then employed. Neither Stokes nor Huge actually regarded the needles or syringes with which treatments were given as potential means for the transfer of the infection.

In 1926, however, a remarkable paper by Flaum, Malmros, and Persson²² anticipated almost all of our present concepts regarding the transmission of infectious hepatitis. Describing an epidemic of hepatitis which occurred among patients in a diabetic clinic, they not only implicated the syringe and needle in the transfer of the disease but even suggested that the virus might have been transferred by means of the lancet used for blood counts. Furthermore, they noted the length of the incubation period in their cases as compared with spontaneous catarrhal jaundice and posed the question whether or not there might be two viruses.

Postvaccinal jaundice was next recorded in Africa where it was observed in the course of yellow fever vaccination. Findlay and MacCallum²³ reported in 1937 and in 1938 that in the course of 4? years they had vaccinated approximately 2,200 persons against yellow fever and observed 52 cases of jaundice occurring from 2 to 7 months after this vaccination. In their 1939 report, Findlay, MacCallum, and Murgatroyd²⁴ stated that there had been a total of 96 cases among 3,100 persons vaccinated, or slightly more than 3 percent. In some groups, the incidence was apparently as high as 15 percent. During this period, the actual method of vaccination underwent several changes. The basic principle consisted of the use of a mouse passage neurotropic strain of yellow fever virus grown in tissue culture in a medium containing Tyrode's solution, chick-embryo tissues, and normal monkey, or normal human, serum. Human serum had been added also as a stabilizing vehicle in the stage of desiccation (lyophilization) of the vaccine.

Findlay and MacCallum were convinced that jaundice was not caused by the yellow fever virus itself. In their 1939 report they again analyzed in detail various factors involved in this episode and came to the conclusion that the causal agent of the jaundice was a virus, that it had been cultivated serially in tissue cultures in symbiosis with yellow fever virus, and that it must have been introduced into tissue cultures in association with human serum. As further proof of the viral nature of the icterogenic agent, they stated that it must have passed filters freely, as the yellow fever virus was filtered frequently during cultivation in vitro. In an effort to eliminate this

²²Flaum, A., Malmros, H., and Persson, E.: Eine nosocomiale Ikterus-epidemie. Acta med. Scandinav. Suppl. 16 : 544-553, 1926.
²³(1) Findlay, G. M., and MacCallum, F. O.: Note on Acute Hepatitis and Yellow Fever Immunization. Tr. Roy. Soc. Trop. Med. & Hyg. 31 : 297-308, November 1937. (2) Findlay, G. M., and MacCallum, F. O.: Hepatitis and Jaundice Associated With Immunization Against Certain Virus Diseases. Proc. Roy. Soc. Med. 31 : 799-806, May 1938.
²⁴Findlay, G. M., MacCallum, F. O., Murgatroyd, F. : Observations Bearing on the Aetiology of Infective Hepatitis (So-Called Epidemic Catarrhal Jaundice). Tr. Roy. Soc. Trop. Med. & Hyg. 32: 575-586, February 1939.

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contaminating virus, they changed their method of vaccine production. When they began to use a newly received strain of yellow fever virus, the 17D strain, which was sent to them from the laboratories of the International Health Division of the Rockefeller Foundation, New York, N.Y., in November 1937, the jaundice failed to appear among approximately 8,000 persons vaccinated.

Jaundice as a result of vaccination against yellow fever began to be recorded from other geographical areas. Soper and Smith²⁵ described, in 1938, an outbreak which followed vaccination against yellow fever in 1936 and 1937 in Brazil. At that time, the virus used was the 17E strain grown in tissue cultures with a human serum mixture. However, this was complicated by the fact that the patients concomitantly received hyperimmune monkey serum. Apparently, more than 30 percent of those vaccinated with this material developed jaundice. No definite conclusion was reached at that time as to the jaundice, but the serum came under suspicion. In 1939, another sharp outbreak of jaundice was observed in Brazil and described by Sawyer.²⁶ A new strain of virus was sent from the New York laboratories to Brazil, and the manufacture of vaccine was resumed in 1940. In addition to the change of the strain of virus, the use of human serum in the preparation of the vaccine was discontinued, and in 1944 it was reported that no further cases of postvaccinal jaundice had occurred.

In the meantime, jaundice following the use of immune serum given as a prophylactic against other diseases was reported elsewhere. In 1938, Propert²⁷ published the observation that, following the injection of a pool of measles-immune serum in children in England, a number of cases of hepatitis occurred, some of them fatal. At the same time, MacNalty²⁸ published a similar report stating that two groups of individuals, numbering 82 and 109 persons, respectively, had been inoculated with the same pool of measles-immune serum, 37 of these had developed jaundice, and 7 had died.

It would seem, then, that at least in certain circles the existence of serum hepatitis had become well appreciated, although actually the general concept was not widespread, nor had it appeared in the general medical literature in the United States.

The Postvaccinal Epidemic

By 1940, the vaccination of individuals against yellow fever had become a widely used and well-recognized prophylactic measure effective in protect‑

²⁵Soper, F. L., and Smith, H. H. : Yellow Fever Vaccination With Cultivated Virus and Immune and Hyperimmune Serum. Am. J. Trop. Med. 18 : 111-134, March 1938.
²⁶Sawyer, W. A., Meyer, K. F., Eaton, M. D., Bauer, J. H., Putnam, P., and Schwentker, F. F. : Jaundice in Army Personnel in the Western Region of the United States and Its Relation to Vaccination Against Yellow Fever. Am. J. Hyg. 40 : 35-107, July 1944.
²⁷Propert, S. A. : Hepatitis After Prophylactic Serum. Brit. M.J. 2 : 677-678, 24 Sept. 1938.
²⁸MacNalty, A. S. : Acute Infectious Jaundice and Administration of Measles Serum. In Great Britain, Ministry of Health. On the State of the Public Health. Annual Report of the Chief Medical Officer of the Ministry of Health for the Year 1937. Publication No. 42. London : His Majesty's Stationery Office, 1938.

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ing individuals against this disease. It had become a routine procedure in certain areas. Furthermore, the annoying occurrence of jaundice following vaccination had apparently been eliminated and this vaccinating procedure certainly must have appeared as a safe and logical one to use on troops. It was recognized as a new and valuable prophylactic measure for the preventive medical officer in global warfare. Early in 1941, with the impending outbreak of hostilities, the Preventive Medicine Service in the Office of the Surgeon General was faced with a decision as to the extent to which yellow fever immunization should be employed in U.S. troops. At that time, the war was being bitterly waged in Africa and, although Japan had not yet declared war against the Allies, the possibility of troop movements to or from Africa, India, and the East and the transfer of U.S. troops to these areas was unpredictable although certainly possible. In particular, attention was called to the possibility of introducing yellow fever from Africa into India, a danger which had long been under discussion and which, had it materialized, would have been an epidemic calamity of the first order.

In the summer of 1940, an epidemic of yellow fever occurred in the Nuba Mountains of the Anglo-Egyptian Sudan.²⁹ There were 15,000 cases and more than 1,500 deaths reported in this epidemic. The proximity of this outbreak to the African war zones, together with the risks to the local civilian populations, had created a great demand for vaccine to be used in this area. Furthermore, the questions had arisen whether or not British troops might have to withdraw from North Africa and Egypt to the Sudan and whether or not U.S. troops might have to be placed in large numbers in this area or other potential epidemic areas, thus giving rise to strong indications for vaccination against yellow fever.

As it is the purpose of this chapter to discuss technical and scientific aspects of the vaccination of U.S. troops against yellow fever and the relation of the vaccine administered late in 1941 and early in 1942 to the subsequent large outbreak of jaundice, matters of determination of policy and the reasons therefor will not be included. For these important details, the reader is referred to volume III of this series.³⁰ Additional details are to be found in the articles by Sawyer.³¹

The policy of vaccinating on a large scale was adopted in 1940 on the recommendation of the Subcommittee on Tropical Diseases of the National Research Council and was put into effect in 1941. This caused unprecedented demands on the supply of yellow fever vaccine. To meet these demands, the manufacture of yellow fever vaccine on a large scale for military use was organized late in 1940 by the International Health Division of the Rockefeller

²⁹Kirk, R.: Epidemic of Yellow Fever in the Nuba Mountains, Anglo-Egyptian Sudan. Ann. Trop. Med. 35: 67-112, October 1941.
³⁰Medical Department, United States Army. Preventive Medicine in World War II. Volume III. Personal Health Measures and Immunization. Washington : U.S. Government Printing Office, 1955, p. 306, Vaccination Against Yellow Fever and footnotes thereto.
³¹See footnote 26, p. 422.

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Foundation. During the period from 1940 to 1942, approximately 11 million doses of this vaccine were supplied by this agency.

A number of changes in the technique of the manufacture of the vaccine were introduced in the course of the large-scale production between 1940 and 1942, and these have been carefully reviewed by Sawyer. The history of the seed virus used is complicated and will not be reviewed here, but the addition of human normal serum was a crucial point in the procedure. During the 4 years of in vitro cultivation before final adoption for human immunization, the 17D strain of yellow fever virus originally derived from the unmodified Asibi strain was used. It was grown in a medium of chick-embryo tissue and Tyrode's solution containing 10 percent normal monkey or human serums. The reason for including human serum in the vaccine was to insure its efficacy as an immunizing agent. The virus of yellow fever is said to be one of the most labile viruses, and the addition of serum to it delays its inactivation process greatly. For large-scale manufacture of the yellow fever vaccine, therefore, large quantities of human serum were needed for the tissue cultures. This was usually obtained from professional blood donors, but in 1941 it became necessary to arrange for additional sources of serum, which was required at the rate of 8 or 10 liters per week. This additional source of serum was obtained through the School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Md., where it was secured from volunteers in that city. The donors consisted largely of medical students, interns, nurses, and laboratory technicians, all presumably healthy. In retrospect, it would seem that it was this "innocent" lot of serum which gave rise to contamination of the vaccine with an icterogenic agent, an accident which could hardly have been predicted at that time.³²

It is important to point out that the serum was inactivated by heat. Onreceipt of the serum from Baltimore, a sterility test was first made on thecontents of each bottle, and it was then immersed in a covered serologic water bath and held at a temperature between 56? and 57? C. for 1 hour.The actual temperature of the serum during inactivation was not measured,but it is known that there is a certain timelag before the temperature of theserum in the flasks and that of the surrounding water reach an equilibrium.It was estimated that this lag may have varied from 10 to 30 minutes, butit is reasonable to believe that all serums were inactivated at a temperatureof 56? C. in 30 minutes. This is important, for no doubt it gave the manufacturers of the vaccine confidence that all viable contaminating agents hadbeen killed, whereas there now is abundant evidence that this temperature isinsufficient to kill the virus of either infectious hepatitis or serum hepatitis.

The widespread military use of this vaccine was begun in the late fallof 1941. As already stated, an unusual number of cases of jaundice began

³²Whether or not the hepatitis virus, originally introduced into the tissue culture by means of the serum, actually grew in the eggs will not be discussed here.-J. R. P. and H. T. G.

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to appear in troops during February 1942. It was apparent by the first week in March 1942 that a disease characterized by jaundice was epidemic in the Army. From stations all over the country, reports came of the unusual incidence. Although the disease resembled so-called epidemic catarrhal jaundice, there was a suspicion that it might have some relationship to the administration of yellow fever vaccine, and after some investigation this deepened into a strong conviction. The evidence leading to this conviction was derived from outbreaks of jaundice which occurred in military units, organizations, posts, and camps in this country as well as outside the continental United States. From these observations, it appeared that invariably the soldiers who developed hepatitis in widely scattered areas and under different environmental conditions had been vaccinated with certain lots of yellow fever vaccine.

The Preventive Medicine Service made extensive use of personnel of the Board for the Investigation and Control of Influenza and Other Epidemic Diseases (Army Epidemiological Board) and its commissions. A number of the members of this Board or of its commissions had become convinced early in April 1942 that the cases resulted from the administration of yellow fever vaccine.

Actually, this decision had been reached independently in a number of areas. In a note from Stockton Field, Calif., on 20 March 1942, Dr. Karl F. Meyer of the George Williams Hooper Foundation stated that he believed the cases of jaundice had resulted from the administration of yellow fever vaccine. On 10 April 1942, Dr. Meyer stated to the senior author upon his arrival in San Francisco, Calif., that it seemed practically assured that the vaccine contained an icterogenic agent which was responsible for the outbreak. Dr. Kenneth F. Maxcy, who was investigating cases at Jefferson Barracks, Mo., at about this same time, and a number of other investigators, arrived at a similar conclusion.

As a result, the use, by the Army and other agencies, of all yellow fever vaccine manufactured by the International Health Division of the Rockefeller Foundation was discontinued. The chief lot numbers finally incriminated as being icterogenic were 331, 334, 335, 338, 367, 368, and 369. A vaccine prepared by the U.S. Public Health Service in its Rocky Mountain Laboratory, Hamilton, Mont., was substituted. Subsequently, the vaccine was prepared without the human serum component. After this action, cases of jaundice following inoculation with yellow fever ceased to occur.

Thus, the evidence incriminating the vaccine was accumulated by the various teams in the field. The indictment of the vaccine, particularly by Dr. Maxcy after his investigation at Jefferson Barracks, made the investigation perhaps one of the most dramatic and effective epidemiological investigations carried out during the war.

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Extent of postvaccinal epidemic

The total number of infectious hepatitis cases reported during 1942 is provisionally set at 49,233 for the total U.S. Army (chart 3). Of these, 33,569 were reported from the continental United States, and 15,664 from oversea theaters. Although the vast majority of these cases were probably due to the vaccineborne infection, it is impossible actually to determine how many were postvaccinal. However, the type of epidemic curve in 1942 certainly suggests that the great majority of these cases followed the use of the yellow fever vaccine. The rapid subsidence of the epidemic followed discon‑

CHART 3.-Reported weekly admissions for jaundice (essentially serum hepatitis) in thetotal U.S. Army, 1 January to 31 December 1942

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tinuation of the vaccine which occurred after the peak of the epidemic had been reached in June 1942. The time relationship is perfectly in keeping with the incubation period of serum hepatitis.

Table 45 contains data concerning admissions for and deaths due to infectious hepatitis and serum hepatitis in 1942 in the various areas. The size of this epidemic of serum hepatitis can be visualized also from a glance at chart 3, which shows the reported admissions of jaundice in troops in the total U.S. Army during 1942. The shape of the epidemic curve and the fact that it occurred out of season are obviously related to the manner in which the Army's vaccination program against yellow fever was carried out.

TABLE 45.-Admissions for and deaths due to infectious hepatitis and serum hepatitis in theU.S. Army, by theater or area, 1942¹

[Admission rate expressed as number of admissions per annum per 1,000 average strength; death rate expressed as number of deaths per annum per 100,000 strength]

Theater or area	Admissions		Deaths
Theater or area	Number	Rate	Number	Rate
Continental United States	33,569	12.63	63	2.37
Overseas:
North America²	4,380	43.53	11	10.93
Latin America	863	8.47	2	1.96
Europe	1,950	23.49	2	2.41
Pacific Ocean Area	6,306	41.77	5	3.31
Southwest Pacific	1,888	26.51	1	1.40
Other areas	277	7.34	---	0
Total overseas	15,664	26.74	21	3.59
Total Army	49,233	15.18	84	2.59

¹The admission data are partially estimated and are based on tabulations of individual medical records and the statistical health report. Mortality data are based on complete tabulations of individual medical records, but they probably represent the minimum number of deaths due to infectious hepatitis and serum hepatitis. Some of the deaths ascribed to acute yellow atrophy of the liver or related conditions were probably caused by viral hepatitis. All data are preliminary.

²Includes Alaska.

During the latter part of 1941, all air corps personnel and the ground troops who were alerted for oversea duty were the first units to be inoculated with the yellow fever vaccine. It was subsequently found that the vaccine administered at this time included three highly icterogenic lots. Between 20 January and 15 April 1942, all other personnel in the Army were vaccinated. For the overall period, six highly icterogenic lots were found. Since the incubation period for serum hepatitis ranges from 60 to 154 days, it becomes apparent that the first peak in chart 3 resulted from the use of the icterogenic lots of vaccine in late 1941. Similarly, the later administration of addi‑

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tional icterogenic lots to a much greater number of troops gave rise to a second and higher peak.

Another feature which should be appreciated is that the long incubation period of serum hepatitis is exceedingly variable. Even when the icterogenic virus has been administered to all members of a given unit at one time, the onset of the resulting cases may be spread over many weeks or months, resulting in the picture of a continuing epidemic. Thus, the day-by-day epidemic curve for Camp Polk, La., which was studied by Parr,³³ appears to be that of a long epidemic, yet it was precipitated by a single, uniform exposure, for all of these men were inoculated on the same day with the same lot and dose of vaccine. The statistics showed that at Camp Polk on 27 February 1942 more than 5,000 soldiers were inoculated with lot number 369 of yellow fever vaccine and that they remained at this camp for the next several months. Among these soldiers, 1,004 cases of jaundice appeared. The range of the incubation period of these 1,004 cases was from 60 to 154 days; the mean incubation period was 96.41 days. Chart 4 well illustrates

CHART 4.-Variation in incubation period of 1,004 cases of serum jaundice following uniformsingle inoculation with yellow fever vaccine at Camp Polk, La., on 27 February 1942

³³Parr, L. W. : Host Variation in the Manifestation of Disease : With Particular Reference to Homologous Serum Jaundice in the Army of the United States. M. Ann. District of Columbia 14 : 443-449, October 1945.

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the manner in which an epidemic precipitated by a common source of infection may be influenced by host variation as expressed by an incubation period of varying duration. It is a demonstration by Parr of one of the features in which this disastrous epidemic may be said to have contributed to the science of epidemiology.

Other indications of the icterogenic nature of the vaccine were the different experiences of the Army and Navy. The Navy, using different lots of vaccine, reported practically no jaundice during 1942. The Navy did not receive icterogenic lots of vaccine, except numbers 334 and 369, and used these lots to a limited extent.

Of further epidemiological importance was the fact that this disease did not spread within the camps to nonvaccinated individuals. If it had, the situation would have been hopelessly confused. This is in keeping with later experimental work which has indicated that the patient with serum hepatitis is not very infectious unless blood is taken from him during the stage of viremia and inoculated into another person. Some evidence for cross infection has been reported by Freeman³⁴ in that four wives of soldiers who had received yellow fever vaccine (three of whom had developed postvaccinal jaundice) acquired hepatitis with jaundice. This must have been a relatively uncommon occurrence. The fact that it may occasionally occur as the result of intimate contact is, however, a point of considerable importance. Freeman believed that the spatial and temporal grouping of cases in the epidemics of serum hepatitis at Fort Belvoir, Va., Fort Sill, Okla., and Fort Lewis, Wash., among troops who had received yellow fever vaccine at approximately the same time, together with an increase in the attack rate in unvaccinated troops in the same period in these forts, indicated a communicable disease rather than one directly due to inoculation of the agent in the vaccine. He advanced the theory that the vaccine predisposed the affected individuals to a naturally occurring infectious hepatitis. The authors believe this to be highly unlikely. An overwhelming preponderance of evidence pointed to the vaccine as the causative agent, although some Army medical officers and some civilian physicians steadfastly opposed this view, and of these a small minority apparently still do to this day.

Clinical aspects

In such a large number of cases of hepatitis, there was no dearth of clinical material. Several clinical studies of large series of cases were made. The best of the early descriptions was that by Turner and coworkers.³⁵ They described their experiences with this disease at Camp Polk, where the

³⁴Freeman, G. : Epidemiology and Incubation Period of Jaundice Following Yellow Fever Vaccination. Am. J. Trop. Med. 26: 15-32, January 1946.
³⁵Turner, R. H., Snavely, J. R., Grossman, E. B., Buchanan, R. N., and Foster, S. O.: Some Clinical Studies of Acute Hepatitis Occurring in Soldiers After Inoculation With Yellow Fever Vaccine, With Especial Consideration of Severe Attacks. Ann. Int. Med. 20: 193-218, February 1944.

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number of hepatitis patients reported during the period from 1 May to 12 September 1942 was 4,083 with 14 deaths-a very large series of cases, indeed.

It is not the function of this review to dwell on the clinical picture of serum hepatitis or its therapy in this epidemic, except as it pertains to the etiology and epidemiology of the viral hepatitides. By and large, Turner and coworkers believed the acute hepatitis in these epidemics was indistinguishable clinically from infectious hepatitis or catarrhal jaundice. They did, however, note special features, which subsequent authors have also stressed. For example, the disease at Camp Polk nearly always began insidiously without a preliminary bout of fever. This is in some contrast to the clinical picture of infectious hepatitis where the onset of the disease is more apt to be abrupt and accompanied by initial fever in a large percentage of cases.

In the fatal cases of serum hepatitis, death usually occurred from 2 to 6 weeks after the onset of illness. Autopsy findings ranged from that of acute yellow atrophy to that of a very irregular liver with islands or "lobules" of regenerated liver cells. Prominent changes in organs other than the liver included edema of the gastrointestinal tract. Extensive descriptions of the pathology of the liver in fatal cases in this outbreak may be found in the paper by Col. Balduin Luck?.³⁶

In retrospect, it would seem that the experience with this epidemic was not altogether unfortunate. It was drastic enough at the time to leave a deep impression in the minds of Army medical officers. Difficulties with serum jaundice were to continue for the rest of the war and indeed to the present time, but few events could have driven home the lesson so forcibly as did this 1942 epidemic. From this experience, it gradually became apparent to the medical profession that jaundice following transfusions and the administration of pooled plasma or, in fact, the use of any serum presents a considerable problem and that serum or syringe hepatitis is an avoidable complication which has demanded increasing attention since it was first recognized.

The fact that there are a variety of methods of artificially inducing hepatitis besides transfusion or serum injection has been slowly and painfully impressed upon the medical profession. For example, it became apparent that cases of serum hepatitis actually could follow the use of improperly sterilized needles and syringes used for giving injections. This was experienced in various types of clinics including diabetes and arthritis clinics, as well as in performing blood counts. It was realized that so-called arsphenamine jaundice actually represented examples of syringe hepatitis transmitted in the course of intravenous therapy. In certain clinics where the rate of postarsphenamine jaundice had been very high, the introduction of improved sterilization techniques caused the incidence of syringe jaundice

³⁶Luck?, B. : I. The Pathology of Fatal Epidemic Hepatitis. II. The Structure of the Liver After Recovery From Epidemic Hepatitis. Am. J. Path. 20: 471-593, 595-619, May 1944.

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to undergo a spectacular decline. The whole question of jaundice following intravenous therapy for syphilis was reviewed by British physicians, both military and civilian, particularly during 1943 and 1944.

Thus, the concept that the syringe could serve as a possible vector of disease has developed. In future military preventive medicine, the contaminated syringe may receive as serious consideration as a vector of disease as mosquitoes or flies.

IMPORTANCE AS A MILITARY PROBLEM

The importance of infectious hepatitis as a military problem in World War II is nowhere better illustrated than in the overall rates for the total Army, both within the Zone of Interior and in oversea areas. During the entire war experience, the total number of cases was about 200,000. Since the average period of hospitalization or illness per case was from 25 to 50 days, a huge amount of time was lost from active duty as a result of this illness. Furthermore, this time loss occurred at critical periods and in critical areas of combat. Table 46 well illustrates the great importance of infectious hepatitis as a military problem.

TABLE 46.-Admissions for infectious and serum hepatitis in the U.S. Army, by broad geographic area and by year, 1942-45

[Rate expressed as number of admissions per annum per 1,000 average strength]

Area	1942-45		1942		1943		1944		1945
Area	Number	Rate	Number	Rate	Number	Rate	Number	Rate	Number	Rate
Continental United States	46,750	3.17	33,569	12.63	3,906	0.75	3,175	0.80	6,100	2.08
Overseas	135,633	12.63	15,664	26.74	24,966	14.79	24,608	6.44	70,395	15.16
Total Army	182,383	7.16	49,233	15.18	28,872	4.20	27,783	3.57	76,495	10.10

The total number of admissions reported for hepatitis (both infectious and serum) from 1942 to 1945 was 182,383 for U.S. troops. The total number of deaths due to infectious hepatitis was recorded as 352. This number probably represents the minimum number of deaths caused by infectious and serum hepatitis. Some of the deaths ascribed to acute yellow atrophy of the liver or related conditions were probably caused by viral hepatitis. It will be noted that the high morbidity rate in 1942 in the total Army is accompanied by a high rate in the United States as well as in oversea areas. Obviously, this was due to the great outbreak of serum hepatitis which affected the rates both in the United States and abroad.

Between 1939 and 1945, infectious hepatitis in the Zone of Interior was presumably not a great problem, and the incidence did not differ greatly from the estimated incidence in the Army before 1939. It should be noted

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however, that the incidence of infectious hepatitis increased in the spring of 1945 and continued high through 1946. Almost half of the cases that year were reported by ports of debarkation, staging areas, and general hospitals. It may be presumed, therefore, that the increased incidence of hepatitis was not due to infection acquired in this country but to troops who had been ill with hepatitis at the time they had been evacuated from oversea areas or to soldiers who had been infected overseas and who became ill on returning to the United States. The distribution of troops returned from overseas, however, was so diverse that this cannot definitely be ascertained. While the rates were increasing in the United States there was also a considerable increase reported from oversea theaters, particularly from the Southwest Pacific, during 1945.

The reason for this rise is not clear. The redeployment of troops in Europe preparatory to their return either to the United States or to the Pacific to take part in the anticipated assault on Japan may have contributed, at least in the European theater, to the increasing rate. Redeployment resulted in the mingling of troops from throughout the European theater in the famous Lucky Strike, Chesterfield, and other staging areas with recruit replacements who, in general, represented groups of susceptible immigrants entering an infected population. This, together with the inevitable breakdown of personal sanitation and the increased opportunity for mingling with the civilian populations in Italy, France, and Germany after combat, may have contributed to the rise in incidence. It is difficult, however, to assess the relative importance of individual factors. There was a parallel and striking increase in venereal disease at this time and in these areas, which certainly indicated more frequent and prolonged contact between soldiers and civilians in Europe.

RESEARCH BY ARMY EPIDEMIOLOGICAL BOARD COMMISSIONS

Organization of Hepatitis Study Group.-The Medical Department of the U.S. Army, and particularly the Preventive Medicine Service of the Office of the Surgeon General, should take considerable pride in the part that the U.S. Army played in the collection of useful information about viral hepatitis, not only as a military problem but also as a civilian problem. The investigations of three commissions of the Army Epidemiological Board were a cooperative venture which demonstrated how a group of widely separated laboratories could pool their information and work together. To facilitate this cooperative undertaking in July 1944, the Board created a special hepatitis committee, an ad hoc committee known as the Hepatitis Study Group.³⁷ The organization was not so closely knit, however, that

³⁷The "Hepatitis Study Group" of the Army Epidemiological Board was never officially organized although it held a number of meetings. Among those who attended were Dr. T. Francis, Jr. ; Capt. Sidney S. Gellis, MC; Maj. W. Paul Havens, Jr. ; Dr. Charles A. Janeway ; Capt. John R. Neefe, MC ; Dr. Joseph Stokes, Jr. ; Lt. Col. (later Col.) Roy H. Turner, MC ; and Dr. John R. Paul, Chairman.

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individual laboratories and members thereof did not retain a sense of independence and individual achievement.

The experimental work of this group was actually carried out primarily by the following three commissions: The Commission on Measles and Mumps, with headquarters in Philadelphia, Pa.; the Neurotropic Virus Disease Commission, in New Haven, Conn.; and the Influenza Commission, in Ann Arbor, Mich. The respective field and laboratory work was carried out by and under the direction of (1) Dr. Joseph Stokes, Jr., and Capt. John R. Neefe, MC, at the Children's Hospital of Philadelphia and the School of Medicine, University of Pennsylvania, (2) Dr. John R. Paul and Maj. W. Paul Havens, Jr., MC, of the Section of Preventive Medicine, School of Medicine, Yale University, New Haven, Conn., and (3) Dr. Thomas Francis, Jr., at the School of Public Health, University of Michigan, Ann Arbor, Mich.

Scope and objective.-Just when it became generally accepted that this group of diseases was viral in nature is not clear, nor has this supposition been established beyond doubt today. It was clear by 1938, however, that the agent was filterable. This discovery stemmed from the prewar work of MacCallum and Findlay in England. That the agent possessed certain other properties common to viruses was established later.

The main objective of all three research groups of the Army Epidemiological Board was essentially that of determining the manner by which hepatitis was spread so that methods of controlling the disease might be devised. One of the first contributions made by their researches was the establishment of a hypothesis of the existence of two disease entities-infectious hepatitis and serum hepatitis. In some ways this distinction would seem to be of academic interest only, but actually it had important repercussions in the field of military preventive medicine. However similar the two diseases may be clinically, our present concept of the prevention of infectious hepatitis is based on the provision of good environmental sanitation, whereas that of the control of serum hepatitis is based on the proper control of blood for transfusions and the adequate sterilization of instruments and needles. Although our present knowledge of the viral hepatitides is still clouded by many obscurities, it has increased immeasurably since the beginning of the war as a result of the research stimulated by the Army's experience with hepatitis during World War II.

Use of Human Volunteers

Details of the experimental work which involved the use of human volunteers will not be discussed here. By 1943, it was apparent that the use of experimental animals for the isolation and demonstration of hepatitis virus was not possible by means of techniques known at the time. Man appeared to be the only available experimental subject. This presented great disadvantages, but also some advantages because the study of both the clinical and experimental aspects of a disease in human beings is of real value. For

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example, one is afforded the opportunity of observing patients for a period of days or weeks before the onset of their illness. The use of volunteers for the study of hepatitis and other diseases became part of the wartime program of the Army Epidemiological Board. Such work was made possible by the Board through provision of opportunities and facilities for these expensive experiments. The contribution made by these volunteers to the welfare of humankind was great, and no discussion of their participation in medical research should fail to take cognizance of their courage and generosity.

A number of different units of volunteers cooperated with the Commission on Measles and Mumps. These units included inmates of the New Jersey State Prison at Trenton, N.J., and groups of conscientious objectors from a special organization for this purpose known as CPS (Civilian Public Service) Unit No. 140 of Philadelphia, Pa. The Commission at Yale University obtained volunteers from various groups of conscientious objectors at work in State institutions in the vicinity of New Haven, including CPS Unit No. 81, organized at the Connecticut State Hospital, Middletown, Conn.; CPS Unit No. 68 organized at the Norwich State Hospital, Norwich, Conn.; and, later, a special branch of CPS Unit No. 140, organized and maintained in one of the fraternity houses at Yale University. In addition, a number of volunteers were found among prisoners at the Federal Correctional Institution, Danbury, Conn., and at the State Prison, Wethersfield, Conn. The University of Michigan group utilized volunteers from the State Prison of Southern Michigan, Jackson, Mich. The relationship of the exploratory work on hepatitis involving the use of volunteers to the development of knowledge of serum hepatitis and infectious hepatitis is illustrated by the results of all the significant transmission experiments shown in table 47 which is a modification of data appearing in Havens' monograph.³⁸ Although the occurrence of nonicteric hepatitis is recognized, only jaundiced cases, in which the diagnosis could be definite, are recorded in this table, with the exception of figures in parentheses in the "jaundiced" column. In this and subsequent tables, authors of reports on work done under the auspices of the Army Epidemiological Board appear in italics.

Infectious Hepatitis

It will be recalled that a primary objective of wartime research on the hepatitides was the determination of their mode or modes of transmission. Many contributions to the knowledge of infectious hepatitis resulted from these researches.

Voegt (p. 417), in Germany, first reported the transmission of hepatitis to volunteers by feeding to them duodenal fluid and blood obtained from

³⁸Havens W. P., Jr. : Infectious Hepatitis. Medicine 27 : 279-326, September 1948.

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patients in the acute phase of the disease. Published accounts of his experiments are quite inadequate. In 1944, MacCallum and Bradley³⁹ of the Jaundice Committee of the British Medical Research Council reported some highly significant experimental results. The report described recent success in transmitting viral hepatitis to arthritic patients who had volunteered for this procedure. Various routes of transmission were used, and infective material included feces given per os. Independently, members of the Neurotropic Virus Disease Commission were also successful during the same summer in producing the disease in volunteers at CPS Units Nos. 68 and 81, who had been fed fecal specimens obtained from soldiers in the Mediterranean area during the epidemic of 1943. A report of this work was first presented at the first meeting of the Hepatitis Study Group, held at the Rockefeller Institute for Medical Research in New York on 12 July 1944 and published in November 1944.⁴⁰

³⁹MacCallum, F. O., and Bradley, W. H.: Transmission of Infective Hepatitis to Human Volunteers. Lancet 2: 228, August 1944.
⁴⁰Havens, W. P., Jr., Ward, R., Drill, V. A., and Paul, J. R.: Experimental Production of Hepatitis by Feeding Icterogenic Materials. Proc. Soc. Exper. Biol. & Med. 57: 206-208, November 1944.

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TABLE 47.-Results of administration, to volunteers, of materials obtained from patients in the acute phase of infectious hepatitis.

[In the "Route" column, O=oral; NP=nasopharyngeal; P=parenteral]

Inoculum	Authors	Year	Route	Volunteers		Incubation period
Inoculum	Authors	Year	Route	Inoculated	Jaundiced	Incubation period
				Number	Number	Days
Feces	Voegt (duod. fl.)¹	1942	O	4	(1)	28
	MacCallum & Bradley²	1944	NP	26	3	27-31
	Havens³	1944-46	O	12	9	15-27
	Neefe et al⁴	1944-46	O	46	25	18-27
	Neefe et al⁴	1944-46	P	3	0	---
	Findlay & Willcox⁵	1945	O	18	(7)	17-28
Serum	Voegt (blood)¹	1942	O	(?)	1	(?)
	Voegt (blood)¹	1942	P	(?)	1	19?
	MacCallum & Bradley²	1944	P	6	3	64-92
	Havens³	1944-46	P	17	8	20-31
	Havens³	1944-46	O	8	7	21-34
	Oliphant⁶	1944	P	21	4	85-106
	Francis et al⁷	1945	P	8	4	35-43
	Neefe et al⁴	1945	P	6	1	35
	Neefe et al⁴	1946	O	3	2	26 & 33
Nasopharyngeal washings	MacCallum & Bradley²	1944	NP	16	0	---
	Neefe et al⁴	1945	NP	8	0	---
	Havens⁸	1946	NP	3	0	---
Urine	Voegt¹	1942	O	(?)	(1)	(?)
	MacCallum & Bradley²	1944	NP & O	19	0	---
	Findlay & Willcox^{5 9}	1945	O	6	(3)	(?)
	Neefe & Stokes¹⁰	1945	O	7	0	---
	Havens⁸	1946	O	3	0	---

¹Voegt, H.: Zur Aetiologie der Hepatitis Epidemica. Munchen. med. Wchnschr. 89: 76, 23 Jan. 1942.
²MacCallum, F. O., and Bradley, W. H.: Transmission of Infective Hepatitis to Human Volunteers. Lancet 2: 228, August 1944.
³(1) Havens, W. P., Jr., Ward, R., Drill, V. A., and Paul, J. R.: Experimental Production of Hepatitis by Feeding Icterogenic Materials. Proc. Soc. Exper. Biol. & Med. 57: 206-208, November 1944. (2) Havens, W. P.; Jr.: Properties of the Etiologic Agent of Infectious Hepatitis. Proc. Soc. Exper. Biol. & Med. 58: 203-204, March 1945. (3) Havens, W. P., Jr.: The Period of Infectivity of Patients With Experimentally Induced Infectious Hepatitis. J. Exper. Med. 83: 251-258, March 1946. (4) Havens, W. P., Jr.: Immunity in Experimentally Induced Infectious Hepatitis. J. Exper. Med. 84: 403-406, November 1946. (5) Havens, W. P., Jr.: Experiment in Cross Immunity Between Infectious Hepatitis and Homologous Serum Jaundice. Proc. Soc. Exper. Biol. & Med. 59: 148-150, June 1945. (6) Havens, W. P., Jr.: Elimination in Human Feces of Infectious Hepatitis Virus Parenterally Introduced. Proc. Soc. Exper. Biol. & Med. 61: 210?212, March 1946.
⁴Neefe, J. R., Gellis, S. S., and Stokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis: Studies in Volunteers Bearing on Immunological and Other Characteristics of the Etiological Agents. Am. J. Med. 1: 3-22, July 1946.

⁵Findlay, G. M., and Willcox, R. R.: Transmission of Infective Hepatitis by Feces and Urine. Lancet 1: 212, 17 Feb. 1945.

⁶Oliphant, J. W.: Infectious Hepatitis: Experimental Study of Immunity. Pub. Health Rep. 59: 1614-1616, 15 Dec. 1944.

⁷Francis, T., Jr., Frisch, A. W., and Quilligan, J. J., Jr.: Demonstration of Infectious Hepatitis Virus in Presymptomatic Period After Transfer by Transfusion. Proc. Soc. Exper. Biol. & Med. 61: 276-280, March 1946.
⁸Havens, W. P., Jr.: The Period of Infectivity of Patients With Homologous Serum Jaundice and Routes of Infection in This Disease. J. Exper. Med. 83: 441-447, June 1946.
⁹In a subsequent publication (Infective Hepatitis in West Africa; Syringe-Transmitted Hepatitis. Month. Bull. Min. Health & Emerg. Pub. Health Lab. Serv. 7: 32-39, February 1948), Findlay has suggested that the apparent infectivity of urine in his experiment was due to the presence of erythrocytes associated with urinary bilharziasis.
¹⁰Neefe, J. R., and Stokes, J., Jr.: An Epidemic of Infectious Hepatitis Apparently Due to a Water Borne Agent. J.A.M.A. 128: 1063-1075, 11 Aug. 1945.

Subsequently, it was demonstrated by various groups that the etiological agent of infectious hepatitis was filterable through an L2 Chamberland or Seitz E.K. filter, that it resisted heating at 56? C. for at least 30 minutes, and that it was transmissible to man in serial passage by feeding or parenteral inoculation of infectious material from feces and blood. The virus was shown to withstand chlorination, namely, one part chlorine residual per million for 30 minutes, and to remain active in materials frozen for 1 or 1? years, but not for 3 years, at -10? to -20? C. The negative results of trans‑

437

mission experiments utilizing urine and nasopharyngeal washings were equally important. Urine and naso-urine and nasopharyngeal washings, as possible conveyers of the virus, have not been completely investigated, and contradictory results have been reported by various groups which have administered urine by mouth to volunteers. In general, however, results indicate that the virus cannot be found in these fluids, or, at least, cannot be found very easily.

A limited number of experiments were conducted to investigate the period of infectivity of patients with infectious hepatitis in relation to the clinical disease (table 48). The results are not clear cut. It is apparently during the period of active disease (acute illness), and not during the greater part of the incubation period or during convalescence, that the virus may be most readily found in the blood or feces. Thus, these experiments indicated that the greatest danger of spread of the disease probably arises from the mildly ill patients who are not jaundiced and who, in the absence of overt evidence of disease, probably circulate in the community in the role of unrecognized carriers. In civilian life, such carriers may be young children in whom the disease is apt to be mild.

TABLE 48.-Results of administration, to volunteers, of materials obtained from patients invarious stages of the incubation period and convalescence of infectious hepatitis

[F=feces; S=serum; the minus sign=before onset; the plus sign=after onset]

Authors	Year	Inoculum	Day material was obtained	Volunteers
Authors	Year	Inoculum	Day material was obtained	Inoculated	Jaundiced
				Number	Number
Havens¹	1946	F	-15	3	0
Francis et al²	1945	S	-3	8	4
Havens¹	1946	F & S	25+ to 31+	10	0
Neefe et al³	1945	F	21 post jaundice	7	0
Neefe et al⁴	1947	Liver	180+	5	0
Neefe et al⁴	1947	S	106+ to 367+	5	0
Neefe et al⁴	1947	F	92+ to 342+	5	0

¹Havens, W. P., Jr.: The Period of Infectivity of Patients With Experimentally Induced Infectious Hepatitis. J. Exper. Med. 83: 251-258, March 1946.

²Francis, T., Jr., Frisch, A. W., and Quilligan, J. J., Jr.: Demonstration of Infectious Hepatitis Virus in Presymptomatic Period After Transfer by Transfusion. Proc. Soc. Exper. Biol. & Med. 61: 276-280, March 1946.
³Neefe, J. R., Stokes, J., Jr., and Reinhold, J. G.: Oral Administration to Volunteers of Feces From Patients With Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis. Am. J.M. Sc. 210: 29-32, July 1945.

⁴Neefe, J. R., Stokes, J., Jr., Garber, R. S., and Gellis, S. S.: Studies on the Relationship of the Hepatitis Virus to Persistent Symptoms, Disability, and Hepatic Disturbance ("Chronic Hepatitis Syndrome") Following Acute Infectious Hepatitis. J. Clin. Invest. 26: 329-338, March 1947.

The extent to which patients convalescent from hepatitis may be carriers of the virus in either blood or feces has really not yet been determined. The number of experiments related to this problem is still too small to say whether or not 10 percent, 5 percent, or 1 percent of such convalescents might become chronic carriers.

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A very important aspect of the Commission's experimental work was the demonstration by Neefe and Stokes (p. 417) of hepatitis virus (infectious hepatitis) in well water. Volunteers contracted infectious hepatitis following ingestion of water from a well which was proved to have been contaminated with feces. The work of these investigators confirmed the hypothesis, previously proposed on epidemiological grounds but not proved, that the disease might be waterborne.

A third series of experiments attempted to demonstrate experimentally the existence of homologous immunity to infectious hepatitis. Neefe and coworkers and also Havens showed that volunteers convalescent for from 6 to 9 months from experimentally induced infectious hepatitis were immune when inoculated with homologous strains (table 49). In addition, Neefe and coworkers showed that the volunteers who had recovered from hepatitis, which had been experimentally induced by a strain of virus obtained from the stools of diseased children in Pennsylvania, were immune when inoculated with a strain of hepatitis virus obtained from the stools of a soldier who had contracted the disease in Sicily. This experiment indicated a certain homogeneity of strains of the virus collected from widely different sources.

TABLE 49.-Results of attempts to demonstrate immunity in volunteers convalescent fromexperimentally induced infectious hepatitis in 1946

[In the "Challenge virus" column, IH =infectious hepatitis, and HSJ =homologous serum jaundice]

Authors	Challenge virus	Convalescents			Controls
Authors	Challenge virus	Inoculated	Jaundiced	Incubation period	Inoculated	Jaundiced	Incubation period
		Number	Number	Days	Number	Number	Days
Havens¹	IH	9	0	---	12	8	21-30
Neefe et al.²	IH	17	0	---	14	6	25-37
Neefe et al.²	HSJ	4	2	101, 102	9	8	60-110

¹Havens, W. P., Jr.: Immunity in Experimentally Induced Infectious Hepatitis. J. Exper. Med. 84: 403-406, November 1946.

²Neefe, J. R., Gellis, S. S., and Stokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis: Studies in Volunteers Bearing on Immunological and Other Characteristics of the Etiological Agents. Am. J. Med. 1: 3-22, July 1946.

Of considerable practical and immunologic importance was the observation by the Philadelphia group working under Dr. Stokes that normal, human gamma globulin in a dose of 0.15 cc. per pound of body weight is an effective prophylactic when administered intramuscularly within 6 days before the onset of infectious hepatitis. Such injection was tried as a control method in a military field study on the effectiveness of gamma globulin as a military prophylactic agent for infectious hepatitis during the fall and winter of 1944-45 in Italy. The field experiments were initiated under combat conditions by Dr. Stokes and Capt. S. S. Gellis. About 1,750 men were inoculated. The results again supported the hypothesis that gamma globulin was a

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potent agent for the prevention of infectious hepatitis and that it could be used in military groups under certain circumstances as a control procedure.

With respect to serum hepatitis, the situation was different. It was shown that gamma globulin, at least when it was administered to patients late in the incubation period of serum hepatitis, was not so effective in preventing the disease. In more than one series of experiments, questionably favorable results followed the administration of two doses of gamma globulin given 1 month apart during the incubation period of serum hepatitis, but no protection was demonstrable when only one dose was given.

Serum Hepatitis

Equally informative results were derived from experimental work on serum hepatitis through its transmission to volunteers (table 50). Although the occurrence of nonicteric hepatitis is recognized, only jaundiced cases, in which the diagnosis could be definite, are recorded in this table. It was on the basis of these transmission experiments that it gradually became apparent to Commission investigators and others during the latter part of 1944 that there must be two types of hepatitis virus. On the basis of these experiments, one could not postulate two different phases of the virus because all attempts to transform infectious hepatitis into serum hepatitis and vice versa ended in failure.

A pioneer in this country on transmission experiments in serum hepatitis was Dr. J. W. Oliphant of the U.S. Public Health Service. In 1943, his group transmitted serum hepatitis to a large number of volunteers by the parenteral inoculation of serum obtained from patients in the acute phase of postvaccinal (yellow fever) hepatitis. These results were corroborated and extended by others (table 50). As in the case of infectious hepatitis, it was shown that the virus was filterable through both Chamberland and Seitz E.K. filters, that it was also resistant to temperatures of 56?to 60?C. for at least 30 minutes, and that it survived a temperature of 4?C. for a long period and a temperature of -10?to -20?C. for 4? years but apparently became inactive after 5 years at the latter temperature. It also survived a desiccated state at room temperature for at least a year, in serum containing Merthiolate in concentration of 1 in 2,000, in a mixture of equal parts of phenol and ether in 0.5 percent concentrations, and in a 0.2 percent concentration of tricresol. It was inactivated in serum, however, following exposure to ultraviolet light for 1 hour at 2,650 angstrom units and after heating at 60?C. for 10 hours in human albumin.

This virus is also transmissible to volunteers in serial passage and evokes homologous immunity, but there is no experimental indication that cross immunity exists between serum hepatitis and infectious hepatitis (table 51). This finding confirms observations in the field that many servicemen who had had serum hepatitis in 1942 contracted infectious hepatitis in Italy in 1943.

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TABLE 50.-Results of administration, to volunteers, of materials obtained from patients in the acute phase of serum jaundice

[In the "Route" column, O =oral; IG=intragastric; P =parenteral; IN=intranasal]

Inoculum	Authors	Year	Route	Volunteers		Incubation period
	Authors	Year	Route	Inoculated	Jaundiced	Incubation period
				Number	Number	Days
Feces	Neefe at al¹	1945	O & IG	19	0	---
	Neefe et al¹	1945	P	5	0	---
	MacCallum²	1945	O	15	0	---
	Havens³	1946	O	6	0	---
Serum	Cameron⁴	1943	P	6	6	30-30+
	Oliphant et al⁵	1943	P	186	33	28-133
	Oliphant et al⁵	1943	P	10	4	120-160
	Oliphant et al⁵	1943	IN	3	0	---
	MacCallum & Bauer⁶	1944	P	16	6	50-127
	MacCallum & Bauer⁶	1944	IN	10	1	⁷82
	Havens et al⁸	1944-46	P	13	7	56-71
	Havens et al⁸	1944-46	O & IN	13	0	---
	MacCallum²	1945	P	19	12	42-80
	Neefe et al⁹	1946	P	25	14	60-135
	Neefe et al⁹	1946	O	10	0	---
Nasopharyngeal washings	Findlay & Martin¹⁰	1943	IN	4	1	50
	MacCallum²	1945	IN	17	0	---
	Neefe et al⁹	1946	IN & O	4	0	---
Urine	Neefe et al⁹	1946	O	1	0	---

¹Neefe, J. R., Stokes, J., Jr., and Reinhold, J. G.: Oral Administration to Volunteers of Feces From Patients With Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis. Am. J.M. Sc. 210: 29-32, July 1945.
²MacCallum, F. O.: Transmission of Arsenotherapy Jaundice by Blood; Failure With Feces and Nasopharyngeal Washings. Lancet 1: 342, 17 Mar. 1945.

³Havens, W. P., Jr.: The Period of Infectivity of Patients With Homologous Serum Jaundice and Routes of Infection in This Disease. J. Exper. Med. 83: 441-447, June 1946.
⁴Cameron, J. D. S.: Infective Hepatitis. Quart. J. Med. 12: 139-155, July 1943.
⁵Oliphant, J. W., Gilliam, A. G., and Larson, C. L.: Jaundice Following Administration of Human Serum. Pub. Health Rep. 58: 1233-1242, 13 Aug. 1943.

⁶MacCallum, F. O., and Bauer, D. J.: Homologous Serum Jaundice; Transmission Experiments With Human Volunteers. Lancet 1: 622-627, 13 May 1944.
⁷One subject developed a mild jaundice on the 36th day, recovered, and developed a serious attack on the 82d day.

⁸(1) Havens, W. P., Jr., Ward, R., Drill, V. A., and Paul, J. R.: Experimental Production of Hepatitis by Feeding Icterogenic Materials. Proc. Soc. Exper. Biol. & Med. 57: 206-218, November 1944. (2) Havens, W. P., Jr.: The Period of Infectivity of Patients With Homologous Serum Jaundice and Routes of Infection in This Disease. J. Exper. Med. 83: 441-447, June 1946.
⁹Neefe, J. R., Gellis, S. S., and Stokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis: Studies in Volunteers Bearing on Immunological and Other Characteristics of the Etiological Agents. Am. J. Med. 1: 3-22, July 1946.
¹⁰Findlay, G. M., and Martin, N. H.: Jaundice Following Yellow-Fever Immunization, Transmission by Intranasal Instillation. Lancet 1: 678-680, 29 May 1943.

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TABLE 51.-Results of attempts to demonstrate immunity and cross-immunity in volunteersconvalescent from experimentally induced serum jaundice
[In the "Challenge virus" column, IH= infectious hepatitis and HSJ =homologous serum jaundice]

Authors	Year	Challenge virus	Convalescents			Controls
Authors	Year	Challenge virus	Inoculated	Jaundiced	Incubation period	Inoculated	Jaundiced	Incubation period
			Number	Number	Days	Number	Number	Days
Oliphant¹	1944	IH	10	0	---	11	4	85-106
Havens²	1945	IH	3	3	20-25	11	5	23-31
Neefe et al³	1946	IH	5	4	28-37	6	5	28-32
Neefe et al³	1946	HSJ	9	0	---	9	8	60-110

¹Oliphant, J. W.: Infectious Hepatitis: Experimental Study of Immunity. Pub. Health Rep. 59: 1614-1616, 15 Dec. 1944.

²Havens, W. P., Jr.: Experiment in Cross Immunity Between Infectious Hepatitis and Homologous Serum Jaundice. Proc. Soc. Exper. Biol. & Med. 59: 148-150, June 1945.

³Neefe, J. R., Gellis, S. S., and Stokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis: Studies in Volunteers Bearing on Immunological and Other Characteristics of the Etiological Agents. Am. J. Med. 1: 3-22, July 1946.

Other experiments which tended to differentiate the two diseases, serum hepatitis and infectious hepatitis, were the unsuccessful attempts to demonstrate the virus of serum hepatitis in the feces of patients in the acute phase of the disease. In addition, serum hepatitis has not been transmitted experimentally by the oral route with two possible exceptions. The incubation period of infectious hepatitis was shown to be rather consistently from 20 to 30 days, and perhaps as long as 45 days, but the incubation period of serum hepatitis has been from 60 to 154 days (chart 5). Apparently, in serum hepatitis, the period of viremia before the development of clinical symptoms of liver disease is very long. Neefe and coworkers recovered virus from the blood 87 days before the onset of jaundice; Paul and coworkers detected virus in the blood 60 days before the appearance of jaundice, and Havens found them 16 days before the appearance of jaundice. Attempts to detect virus in the blood during convalescence (as in infectious hepatitis) were unsuccessful when the tests were made at intervals of 1 to 5 months after the onset of the disease (table 52). These limited experimental findings should not be interpreted as indicating that a convalescent or post-convalescent carrier state does not exist in viral hepatitis. Indeed, since 1945 there have been observations, largely unpublished, which indicate that an occasional soldier or ex-soldier with a history of jaundice or of exposure to jaundice during the war has apparently harbored the virus for years and his carrier state has become manifest when a recipient of his blood has become jaundiced.

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CHART 5.-A comparison of incubation periods of infectious hepatitis and homologous serumjaundice observed in a series of experimental cases

TABLE 52.-Results of administration, to volunteers, of materials obtained from patients invarious stages of the incubation period and convalescence of serum jaundice
[The minus sign = before onset of disease; the plus sign = after appearance of jaundice]

Authors	Year	Day material was obtained	Volunteers
Authors	Year	Day material was obtained	Inoculated	Jaundiced
			Number	Number
Neefe et al¹	1944	-87	2	²2
Paul et al³	1945	-60	8	3
Havens⁴	1946	-16	4	1
Havens⁴	1946	28 to 32	5	0
MacCallum & Bauer⁵	1944	66+	5	0
MacCallum & Bauer⁵	1944	141+	5	0
Oliphant et al⁶	1943-44	75 post jaundice	15	0

¹Neefe, J. R., Stokes, J., Jr., Reinhold, J. G., and Lukens, F. D. W.: Hepatitis Due to the Injection of Homologous Blood Products in Human Volunteers. J. Clin. Investigation 23: 836-855, September 1944.

²No definite statement of jaundice.
³Paul, J. R., Havens, W. P., Jr., Sabin, A. B., and Philip, C. B.: Transmission Experiments in Serum Jaundice and Infectious Hepatitis. J.A.M.A. 128: 911-915, 28 July 1945.
⁴Havens, W. P., Jr.: The Period of Infectivity of Patients With Homologous Serum Jaundice and Routes of Infection in This Disease. J. Exper. Med. 83: 441-447, June 1946.
⁵MacCallum, F. O., and Bauer, D. J.: Homologous Serum Jaundice; Transmission Experiments With Human Volunteers. Lancet 1: 622-627, 13 May 1944.
⁶Oliphant, J. W., Gilliam, A. G., and Larson, C. L.: Jaundice Following Administration of Human Serum. Pub. Health Rep. 58: 1233-1242, 13 Aug. 1943.

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MEDITERRANEAN AREA AND MIDDLE EAST THEATER

In no areas did the problem of infectious hepatitis reach greater proportions than in North Africa, in the Middle East, and in Sicily and Italy during the period 1943-45. The problem in this region deserves special mention.

British Experience in Mediterranean, 1941-42

Shortly after U.S. troops arrived in Egypt in the fall of 1942, and in Morocco and Algeria after the North African landings in early November 1942, it was learned first hand from British medical officers that "infective hepatitis," to use the British term, was indeed a very serious problem in their troops. As mentioned before, the British were familiar enough with epidemic hepatitis in that part of the world, and no doubt they were not surprised to see its return in 1940. In both 1941 and 1942, the hepatitis season coincided with the period of severe fighting in the North African desert. In the 1942 epidemic, there was an abrupt rise in incidence in August with a further rise in October, and a peak was reached in November (chart 6). There were regiments in the British Eighth Army, for example, in

CHART 6.-Monthly incidence rates for infectious hepatitis in British troops in the MiddleEast, December 1940 to August 1944

444

which 8 or 9 percent of the total strength was ineffective because of hepatitis. Often, as many as one-third of a regiment's officers were involved, for officers contracted the disease at a rate of four to five times that of other ranks.⁴¹

The 1942 epidemic in North Africa occurred at a very crucial time for the British since it started in early October, which was just when the British counteroffensive at El Alamein began. It soon was apparent that a period of duty amid the highly unsanitary conditions along the Alamein Line was a predisposing cause of the epidemic. The disease also developed among the Italian prisoners captured there at the time. In Kirk's⁴² study of this situation, emphasis was laid on the possibility that the disease was flyborne. Flies were present at the time of the epidemic in enormous numbers, and the ground was filthy with excreta and imperfectly buried German and Italian corpses. The disease did not appear to spread later in general hospitals, base camps, or prisoner-of-war cages, where sanitation was good and fly control considered satisfactory. This indicated to observers that contact alone was insufficient to spread the disease. With this experience fresh in their minds, various British medical officers expressed themselves verbally as believing the military evidence to indicate that infective hepatitis was spread by feces. The British group, and in particular Maj. C. E. van Rooyen, R.A.M.C., who was stationed at that time in Cairo, was anxious to try experiments on volunteers to prove this hypothesis, but the opportunity to carry out such experiments did not arise. In May 1943, Major van Rooyen expressed his views to a team of investigators, members of the Neurotropic Virus Diseases Commission of the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army.⁴³ This team had been sent to Cairo early in 1943 by the Preventive Medicine Service to investigate epidemiological and other features of disease of military importance in the Middle East, such as sandfly fever, poliomyelitis, and infectious hepatitis. During the spring and summer of 1943, however, hepatitis was no problem to the U.S. forces in the Mediterranean area, although this situation was not to last long.

Experience of U.S. Forces, 1942-45

During the fall and winter fighting of 1942 to 1943 (chart 7) in Algeria and Tunisia, and all through the spring and early summer of 1943,

⁴¹Spooner, E. T. C.: The 1942 Epidemic of Infective Hepatitis in the Middle East. Proc. Roy. Soc. Med. 37: 171-172, February 1944.
⁴²Kirk, R.: Spread of Infective Hepatitis. Lancet 1 : 80-81, 20 Jan. 1945.
⁴³Members of this team included Dr. John R. Paul, Director ; Maj. (later Lt. Col.) Albert B. Sabin, MC; Maj. (later Col.) Cornelius B. Philip, SnC ; and Capt. (later Maj.) W. Paul Havens, Jr., MC. The Commission, known in the U.S. Army Forces in the Middle East and in the Mediterranean Theater of Operations, U.S. Army, as the Virus Commission, had its headquarters, laboratories, and experimental ward established in May-December 1943 at the 38th General Hospital in the Desert Camp, Russel B. Huckstep, outside Cairo, Egypt. Here the first transmission experiments on sandfly fever virus, to be conducted under U.S. Army auspices, were carried out, experiments which also resulted in the inadvertent transmission of serum hepatitis virus to volunteers.

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CHART 7.-Monthly incidence rates for infectious hepatitis among U.S. Army troops in theNorth African Theater of Operations, December 1942 to February 1944

the relative number of hepatitis cases among local U.S. forces in the Mediterranean theater, as opposed to U.S. Army Forces in the Middle East, was insignificant (chart 8). The incidence of hepatitis was very low in North Africa at that time in comparison with its later magnitude. The situation was a little different in Egypt where the troops had arrived earlier. There, although the number of troops was small, the rate was appreciable. The annual admission rate (June through December 1942) for the Middle East theater, which included Egypt, was 16.7.

This freedom from infectious hepatitis during the first year of the North African occupation was merely a calm before the storm. Starting late in the summer of 1943, close to the time of the invasion of Sicily, the incidence of the disease rose to unprecedented heights. It presented very serious problems to the officers of the Medical Department who were suddenly confronted during combat with an enormous number of cases of a disease for which the means of spread were not clearly understood, no methods of prevention were known, and no specific therapy was available. Clinically, however, this disease was quite similar to catarrhal jaundice or postvaccinal jaundice (serum hepatitis) with which the Army had had all

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CHART 8.-Monthly attack rate for infectious hepatitis in U.S. Army troops in the NorthAfrican and Mediterranean Theaters of Operations, March 1943 to March 1945

too much recent experience. In that respect at least, the disease was not entirely new as a clinical problem in military medicine.

Cases of hepatitis began to appear almost simultaneously among troops in Egypt, North Africa, and Sicily. By October and early November the number of cases had reached great proportions, and hospitals in Cairo, Algiers, Tunis, and Palermo, Sicily, were overflowing with hepatitis patients. The outbreak involved U.S. and British troops alike. The size of the epidemic and the number of admissions for these diseases during each of the years 1942-45 in the Mediterranean and the Middle East theaters is shown in table 53.

The responsibility of caring for all these patients in the fall and winter of 1943-44 was enormous, carried on, as it was, just in the rear of combat areas. To accomplish the task of quickly devising means of control seemed impossible at that time, but attempts to do so were made. Early in September 1943, just at the time of the landings at Salerno, Italy, and soon after the beginning of the epidemic of hepatitis, Brig. Gen. James S. Simmons, Chief, Preventive Medicine Service, Office of the Surgeon General, representing the Army Epidemiological Board, visited Sicily, North Africa, and Egypt. At Cairo, he made the special request that the Neuro‑

447

tropic Virus Diseases Commission there concentrate its attention on epidemiological and etiological aspects of infectious hepatitis.⁴⁴

TABLE 53.-Admissions for infectious and serum hepatitis among U.S. troops in theMediterranean and Middle East theaters, by year, 1942-45
[Preliminary data based on tabulations of individual medical records and summaries of statisticalhealth reports]

[Rate expressed as number of admissions per annum per 1,000 average strength]

Year	Mediterranean theater		Middle East theater
Year	Number of admissions	Rate	Number of admissions	Rate
1942	41	1.79	101	16.71
1943	18,613	40.75	302	5.69
1944	11,794	18.16	296	6.40
1945	7,035	19.88	240	5.87

At this time, the approach of investigators to the study of the Mediterranean epidemic of hepatitis was quite naturally colored and considerably confused by their recent experience during the outbreak of postvaccinal or serum hepatitis in the United States during 1942. Various theories current in 1943 as to how the military disease might be spread and controlled included the following: (1) That it was a contact disease spread by droplet infection and that measures conceivably useful in the control of respiratory disease should be considered; (2) that it was transmitted through the agency of human excrement and spread primarily through human carriers of the virus, as is typhoid fever; (3) that some unknown, extrahuman factor, such as rodents, insects, or pigs, was responsible for its spread; (4) that the disease was an example of bacterial warfare; and (5) that it was due to or made worse by malnutrition and inadequate diets.

As a result of a series of epidemiological observations on the part of members of the aforementioned commission, including observations in connection with a field trip to Algiers, Sicily, and Tunis in November 1943, the following points had become apparent:

1. The incubation period of this "Mediterranean epidemic hepatitis" was much shorter than that of serum hepatitis, being about 18 to 25 days instead of about 90 days. The situation was complicated by the fact that serum, or long incubation period, hepatitis was also present in that general area. Serum hepatitis had already been demonstrated in Cairo, experimentally by Cameron⁴⁵ in 1942, and inadvertently in 1943 by the frequency

⁴⁴The Neurotropic Virus Diseases Commission included at this time the members already mentioned (p. 444). Medical officers who participated in these discussions and plans and later helped to implement the field studies and laboratory investigations included Col. (later Brig. Gen.) Crawford F. Sams, MC; Lt. Col. (later Col.) Thomas G. Ward, MC, USAFIME, and Col. W. S. Stone, MC, NATOUSA
⁴⁵Cameron, J. D. S.: Infective Hepatitis. Quart. J. Med. 12 : 139-155, July 1943.

448

with which arsphenamine jaundice occurred in certain clinics. The disease had also been demonstrated by the Commission in Cairo in their transmission experiments on sandfly fever (p. 444).

2. The disease was not well known by native physicians except as a children's disease and was very uncommon in native adults.⁴⁶ These facts suggested that, as in poliomyelitis, the native population was largely immune as a result of childhood or infantile infection.

3. A number of patients (U.S. soldiers) seen in U.S. military hospitals in the fall and winter of 1943-44 had had serum (post-yellow-fever vaccine) hepatitis in 1942 in the United States, indicating that a previous attack of serum hepatitis did not confer even short-term immunity for "Mediterranean infectious hepatitis."

4. Epidemics of infectious hepatitis were of great severity in various tactical units, particularly in the Air Forces, with attack rates which occasionally ran as high as 25 or 30 percent of the entire strength of the command. These attack rates represented patients who were actually jaundiced. There might well have been an equal percentage of men who simultaneously acquired the nonicteric form of the disease, resulting in a high noneffective rate.

5. There had been a tendency to associate outbreaks of dysentery with those of hepatitis in some units, although in the great majority of instances the dysentery outbreak came first, in July and August, and was followed in September and October with a straggling outbreak of hepatitis. This experience recalls the experience of 25 years before among the French and British armies in the Dardanelles during World War I (p. 417), when French army officers expressed the belief that epidemic jaundice might be a complication of various enteric infections. That the two conditions coexisted in many military units in the summer of 1943 in North Africa and Italy, there was no doubt, but an analysis of the situation usually revealed a fairly wide separation in time between the incidence peak of dysentery and that of hepatitis.

In this connection, in certain Air Force units, the story of acquisition of either dysentery or hepatitis in North Africa or Sicily in 1943 was often the same. An enemy airfield or a series of fields was captured, and the U.S. unit moved in with all possible speed. The field was found to be very dirty. Damaged latrines were used first by the occupying unit and then were gradually cleaned up and repaired. This seemed an ideal situation for bacterial warfare with an intestinal disease, and the matter of damaged or soiled latrines was often discussed in this light.

⁴⁶In 1944, a number of native, adult cases of viral hepatitis were seen in an Egyptian military hospital in Cairo, where a special ward was designated at that time as a Hepatitis Ward. It is of some epidemiologic significance to recall that nearly all the military patients in this ward were soldiers who had been born and brought up in outlying Egyptian villages and not in big cities.-J. R. P.

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With these epidemiological observations at hand, it seemed to the Commission that if any methods to prevent or control hepatitis among troops in Italy were to be devised, certain experiments to establish the means of transmission of infectious hepatitis would be necessary. Accordingly, in February 1944 this unit returned to the United States bringing infectious materials (blood, feces, et cetera) collected in the epidemic area. Under the auspices of the Army Epidemiological Board, a laboratory for the study of acute hepatitis was established in the Section of Preventive Medicine of the Yale University School of Medicine which contributed to efforts to solve some of the complex problems that hepatitis presented to military medicine. Among other groups working on this problem under the auspices of the Army Epidemiological Board at that time was the laboratory established in connection with the Children's Hospital of Philadelphia under the direction of Dr. Joseph Stokes, Jr., Professor of Pediatrics, University of Pennsylvania, and Director of the Commission on Measles and Mumps. The contribution of Dr. Stokes' group in this infectious hepatitis study is noteworthy (p. 438).

By this time, it was quite clear to the Army Epidemiological Board that hepatitis in the Mediterranean area was a military disease of considerable magnitude. Consequently, the services of consultants were enlisted. Dr. Thomas Francis, Jr., Director of the Commission on Influenza, was sent by the Office of the Surgeon General to Italy in April 1944 to report further on the situation in respect to hepatitis. In the fall of that year a third consultant group consisting of Dr. Stokes, and Capt. Sidney S. Gellis, MC, of the Commission on Measles and Mumps, also visited this theater. They were charged with the special mission of attempting to determine the relative value of gamma globulin injections as a preventive measure for infectious hepatitis in troops heavily exposed to this disease.

In the meantime, medical officers of the Mediterranean theater had been quick to set up a clinical and research unit on hepatitis in Naples, Italy, in connection with the 12th General Hospital and the 15th Medical General Laboratory there.⁴⁷ This unit was started late in the fall of 1943. It reported a number of clinical studies on acute and subacute hepatitis which were based upon a large series of clinical cases and which emphasized for the first time the tendency of the disease to become chronic in a relatively small percentage of cases characterized by a protracted illness or relapse.

The campaign in Italy was one of the longest for U.S. troops during the war, lasting for approximately 18 months, from September 1943 until the Armistice in May 1945. In particular, the winter of 1943-44 was a

⁴⁷The following officers were identified with the clinical and research unit at Naples in 1944-45: Col. Marion H. Barker, MC, Chief, Medical Service, 12th General Hospital ; Maj. (later Lt. Col.) R. B. Capps, MC ; Capt. H. B. Wilson, MC ; Lt. Col. Tracy B. Mallory, MC, Chief, Pathology Section, 15th Medical General Laboratory ; and Capt. (later Maj.) F. C. Robbins, Chief, Virus and Rickettsial Section.

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period of bitter fighting in bad weather over difficult mountainous and marshy terrain. The next fall and winter, 1944-45, the hepatitis rate again soared to high levels, although it did not reach the peak which it had attained in the fall of 1943.

The whole epidemiological story of hepatitis in MTOUSA has been exceedingly well documented by Gauld.⁴⁸ There are certain aspects of this story which may bear reiteration. During the period 1943-45, infectious hepatitis proved to be the greatest cause of disabling illness among U.S. forces in the Mediterranean and North African theaters. It also ranked as one of the chief medical causes of death even though the actual case fatality rate, about 1.8 per 1,000, was not high. The British experience was in many respects similar, whereas Brazilian troops apparently escaped infection. French Arab troops serving in Italy in 1943 seemed to be free of the disease, but its incidence was high among them in 1944. In general, however, the high incidence was found in troops from Europe and the United States who came as susceptible immigrants into this endemic area.

The seasonal distribution of the disease among U.S. troops in this area is important (chart 8). It will be seen that the seasonal upswing began in August in both 1943 and 1944 and that the peaks occurred in November and December respectively. This curve may be compared with that representing British experience in North Africa in which the peak occurred earlier in the year (chart 6). It should be pointed out that British armies were operating in 1941 and 1942 in warmer climates along the North African front. As shown by Gauld, the seasonal increase in the German Army also began earlier, if one may judge by the monthly incidence of hepatitis in the Fourteenth German Army as presented in a captured document (chart 9). Gauld believed that the seasonal distribution in U.S. troops was strongly suggestive of a respiratory mode of spread rather than of transmission either through the gastrointestinal tract or by an insect vector. However, he also believed that there was no doubt that the disease could be spread by filth and that one outbreak of hepatitis in the 86th Mountain Infantry Regiment appeared to have resulted from the drinking of contaminated well water. It seemed quite possible to him that some, if not all, of the explosive outbreaks were similarly spread.

Gauld found that a certain degree of immunity to hepatitis was manifested in seasoned troops. He further observed that there was a decrease in the relative incidence of the disease as the age of individual soldiers advanced. Of significance also was his confirmation of the fact that men who had been vaccinated against yellow fever in 1941-42 and who had acquired serum hepatitis at that time were not protected from acquiring infectious hepatitis later. Indeed, the attack rate among such men was significantly higher than among others.

⁴⁸Gauld, R. L.: Epidemiological Field Studies of Infectious Hepatitis in the Mediterranean Theater of Operations, I-VIII. Am. J. Hyg. 43: 248-313, May 1946.

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CHART 9.-Monthly attack rates for infectious hepatitis in the Fourteenth Army(German), 1944

In brief, the story of infectious hepatitis among U.S. troops in combat in the Mediterranean area is one of a severe and protracted epidemic which occurred in two waves during 2 successive years and produced 40,000 cases. The 1943 epidemic is an outstanding example of what happens when susceptible troops occupy an endemic area during the summer, it being apparent that hepatitis is endemic in the eastern half of the Mediterranean littoral.

EUROPEAN THEATER OF OPERATIONS

Serum Hepatitis

In common with all other theaters of operations and the continental United States, the European theater also experienced an outbreak of serum hepatitis in 1942.⁴⁹ On 13 May 1942, word was received by the Chief Surgeon, ETOUSA (European Theater of Operations, U.S. Army), from the Department of Health for Scotland that among the troops arriving at Glas‑

⁴⁹Gordon, J. E.: A History of Preventive Medicine in the European Theater of Operations, U.S. Army, 1941-45. [Official record.]

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gow there were 26 cases of jaundice. As these cases appeared in a shipment of 20,000 troops, the health authorities in Scotland believed that the disease was probably infectious but not epidemic and allowed them to proceed to their destination in Northern Ireland where investigations were begun on 20 May by members of the American Red Cross-Harvard Field Hospital Unit. By this time the outbreak involved some 86 soldiers. It should be pointed out that although The Surgeon General had caused the yellow fever vaccine containing human serum to be withdrawn on 15 April, word had not reached individual theaters (at least the lower echelons) of the nature of the outbreak of jaundice because the circular letter from The Surgeon General (Circular Letter No. 45) was not published until 13 May 1942. It was believed that widespread knowledge of the incriminated yellow fever vaccine was of potential value to the enemy and also that it might affect adversely the morale of troops being vaccinated at staging areas and ports of embarkation in the United States.

Epidemiological and laboratory investigation of this outbreak was begun immediately, and medical officers who had arrived from the United States with the affected troops were able to inform the Division of Preventive Medicine, ETOUSA, of the large number of cases of jaundice which had by then begun to appear in the Army stationed in the United States. The relationship of the outbreak to the various lots of yellow fever vaccine was studied, and it was found that the attack rate was higher with certain lots than with others; for example, the percentages of those infected by lots numbers 338, 351, and 368 were 25, 13, and 15, respectively. The maximum incidence was at about the 14th week after inoculation, and cases were grouped symmetrically about that point. Through the cooperation of the Wellcome Research Institution in London, attempts were made to inoculate animals by means of the blood of patients. Monkeys, mice, embryonated eggs, and chick embryo tissue cultures were inoculated with the blood from patients, but the results were completely negative. Material from a fatal case was also negative. A comparison of the yellow fever neutralizing antibodies in patients with serum hepatitis and in English soldiers who had been inoculated against yellow fever, by means of 6-week-old Swiss mice and the intraperitoneal mouse protection test, showed no essential difference between the two groups.

The total number of cases in this outbreak of postvaccinal hepatitis was 1,915, of which 1,591 occurred in Northern Ireland and 324 in Great Britain.⁵⁰ Because of the great difference in numbers of troops stationed in Northern Ireland and Great Britain, the attack rates were approximately the same in both areas. Although the vast majority of these cases could be directly associated with inoculation with one or another lot of yellow fever vaccine, some of the 1,915 cases may have represented infectious hepa‑

⁵⁰Figures for this outbreak of postvaccinal hepatitis in the United Kingdom were drawn from individual units by a special team of investigators from the Preventive Medicine Division, Office of the Chief Surgeon, ETOUSA.

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titis, but the extent to which this was so cannot be ascertained with any certainty. As noted before, infectious hepatitis was not reportable on the statistical health report until 22 May 1942.

Iceland also experienced an epidemic of serum hepatitis. By 1 September 1942, approximately 1,320 patients had been hospitalized for jaundice, and about 200 more jaundice patients had been treated in quarters. Most of the cases occurred in troops who had arrived in Iceland during March and April 1942 and who, with a few exceptions, had been vaccinated against yellow fever with lot number 368. There were no deaths in Iceland.

The total number of cases of serum hepatitis in Europe and Iceland in 1942 was approximately 3,435. Two deaths occurred, both of them in Great Britain. Serum hepatitis did not again become a serious problem until 1944 when transfusions of blood and blood products became common due to the number of casualties occurring on the Continent. By this time, the Army was well aware of the danger. Studies made early in the war by the British Ministry of Health and the jaundice committee of the British Medical Research Council had adequately established the difference in jaundice rates among transfused wounded and untransfused wounded in emergency hospitals.

Infectious Hepatitis

After the subsidence of the yellow fever vaccine-induced epidemic by September 1942, the rate of hepatitis (presumably infectious hepatitis) was maintained in the European theater at relatively low levels, varying between 2 and 5 cases per 1,000 per annum, until the end of 1943. There was a sharp rise in rate in November and December 1943, shortly after the arrival of troops from the epidemic area in Italy. These troops comprised 4 infantry divisions and the First Engineer Special Brigade which were to form the nucleus of the First U.S. Army. A month or so after their arrival in England, the rate for U.S. troops in the United Kingdom rose to about 12.9 cases per 1,000 per annum, and this cadre experienced the highest incidence of the disease. Due perhaps to the sanitary facilities available in England, which even during maneuvers amounted to a garrison type of sanitation, there was no great spread of hepatitis to other troops training in England. However, the seeding of men from these organizations throughout the First U.S. Army might have played a significant role in the spread of hepatitis later during combat in Europe when such sanitary facilities were not available. Fortunately, the infection did not spread in the First U.S. Army, and hepatitis was never a great problem in that army, the rate remaining below 3 cases per 1,000 per annum until the spring of 1945 when, as in other armies in all theaters, there was an increased incidence, and the rate rose to 12 cases per 1,000 per annum (chart 10). There had been a sharp rise to 17 cases per 1,000 in the fall of 1944 and the winter of 1944-45, which had been in keeping with the experience at that season in Italy a year

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CHART 10.-Monthly incidence rates for hepatitis in the European Theater of Operations,January 1944 to December 1946

earlier. This characteristic seasonal upswing suggested infectious hepatitis rather than serum hepatitis.

The manner in which hepatitis spread among U.S. armies on the Continent is interesting. The disposition of the armies advancing toward the east through Europe in 1944 and 1945 was approximately as follows: The Seventh U.S. Army occupied the southernmost position with the Third U.S. Army on its left flank. The First U.S. Army was on the left flank of the Third Army, and the Ninth U.S. Army was at the far end of the line in Holland. Interchange of units and personnel among these armies was greatest between the Seventh and Third and was somewhat less between the First and Seventh.

The Seventh Army is of the greatest interest with respect to infectious hepatitis during 1944 and 1945. The epidemic spread in U.S. troops on the Continent was chiefly in this army and, as might be expected, in those units

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of the other armies; that is, the Third and First Armies, which were in contact with it.

The Seventh Army was made up of a nucleus of infantry divisions which had been a part of the Fifth Army in Italy; namely, the 3d, 36th, and 45th Infantry Divisions. These divisions had had considerable experience with hepatitis, and jaundice was still common among them when they invaded southern France on 15 August 1944. Hepatitis in the Seventh Army was thoroughly studied by Gauld who concluded that the infection had been introduced into the European theater by troops which had previously served in North Africa or Italy.

TROPICAL AND SUBTROPICAL AREAS

The Pacific

General considerations.-Tactically, the character of the campaign in the Pacific from August 1942 until August 1945 differed from that of other theaters of war, in that operations consisted of the introduction of various types of U.S. troops onto islands of different sizes and into populations of diverse types among whom the endemicity of infectious hepatitis varied. The character of the introduction of the troops into the islands varied from some of the most difficult and hard-fought landing operations in the whole war to the relatively easy occupation of smaller islands from which the Japanese had withdrawn. These differences created epidemiological problems different from those encountered in North Africa, the Middle East, Italy, and Europe. When it is remembered that the statistics for such a theater as SWPA (the Southwest Pacific Area) were drawn from the Philippines, the Netherlands East Indies, New Guinea, and the major part of the Solomons, as well as the mainland of Australia, it is obvious that the situations which they represent were various from the standpoint of epidemiological significance, and that more significant findings might be anticipated from more discrete studies of epidemics or outbreaks in individual islands or in individual units. Actually, the hepatitis rates in the Southwest Pacific steadily increased throughout the war until, in 1945, both the rate and the total number of troops affected were greater than in any other theater (chart 11). Unfortunately, the number of published studies concerning individual outbreaks or groups of cases were small, at least in comparison with the studies of Barker and his coworkers,⁵¹ of Gauld,⁵² and of Havens.⁵³ Furthermore, the Army Epidemiological Board commissions made no studies on hepatitis in the Pacific area.

⁵¹(1) Barker, M. H., Capps, R. B., and Allen, F. W. : Acute Infectious Hepatitis in the Mediterranean Theater ; Including Acute Hepatitis Without Jaundice. J.A.M.A. 128 : 997-1003, 4 Aug. 1945. (2) Barker, M. H., Capps, R. B., and Allen, F. W. : Chronic Hepatitis in the Mediterranean Theater of Operations ; A New Clinical Syndrome. J.A.M.A. 129: 653-659, 3 Nov. 1945.
⁵²Gauld, R. L.: Field Studies Relating to Immunity in Infectious Hepatitis and Homologous Serum Jaundice. Am. J. Pub. Health 37: 400-406, April 1947.
⁵³Havens, W. P., Jr. : Epidemiological Studies on Infectious Hepatitis. Am. J. Pub. Health 36 : 37-44, January 1946.

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CHART 11.-Hepatitis cases and incidence rates in the Southwest Pacific Area, January1942 to December 1945

In SWPA, there were two well-defined examples of increased rates of hepatitis (including both infectious and serum hepatitis) which reached epidemic proportions. The first, in 1942, was characterized by a very high admission rate in the relatively small number of U.S. troops in Australia. This outbreak was associated with postvaccinal (yellow fever) hepatitis. The second, which began in May 1944, involved troops in a number of areas, notably Biak Island; the New Guinea towns of Hollandia, Aitape, and Finschhafen; and the Admiralty Islands. The latter outbreak reached its height about August 1944 and declined sharply until the late fall when it began a dizzy and spectacular rise throughout the winter months to the following May. Rates for the theater exceeded 82 per 1,000 per annum. The tremendous importance of infectious hepatitis in this theater is indicated by the fact that, during the year 1944, 5,025 patients were treated for the disease, and in his report for that year the Chief Surgeon estimated that, if 17 man-days were lost per individual treated (a conservative estimate), approximately 85,425 man-days were lost. In 1945, some 39,277 cases were treated, and 667,709 man-days lost.

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Investigation of individual outbreaks.-The outbreak on Biak Island was investigated by Maj. James L. Borland, MC. At the direction of the Commanding General, Sixth U.S. Army, Major Borland studied in October 1944 an outbreak involving some 1,500 cases of infectious hepatitis which occurred between 1 June 1944 and 13 October 1944. The epidemic involved several different units on Biak which had different mess, latrine, and waterpoint facilities and were separated geographically by some distance. The cases began to occur in each unit at approximately the same time, and the peak was reached at the same time in the several units. There was no evidence of spread within the tents of a given unit; the outbreak was spotty and demonstrated no constant time relationship between initial and subsequent cases within the unit affected. However, Borland noted that there was a geographic similarity between the units chiefly involved, in that they were situated along two rows of cliffs which had been cleared of brush and cover about 6 weeks before the peak of the epidemic. In the units which had moved into bivouac areas that had been cleared previously, there were practically no cases, while in headquarters groups which tended to locate in areas with cover and to retain the cover, there was a relatively higher incidence. From his investigations, Borland concluded that the disease could not have been spread by contact but may have been spread by a vector, either a small night-biting phlebotomus or the common fly. Unfortunately, no accurate entomologic assistance was available, and the area had been fairly well cleared by the time the investigation was under way. It is of some interest that in this epidemic there was a concomitant outbreak of a 2- to 3-day fever indistinguishable from the fever associated with the early stages of the hepatitis. Borland attempted the transmission of hepatitis to ferrets, guinea pigs, and white mice without success.

Although this study did not contribute to fundamental knowledge of the disease, the suggestion of transmission by a night-biting gnat or phlebotomus should not be lightly dismissed, as it is theoretically possible that just as the syringe or needle may transmit serum hepatitis by minute quantities of serum, so may mechanical transfer by means of biting insects be one means of spread of infectious hepatitis. This possibility was also suggested by other investigators.

The outbreak in Hollandia from August to October 1944 was studied by Maj. Ray E. Trussell, MC,⁵⁴ and a report of this investigation has been published. This outbreak embraced 100 cases in 6 small military units. Trussell's conclusions were that the most likely mode of spread was the mechanical transference of the infectious agent by flies from infected feces, and by foodhandlers, utensils, dishwater, and food in the most severely affected unit. This more orthodox interpretation of the means of spread may well have

⁵⁴Trussell, R. E.: Epidemiologic Aspects of an Outbreak of Infectious Hepatitis. Am. J. Hyg. 45: 33-42, January 1947.

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applied to this particular outbreak, although it does not necessarily eliminate the possibility of a biting insect.

As the Pacific campaign increased its tempo and the troops moved into the Philippines, the hepatitis rates which had declined after the end of the campaign in New Guinea and the Solomons again began to rise. At one time, the troops fighting on Luzon had a rate of 415 per 1,000 per annum.⁵⁵ In the Philippine Islands, combat troops of the Sixth U.S. Army suffered much more from infectious hepatitis than did service troops in the first quarter of 1945.

Meanwhile, in Western Pacific areas adjacent to SWPA, infectious hepatitis proved to be one of the leading causes of disability. In his report for 1945, the Chief Surgeon of this area stated that from an epidemiological standpoint there was considerable evidence that disease rates were high where there were breaks in environmental sanitation. On Angaur, Guam, Saipan, Tinian, and Iwo Jima, hepatitis occurred. It is of great interest, however, that the rate on Iwo Jima, despite the very heavy fighting on that island, was 0.4 per 1,000 per annum, very low indeed, and that this paralleled the very low incidence of the spread of infectious gastrointestinal disease on that island.⁵⁶

The incidence on the island of Angaur increased sharply after the arrival of a heavy bombardment group which had become seriously infected on Leyte, illustrating an old observation that once troops have become infected and are moved into areas adjacent to previously uninfected troops the rate in the previously uninfected group tends to rise. Of passing interest is the report of 174 cases of the 27th Infantry Division on Esp?ritu Santo. All of these patients had been in combat on Saipan, and all of them gave a history of diarrhea. Of 142 patients more closely studied, 123 gave a history of a denguelike fever 24 to 32 days before onset of the hepatitis, which suggested to those on the scene the possibility that this might be a disease caused by a filterable virus of the denguelike group of viruses having a predeliction for the biliary tract. The close connection between the combat period on Saipan, the "dengue," and the diarrheas suggested to observers that this disease was not infectious hepatitis as they had thought of it before.⁵⁷

In summary, infectious hepatitis rates in the Southwest Pacific Area gradually rose throughout the war, reaching in 1945 rates higher than those reported from any other theater of operations. The studies of Major Trussell and the report of Major Borland illustrate prevailing local opinions regarding its manner of spread. Trussell believed, and cited evidence to support his view, which is the prevailing belief today, that disease was spread by transmission of the agent through fecal contamination, either directly or by

⁵⁵Annual Report, Chief Surgeon, General Headquarters, U.S. Army Forces, Pacific, 1945.
⁵⁶Turner, Glenn O.: History of Internal Medicine of the Western Pacific Base Command. [Official record.]
⁵⁷Essential Technical Medical Data, South Pacific Base Command, for October 1944, enclosure 2 thereto.

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flies, food, or water. Borland, on the other hand, believed that some arthropod vector, possibly a small night-biting phlebotomus, might be responsible in certain instances, and he cited evidence which he admits is not wholly convincing but which lends weight to this possibility.

Infectious Hepatitis in the China-Burma-India Theater

The surgeon of the China-Burma-India theater was alerted by a cable from the Office of the Surgeon General on 30 May 1942 which warned of the possibility of serum hepatitis following yellow fever inoculation. Although the concentration of troops in India at that time was small and was limited largely to service troops, there had been seven cases among the members of the U.S. Military Mission to Burma who had walked out with Lt. Gen. (later General) Joseph W. Stilwell. The General himself developed jaundice on 3 June 1942.⁵⁸ He had received vaccine from lot number 334 on 2 February 1942. Aside from its human interest, this case is interesting in view of General Stilwell's subsequent death and the post mortem findings in the liver.

After the subsidence of the outbreak of cases due to yellow fever vaccine, an illness occurred sporadically, which, was, presumably, naturally acquired infectious hepatitis. The seasonal incidence of hepatitis here was the same as in the North African Theater of Operations; that is, it increased in the late summer, and the peak was reached in September and October. The sharpest outbreak occurred at the Chakulia Base, Bihar Province, India, in August 1944 when 122 cases were admitted to the station hospital from a relatively small number of troops.

Relation to other diseases.-Considering the very high rates of incidence of diarrhea and dysentery among the troops in the China-Burma-India theater and the sanitary conditions prevailing throughout most of the theater, the rates for hepatitis were not so high as might have been expected (table 54). In India and Burma the majority of U.S. troops were concentrated in areas adjacent to the great port cities of Bombay and Calcutta, or along the Burma road in Assam and north Burma, while in China the troops were chiefly air corps troops until after 1944, when ground troops were in Y?nnan. In all these areas, despite vigilance and relatively good camp sanitation, the rates of diarrhea and dysentery, as well as of insect-borne diseases such as dengue, malaria, and scrub typhus, were all relatively high, yet the hepatitis rates showed no proportionate height save a possible correlation with rates of diarrhea and dysentery (chart 12).

The venereal disease rate was also high. This is of importance since syphilis throughout the war and gonorrhea after the introduction of penicillin were treated perenterally, and since the possibility exists that mechanical transfer by syringe is important in infectious hepatitis as well as in syringe

⁵⁸Blumgart, H. L., and Pike, G. N.: History of Internal Medicine in the India-Burma Theater. [Official record.]

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or serum hepatitis. However, there was no evident correlation of hepatitis rates with venereal disease rates.

TABLE 54.-Infectious hepatitis in the China-Burma-India theater, by year, 1942-45
[Preliminary data based on tabulations of individual medical records and summaries of statistical health reports]
[Rate expressed as number of admissions per annum per 1,000 average strength]

Year	Admissions
Year	Number	Rate
1942	135	15.44
1943	520	13.13
1944	1,681	9.96
1945	1,780	8.04
Total	4,116	9.39

CHART 12.-Monthly incidence rates for infectious hepatitis and for diarrhea and dysentery, U.S. Army troops in China-Burma-India theater, March 1942 to December 1945

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The only study of any size carried out in CBI was that made by Ware, Hendricks, and Bren (cited by Blumgart and Pike) on the outbreak of serum hepatitis in 1942. They reported clinical findings on some 405 patients. The authors have been unable to find any other significant epidemiological or laboratory studies carried out in the China-Burma-India theater.

Infectious Hepatitis in Latin America

Whether one considers the overall incidence in Latin America, or that of its various subdivisions such as the Department of Antilles or the Department of Panama, it is apparent that except for the general rise due to yellow fever vaccine (serum) hepatitis in 1942, the rates for hepatitis were surprisingly low and compare favorably with those in the Zone of Interior (table 55). As in the China-Burma-India theater, diseases spread by way of the oral-intestinal route were common. The venereal diseases and malaria were also prevalent. Although clinical studies on infectious hepatitis were carried out in Army installations in these areas, no significant epidemiological or laboratory studies have been reported.

TABLE 55.-Infectious hepatitis in the U.S. Army in Latin America, by year, 1942-45

[Preliminary data based on tabulations of individual medical records and summaries of statisticalhealth reports]
[Rate expressed as number of admissions per annum per 1,000 average strength]

Year	Admissions
Year	Number	Rate
1942	863	8.47
1943	86	0.71
1944	207	2.41
1945	220	3.02
Total	1,376	3.61

SUMMARY AND EVALUATION OF EXPERIENCE

In considering the epidemiology of the naturally occurring infectious hepatitis in the largest tropical and semitropical theaters, it must be admitted that the knowledge gained during World War II was singularly sparse, in view of the magnitude of the problem, at least in regard to mode of spread. Moreover, the question as to why hepatitis became epidemic in troops only in certain geographical areas must be left unanswered.

Adequate proof exists that the disease may be transmitted by means of the oral-intestinal route and by the parenteral route to human volunteers. Nevertheless, a statistical comparison of the incidence of hepatitis in these theaters with the incidences of other diseases spread via the oral-intestinal and parenteral routes could raise some doubt that these routes are the sole or predominant means of spread in the hepatitis epidemics.

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One might expect that, were the virus always spread in natural epidemics by the oral-intestinal route alone, the incidence of hepatitis in troops situated in areas where there was a high rate of diarrhea and dysentery might show some correlation with the relative incidence of diarrhea and other enteric diseases. As has been seen, in India, China, Burma, and the Southwest Pacific, as well as in Latin America, there was no particularly obvious correlation. On the other hand, if parenteral spread were an important factor, one might reasonably expect a correlation between the incidence of hepatitis and the rate of venereal disease since syphilis and gonorrhea were treated by parenteral medication; but, again, no such correlation is apparent. One may conclude that all is not yet known about the spread of hepatitis in military populations in different parts of the world.

In retrospect, it is apparent that viral hepatitis represented one of the most unexpected and most serious of the medical problems which confronted the U.S. Army in World War II. The most serious aspect of this problem was its numerical size; recognized cases numbered in the neighborhood of 200,000. This experience has established hepatitis in the minds of those who had to deal with the problem as a military disease of the first magnitude during World War II. Of great concern and great importance was the unexpected epidemic of serum hepatitis which occurred at the beginning of U.S. participation in the war. It represented the first large military epidemic of serum hepatitis ever to be recorded.

The research work on the hepatitides done under the auspices of the Medical Department of the U.S. Army by certain of the commissions of the Army Epidemiological Board, as well as by groups in the Medical Department, made a most important contribution to the knowledge of these diseases as well as to military history. In this report we have tried to record the epidemiological circumstances under which hepatitis occurred among the U.S. Armed Forces, and the information learned from these circumstances. Major contributions to knowledge were the identification of catarrhal jaundice with the viral hepatitides; the means for experimental study of these diseases; the indications that two varieties of viral hepatitis, infectious hepatitis and serum hepatitis, exist; information concerning the various ways in which each form of the virus can be transmitted; the clinical pictures and the revelation of the tendency in a few cases to chronicity and to relapse and of the circumstances under which the disease occurred most frequently. Although it cannot be said that World War II experiences resulted in a satisfactory method of preventing hepatitis or in a satisfactory method of therapy, much new information was accumulated about these diseases, and the difference between the knowledge of the disease in 1942 and that in 1946 is, to say the least, extraordinary. Credit for a large part of this achievement can rightfully be assigned to the Preventive Medicine Service, Office of the Surgeon General, and to the Army Epidemiological Board.

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