Contents

CHAPTER XIII

Viral Hepatitis

W. Paul Havens, Jr., M.D.

The emergence of viral hepatitis as one of the most important causes of loss of time among U.S. troops during World War II was as unexpected as it was dramatic. Conditioned largely by memories and descriptions of the medical experiences in World War I in which this disease played an almost unnoticed role in our forces both here and abroad, it is no wonder that those charged with the preparation of programs for the control and treatment of infectious diseases turned their attention first to respiratory infections. Records of the bitter ravages of influenza and secondary bacterial pneumonias doubtless prompted the Preventive Medicine Service of the Surgeon General's Office to establish early in 1941 the Board for the Investigation and Control of Influenza and Other Epidemic Diseases in the Army. This board was approved by the Secretary of War in January 1941 and, eventually, became known as the Army Epidemiological Board. The investigation of such diseases as yellow fever, typhus, malaria, dengue, sandfly fever, and venereal infections, among others, was given high priority, but viral hepatitis received little or no consideration as a potential troublemaker.

In retrospect, the grim record of 71,691 cases of jaundice (of which many were doubtless infectious hepatitis) among white Union troops in our Civil War,¹ as well as the oft repeated story of the military importance of this disease among foreign troops in Germany,² in the Mediterranean littoral,³ in the Dardanelles,⁴ and in Rumania⁵ during the 18th and 19th centuries, and in World War I, had little impact on our thinking. This is readily understandable in view of the remoteness of these experiences both temporally and spatially. In addition, it is curious but true that our concept of the nature of viral hepatitis was generally somewhat more naive than that of certain of our European medical colleagues despite the fact

¹Medical and Surgical History of the War of the Rebellion. Medical History. Washington: Government Printing Office, 1888, pt. III, vol. I, pp. 874-879.
²Monro, Donald: An Account of the Diseases Which Were Most Frequent in British Military Hospitals in Germany, From January 1761 to the Return of the Troops to England in March 1763. London: Millar, Wilson, and Durham, 1764.
³Larrey, D. J.: Relation Historique et Chirurgical de l'Expédition de l'Armée d'Orient en Egypte et en Syrie. Paris: Demonville et Soeurs, 1803.
⁴Sarrailhé, A., and Clunet, J.: La "Jaunisse des camps" et l'épidémie de paratyphoïde des Dardanelles. Bull. et mén. Soc. méd. d. hôp. de Paris, 3 sér., 40: 563-567, 1916.
⁵Cantacuzène, J.: Sur une épidémie d'ictëre observée en Roumanie pendant la campagne de 1917. Presse méd. 26: 541-543, 24 Oct. 1918.

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that occasional pioneers in this country, including Blumer⁶ and Rich,⁷ had pointed the way to a better understanding of the disease.

It is particularly ironic that the concern about another acute infection producing necrosis of the liver-yellow fever-and the aggressive efforts made to expedite the production of enormous supplies of vaccine against it did not potentiate our awareness of the importance of viral hepatitis. Our introduction, in 1942, was a rude one and was marked by the great epidemic of homologous serum hepatitis transmitted by the injection of yellow fever vaccine stabilized with human serum containing a strain of hepatitis virus. Unfortunately, this catastrophe was not to be the last. Subsequently, in 1942-45, as our troops appeared in the Middle East, in North Africa, in the Far East, in Europe, and in the Pacific Ocean Areas, they were riddled by the naturally occurring epidemic disease, infectious hepatitis. It is pertinent to point out here that recognition of the differences between the transmitted disease and the naturally occurring one was not immediate, and, indeed, it was not until 1944-45 that two separate entities, serum hepatitis and infectious hepatitis, were generally recognized. However, it is a tribute to the vigor and sagacity of a number of military medical officers and their civilian consultants that many of the problems associated with this unexpected and unwelcome situation were quickly recognized and that many of the etiologic, clinical, and epidemiologic unknowns were solved.

Viral hepatitis, with close to 200,000 cases, erupted in the period between 1942 and 1945 as a matter of prime importance to our Armed Forces. It is the purpose of this account to set down the experiences of the Army with serum hepatitis and infectious hepatitis during the period of World War II (table 65).

TABLE 65.-Admissions for infectious and serum hepatitis in the U.S. Army, by broad geographicarea and by year, 1942-45

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

⁶Blumer, G.: Infectious Jaundice in the United States. J.A.M.A. 81: 353-358, 4 Aug. 1923.
⁷Rich, A. R.: The Pathogenesis of the Forms of Jaundice. Bull. Johns Hopkins Hosp. 47: 338-377, December 1930.

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SERUM HEPATITIS

Historical Background

Doubtless, the earliest record of serum hepatitis is a report by Lürman⁸ of an outbreak of jaundice occurring in shipworkers several weeks after vaccination with human glycerinized lymph. Stokes and his coworkers,⁹ in the United States, and Ruge,¹⁰ in Germany, subsequently reported the occurrence of jaundice in patients undergoing antisyphilitic therapy, although they apparently considered its cause to be infectious jaundice occurring in patients made more susceptible either by their syphilitic infection or by the treatment given for it. It was reserved for Flaum and his associates,¹¹ in 1926, to point out that, in a clinic caring for persons with diabetes, those patients who acquired hepatitis were doubtless infected by contaminated needles or syringes; further, they suggested that the long incubation period of this disease distinguished it from the shorter incubation period of infectious hepatitis and raised the question whether two viruses might not exist. The prescience of these workers merits special mention, particularly in view of the considerable period of time that elapsed before their speculations were proved to be true.

In the late 1930's, Findlay and his associates¹² described the occurrence of jaundice in Africa in persons who had been immunized against yellow fever with a vaccine containing human serum and suggested the viral nature of the icterogenic agent. During the same period, Soper and Smith¹³ and Fox and his associates¹⁴ described outbreaks of jaundice in Brazil, following the use of yellow fever vaccine stabilized with human serum.

In addition, in England in 1938, both Propert¹⁵ and McNalty¹⁶ also incriminated human serum as the probable medium of transmission

⁸Lürman, A.: Eine Icterusepidemie. Berl. kiln. Wchnschr. 22: 20-23, 1885.
⁹Stokes, 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.
¹⁰Ruge, H.: Zehn Jahre Gelbsucht in der Marine (1919-1929), Beobachtungen an 2500 Fällen. Ergebn. d. inn. Med. u. Kinderh. 41: 1-112, 1931.
¹¹Flaum, A., Malmros, H., and Persson, E.: Eine nosocomiale Ikterus-epidemie. Acta med. Scandinav. Suppl. 16: 544-553, 1926.
¹²(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. (3) Findlay, G. M., MacCallum, F. O., and Murgatroyd, F.: Observations Bearing on the Aetiology of Infectious Hepatitis (So-Called Epidemic Catarrhal Jaundice). Tr. Roy. Soc. Trop. Med. & Hyg, 32: 575-586, February 1939.
¹³Soper, 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.
¹⁴Fox, J. P., Manso, C., Penna, H. A., and Para, M.: Observations on Occurrence of Icterus in Brazil Following Vaccination Against Yellow Fever. Am. J. Hyg. 36: 68-116, July 1942.
¹⁵Propert, S. A.: Hepatitis After Prophylactic Serum. Brit. M.J. 2: 677-678, 24 Sept. 1938.
¹⁶McNalty, 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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of hepatitis. They described the occurrence of the disease in children, following the injection of pooled measles immune serum.

Thus, it would appear that by 1940 serum hepatitis was either suspected or regarded in some parts of the world as a disease potentially transmissible by human serum containing an icterogenic agent. Despite this recognition in certain circles, the subject received little attention in the United States, and although an account of it had already been published here in 1939,¹⁷ the concept of the true nature of serum hepatitis, and indeed of infectious hepatitis, had not yet reached a level of widespread general awareness in our medical profession. This, combined with the facts that (1) serum hepatitis had never been recognized as a military disease and (2) the human serum used in the vaccine had been heated to 56°C., for at least 30 minutes, apparently lulled any suspicion that might have arisen. It is easy to see, then, how the pressure created by the decision to immunize large numbers of troops that might be going into areas where yellow fever was highly endemic or epidemic made defensible the acceptance of the calculated risk of producing and inoculating millions of doses of yellow fever vaccine stabilized with human serum. That this would end in a catastrophe that evoked unjustly critical editorials¹⁸ in certain segments of our press and outraged demands for congressional investigation by a member of the House of Representatives¹⁹ was not anticipated.

The Epidemic and Its Characteristics

Although the exact number of cases of serum hepatitis that occurred in 1942 is not known, it is presumed that most of the 49,233 admissions to hospitals for hepatitis reported for the total U.S. Army were caused by the injection of yellow fever vaccine stabilized by human serum containing an icterogenic virus. Of these total Army figures, 33,569 cases were reported from the continental United States and 15,664 from theaters outside the continental United States.

Late in the autumn of 1941, the immunization of U.S. troops against yellow fever was initiated on a large scale. This program had been recommended by the Subcommittee on Tropical Diseases of the National Research Council in 1940 primarily because of the epidemic of yellow fever that year in the Nuba Mountains of the Anglo-Egyptian Sudan and the possibility that U.S. troops might eventually operate in Africa, India, and

¹⁷See footnote 13, p. 333.
¹⁸Editorial: J.A.M.A. 120: 1110, 1 Aug. 1942.
¹⁹Representative J. Parnell Thomas (R-N.J.), ranking minority member of the House Military Affairs Committee, on 30 July 1942, urged congressional investigation of the cause of the 28,585 cases of yellow jaundice in the Army, apparently from the use of yellow fever vaccine. "The disclosures on the number of cases of jaundice are a national disgrace and the country is entitled to know what happened." Thomas continued: "I am sure that the parents of the stricken youths whose life expectation may have been reduced by the attack are not satisfied with the report that the Army hopes the situation has been cleaned up. The Nation is entitled to know what happened and who is to blame."

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the East. The decision to immunize large numbers of men created a huge demand for yellow fever vaccine, and the burden for its production was undertaken, late in 1940, by the International Health Division of the Rockefeller Foundation, New York, N.Y. It is not the purpose of this paper to discuss the various aspects of this immunization program or the decisions that led to its adoption, but this whole subject has been carefully reviewed and documented by Long²⁰ and by Paul and Gardner.²¹

The first cases of hepatitis that were subsequently to be identified as serum hepatitis caused by yellow fever vaccine appeared in February 1942, and by the end of the first week in March of that year, it became clear from reports emanating from widely separated areas that an epidemic disease associated with jaundice had appeared in the Army. Although early suspicions were directed toward the possibility that yellow fever itself or epidemic catarrhal jaundice might be involved, it was rather quickly recognized that the occurence of jaundice in men throughout this country and in far-flung places abroad was associated with the previous injection of yellow fever vaccine and, indeed, with certain specific lots of it.

The possibility was early considered that the administration of the vaccine might have activated a virus latent in the host, causing hepatitis; however, the true nature of the situation was soon appreciated, and the human serum used to stabilize the vaccine was indicated as carrying an icterogenic agent that produced hepatitis. A speedy solution of this aspect of the problem was made possible by the work of a number of different groups and individuals working together and independently. The history of this indictment and the fascinating tale of the incrimination of certain lots of human serum that came from the Johns Hopkins University School of Medicine, Baltimore, Md., were well recorded by Sawyer and his associates.²² Suffice it to say that Dr. Kenneth F. Maxcy, of the Army Epidemiological Board, and Dr. Karl F. Meyer, of the George Williams Hooper Foundation, were among those who furnished the penetrating and incisive epidemiologic evidence that made the solution possible. As a result, The Surgeon General, Maj. Gen. James C. Magee, on 14 April 1942, approved the recommendation to suspend the use of the yellow fever vaccine made by the International Health Division of the Rockefeller Foundation for 2 months, and to use the U.S. Public Health Service vaccine produced in its Rocky Mountain Laboratory, Hamilton, Mont. Subsequently,

²⁰Long, Arthur P.: The Army Immunization Program. In Medical Department, United States Army. Preventive Medicine in World War II. Volume III. Personal Health Measures and Immunization. Washington: U.S. Government Printing Office, 1944, pp. 271-341.
²¹I am deeply indebted to Dr. John R. Paul with whom I worked closely from 1943 to 1946 in Egypt and in New Haven, Conn. Many of the points of view expressed in this history were derived from this association and from subsequent ones over the years. His concepts concerning hepatitis and its military importance were eventually set down in the following document: Paul, John R., and Gardner, Horace T.: Viral Hepatitis. In Medical Department, United States Army. Preventive Medicine in World War II. Volume V. Communicable Diseases. Washington: U.S. Government Printing Office, 1960, pp. 411-462.-W, P. H., Jr.
²²Sawyer, 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.

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human serum was omitted from the vaccine entirely. Justification of this action was borne out by the fact that, after it, cases of serum hepatitis following immunization with yellow fever vaccine failed to occur.

From its point of recognition in the week ending on 7 March 1942, the epidemic in the United States progressed rapidly and reached its peak of incidence in the week ending on 20 June, after which there was a steady, progressive decline (chart 2). A similar situation was recognized in widely

CHART 2.-Weekly admissions for jaundice (essentially serum hepatitis) in the U.S. Army in continental United States, January-December 1942

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CHART 3.-Weekly admissions for jaundice (essentially serum hepatitis) in the U.S. Army

overseas, January-December 1942

separated localities abroad during the first 2 weeks in March, but the peak of incidence of the disease appeared to occur 1 or 2 weeks later than in the continental United States. The decline of incidence abroad was also similar to that in this country (chart 3).

The first information about jaundice on board American troop ships came by way of a telephone message from Dr. Andrew Davidson, Chief Medical Officer of Health for Scotland, on Wednesday, 13 May 1942, advising that there were 26 cases among approximately 20,000 troops. These men continued to their destination in Northern Ireland, and during the ensuing weeks, the number of cases increased. Almost all these patients were sent to the 5th General Hospital, near Belfast. By 20 May 1942, 83 patients had been admitted to the wards, and by the end of the next week, 231 patients had been admitted. A number of clinical and laboratory investigations were initiated, and the relationship of the epidemic with the previous injection of yellow fever vaccine stabilized with human serum was established. A total of 1,915 cases occurred, of which 1,591 were in Northern Ireland and 324 in Great Britain.

In the course of the inquiry made in Northern Ireland during the period of 20-27 May 1942, repeated reference was made to "Honolulu disease" by a number of the medical officers who had accompanied the affected troops from the United States, and the statement was made that the jaundice prevalent in U.S. troops in Ireland was identical with that condition. Honolulu disease appeared to have originated at Fort Sam

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Houston, Tex., in January 1942, where it was studied by staff members of the Rockefeller Foundation who were said to have come to the conclusion that the jaundice there was due to the ingestion of infected pork and that the infectious agent was a filtrable virus. It was regarded as communicable, and the incubation period was fixed at about 10 to 14 days. Subsequently, troops from this post moved to Fort Ord, Calif., for embarkation to the Hawaiian Islands. Two convoys, members of the 27th Infantry Division, were moved to the Islands. One, including 5,252 men, left San Francisco, Calif., on 10 March and arrived in Honolulu on 14 March 1942. The second convoy left on 30 March and arrived on 3 April, carrying about 5,800 men. During the passage to Hawaii, 1 case of jaundice developed in the first convoy and 11 in the second convoy. On arrival in Honolulu, additional cases began to appear at about 2-week intervals, tending to occur in crops. By 3 April 1942, there were 500 patients in hospitals in Honolulu with jaundice. Although it was the belief of some of the physicians in Hawaii that the condition was unrelated to the administration of yellow fever vaccine, it indeed seemed to represent the same situation as occurred in the Zone of Interior, in Northern Ireland and Great Britain, and in other parts of the world. Its appearance, in January 1942, suggested that lots of vaccine inoculated as early as October 1941 were probably involved.²³

An epidemic of serum hepatitis with approximately 1,520 cases occurred in Iceland in 1942, beginning with troops arriving there during March and April. Most of these men had been vaccinated against yellow fever with lot No. 368. In Canada, U.S. troops had the first case of serum hepatitis in the middle of May 1942, with an increasing number of new cases until a peak was reached around the first or second week of July. A few new cases appeared after this in August, but none thereafter. In the Central Pacific Area, serum hepatitis made its advent in troops arriving at Oahu between 10 and 16 March 1942, and in the Southwest Pacific Area, an outbreak occurred in 1942 among U.S. troops in Australia. In the entire Pacific Ocean Area, several hundred patients were hospitalized.

²³At the time of the Pearl Harbor raid and subsequent thereto, Fort Armstrong was the post guarding the entrance to Honolulu Harbor. As one of his duties, the Port Surgeon was required to board and inspect all troop convoys before they docked. The occurrence of one case of jaundice of undetermined origin in the first convoy of troops cited above did not appear to warrant restriction of the whole convoy, and the Hawaiian Department surgeon, Col. Edgar King, MC, transmitted instructions to permit the convoy to dock, which was done. Soon after debarking, other cases of jaundice developed, and it was then thought that they represented mild cases of yellow fever contracted from the yellow fever inoculations. This introduced an immediate problem since the mosquito vector of yellow fever, Aedes aegypti, was present in Hawaii. Emergency measures were set in motion by quickly erecting a tent camp next to the Honolulu docks and surrounding it by a fence for quarantine purposes. The debarked troops were returned to dockside, placed in this quarantine, and mosquito control measures instituted. Daily inspections of the troops were carried out and all new cases of fever or jaundice hospitalized. When word was received concerning cases of jaundice aboard the second convoy, the quarantine camp was immediately expanded and these troops debarked directly into it when they arrived. Of course, many more cases developed subsequently, and the affected personnel were hospitalized. Finally, the number of cases subsided, the true nature of the jaundice was revealed, and the quarantine was lifted.-A. L. A.

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Seven different lots of yellow fever vaccine (Nos. 331, 334, 335, 338, 367, 368, and 369) were identified as those that produced the outbreak of serum hepatitis. Six of these lots were highly icterogenic, and to three of them (Nos. 367, 368, and 369) were traced the greatest number of cases. Personnel of the entire Air Corps and those of the Ground Forces troops who were scheduled for duty overseas were immunized with yellow fever vaccine in the latter part of 1941. Among the lots used were three highly icterogenic ones. The second phase of immunization occurred between 20 January and 15 April 1942 when all the personnel in the Army were vaccinated. The remaining icterogenic lots of vaccine were used during this time. The first peak of the epidemic, occurring in March-May 1942, represented cases occurring in men immunized in the previous autumn; the second peak, occurring from late May through July, was made up of cases occurring in men immunized during the second period of vaccination.

It was early appreciated that the incubation period of this disease was unusually long and, in addition, highly variable, ranging from 60 to 150 days. This variability was emphasized by Parr,²⁴ who studied a large outbreak at Camp Polk, La., where 5,000 men were inoculated with lot No. 369, on 27 February 1942; 1,004 cases of hepatitis with jaundice occurred among these men. The differences in incubation period were interpreted as the result of variations in the state of health of the hosts.

A striking characteristic of the outbreaks that occurred both in the continental United States and abroad was the apparent failure of the disease to spread to persons who had not been similarly immunized. Occasional incidents were reported, however, in which the wives of men with postvaccinal hepatitis acquired hepatitis. This lack of communicability by personal contact except possibly under most intimate terms was a matter of great interest, particularly to those charged with the responsibility of attempting to determine the relationship between serum hepatitis and the naturally occurring epidemic disease.

There were those, however, who felt that actually a considerably greater communicability existed, and postulated the concept that the immunization with the yellow fever vaccine had not been directly responsible for the occurrence of hepatitis but rather that it rendered the men more susceptible to the naturally occurring disease. Freeman²⁵ described outbreaks at Fort Belvoir, Va., Fort Sill, Okla., and Fort Lewis, Wash., in which an increase in incidence of hepatitis among unvaccinated troops occurred during outbreaks in men who had been immunized with icterogenic lots. It seems fair to say that this concept was probably not valid in view of the vast amount of evidence incriminating certain lots of serum

²⁴Parr, 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.
²⁵Freeman, G.: Epidemiology and Incubation Period of Jaundice Following Yellow Fever Vaccination. Am. J. Trop. Med. 26: 15-32, January 1946.

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as icterogenic. However, complete unanimity of opinion on this subject was not attained.

Among the curious strokes of fate was the statistical improbability that allowed the absence of postvaccinal hepatitis in the Navy. They had received only two lots of icterogenic vaccine (Nos. 334 and 369) and had used them sparingly. Thus, at the meeting, on 14 April 1942, at which the recommendation to discontinue yellow fever vaccine produced by the International Health Division of the Rockefeller Foundation was approved by Surgeon General Magee, Capt. (later Rear Adm.) Charles S. Stephenson, MC, of the Navy, was able to state that there had been no jaundice among Navy personnel following immunization with this vaccine. About half a million men had been immunized before the end of December 1941, and its use had been continued since that time.

Clinical Aspects

Numerous opportunities occurred for large clinical studies, and a number of good ones were made. It was early recognized that, after onset of the disease, the clinical course was indistinguishable from that of epidemic hepatitis or so-called catarrhal jaundice. For this reason, the major discussion of the clinical aspects will be reserved for inclusion in the section dealing with infectious hepatitis.

Certain special features were observed, however, that served to differentiate serum hepatitis from the epidemic disease. Important among these was the type of onset that was described as insidious in contrast to the more abrupt beginning of infectious hepatitis. Fever of any significance was unusual in patients with serum hepatitis in contrast to the common occurrence of fever, often of considerable degree, in patients at the onset of the epidemic disease. In addition, arthralgia, urticaria, and itching were common enough in patients at the onset of serum hepatitis to mark these symptoms as clinical differences between the two conditions.

Among the best clinical accounts was that of Turner and his colleagues²⁶ who described an outbreak at Camp Polk among men who had been immunized with yellow fever vaccine lot No. 369. The epidemic was heralded by a sharp increase in admissions of patients with jaundice to the hospital during the first week in May, progressing to its peak during the week of 20 June, and declining thereafter with a low level attained in the first week in September. The incubation periods ranged from 8 to 23 weeks. During the period of 1 May-12 September 1942, 4,083 patients were observed and, of these, 14 died. It was of interest that those who died had their first symptoms in the early part of the outbreak, from 15 May to 10 June, and the disease appeared to be milder in those patients who were

²⁶Turner, 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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admitted after the incidence was declining. Since these men were inoculated at the same time, the question may be raised whether prolongation of the incubation period might have been another manifestation of the mildness of the disease.

Because every effort was made to get patients into the hospital promptly, it was possible to study a goodly percentage of these men early in the course of disease. Fifty-two percent were admitted during their first week of illness and 41 percent during their second or third week of illness. The remaining 7 percent straggled in thereafter. The onset of disease was usually vague and insidious, with mild afternoon fatigue and malaise, followed subsequently by the appearance of anorexia, weakness, nausea, abdominal pain and distress, and vomiting. Other symptoms of note, although less common, were arthralgia, pain in the back, urticaria, burning of the eyes, lassitude, and headache. Despite the frequency of these symptoms, attention was called to the fact that a fair number of patients with jaundice were completely asymptomatic. Fever was not common and, if it occurred, lasted only 2 or 3 days. Diurnal variations of anorexia, abdominal distress, and even enlargement of the liver were described, with an increase in signs and symptoms at the end of the day. In a certain number of patients, sudden attacks of severe weakness and sweating occurred, suggesting hypoglycemia, and relief was afforded by the ingestion of a meal of carbohydrates. A small percentage of patients had actual pain in the right upper quadrant of the abdomen or the lower part of the right side of the chest, radiating up to the neck and the right shoulder. This was often made worse by walking or deep breathing. Although suggestive of diaphragmatic irritation, no report was made of hearing a friction rub. On occasion, pain in the right lower quadrant of the abdomen simulated acute appendicitis, and it was sometimes not possible to make a differential diagnosis without laparotomy.

Aside from jaundice, enlargement and tenderness of the liver were the two most striking findings, occurring in 40 percent (hepatomegaly) and 20 percent (hepatic tenderness) of patients. Petechial hemorrhages in the skin and mucous membranes were frequently observed in the seriously sick patients but also, on occasion, in the mildly sick. They extended over the lateral aspects of the chest and arms and were often widespread. Occasional patients had spider nevi that disappeared during convalescence.

Classification of cases in relation to degree of severity was made on the basis of three different criteria-the intensity and the duration of jaundice and the maximum loss of weight. Under these terms, 81 percent were regarded as mildly sick, 17 percent moderately severely sick, and 2 percent severely sick. Included in those regarded as mildly sick was a group of patients with so-called "trivial illness." The diagnosis of hepatitis in these patients was made not infrequently on the basis of symptoms and the presence of bilirubinuria without clinical jaundice. It is indeed of

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interest that the diagnosis of hepatitis without jaundice, subsequently to become a controversial subject in some quarters, should have been made so early in this clinical experience. However, it is obvious that the epidemiologic pattern of disease in men who had been inoculated with a highly icterogenic lot of yellow fever vaccine (No. 369) supported the validity of this concept. Of even greater interest, however, was the suggestion that, although there was little unequivocal evidence of a subclinical form of the disease, the medical officers involved in this study felt that there was sufficient to cause them to believe in the existence of this entity also.

It was appreciated that worsening of the course of the disease could occur quite subtly and quickly, and certain guides in prognosis came to be used. Considerable confidence was placed in the capacity of patients to respond vigorously to the parenteral administration of vitamin K as a favorable sign. Frequent measurements of the degree of bilirubinuria, the gain or loss of weight, and the amount of food consumed were made, and continued anorexia and loss of weight with deepening jaundice were regarded as ominous.

Among the fatal cases, death occurred from 24 to 101 days after onset of the disease. In a goodly percentage of them, death came later rather than earlier in the course of the disease, and attention was called to the fact that, in patients who lived for a longer period, alterations in type of hepatic involvement occurred as well as changes in other organs. Thus, it was believed that, during the more prolonged course of the disease that eventually terminated fatally, the continuing necrosis and regeneration brought about structural changes in the liver, resulting in (1) certain manifestations of intrahepatic obstructive jaundice and (2) changes in vascular patterns, with increase of portal pressure. Portal hypertension with congestive splenomegaly did occur and, on occasion, with excessive hemolysis and rupture of esophageal varices.

Lucké²⁷ described in detail the findings at necropsy of a larger group of fatal cases, and they will be dealt with more fully in the section on "Infectious Hepatitis." At this point, they may be summarized as ranging from massive acute hepatic necrosis in those dying early to varying degrees of hepatic necrosis and regeneration with alterations of the lobular architecture in those succumbing later in the course of the disease. Edema and hemorrhagic changes in the gastrointestinal tract were common.

Complications

Complications fundamentally related to the underlying disease included neurologic disturbances, gastrointestinal hemorrhage, ascites,

²⁷Lucké, B.: Pathology of Fatal Epidemic Hepatitis. II. Structure of Liver After Recovery From Epidemic Hepatitis. Am. J. Path. 20: 471-593, 595-619, May 1944.

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macrocytic anemia, gingivitis, renal dysfunction, hemorrhages into the skin and mucous membrane, and morbilliform rashes. Most of them were evidence of increased severity of the disease, although on occasion milder cases did have numerous petechial hemorrhages in the skin and mucous membranes. Neurologic disturbances were often bizarre. Severe emotional and mental disarray were followed often by tremor and coma. Gastrointestinal hemorrhage occurred not only from rupture of esophageal varices but also from direct bleeding into the gastrointestinal tract from multiple small points. In fatal cases, hemorrhage into the mesentery was observed, and in at least one patient, this was associated with considerable abdominal pain and tenderness before death. Gingivitis was thought to be due to multiple minute hemorrhages in the gums. Renal dysfunction was manifested largely by albuminuria, although in seriously sick patients or fatal cases azotemia occurred. Of particular interest was the description of the so-called tremor syndrome. It was observed during convalescence or even after apparent recovery and consisted of a slow, coarse tremor of the extremities at rest, made worse by movement. This, at times, appeared to be associated with weakness, and one patient was described as having his knees "buckle under him" so that he fell down. There was no apparent association of this with hypoglycemia, and the ingestion of food gave no relief.

Delayed recovery occurred in a small percentage of patients, whose complaints were primarily concerned with easy fatigue and disorders of the gastrointestinal tract. Anorexia, intolerance for fatty foods, pain in the right upper quadrant of the abdomen after exercise, anxiety, and tremor were common symptoms. They appeared to reflect, in most instances, what was subsequently termed the "posthepatitis" syndrome.²⁸ In a survey of 200 soldiers who had been sent back to the United States from overseas after several months of hospitalization because of such delayed recovery, Col. Julien E. Benjamin, MC, and Maj. Ralph C. Hoyt, MC,²⁹ found that most of the soldiers were without objective evidence of hepatic disease and required only an adequate diet, physical reconditioning, and indoctrination to restore them to health. In many instances, the cause of disability was a neurosis that had been latent but reactivated by the advent of hepatitis. Of 127 of these soldiers whose capacity to excrete intravenously administered Bromsulphalein (sulfobromophthalein) was measured, only 11 (8.7 percent) had abnormal tests and most of these eventually returned to normal.

Treatment

Treatment was concerned with rest and frequent feedings of carbohydrates. The prescribed diet was high in carbohydrate and protein and

²⁸Caravati, C. M.: Posthepatitis Syndrome. South. M.J. 37: 251-257, May 1944.
²⁹Benjamin, J. E., and Hoyt, R. C.: Disability Following Postvaccinal (Yellow Fever) Hepatitis; Study of 200 Patients Manifesting Delayed Convalescence. J.A.M.A. 128: 319-324, 2 June 1945.

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low in fat. Clinical trials of the administration of various vitamin supplements, methionine and choline, apparently did not expedite recovery. In seriously sick patients, it was believed that the course of their disease was not favorably altered by administration of vitamins, transfusions of blood or plasma, or intravenous infusions of dextrose in saline. However, it is hard to believe that the provision of adequate amounts of fluid and electrolytes with dextrose might not have played a role in the recovery of certain patients.

Other Sources of Serum Hepatitis

Despite the fact that the major outbreak of homologous serum hepatitis was terminated by the omission of human serum from yellow fever vaccine, this was not to end our experience or that of others with this disease. The tremendous need for transfusions of blood and plasma and the lack of effective methods of ridding these materials of viable hepatitis viruses made serum hepatitis a continuing problem.³⁰ Maj. Paul B. Beeson, MC,³¹ in England, predicted early in 1943 the hazards attending the use of such transfusions, and on 1 June 1945, in a survey of 1,762 cases of hepatitis under treatment in general hospitals in the United States, Sartwell³² justified this prophecy. Of these patients, 500 gave a history of receiving transfusions of blood or its products before the onset of hepatitis, and of the 500, a large proportion appeared to have been infected by this means. There is every reason to believe that the early awareness of this hazard in the minds of British and United States medical officers in England was important in the education of our medical officers in the Zone of Interior in the recognition of this disease.

The pooling of plasma from large numbers of persons augmented the risk of infection, and the course of the disease was often much more severe in patients debilitated by trauma and exhaustion. Because of these problems, efforts were made in 1944-45 to determine whether the prophylactic effect of normal human gamma globulin that had been recently demonstrated in infectious hepatitis might also be true for serum hepatitis. Grossman and his associates³³ were successful in demonstrating protection when two intramuscular injections of 10 ml. each were given 1 month

³⁰(1) Morgan, H. V., and Williamson, D. A. J.: Jaundice Following Administration of Human Blood Products. Brit. M.J. 1: 750-753, 19 June 1943. (2) Homologous Serum Jaundice. (Memorandum prepared by medical officers of the Ministry of Health.) Lancet 1: 83, 1943. (3) Editorial: Hepatitis After Transfusion. Brit. M.J. 2: 279, 1944.
³¹Beeson, P. B.: Jaundice Occurring One to Four Months After Transfusion of Blood or Plasma. Report of Seven Cases. J.A.M.A. 121: 1332-1334, 24 Apr. 1943.
³²Sartwell, P. E.: Infectious Hepatitis in Relation to Blood Transfusion. Bull. U.S. Army M. Dept. 7: 90-100, January 1947.
³³Grossman, E. B., Stewart, S. G., and Stokes, J., Jr.: Posttransfusion Hepatitis in Battle Casualties and a Study of Its Prophylaxis by Means of Human Immune Serum Globulin. J.A.M.A. 129: 991-994, 8 Dec. 1945.

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apart following transfusion, while Duncan and his associates³⁴ failed to find any protective effect when a single injection was given.³³

The painfully won awareness of other methods of artificial transmission of hepatitis also emerged during these years of World War II. Inadequately sterilized syringes and needles were indicated in its transmission in procedures involving withdrawal of blood for laboratory determinations or injection of medications.³⁶ Clinics for the care of patients with syphilis, diabetes, and arthritis achieved recognition as areas of high risk for the accidental transmission of hepatitis, and ample proof of the role of the needle and the syringe was afforded by a sharp reduction in the incidence of the disease following the institution of adequate sterilization of these instruments. It can truly be said that the widespread recognition of these various hazards constituted a major advance in medical knowledge, initiated largely by military experience but penetrating deeply into civilian practice.

INFECTIOUS HEPATITIS

Historical Background

The importance of infectious hepatitis in medical military history has long been recognized. Troops concentrated during war appear to have been particularly vulnerable, and in this country and abroad the military history of the last two centuries is replete with accounts of epidemics of jaundice, many of which doubtless represented this disease. During World War I, British³⁷ and French troops³⁸ in the Mediterranean area and in the Dardanelles suffered serious outbreaks, and during World War II, it was a major cause of loss of time in both Allied and Axis forces.³⁹

Attention has been called to the fact that the concept of the nature of infectious hepatitis generally held in this country was somewhat naive at the beginning of World War II. The term "catarrhal jaundice" was widely used to define sporadically appearing cases or outbreaks of jaundice.

³⁴Duncan, G. G,, Christian, H. A., Stokes, J., Jr., Rexer, W. F., Nicholson, J. T., and Edgar, A.: Evaluation of Immune Serum Globulin as Prophylactic Agent Against Homologous Serum Hepatitis. Am. J.M. Sc. 213: 53-57, January 1947.
³⁵The discrepancy in these results became a matter of discussion intermittently during the ensuing years and, eventually, prompted the studies of Mirick and his coworkers who, in 1962, reported that the intramuscular administration of 10 ml. of gamma globulin on two occasions, 1 month apart, to recipients of transfusions of whole blood significantly reduced the incidence of hepatitis with jaundice, although the attack rate of anicteric hepatitis was similar to that in transfused patients who had not received gamma globulin. See Mirick, G. S., Ward, R., and McCollum, R. W.: Gamma Globulin in the Control of Hepatitis Following Blood Transfusion. Vox Sang. 7: 125-126, 1962.
³⁶(1) Role of Syringes in Transmission of Jaundice. (Memorandum prepared by medical officers of the Ministry of Health.) Lancet 2: 116, 1945. (2) Mendelssohn, K., and Witts, L. J.: Transmission of Infection During Withdrawal of Blood. Brit. M.J. 1: 625-626, 5 May 1945.
³⁷Martin, C. J.: Concerning the Pathology and Etiology of the Infectious Jaundice Common at the Dardanelles, 1915. Brit. M.J. 1: 445-447, 7 Apr. 1917.
³⁸See footnote 4, p. 331.
³⁹See footnote 21, p. 335.

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Despite the fact that Eppinger⁴⁰ and Rich⁴¹ had long since described diffuse hepatocellular necrosis in patients with this disease at necropsy, the early concept of Virchow⁴² that catarrhal jaundice resulted from the obstruction caused by a plug of mucus in the ampulla of Vater was widely accepted, resisting even the reports of later investigators, including Roholm and Iversen,⁴³ who described inflammatory and degenerative changes in the hepatic parenchymal cells in specimens of the liver obtained by biopsy from patients with infectious hepatitis. It was actually not until we were well along in World War II that the true nature of this infection was generally appreciated by our civilian physicians and medical officers in this country and abroad.

Knowledge of the causative organism of this disease was slow to develop, and recognition of its viral etiology, although suspected somewhat earlier, was largely a product of studies carried on during World War II. Prior investigations were concerned with the possible role of Leptospira icterohemorrhagiae, and during World War I, the recovery of certain strains of salmonellae from the blood or feces of patients with jaundice, as well as the development of antibodies in their blood to certain strains of salmonellae, suggested that these organisms might be etiologically involved.⁴⁴ In view of information made available during World War II, it is likely that these latter observations reflected the simultaneous occurrence of two diseases whose manner of spread (the intestinal-oral route) was the same.⁴⁵

It would appear that infectious hepatitis enjoyed little prominence in the U.S. Army during the decade before World War II. Up until 1939, it was reportable not as an entity but under such entries as "spirochetal hemorrhagic jaundice," "other protozoal diseases," or "other disease of the gallbladder and biliary passages"; after that, and until 1943 when the term "hepatitis" was used, it was variously reported or coded as "spirochetal jaundice," "cholangitis," or "other disease of the gallbladder and biliary ducts." During the period from 1938 to 1941, the incidence ranged from 1.2 to 1.93 per annum per 1,000 average strength. This was not unlike the incidence recorded from 1931 through 1937 when a few cases of disease specifically involving the gallbladder or ducts were also included with cholangitis. Similar figures characterized the situation in the British Army in England; however, in contrast to both was the experience of the British garrison in Malta in which there was a steady increase in the

⁴⁰Eppinger, H.: Die Pathogenese des Ikterus. Verhandl. d. deutsch. Gesellsch. f. inn. Med. 34: 15-39, 1922.
⁴¹See footnote 7, p. 332.
⁴²Virchow, R.: Ueber das Vorkommen und den Machweis des Hepatogenen, Insbesondere des Katarrhalischen Icterus. Virchows Arch. f. path. Anat. 32: 117-125, 1865.
⁴³Roholm, K., and Iversen, P.: Changes in Liver in Acute Epidemic Hepatits (Catarrhal Jaundice) Based on 38 Aspiration Biopsies. Acta path. et microbiol. Scandinav. 16: 427-442, 1939.
⁴⁴See footnote 4, p. 331.
⁴⁵Havens, W. P., Jr., and Wenner, H. A.: Infectious Hepatitis Complicated by Secondary Invasion With Salmonella. J. Clin. Investigation 25: 45-52, January 1946.

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incidence of hepatitis from 1932 to 1939 when it reached 13.9 per 1,000.⁴⁶ In retrospect, it should not have been surprising that our immunologically naive troops sustained tremendous casualties from this disease after they entered the Mediterranean area that was to serve as the scene of a great outbreak as well as the seeding place of the disease in troops who were eventually to go to the European theater and act as a reservoir for its spread there. In the vast Pacific area as well, infectious hepatitis was to loom as one of the most important causes of morbidity (table 66).

TABLE 66.-Admission rates for infectious hepatitis and serum hepatitis among U.S. Army  personnel at all medical treatment facilities in selected areas, 1942-45

[Preliminary data based on tabulations of individual medical records and summaries of statistical health reports]
[date expressed as number of cases per 1,000 average strength per annum]

Although a number of interesting observations were made, particularly from the epidemiologic standpoint in the latter two areas, the major studies that eventually reached publication were carried on in the Mediterranean area, and it is with these activities that this section is largely concerned.

Mediterranean Area and Middle East Theater

Relatively small numbers of U.S. troops went into Egypt in the early autumn before the subsequent major landings in North Africa in November 1942. It became known very shortly that French, British Commonwealth, and Axis troops had had a bitter experience with epidemic hepatitis at various times during the period from 1939 to 1942 in the North African desert. The French stationed large bodies of troops in southern Tunisia during the spring and summer of 1939 to handle any threat the Italians might make from Libya. Hepatitis appeared among them in September 1939, reaching its peak in December, and declining in January 1940.⁴⁷ Jaundice first developed among the German troops near Sirte and Benghazi during the fall of 1940, rapidly became a serious problem among

⁴⁶Dixon, H. B. F.: Notes on Infective Hepatitis in Malta, 1938-1942. J. Roy. Army M. Corps 82: 44-48, January 1944.
⁴⁷Essential Technical Medical Data, North African Theater of Operations, U.S. Army, for September 1944, dated 1 Oct. 1944.

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them, and later spread to the Italian ground troops and air force. Thousands of cases occurred but the Germans appeared more vulnerable than the Italians, with a ratio of three to one cases. In May 1943, the closing of the Tunisian campaign revealed that large numbers of German and Italian prisoners were jaundiced.⁴⁸ Australian troops were involved late in 1941 while attempting to hold Tobruk, and in the following year they, the New Zealanders, and the British Eighth Army were caught up in a great epidemic during and after the campaign for El Alamein.

In 1942, the epidemic was well on its way in August and reached a peak in November. In U.S. troops in Egypt during that autumn and winter, the disease first occurred in the fliers and ground troops of the Ninth Air Force, as these men operated between Alexandria, Benghazi, and Tobruk. Despite the fact the U.S. troops in Egypt had an appreciable amount of hepatitis among the small numbers of men there, the incidence among U.S. forces in North Africa (Algeria and Tunisia) was low during the autumn and winter of 1942-43 and remained so into the summer of 1943.

This security was not to last for long, however, and in the late summer of 1943 began the volcanic experience that was to erupt into the most expensive and devastating problem that we were to encounter in relation to infectious hepatitis. It came to be, during 1943-45, the most important cause of man-days lost due to illness among U.S. forces in the Mediterranean-North African theater. As a cause of death due to medical disease it ranked high, although the case fatality was low (about 1.8 per 1,000). That this should have occurred coincident with the invasion of Sicily and should involve British Commonwealth and American troops in Egypt, in North Africa, and subsequently in Sicily and Italy was a hindrance of inestimable magnitude to military activity and strained the medical facilities almost beyond their capabilities. It is no exaggeration to say that the hospitals from Cairo to Palermo were filled with patients with hepatitis, with beds occupying the corridors and every other available space. The task of caring for all these patients in addition to the mounting numbers of battle casualties was indeed a formidable one.

Thus, for the second time within a short period, U.S. forces and their medical officers and civilian consultants were confronted with a great epidemic of hepatitis, this time, however, the naturally occurring disease. Our first major experience with hepatitis in the North African theater started when the disease appeared in a seasoned combat division in the late summer of 1943. These men had been in prolonged combat at Hill 609 and later in bivouac and guarding Axis prisoners. A severe outbreak of diarrhea occurred among them in May, June, and the first half of July, and hepatitis began to appear at the end of July. The incidence increased

⁴⁸Report, Col. Marion H. Barker, MC, to Surgeon, Mediterranean Theater of Operations, APO 512, 23 July 1945, subject: Final Report on Infectious Hepatitis in MTOUSA.

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sharply in this division and the disease spread rapidly to others.⁴⁹ This was to harass us during the next 18 months in the long and bitter campaign in Italy where the incidence rose astronomically in the autumn and winter of 1943-44 and again, although in lesser magnitude, in 1944-45 (table 67).

TABLE 67.-Incidence of hepatitis among U.S. troops in the Mediterranean and Africa-Middle East theaters, 1942-45

[Preliminary data based on summaries of statistical health reports]
[Rate expressed as number of cases per annum per 1,000 average strength]

It was quite natural that those interested in and charged with the responsibility of solving the many problems associated with this situation should be influenced by their recent experiences with the outbreak of the artificially transmitted disease, serum hepatitis. However, it was impossible to apply some of the information previously gained without confusing the present circumstances. As might be expected, attempts were made early to think in terms of the long incubation period of homologous serum hepatitis in considering certain epidemiologic problems confronting us in North Africa. That this was untenable was soon appreciated, and our awareness of this was expedited by consultation with British medical officers who marked the incubation period of the epidemic disease as between 30 and 40 days. That this or possibly an even shorter period was indeed true was borne out by experiences encountered later in fresh U.S. troops who contracted hepatitis 1 month after arrival in Italy and only 6 weeks after leaving the Zone of Interior.

Outstanding among the problems associated with this vast epidemic was the lack of knowledge of how the disease was transmitted. In the desert campaigns in 1940-42, British, German, and Italian forces had been ravaged by infectious hepatitis. In early October 1942, just as the British launched their counteroffensive at El Alamein, the disease again became a problem, and as the battle progressed, the acquisition of hepatitis by troops became clearly associated with their exposure to unsanitary conditions that were almost unbelievable. The British were impressed with the

⁴⁹Report, Col. Marion H. Barker, MC, Maj. Richard B. Capps, MC, and Maj. Frank W. Allen, SnC, to Surgeon, MTOUSA, APO 512, U.S. Army, subject: Clinical Monograph on Infectious Hepatitis.

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likely role of feces in the spread of the disease. Along the "Black Area" of the Alamein Line, the ground was covered by human excrement and incompletely buried corpses of German and Italian troops. Myriads of flies were present, and Lt. Col. Raymond Kirk,⁵⁰ of the New Zealand General Hospital, reported the occurrence of 1,060 cases among 7,000 troops in the area. He suggested that the disease might well be flyborne on the basis of the rapid spread of disease among troops living and fighting under these unsanitary conditions in contrast to the failure to spread in hospitals and prisoner-of-war camps where hygiene was good and fly abatement was successful. Others hypothesized that the method of spread of disease was by (1) droplet infection among contacts; (2) vectors, such as rodents, insects, or pigs; and (3) man, as a manifestation of bacterial warfare. The possibility that it was due to or made worse by malnutrition and inadequate diets was also mentioned.

An early proponent of the importance of feces in the spread of epidemic hepatitis was Maj. C. E. van Rooyen, RAMC, who was stationed at the 15th Scottish General Hospital in Cairo. Major van Rooyen who was interested in testing this hypothesis in volunteers expressed this view on more than one occasion to certain members of the Commission on Neurotropic Virus Diseases, Army Epidemiological Board.⁵¹ This group had been in Cairo since early 1943, sent by the Preventive Medicine Service of the Office of The Surgeon General to work on certain diseases of military importance in the Middle East, and sandfly fever and poliomyelitis had engaged their efforts during the first part of their stay.

Early in September 1943, Brig. Gen. James S. Simmons, MC, Chief, Preventive Medicine Service, representing the Army Epidemiological Board, came to Cairo after visits to Sicily and North Africa. At his request, certain members of the Commission on Neurotropic Virus Diseases directed their attention to the epidemiologic and etiologic aspects of infectious hepatitis and, among other things, made a field trip to Algiers, Sicily, and Tunis, in November 1943. As a result of the observations made on this trip and on others, certain concepts were elaborated concerning the length of the incubation period of epidemic hepatitis, its age distribution, and its relationship to serum hepatitis. The incubation period appeared to range from 18 to 25 days; the paucity of cases among adult natives suggested it was a disease of childhood, with immunity acquired early; and U.S. soldiers recovered from serum hepatitis were not immune to epidemic hepatitis when exposed in the Mediterranean theater. The vulnerability of air forces personnel was particularly noticeable, and it was not unusual for complete units to be grounded because of the high incidence (25 to 30 percent) of disease among them. The coexistence of dysentery and hepatitis in many military units stimulated interest in their relationship; how-

⁵⁰Kirk, R.: Spread of Infective Hepatitis. Lancet 1: 80-81, 20 Jan. 1945.
⁵¹Members included Dr. John R. Paul, Director; Maj. (later Lt. Col.) Albert B. Sabin, MC; Maj. (later Lt. Col.) Cornelius B. Philip, SnC; and Capt. (later Maj.) W. Paul Havens, Jr., MC.

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ever, there was usually rather wide separation in time between the peak of dysentery and the peak of hepatitis.

In February 1944, Dr. John R. Paul and Maj. W. Paul Havens, Jr., MC, of the Commission on Neurotropic Virus Diseases, returned to the United States and established under the auspices of the Army Epidemiological Board a laboratory for the study of acute hepatitis in the Section of Preventive Medicine of the Yale University School of Medicine, at New Haven, Conn. The experiments conducted there employing human volunteers will be discussed in a later section.

The whole epidemiologic pattern of hepatitis in the Mediterranean theater was described by Gauld.⁵² He depicted the drawn-out progress of an infectious disease among large numbers of susceptible young adults thrust into an area where it was widely endemic and where the conditions for spread were highly favorable. In general, the highest morbidity occurred in the immunologically more naive troops from the United States and Europe in contrast to a lower incidence among troops from civilizations of less well established sanitary practices, although there were exceptions to this. Gauld was particularly interested in the respiratory route as a possible way of spread of hepatitis, and the sharp increase in incidence among American troops in 1943 and 1944, both in August and in November and December, respectively, suggested to him that this might be important, although he took cognizance of the evidence that the disease could be spread by filth through the medium of personal contact. Explosive outbreaks were rare, and of the two observed only one was well enough documented to warrant mention. This occurred in the 86th Mountain Infantry Regiment and appeared to have resulted from the drinking of contaminated well water.

In some groups of U.S. troops, the incidence of the disease was significantly greater among officers than among enlisted men. The incidence decreased as the age of the individual soldiers advanced, and a certain degree of immunity to hepatitis was manifested in the seasoned troops. The attack rate among seasoned U.S. troops in 1944-45 was 42 per 1,000 compared with a morbidity of 109 per 1,000 among fresh reinforcements. 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.⁵³

Infectious hepatitis was unimportant in the European theater until the winter and spring of 1944-45. True, there had been a brief flurry of

⁵²Gauld, R. L.: Epidemiological Field Studies of Infectious Hepatitis in the Mediterranean Theater of Operations. Am. J. Hyg. 43: 248-313, May 1946.
⁵³Gauld, R. L.: Field Studies Relating to Immunity in Infectious Hepatitis and Homologous Serum Jaundice. Am. J. Pub. Health 37: 400-406, April 1947.

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the disease in the United Kingdom in the winter of 1943-44 among troops arrived from the epidemic area in Italy in November 1943; however, this appeared to be self-limited. The First U.S. Army, of which these troops became a part, was not involved in any widespread epidemic until the winter and spring of 1945 when the incidence rose to 12 per 1,000 per annum.⁵⁴

During the winter of 1944-45, the incidence of the disease in the European theater rose sharply to 17 per 1,000 per annum, potentiated largely by the entry of troops who had served in Italy and Africa. The Seventh U.S. Army invaded southern France, on 15 August 1944, from Italy and was initially made up of three infantry divisions from the Fifth U.S. Army. It was apparently thoroughly seeded with infectious hepatitis, and as it advanced northward, it contacted troops from the Normandy beachhead and received directly into its ranks units that had just come from the United States. The story of the role of the Seventh U.S. Army in the introduction and spread of hepatitis among its own new nonimmune troops and among its contacts, the First and Third U.S. Armies, was well recorded by Gauld⁵⁵ and Gowen.⁵⁶ It was their impression that localized outbreaks again were rare and that the disease had a widespread distribution, with its manner of spread by some form of person-to-person contact.

Pacific Area

In the vast Pacific area, infectious hepatitis also assumed a tremendous importance, and actually its morbidity in the Southwest Pacific increased from 1943 to 1945 when it and the number of troops involved exceeded that of any other theater; 39,277 cases were treated in 1945, causing an incalculable loss of time. Likewise in the Western Pacific Area, hepatitis proved to be a leading cause of disability.

The epidemiology of the disease, as it made its appearance in various far-flung islands, presented different problems from those involved in the Mediterranean and European theaters. Occasional outbreaks were investigated, including one on Biak Island by Maj. James L. Borland, MC,⁵⁷ and another on Hollandia by Maj. Ray E. Trussell, MC,⁵⁸ in October 1944. The former was concerned about the possibility of spread by a vector such as a night-biting Phlebotomus or common fly, while the latter attributed the spread of disease to mechanical transfer from infected feces by flies or

⁵⁴Whether the early seeding in 1943-44 of the First U.S. Army by men from Italy with hepatitis contributed to the spread of the disease subsequently when these troops were in combat in Europe was questioned later by Paul and Gardner (see footnote 21, p. 335).
⁵⁵Gauld, R. L.: Epidemiology of Hepatitis-Military Experience. [Unpublished manuscript.]
⁵⁶Gowen, G. H.: Observations on Infectious Hepatitis in Seventh Army, 1944-45. Bull. U.S. Army M. Dept. 6: 456-461, October 1946.
⁵⁷Essential Technical Medical Data, U.S. Army Forces in the Far East (Southwest Pacific Area), for December 1944, dated 15 Feb. 1945, Appendix H thereto.
⁵⁸Trussell, R. E.: Epidemiologic Aspects of an Outbreak of Infectious Hepatitis. Am. J. Hyg. 45: 33-42, January 1947.

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by infected foodhandlers and contaminated food and utensils. Much of the clinical and epidemiologic experience in this area was recorded by Col. Henry M. Thomas, Jr., MC.⁵⁹

China-Burma-India and Latin American Theaters

The incidence of infectious hepatitis in the China-Burma-India theater was moderately high, but in Latin America, it was low. This is of interest since the rates of enteric infections were high in both of these areas and yet there was no correlation between them and the attack rates for infectious hepatitis.

Clinical Pattern

Clinical descriptions of the course of the disease in two large groups of U.S. troops were made by Havens⁶⁰ in 1944 from the 38th General Hospital in Egypt and by Barker, Capps, and Allen,⁶¹ in 1945, from the 12th General Hospital in Naples. The former outlined the initial experience of U.S. troops in the Middle East with infectious hepatitis in the autumn and winter of 1942-43 and again in 1943-44.

The latter in association with the 15th Medical General Laboratory set up a center for the care and study of patients with infectious hepatitis in the Mediterranean theater. This came about as the result of a suggestion made, in December 1943, to the Surgeon, Peninsular Base Section, by Col. Perrin H. Long, MC, Consultant in Medicine, Mediterranean theater. Colonel Long had suggested that, when the 12th General Hospital arrived from North Africa, Lt. Col. (later Col.) Marion H. Barker, MC, be assigned the problem of finding out what he could about infectious hepatitis. The suggestion was carried out in January 1944, and in March 1944, Maj. (later Lt. Col.) Richard B. Capps, MC, of the 12th General Hospital, was assigned to assist Colonel Barker.

With the 12th General Hospital, the 15th Medical General Laboratory joined forces, and its commanding officer, Col. Virgil H. Cornell, MC, and members of his staff, including Lt. Col. Tracy B. Mallory, MC, Maj. (later Lt. Col.) Ross L. Gauld, MC, Maj. Frank W. Allen, SnC, Capt. (later Maj.) Frederick C. Robbins, MC, and Capt. Hugh B. Wilson, MC, contributed their technical advice and skill toward the solution of the numerous problems. A number of clinical studies were described, and the correlation of histologic alterations of the liver obtained by biopsy with clinical status

⁵⁹Technical Memorandum No. 16, Office of the Chief Surgeon, U.S. Army Forces in the Far East, 1 Oct. 1944.
⁶⁰Havens, W. P., Jr.: Infectious Hepatitis in Middle East; Clinical Review of 200 Cases Seen in a Military Hospital, J.A.M.A. 126: 17-23, 2 Sept. 1944.
⁶¹Barker, 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.

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was made. Attention was drawn to the danger of relapse or the development of chronic disease, and the need for adequate rest was emphasized.⁶²

Although hepatitis without jaundice was a recognized entity among our Allied military medical colleagues and despite the fact that attention had been called to its existence in the clinical descriptions of serum hepatitis following the reception of yellow fever vaccine by our troops, there were many of our medical officers who at first were reluctant to accept its recognition as a part of the broad clinical spectrum of infectious hepatitis. However, it was not long before educational progress was made along this line, and its existence was generally admitted. Nonicteric hepatitis was regarded as a milder form of the disease, with a shorter duration. How often it occurred could not be determined owing to the lack of specific serologic diagnostic tests; however, that it occurred far more frequently than suspected is doubtless true. Gowen⁶³ suggested that its ratio to hepatitis with jaundice was as much as 8:1 in Tunisia, on the basis of epidemiologic and clinical evidence. The occurrence of malaise, anorexia, easy fatigue, nausea, and vomiting, with evidence of hepatic dysfunction, in soldiers who, although not jaundiced, were stationed in epidemic areas was enough to suggest the diagnosis of nonicteric hepatitis. In many of these patients, the liver was palpable and tender. Although recovery was usually prompt, relapse with jaundice on occasion occurred.

Icteric hepatitis

When jaundice was present, the disease could usually be divided into two phases-preicteric and icteric. Among the troops studied in Egypt and Italy, approximately 83 percent had a well-defined preicteric phase and about 17 percent presented themselves with jaundice as the first evidence of the disease (fig. 39).

The preicteric phase ranged in length from 1 day to 3 weeks, averaging 5 days. In some patients, this was biphasic, with a short remission of signs and symptoms from 4 to 5 days after onset followed by their recurrence and eventually jaundice. All grades of severity of constitutional reaction occurred; however, it was not possible to predict the degree of severity of the total course of disease from the character of its beginning. Anorexia, beginning insidiously, was the most common initial symptom and, indeed, often directed the group medical officer's attention to the diagnosis. That this was a more sensitive indicator of hepatitis in the field, where rations were less than appealing to a capricious appetite, is understandable. Easy

⁶²(1) Circular Letter No. 19, Office of the Surgeon, Headquarters, North African Theater of Operations, U.S. Army, 28 Mar. 1944. (2) Circular Letter No. 37, Office of the Surgeon, Headquarters, North African Theater of Operations, U.S. Army, 8 July 1944. (3) Circular Letter No. 21, Office of the Surgeon, Headquarters, Mediterranean Theater of Operations, U.S. Army, 20 June 1945.
⁶³See footnote 56, p. 352.

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FIGURE 39.-Schematic diagram illustrating the clinical course of an average case of infectious hepatitis in an adult. (Paul, J. R., and Havens, W. P., Jr. Tr. A. Am. Physicians 59: 133-141, 1946.)

fatigability and disinterest in occupation, with nausea after meals, soon occurred, and toward the end of the preicteric phase, vomiting was not uncommon. Actual abdominal pain was unusual, although on occasion it did occur in the right upper or lower quadrant, and acute cholecystitis or acute appendicitis was at times suspected and unwarranted operations performed. Under such circumstances, the gallbladder or appendix was normal, and enlarged mesenteric lymph nodes were found. Discomfort in the upper quadrant of the abdomen occurred early in a goodly percentage of patients and was described as distress or fullness in the epigastrium and right upper quadrant, made worse by eating and activity. Riding in a jeep was particularly aggravating and not infrequently was the event that precipitated sufficient discomfort to cause a soldier to go to sick call. Constipation, flatulence, and diarrhea were present in a small percentage of patients, as were symptoms of infection of the upper respiratory tract.

Among the patients having a definite preicteric phase, the onset was abrupt in 53 percent of those described by Havens⁶⁴ and in 80 percent of those described by Barker and his associates.⁶⁵ It was ushered in with fever, chilliness (rarely frank chills), malaise, headache, and generalized muscular aches. Prostration was not uncommon, and aching eyes with pain of the eyeballs were associated complaints. Fever was usually remittent, with a daily maximum temperature of 102°-103° F., declining to

⁶⁴See footnote 60, p. 353.
⁶⁵See footnote 61, p. 353.

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normal during the ensuing 5 to 7 days. Some patients had a frank chill daily, followed by fever with a temperature of 104° F., for the first few days. Symptoms directing attention to the gastrointestinal tract, including anorexia, nausea, vomiting, and upper abdominal distress, developed in these patients as they did in those without fever. Within 48 hours after the temperature reached normal, clinical jaundice was evident.

Palpation of the abdomen often elicited tenderness particularly in the right upper quadrant and epigastrium where pressure evoked a sense of nausea. The liver and spleen were uncommonly palpable in this early phase of the disease; however, percussion with the first over the right lower ribs frequently caused discomfort or pain in the area of the liver. Barker and his associates called attention to the rather constant early appearance of cervical adenopathy occurring as "a soft, slightly tender, lima bean sized gland * * * found along the posterior border of the sternocleidomastoid muscle low in the neck." It was often easy to demonstrate this visually by having the patient bend his neck away from the involved side. Also of particular importance was the occurrence of bilirubinuria that usually appeared later in the preicteric phase but from 48 to 72 hours before clinical jaundice. More than one soldier made his own diagnosis of infectious hepatitis by noting a change in the color of his urine.

The duration of the icteric phase ranged from as short a time as 4 days to as long a period as 4 months, with an average of 2 to 4 weeks, in different groups of patients. Fever was uncommon; when present, it lasted a short time. Jaundice reached its maximum within 3 to 10 days in most patients. As it increased, the malaise and gastrointestinal symptoms worsened, and during this period, nausea and vomiting were at times severe enough to require the administration of fluid parenterally. It was not unusual for patients to have reasonable appetites in the morning but to complain of a sense of fullness after lunch that progressed to the point of such discomfort after the evening meal that vomiting, either spontaneous or self-induced, occurred. In the mildly sick patients, these symptoms were slight and of short duration, but in those who were seriously sick, they persisted as long as 3 to 4 weeks. In such seriously sick patients, lassitude, emotional instability, and depression occurred. Increasing jaundice was accompanied by diminishing amounts of pigment in the feces, and among the sicker patients, acholic stools were found. Disorder of bowel function was common in this group, with constipation or, on occasion, diarrhea. Itching occurred in only a small percentage of patients.

The liver was enlarged and tender in a large percentage of patients by the time jaundice was evident, and although their presence did not always coincide, both were found in 43 percent of one group of patients. Splenomegaly was found in 10 to 15 percent of patients, and posterior cervical

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lymphadenopathy persisted into the icteric phase in a small percentage. Bradycardia was unusual and occurred during the first 2 weeks of icterus.

Jaundice usually reached its maximum in 10 days, and at this point, a remarkable clinical change occurred, with sharp regression of symptoms and return of sense of well-being. Appetite improved and was frequently voracious. Hepatic tenderness subsided, and the liver diminished in size so that it was usually no longer palpable 2 weeks after the appearance of jaundice. Loss of weight in amounts of 5 to 10 or even 20 pounds in the more seriously sick patients was usual, but strength was regained fairly promptly in the mildly or moderately sick patients. Even in this group, however, activity was often followed by upper abdominal fullness and discomfort for several days after the disappearance of all other symptoms.

The duration of hospitalization became a matter of considerable importance and discussion. The first documented experience of U.S. soldiers with infectious hepatitis in World War II was in the Middle East in 1942-43. In this group, described by Havens,⁶⁶ the duration of hospitalization ranged from 7 to 87 days, with an average of 29.8 days. Somewhat later, in 1944, Barker and his associates⁶⁷ described the course of the disease in another large group of soldiers in Italy and pointed out that the average duration of hospitalization ranged between 6 and 8 weeks. It is likely that the exhaustion and physical disability caused by battle conditions that the latter group had sustained before acquiring hepatitis prolonged the course of their disease. The period in hospital included 3 to 5 weeks of rest in bed, followed by 7 to 10 days as an ambulant, followed by 7 to 10 days of exercise before returning to duty. It was emphasized that patients who had apparently clinically recovered and who were without jaundice while at rest in bed not infrequently developed signs and symptoms of the disease, with or without jaundice, following increased activity. Because of this, an exercise tolerance test was devised to select those patients who required further hospitalization. Using these criteria, about 10 percent of patients with icteric hepatitis had not made complete recovery after 3 months of hospitalization.

Infectious hepatitis, in spite of its high morbidity and frequently prolonged course, was, in general, a benign and self-limited disease. The case fatality was low-less than 4 per 1,000. Complications were rare and included pneumonia, myelitis, and aseptic meningitis. Seborrheic dermatitis and labial herpes occurred in a small percentage of patients.

Relapse

Although the vast majority of patients made an uneventful recovery, there were those who suffered an interruption of convalescence, with a return of symptoms and signs of the disease. Relapse was often mild,

⁶⁶See footnote 60, p. 353.
⁶⁷See footnote 61, p. 353.

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although at times it was more severe than the initial attack. Its incidence was variable, ranging from 1½ to 10 percent, and the factors that caused it were not completely defined. Indulgence in alcoholic beverages and excessive activity before recovery were incriminated in some cases; however, a certain number of patients relapsed in spite of what appeared to be ideal treatment. Patients who did sustain relapse made eventual complete recovery in almost all cases, but Barker and his associates⁶⁸ felt strongly that this could only be defined by the capacity of the patient to perform graded exercise tolerance tests without having a return of symptoms, signs, or laboratory evidence of hepatitis.

Chronic Hepatitis

A small percentage of patients with acute hepatitis had evidence of hepatic disease long after the expected time of recovery. Barker and his associates⁶⁹ found 18 percent in one group of 431 soldiers in this category, 4 months after the onset of disease, and emphasized the prolonged treatment required to effect recovery. These patients had a characteristic history of hepatitis, with or without jaundice, followed by partial recovery and subsequent return of weakness, anorexia, and epigastric discomfort. The liver was often enlarged and tender, and while jaundice was not always present, the results of the Bromsulphalein excretion test and thymol turbidity test were abnormal. Unfortunately, adequate followup of these patients was not possible in all instances; however, it was the impression that recovery was complete in most cases. That evidence of continuing hepatic disease could exist for many months, culminating in complete recovery, was well established by these observations. It was postulated that the development of cirrhosis was rare, although serial biopsies of the livers of civilian patients in various stages of hepatitis had previously suggested that it did occur.⁷⁰

Two other groups of patients were distinguished from those just described with persistent activity of the disease: (1) those with subjective complaints but without any objective evidence of hepatic disease, and (2) those with vague mild complaints and slight stable abnormality of serum bilirubin and Bromsulphalein excretion, with or without enlargement of the liver. The former group fell in the same category as those patients described previously in the section on serum hepatitis as having "posthepatitis syndrome."⁷¹ The latter when tested by exercise tolerance manifested no clinical worsening and were regarded as having an inactive disease with mild residual hepatic dysfunction.

⁶⁸See footnote 61, p. 353.
⁶⁹Barker, 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.
⁷⁰Krarup, N. B., and Roholm, K.: Development of Cirrhosis of Liver After Acute Hepatitis, Elucidated by Aspiration Biopsy. Acta. med. Scandinav. 108: 306-331, 1941.
⁷¹See footnote 28, p. 343.

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Pathology

In the Hepatitis Study Center, composed of the 12th General Hospital and the 15th Medical General Laboratory, in Naples, biopsies of the liver were performed on patients in various phases of nonfatal infectious hepatitis.⁷² During the acute icteric period, the following were found: Periportal cellular infiltration, predominantly mononuclear; swelling of the reticuloendothelial cells and intralobular infiltration; focal necrosis with acidophilic degeneration of hepatic cells; lobular disarray; numerous mitotic figures and multinucleate cells; and biliary thrombi in dilated canaliculi. The pattern of the lobular reticular framework was usually intact, although on occasion it was distorted with areas of condensation apparent. Similar changes were found in the preicteric phase or in nonicteric hepatitis except that biliary stasis was rarely seen. Of particular interest was the demonstration of the wide variation in time of recovery, as manifested by the histologic appearance of the liver. Although complete regeneration was found after 1 or 2 months in some patients, in others evidence of activity persisted for several months. No evidence of cirrhosis was found in 89 nonfatal cases.

The possibility that the severe progressive chronic hepatic disease described earlier among civilians⁷³ might eventuate in some soldiers prompted biopsy of the livers of men whose recovery had been long delayed.⁷⁴ Of 40 such patients examined from 100 to 500 days after onset, the specimens of liver studied were normal in 15; doubtful in 10; and in 15 there were periportal and lobular inflammation and focal hyaline necrosis. Unfortunately, these patients were lost to followup examinations so that nothing could be said about their eventual outcome. Thus, it was suggested that, although the incidence of continuing disease was indeed low, the possibility of its rare occurrence demanded recognition. Opinion in this regard was not unanimous, and Lucké⁷⁵ was impressed with the concept that nonfatal viral hepatitis was followed by complete recovery and restitution of normal hepatic structure. At all events, the preponderance of evidence indicated that the occurrence of cirrhosis in soldiers following nonfatal epidemic hepatitis was rare.⁷⁶

In fatal cases, the pathologic changes were described in two groups by Lucké⁷⁷ and by Lucké and Mallory:⁷⁸ (1) the fulminant form in which death occurred within 10 days after onset, and (2) the subacute form in which death occurred from 3 to 8 weeks after onset. The liver was smaller

⁷²Mallory, T. B.: The Pathology of Epidemic Hepatitis. J.A.M.A. 134: 655-662, 21 July 1947.
⁷³See footnote 70, p. 358.
⁷⁴See footnote 72.
⁷⁵See footnote 27, p. 342.
⁷⁶It is pertinent to point out that at present (1963) some investigators feel that cirrhosis never follows epidemic hepatitis. However, the evidence adduced for this concept is far from complete.-W. P. H., Jr.
⁷⁷See footnote 27, p. 342.
⁷⁸Lucké, B., and Mallory, T.: Fulminant Form of Epidemic Hepatitis. Am. J. Path. 22: 867-945, September 1946.

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than normal, soft and smooth, and massive central necrosis completely destroyed the parenchyma in the fulminant form. There was no evidence of regenerative hyperplasia, and mononuclear cellular infiltration was found at the periphery of the lobule. In the subacute form, the liver was also often reduced in size but not infrequently the surface was irregular, with red depressed areas surrounded by yellow-green nodules. Parenchymal destruction was irregular and associated with areas of regeneration. Destruction of lobular architecture had occurred. Inflammatory reaction, again of a mononuclear type, was present but less intense in the portal areas and interlobular boundaries. The central and efferent veins were often involved in endophlebitis.

In both forms of the disease, lymphoid hyperplasia and splenomegaly were frequently present. Ascites was common, and hemorrhage, edema, and inflammation of the gastrointestinal tract were often found. The kidneys were enlarged with fat storage in the fulminant cases, and bile nephrosis in those of longer duration. Alterations in the central nervous system included swelling of ganglion cells, distortion of nuclei, meningeal lymphocytic infiltration, and perivascular lymphocytic cuffing in the basal ganglions.

The pathologic changes which have been briefly described here are well illustrated by the authors; selected plates, from the published literature, are reproduced here as plates I through VI, through the courtesy of the American Journal of Pathology.

Clinical Laboratory Studies

The laboratory tests that could be performed were often quite limited by the exigencies of the situation; however, in some areas, a considerable amount of data was accumulated. The number of erythrocytes and the amount of hemoglobin were normal except in certain patients who had prolonged debilitating disease. Of particular interest, however, was the pattern of leukocytic response that occurred, characterized by the appearance of leukopenia with both neutropenia and lymphopenia early in the acute febrile phase of the disease. Relative lymphocytosis subsequently occurred, and numerous atypical lymphocytes identical with those commonly associated with infectious mononucleosis made their appearance. In general, the hematologic pattern had returned to normal by the end of the second week of the disease.⁷⁹ Determinations of the coagulation and bleeding time and the fragility of erythrocytes were found to be normal in small groups of patients.⁸⁰ Prolongation of the prothrombin time in severe degree was regarded as an ominous sign, particularly if there was no favorable response to the parenteral administration of vitamin K. The

⁷⁹(1) Havens, W. P., Jr., and Marck, R. E.: Leukocytic Response of Patients With Experimentally Induced Infectious Hepatitis. Am. J.M. Sc. 212: 129-138, August 1946. (2) See footnote 61, p. 353.
⁸⁰See footnote 60, p. 353.

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PLATE I.-Duration of hepatitis, 36 days. Undersurface of a liver which weighed 1,320 gm. The liver is shrunken, particularly the left lobe. The surface of the right lobe shows a number of flat or elevated nodular areas, between which the tissue is finely wrinkled. The surface of the left lobe is deeply furrowed. At the hilum is a cluster of enlarged edematous lymph nodes. (Hemorrhages in heart and gut of this case are shown in plate VI.)

sedimentation rate of erythrocytes was usually normal early in the acute phase, increasing after the appearance of jaundice.⁸¹

Numerous attempts were made to develop specific serologic tests, but none of these was successful. Saline extracts of normal liver and liver from fatal cases of hepatitis were used as antigens in complement fixation⁸² and precipitin tests.⁸³ Although positive tests were found in as many as one-third of the patients, they were of no practical value. A heterophile antibody absorbable on boiled guinea pig kidney and human liver was found in the acute phase serums of some patients,⁸⁴ and falsely positive Wassermann and Kahn⁸⁵ reactions were also described in as many as 20 percent of some groups of patients.⁸⁶

⁸¹Unpublished personal observations.-W. P. H., Jr.
⁸²Eaton, M. D., Murphy, W. D., and Hanford, V. L.: Heterogenetic Antibodies in Acute Hepatitis. J. Exper. Med. 79: 539-557, May 1944.
⁸³Olitzki, L., and Bernkopf, H.: Precipitation in Infective Hepatitis. J. Infect. Dis. 77: 60-67, July-August 1945.
⁸⁴See footnote 82.
⁸⁵Kuzell, W. C., and Puccinelli, V.: False Positive Serology in Infectious Hepatitis. M. Bull. North African Theat. Op. (No. 3) 2: 57-59, September 1944.
⁸⁶Subsequent efforts to detect this heterophile antibody and falsely positive Wassermann and Kahn reactions were unsuccessful, with rare exceptions. See Havens, W. P., Jr., Gambescia, J. M., and Knowlton, M.: Results of Heterophile Antibody Agglutination and Kahn Tests in Patients With Viral Hepatitis. Proc. Soc. Exper. Biol. & Med. 67: 437-440, April 1948.

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PLATE II.-(Top) Duration of hepatitis, 19 days. Cut surface of a liver which weighed 890 gm. Over one-half of the organ has a fleshy, red appearance; here all liver cells have been destroyed. The yellow nodular patches are relatively ischemic and are composed of large "lobules" of regenerating tissue. (The microscopic appearance of the red part is shown in plate III (top).)

(Bottom) Duration of hepatitis, 43 days. Vertical cut section of a liver which weighed 850 gm. The large red fleshy area consists entirely of vascular stroma and bile ducts; all liver cells have been destroyed. The remainder of the organ is composed of yellowish green nodular areas of regenerating parenchyma.

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The desirability of early diagnosis, before jaundice appeared, or in patients with nonicteric hepatitis, as well as the need to determine when recovery had occurred, focused attention on certain laboratory determinations. Doubtless, the most commonly used test in the field was the determination of bilirubin in the urine. Bilirubinuria appeared in the latter part of the preicteric phase and, as mentioned before, often served as a diagnostic aid to the soldier himself. The icterus index was widely used as a measure of the amount of jaundice where facilities were not available for determining the serum bilirubin. After jaundice had disappeared, the Bromsulphalein excretion test was used, when possible, to determine if activity of hepatitis persisted. In small groups of volunteers⁸⁷ under controlled conditions, it was shown that the excretion of intravenously administered Bromsulphalein was impaired on the third day of the disease, with bilirubinuria appearing the following day. The cephalin-cholesterol flocculation test was positive by the fifth day, when the 1-minute direct serum bilirubin was increased above normal. By the seventh day, the total serum bilirubin and the urinary urobilinogen were above normal. The thymol turbidity and colloidal gold tests were positive in the early part of the icteric phase. Bilirubinuria disappeared before clinical jaundice, and the serum bilirubin usually was normal in the fifth or sixth week of the disease. Bromsulphalein excretion tests performed shortly thereafter were usually normal. The cephalin-cholesterol flocculation and thymol turbidity tests became negative in 6 to 10 weeks and in 8 to 12 weeks, respectively. The persistence of a strongly positive thymol turbidity test was regarded as indicating persisting activity of the disease.⁸⁸

Among the interesting phenomena encountered were tiny motile spirochetal-like filaments visualized by dark-field microscopy in the serums of patients with hepatitis.⁸⁹ More than 1 hour was spent convincing their

⁸⁷See footnote 81, p. 361.
⁸⁸Serums obtained from volunteers with experimentally induced infectious hepatitis were subsequently subjected to determinations of serum proteins. The characteristic pattern of change was a sharp, early decline in serum albumin with a rise in globulins, largely gamma globulin. The albumin returned to normal levels by the fifth week, but the globulins remained somewhat elevated often for a few weeks thereafter. Persistence of large amounts of serum gamma globulin was associated with activity of the disease. See Havens, W. P., Jr., and Williams, T. L.: Changes in Serum Proteins in Patients With Experimentally Induced Infectious Hepatitis. J. Clin. Invest. 27: 340-345, May 1948.
⁸⁹Kuzell, W. C.: "Artifact Spirochetes" in Infectious Hepatitis. Bull. U.S. Army M. Dept. 89: 112-114, June 1945.

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PLATE III.-(Top) Duration of hepatitis, 19 days. Microscopic appearance of the red fleshy area of the liver shown in plate II (top). The parenchyma has been destroyed. The lobular outlines are indicated by numerous small biliary ducts. The sinusoids are greatly engorged. Masson's trichrome stain. (X 250)

(Center) Duration of hepatitis, 93 days. Microscopic appearance of pale nodular areas of regenerative hyperplasia. Cords of liver cells form a pseudolobule which is noticeably ischemic. Elsewhere small bile ducts and large tubules composed of hepatic cells are scattered throughout the collapsed stroma; these large tubules are reminiscent of the liver in the early stage of embryonic development. (X 250)

(Bottom, left) Duration of hepatitis, 18 days. Numerous macrophages with yellow-brown granules are scattered throughout the lobular stroma from which the liver cells have been removed. (X 500) (Bottom, right) A section from an area similar to the one shown on the left, but stained with Sudan III. The pigment granules take the fat stain well. (X 500)

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observers that they were artifacts and not the causative organisms of hepatitis.

Roentgenographic evidence of gastroduodenitis and gastroscopic evidence of acute gastritis were demonstrated in volunteers⁹⁰ with experimentally induced hepatitis, corroborating the clinical and pathologic data that emphasized the involvement of the gastrointestinal tract in this disease.

The elevated temperatures and often severe constitutional symptoms in the preicteric phase made diagnosis difficult, particularly in areas such as Sicily, North Africa, the Middle and Far East, and the Pacific where a number of other acute infections, largely unfamiliar to our medical officers, were present. Thus, it should not be surprising that this disease was an important cause of "fever of undetermined origin" in its preicteric phase. Our British medical colleagues pointed out that in this phase pressure over the epigastrium frequently caused nausea, and this proved to be a valuable sign. Barker and his associate⁹¹ regarded tenderness to percussion over the liver, posterior cervical adenopathy, and splenomegaly as important diagnostic aids. The occurrence of leukopenia and relative lymphocytosis was also of some assistance, but the appearance of bilirubinuria was doubtless the most important evidence pointing to the diagnosis. During the febrile preicteric period, the diseases considered were malaria, sandfly fever, dengue, pharyngitis with fever, acute bacillary dysentery, typhoid and paratyphoid fevers, acute appendicitis, acute cholecystitis, and infectious mononucleosis. After the appearance of jaundice, the diagnostic dilemma was less, although on occasion poisoning due to carbon tetra-

⁹⁰Havens, W. P., Jr., Kushlan, S. D., and Green, M. R.: Experimentally Induced Infectious Hepatitis; Roentgenographic and Gastroscopic Observations. Arch. Int. Med. 79: 457-464, April 1947.
⁹¹See footnote 61, p. 353.

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PLATE IV.-(Top) Duration of hepatitis, 36 days. Heart showing petechiae of epicardium and ecchymosis beneath the endocardium of the interventricular septum, near the bases of the aortic cusps.

(Bottom) Colon with mesocolon and epiploic appendages. An extensive hemorrhage is seen in the mesocolon.

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chloride, Weil's disease, acute cholangitis, or even yellow fever had to be considered. Jaundice due to excessive hemolysis or extrahepatic obstruction rarely occurred and did not constitute a problem in diagnosis. Epidemiologic evidence, the subsequent course of the disease, the number and type of leukocytes in the blood, the results of tests of hepatic function, and the demonstration of specific causative agents or their antibodies furnished the correct diagnosis in most instances. Confusion with infectious mononucleosis with jaundice was resolved by the heterophile antibody test, which is negative in infectious hepatitis.

Treatment was supportive and symptomatic. The administration of methionine, choline, crude liver extract, normal human gamma globulin,⁹² and the antibiotic and chemotherapeutic agents then known was of no benefit. Emphasis was placed on rest in bed and diet, although it is fair to say that there was not complete agreement on their exact specifications with some of our Allied medical colleagues or even among our own medical officers. Actually, most of the precepts of therapy that emerged by the end of the war were derived from the principles set down by Barker and his associates⁹³ whose experience was largely with troops who had been exhausted by physical hardship before acquiring hepatitis. In addition, these patients were frequently hospitalized under conditions in which it was not easy to furnish a diet that would be welcome to men whose appetites at best were capricious. It is doubtless true that their therapeutic regimen could have been modified with impunity for men who started their disease in relatively good physical condition and who were hospitalized under circumstances favorable for obtaining attractive food. That this was the case was substantiated by the experience in Egypt⁹⁴ at the 38th General Hospital where the therapeutic regimen was more relaxed without prolonging the course of disease.

Nevertheless, it is important to remember that when Barker and his colleagues set up their study group in Naples, the therapy of patients with hepatitis was without order and was dependent on the ideas of many differ-

⁹²Gellis, S. S., Stokes, J., Jr., Forster, H. W., Jr., Brother, G. M., and Hall, W. M.: Use of Human Immune Serum Globulin (Gamma Globulin) in Infectious (Epidemic) Hepatitis in the Mediterranean Theater of Operations; Studies on Treatment in Epidemic of Infectious Hepatitis. J.A.M.A. 128: 1158-1159, 18 Aug. 1945.
⁹³See footnote 61, p. 353.
⁹⁴See footnote 60, p. 353.

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PLATE V.-(Top) Clinical duration of hepatitis, 4 days. Upper surface of the liver, which weighed 1,200 gm. The surface of the right lobe is smooth; there are a number of subcapsular hemorrhages. The surface of the left lobe is finely wrinkled, (Center, left) Cut surface of liver shown at top. The appearance is similar to that of an acutely congested and hyperplastic spleen. 

(Center, middle and right, and bottom row) Representative areas of cut surfaces of livers from two of five cases of fulminant hepatitis; all have an exaggerated "nutmeg" mottling. Naked-eye examinations of these livers gave no indication of the extent of the parenchymatous destruction or of the prominence of inflammatory infiltration. The duration of the disease and the weight of the liver in the two cases (center middle and right) were, respectively, 3 days and 4 days; 1,205 gm. and 1,200 gm. For the three cases (bottom row), the duration of the disease and the weight of the liver were, respectively, 5, 8, and 8 days; 1,025 gm., normal size, and shrunken.

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ent medical officers, most of whom actually had little comprehension of the disease or of its therapeutic requirements. It was indeed the frequency of relapse in patients sent back to duty too soon that prompted the emphasis on prolonged rest in bed (3-5 weeks), followed by a gradual exercise tolerance test (7-10 days) when jaundice disappeared and the excretion of intravenously injected Bromsulphalein measured 10 percent or less. Only after a convalescent was able to pass such a test was he regarded as fit for duty.⁹⁵

The dietary regimen recommended by Barker and his colleagues⁹⁶ was high in carbohydrates (350 gm.) and protein (250 gm.) and low in fat (40 gm.). The reason for reduction in fat was far from clear; however, restriction of this foodstuff had long been practiced in the therapy of catarrhal jaundice and doubtless this influenced the recommendation. Actually, it was shown in other patients⁹⁷ that the ingestion of a diet rich in protein and carbohydrate without restriction of fats was well tolerated and associated with equally speedy recovery.⁹⁸

⁹⁵Over the years after World War II, the duration of hospitalization for hepatitis increased until it became as long as 89 days in certain groups during the Korean War. This was doubtless a natural outcome of the failure to discern the reason for the occurrence of relapse or prolonged disease and the belief that more rest would prevent them. The point was finally reached when this concept was questioned, and it was subsequently shown by Chalmers and his associates that men could be sent back to duty quite safely in shorter periods. In addition, they demonstrated that allowing men out of bed around the room or ward except for an hour's rest after each meal did not prolong the course of the disease but actually hastened an earlier return to duty. See Chalmers, T. C., Reynolds, W. E., Eckhardt, R. D., Cigarroa, J. G., Dean, M., Reifenstein, R. W., Smith, C. W., and Davidson, C. S.: Treatment of Acute Infectious Hepatitis in Armed Forces. Advantages of ad lib. Bed Rest and Early Reconditioning. J.A.M.A. 159: 1431-1434, 10 Dec. 1955.
⁹⁶See footnote 61, p. 353.
⁹⁷See footnote 60, p. 353.
⁹⁸The difficulties encountered in the field in particular in providing such a diet were considerable, and it was often not easy to make a solution of powdered milk in water palatable as a source of protein. It was not unusual that dietary excesses should have evolved, and, on occasion, regimens including as much as 350 gm. of protein were advised. This in combination with large amounts of carbohydrate and little fat was far from appealing to jaded appetites. However, as with the duration of rest in bed, a more realistic dietary approach eventually emerged, recommending well-balanced, high-caloric meals similar to those described in the early experience with hepatitis in Egypt (see footnote 60, p. 353). Of importance in this evolution was the demonstration of the advantage of a diet of 2,000 to 3,000 calories, made up of 19 percent protein, 120 to 150 gm. of fat, and the remainder in carbohydrates, by Chalmers and his associates (see footnote 95).

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PLATE VI.-(Top) Duration of epidemic hepatitis, clinically less than 1 day. Microscopic appearance of the liver at low magnification. The hepatic parenchyma has been destroyed. The portal regions and the perilobular boundaries are densely infiltrated with inflammatory cells. (X 25)(Bottom) Duration of epidemic hepatitis, 3 days. Photomicrograph of the liver at low magnification. The hepatic cells have been destroyed. The lobular remnants are engorged with blood. The peripheries are outlined by bands of inflammatory cells. (X 25)

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Early in the course of the disease when anorexia, nausea, or vomiting were problems, the intravenous administration of 2,000 to 3,000 ml. of 5 percent dextrose in isotonic solution of sodium chloride was of value. When oral feedings could be taken, they were better tolerated in the early phase of the disease in small, frequently administered amounts.

As recovery progressed, the caloric intake was maintained at 3,000-4,000 calories per day. There was no reason to believe that supplemental vitamins were of any value; however, the administration of vitamin K parenterally (Hykinone, 2.4 mg. (1/28 gr.)) daily for several days frequently brought about an increase of plasma prothrombin when it was low. The danger of using opiates and barbiturates was stressed. Alcoholic beverages were interdicted throughout the course of the disease and for 6 months after recovery, although there was no evidence that modest amounts were harmful after recovery and it is likely that the injurious effects of small amounts were stressed without adequate evidence.

Prophylaxis and Control

The association of epidemics with poor sanitation and the subsequent incrimination of the intestinal-oral route as a way of spread of the disease directed measures toward (1) improvement of the general sanitation of camps, (2) fly abatement, (3) sterilization of food receptacles, (4) elimination of possibly infected foodhandlers, and (5) prevention of fecal contamination of food, water, and milk. Under conditions of battle, these measures were obviously impossible to carry out, and reference has been made to the frightful sanitary situation prevailing in certain sectors of the Alamein Line, and early site of the great epidemic in North Africa. An important problem appeared, although late, with the realization that the Lyster bag technique of treatment of water that was ordinarily practical was not effective in destroying the hepatitis virus.⁹⁰

⁹⁰(1) Neefe, J. R., Stokes, J., Jr., Baty, J. B., and Reinhold, J. G.: Disinfection of Water Containing Causative Agent of Infectious (Epidemic) Hepatitis. J.A.M.A. 128: 1076-1080, 11 Aug. 1945. (2) Subsequently, Neefe and his associates showed that coagulation, settling, and filtration of water before treating it with chlorine made possible the inactivation of hepatitis virus. See Neefe, J. R., Baty, J. B., Reinhold, J. G., and Stokes, J., Jr.: Inactivation of the Virus of Infectious Hepatitis in Drinking Water. Am. J. Pub. Health 37: 365-372, April 1947.

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Specifically, some success was achieved in the prevention of the disease in certain groups of heavily exposed troops in the campaign in Italy by the intramuscular administration of normal human gamma globulin.¹⁰⁰

The enormity of the problem created by the outbreaks of serum hepatitis and infectious hepatitis in both Allied and Axis troops, in addition to the failure to propagate the causative agents by the various laboratory techniques known at that time, urged the use of human volunteers as the means of acquiring necessary information. Experimental studies were carried on in Germany, in the Middle East, in England, and in the United States, and although the natural limitations of this method of investigation were great, an imposing amount of knowledge was accumulated in the period of World War II. In reviewing these data, it is evident that the positive results were of greater value than the negative ones, although it is also apparent that there was sufficient consistency among the negative results reported by various investigators to give them considerable worth. The prolonged course of disease in viral hepatitis made it an undesirable candidate for investigation in volunteers; however, its extremely low mortality made defensible the acceptance of the challenge created by the exigencies of the times. Much is owed to the relatively small number of volunteers who contributed so generously of themselves, and their roles can never be forgotten. To those who shared these experiences, they were frequently harrowing, on one occasion accompanied by tragedy, but never without dignity.

In the United States, Dr. J. W. Oliphant, of the U.S. Public Health Service, was the pioneer in these studies. Faced with the huge outbreak of serum hepatitis following the use of yellow fever vaccine, he produced this disease in volunteers by the parenteral inoculation of icterogenic serum in 1943. After this, studies in volunteers were carried on under the auspices of the Army Epidemiological Board. It is pertinent to point out here that the Medical Department of the U.S. Army and, in particular, the Preventive Medicine Service of the Office of The Surgeon General have reason to be proud of the contributions made with their support to our knowledge of viral hepatitis. Under the aegis of the Army Epidemiological Board, three of its Commissions were primarily concerned with carrying out in this country and abroad various studies: the Commission on Measles and Mumps, the Commission on Neurotropic Virus Diseases, and the Commis-

¹⁰⁰(1) Gellis, S. S., Stokes, J., Jr., Brother, G. M., Hall, W. M., Gilmore, H. R., Beyer, E., and Morrissey, R. A.: Use of Human Immune Serum Globulin (Gamma Globulin) in Infectious (Epidemic) Hepatitis in the Mediterranean Theater of Operations; Studies on Prophylaxis in 2 Epidemics of Infectious Hepatitis. J.A.M.A. 128: 1062-1063, 11 Aug. 1945. (2) What was then regarded as prevention subsequently was determined to be a modification of the disease by Krugman and his associates. See Krugman, S., Ward, R., Giles, J. P., and Jacobs, A. M.: Infectious Hepatitis; Studies on the Effect of Gamma Globulin and on the Incidence of Inapparent Infection. J.A.M.A. 174: 823-830, 15 Oct. 1960.

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sion on Influenza. The laboratories of these Commissions were widely separated-in Philadelphia, Pa., New Haven, Conn., and Ann Arbor, Mich.-and to facilitate a ready exchange of ideas without loss of individual independence, the Army Epidemiological Board established the "Hepatitis Study Group" in July 1944. 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 of the Yale University School of Medicine, New Haven; and (3) Dr. Thomas Francis, Jr., at the School of Public Health, University of Michigan, Ann Arbor.

The Commission on Measles and Mumps worked with a number of different units of volunteers, including 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 the Civilian Public Service Unit No. 140 of Philadelphia, Pa. The Commission on Neurotropic Virus Diseases found volunteers in various groups of conscientious objectors working in State institutions in the vicinity of New Haven, including Civilian Public Service Unit No. 81 at the Connecticut State Hospital, Middletown, Conn., Civilian Public Service Unit No. 68 at the Norwich State Hospital at Norwich, Conn., and subsequently a special Branch of Civilian Public Service Unit No. 140 of New Haven, Conn., housed in a fraternity house at Yale University. Volunteers were also found among prisoners at the Federal Correctional Institution in Danbury, Conn., and at the State Prison in Wethersfield, Conn. The Commission on Influenza found volunteers in the State Prison of Southern Michigan, Jackson, Mich.

The results of the various studies carried on by these groups as well as by certain other investigators abroad are described in the sections on "Serum Hepatitis" and "Infectious Hepatitis," which follow.

Serum Hepatitis

The pioneer experiments of Oliphant and his colleagues¹⁰¹ were reported in 1943 and described the transmission of hepatitis to volunteers by the parenteral inoculation of serum obtained from patients in the acute phase of homologous serum hepatitis, resulting from the administration of known icterogenic yellow fever vaccine. Cameron,¹⁰² working in the Middle East, also reported in the same year the transmission of hepatitis

¹⁰¹Oliphant, J. W., Gilliam, A. G., and Larson, C. L.: Jaundice Following Administration of Human Serum. Pub. Health Rep. 58: 1233-1242, 13 Aug. 1943.
¹⁰²Cameron, J. D. S.: Infectious Hepatitis. Quart. J.M. 12: 139-155, July 1943.

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to volunteers by inoculating blood obtained from patients acutely sick with the disease. These results were corroborated and extended by others.¹⁰³

In contrast, attempts to demonstrate virus in the feces of patients in the acute phase of the disease by oral or parenteral inoculation were unsuccessful,¹⁰⁴ as were, with two possible exceptions¹⁰⁵ attempts to transmit the disease experimentally by feeding serum or nasopharyngeal washings. Limited attempts to detect virus in nasopharyngeal washings and urine were unsuccessful, with the possible exception of a single report by Findlay and Martin,¹⁰⁶ who described the occurrence of jaundice in a volunteer 50 days after intranasal inoculation of nasopharyngeal washings from a patient in the acute phase of hepatitis caused by the administration of yellow fever vaccine. Unfortunately, the number of experiments performed were insufficient to offer conclusive evidence whether serum hepatitis virus was in the urine, the nasopharyngeal washings, or the feces, or whether the disease could be produced by the ingestion of infectious material. In regard to the latter, however, Havens and his colleagues¹⁰⁷ and Neefe and his associates¹⁰⁸ were unable to transmit serum hepatitis to volunteers by feeding infectious serum that produced the disease regularly when inoculated parenterally.

The accidental contamination of pools of serum or plasma by the blood of apparently healthy persons carrying virus suggested that a carrier state might exist more often than was hitherto suspected. The importance of this was augmented by the tremendous use of human blood and plasma and stimulated the investigation of the period of infectivity of patients with this disease. Only a limited number of experiments were done; however, virus was found in the blood of volunteers during the

¹⁰³(1) MacCallum, F. O., and Bauer, D. J.: Homologous Serum Jaundice: Transmission Experiments With Human Volunteers. Lancet 1: 622-627, 13 May 1944. (2) Neefe, J. R., Miller, T. G., and Chornock, F. W.: Homologous Serum Jaundice; Review of Literature and Report of Case. Am. J.M. Sc. 207: 626-638, May 1944. (3) Neefe, 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. Invest. 23: 836-855, September 1944. (4) MacCallum, F. O.: Transmission of Arsenotherapy Jaundice by Blood; Failure With Faeces and Nasopharyngeal Washings. Lancet 1: 342, 17 Mar. 1945. (5) Paul, 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. (6) Paul, J. R.. and Havens, W. P., Jr.: Recent Advances in the Study of Infectious Hepatitis and Serum Jaundice. Tr. A. Am. Physicians 59: 133-141, 1946. (7) Neefe, 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.
¹⁰⁴(1) Neefe, 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. (2) See footnote 103 (4). (3) 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.
¹⁰⁵(1) Findlay, G. M., and Martin, N. H.: Jaundice Following Yellow-Fever Immunization; Transmission by Intranasal Instillation. Lancet 1: 678-680, 29 May 1943. (2) See footnote 103 (1).
¹⁰⁶See footnote 105 (1).
¹⁰⁷(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) See footnote 104 (3).
¹⁰⁸(1) Neefe, J. R., Stokes, J., Jr., and Gellis, S. S.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis; Experimental Study of Immunity and Cross Immunity in Volunteers; Preliminary Report. Am. J.M. Sc. 210: 561-575, November 1945. (2) See footnote 103 (7).

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incubation period as well as in the acute phase of the disease by Neefe and his coworkers¹⁰⁹ (87 days before the onset of hepatitis), by Paul and his associates¹¹⁰ (60 days before the appearance of jaundice), and by Havens¹¹¹ (16 days before the appearance of jaundice). During convalescence, at intervals of 1 to 5 months after the onset of disease,¹¹² similar attempts to recover virus were unsuccessful. It was not determined whether a carrier state might exist after recovery or whether patients with relapse or chronic hepatitis were infectious.

Evidence suggesting that serum hepatitis virus evoked homologous immunity was furnished by Neefe and his group,¹¹³ who reinoculated nine volunteers convalescent 6 to 9 months from experimentally induced homologous serum hepatitis. None of the convalescents became sick, while eight out of nine controls contracted serum hepatitis, with incubation periods ranging from 60 to 110 days. However, there was no apparent cross-immunity between homologous serum hepatitis and infectious hepatitis as far as could be determined from the studies of Havens¹¹⁴ and of Neefe and his colleagues.¹¹⁵ Volunteers convalescent from the former disease contracted the latter when reinoculated with a strain of infectious hepatitis virus. The report of Oliphant,¹¹⁶ who described complete protection in 10 volunteers convalescent from serum hepatitis when they were reinoculated with a strain of virus presumed to be infectious hepatitis, requires consideration in this regard. Although the strain of virus he used to challenge his convalescents was obtained in Italy where infectious hepatitis was epidemic, it is important to note that it produced hepatitis in the controls after a long incubation period of 85 to 106 days, suggestive of the behavior usually associated with serum hepatitis virus. The geographic coexistence of serum hepatitis and infectious hepatitis viruses that produce disease with long and short incubation periods, respectively, was evident from the reports of Paul and Havens¹¹⁷ and of Cameron¹¹⁸ in the Middle East, and it would appear that Oliphant's experience reflected a similar situation.

As a result of such studies in volunteers, it was shown that the serum hepatitis virus was (1) filterable through Berkefeld N and Seitz E K filters, (2) resistant to temperatures of 56° to 60° C. for at least 30 minutes, and (3) transmissible to man in serial passage by parenteral inoculation of infectious material. The studies also showed that the virus survived at a

¹⁰⁹See footnote 103 (3), p. 374.
¹¹⁰See footnote 103 (5), p. 374.
¹¹¹See footnote 103 (3), p. 374.
¹¹²See footnote 101, p. 373; footnotes 104 (3) and 105 (1), p. 374.
¹¹³See footnote 103 (7), p. 374.
¹¹⁴Havens, W. P., Jr.: Experiment in Cross Immunity Between Infectious Hepatitis and Homologous Serum Jaundice. Proc. Soc. Exper. Biol. & Med. 59: 148-150, June 1945.
¹¹⁵See footnote 103 (7), p. 374.
¹¹⁶Oliphant, J. W.: Infectious Hepatitis: Experimental Study of Immunity. Pub. Health Rep. 59: 1614-1616, 15 Dec. 1944.
¹¹⁷See footnote 103 (6), p. 374.
¹¹⁸See footnote 102, p. 373.

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temperature of 4° C. for a long period;¹¹⁹ at a temperature of -10° to -20° C. for 4½ years, but apparently became inactive after 5 years at this temperature;¹²⁰ in a desiccated state at room temperature for at least a year;¹²¹ and in serum containing Merthiolate in concentration 1 : 2,000,¹²² in a mixture of equal parts of phenol and ether in 0.5 percent concentration,¹²³ and in an 0.2-percent concentration of tricresol¹²⁴ (tables 68, 69, and 70).

Infectious Hepatitis

The first successful transmission of infectious hepatitis to volunteers was described in Germany in 1942 in a short report by Voegt,¹²⁵ who fed them duodenal fluid and blood obtained from patients in the acute phase of the disease. In 1944, MacCallum and Bradley,¹²⁶ in England, and members of the Commission on Neurotropic Virus Diseases of the Army Epidemiological Board, in the United States,¹²⁷ were independently and almost simultaneously successful in producing the disease in volunteers by feeding feces and serum obtained from a patient in the acute phase of infectious hepatitis. The source of this strain of hepatitis virus was a soldier who had sickened on the Anzio beachhead in 1943. Because of pain in the right lower quadrant of the abdomen, an appendectomy was performed. The appendix was normal, but mesenteric adenitis was found. The patient was transferred back to the 38th General Hospital in Egypt where he subsequently became jaundiced and had a typical course of infectious hepatitis. The role of feces and the intestinal-oral route in the transmission of the disease was thus well established.

Also of epidemiologic importance was the subsequent recovery of the hepatitis virus in 1945 by Neefe and Stokes¹²⁸ from water drawn from

¹¹⁹See footnote 101, p. 373.
¹²⁰Blanchard, M., Jr., and Stokes, J., Jr.: Personal communication.
¹²¹See footnote 103 (3), p. 374.
¹²²Beeson, P. B., Chesney, G., and McFarlan, A. M.: Hepatitis Following Injection of Mumps Convalescent Plasma. Lancet 1: 814-815, 24 June 1944.
¹²³See footnote 30 (2), p. 344.
¹²⁴(1) See footnote 12 (2) and (3), p. 333. (2) Attempts to find a method of sterilizing serum of hepatitis virus appeared to be successful in that exposure to ultraviolet light for 1 hour at 2650 Angstrom units inactivated the virus experimentally. (See Oliphant, J. W., and Hollaender, A.: Homologous Serum Jaundice; Experimental Inactivation of Etiologic Agent in Serum by Ultraviolet Irradiation. Pub. Health Rep. 61: 598-602, 26 Apr. 1946.) Subsequent attempts some years later during the war in Korea to adapt this technique to large-scale sterilization of plasma were, unfortunately, unsuccessful. (See Sborov, V. M., Giges, B., and Mann, J. D.: Incidence of Hepatitis Following Use of Pooled Plasma; Followup Study in 587 Korean Casualties. A.M.A. Arch. Int. Med. 92: 678-683, November 1953.) (3) Heating the virus to 60° C. for 10 hours in human albumin was subsequently shown to inactivate the virus. (See Gellis, S. S., Neefe, J. R., Stokes, J., Jr., Strong, L. E., Janeway, C. A., and Scatchard, G.: Chemical, Clinical, and Immunological Studies on Products of Human Plasma Fractionation; Inactivation of the Virus of Homologous Serum Hepatitis in Solution of Normal Human Serum Albumin by Means of Heat. J. Clin. Invest. 27: 239-244, March 1948.)
¹²⁵Voegt, H.: Zur Aetiologie der Hepatitis Epidemica. München. med. Wchnschr. 89: 76, 23 Jan. 1942.
¹²⁶MacCallum, F. O., and Bradley, W. H.: Transmission of Infective Hepatitis to Human Volunteers. Lancet 2: 228, 12 Aug. 1944.
¹²⁷See footnote 107 (1), p. 374.
¹²⁸Neefe, 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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TABLE 68.-Results of administration, to volunteers, of materials obtained from patients in the acute phase of serum hepatitis

a well in a children's camp in Pennsylvania during an epidemic of the disease. The volunteers who ingested this water that was proved to have fecal contamination and the volunteers who ingested feces obtained from children with infectious hepatitis in the camp contracted the disease, giv-

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TABLE 69.-Results of administration, to volunteers, of materials obtained from patients in various stages of the incubation period and convalescence of serum hepatitis

[The minus sign = before onset of the disease; the plus sign = after appearance of jaundice]

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. Invest. 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.

TABLE 70.-Results of attempts to demonstrate immunity and cross-immunity in volunteers convalescent from experimentally induced serum

[In the "Challenge virus" column, IH = infectious hepatitis and SH =serum hepatitis]

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.

ing unequivocal proof to the concept previously based on epidemiologic evidence, that common source waterborne outbreaks could and did occur.

Attempts were also made to determine the infectivity of urine and nasopharyngeal washings in limited experiments. The results following

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the ingestion of urine were contradictory, and although Voegt¹²⁹ and Findlay and Willcox¹³⁰ reported success, MacCallum and Bradley,¹³¹ Havens,¹³² and Neefe and Stokes¹³³ failed to transmit the disease in this way. With one possible exception,¹³⁴ the results of testing nasopharyngeal washings were also negative.¹³⁵ However, the small number of volunteers employed in these latter experiments and the possibility that both urine and nasopharyngeal washings were obtained from the patients at a time when insufficient amounts of virus were present denied the right to draw any conclusions concerning the infectivity of either urine or nasopharyngeal washings.

After the demonstration of the presence of virus in the blood and feces of patients in the acute phase of the disease, attention was directed to determining when the virus appeared in these materials and how long it remained there. This was of particular concern in relation to the possibility that patients with relapse or chronic hepatitis might be infectious or that those who had made a complete recovery might remain carriers of the virus. The period of infectivity of patients with infectious hepatitis was therefore investigated in a few experiments. Virus was found in the blood 3 days before the onset of symptoms.¹³⁶ However, a single attempt to detect it in the blood halfway through the incubation period of experimentally induced infectious hepatitis was unsuccessful, as were attempts to recover the virus from the blood and feces 1 month¹³⁷ after onset, and from the feces 3 months¹³⁸ after the disappearance of jaundice.¹³⁹ The whole question of whether a "carrier state" existed either in the blood or in the feces remained unanswered, although there was epidemiologic evidence, particularly from civilian experience, to suggest that it did.

¹²⁹See footnote 125, p. 376.
¹³⁰(1) Findlay, G. M., and Willcox, R. R.: Transmission of Infective Hepatitis by Faeces and Urine. Lancet 1: 212, 17 Feb. 1945. (2) Findlay later suggested that the apparent infectivity of urine in his experiment was due to the presence of erythrocytes associated with urinary bilharziasis. However, recent experiments by Krugman (personal communication) and his associates indicate that the virus is excreted in the urine in the acute phase of the disease and may be transmitted to volunteers by feeding,
¹³¹See footnote 126, p. 376.
¹³²Havens, W. P., Jr.: Period of Infectivity of Patients With Experimentally Induced Infectious Hepatitis. J. Exper. Med. 83: 251-258, March 1946.
¹³³See footnote 128, p. 376.
¹³⁴See footnote 126, p. 376.
¹³⁵See footnote 128, p. 376, and footnote 132.
¹³⁶Francis, 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.
¹³⁷See footnote 132.
¹³⁸See footnote 104, p. 374.
¹³⁹From patients complaining of symptoms 6 to 9 months after the onset of hepatitis, Neefe and his associates obtained specimens of liver (by biopsy), blood, and feces, and fed them to volunteers who developed certain vague symptoms and slight alterations of tests of hepatic function. The results, however, were not clearly defined, and no conclusion was made concerning whether such patients harbored the virus or might be infectious. See Neefe, 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.

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Experimentally, a limited amount of data indicated that immunity develops during recovery from hepatitis. Both Havens¹⁴⁰ and Neefe and his associates¹⁴¹ showed that volunteers convalescent 6 to 9 months from experimentally induced infectious hepatitis were immune when reinoculated with the homologous strain. In addition, Neefe and his group¹⁴² showed that volunteers recovered from hepatitis experimentally induced by a strain of virus obtained from the stools of children with the disease in Pennsylvania were immune when inoculated with a strain of hepatitis virus obtained from the stool of a soldier who contracted the disease in Sicily.¹⁴³

Evidence thus became available that more than one strain of hepatitis virus might cause hepatitis in man, and at least two strains of virus were described as being immunologically distinct.¹⁴⁴ These strains of virus were termed "infectious hepatitis" and "homologous serum hepatitis," and the similarities and differences between them will be discussed more fully at the end of this section. However, it may be mentioned here that, in a limited number of experiments, volunteers convalescent from hepatitis produced by one strain of virus were not immune when reinoculated with the other strain of virus.¹⁴⁵ In regard to immunity, it was shown by Stokes and Neefe¹⁴⁶ and by Havens and Paul¹⁴⁷ that normal human gamma globulin in amounts of 0.06 to 0.12 ml. per pound of body weight, administered intramuscularly, prevented the epidemic disease.¹⁴⁸

As a result of these studies and others in volunteers, it was also demonstrated that the etiologic agent of infectious hepatitis was filterable through an L2 Chamberland or Seitz E K filter, that it was resistant to a temperature of 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.¹⁴⁹ The virus withstood chlorination, namely, one part chlorine residual per million for 30 minutes,¹⁵⁰ and remained active in materials frozen for 1 to 1½ years, but not for 3 years, at -10° to -20° C. Another strain of virus was inactive after storage at Dry Ice temperature for 32 months¹⁵¹ (tables 71, 72, and 73).

¹⁴⁰Havens, W. P., Jr., Immunity in Experimentally Induced Infectious Hepatitis. J. Exper. Med. 84: 403-406, November 1946.
¹⁴¹See footnote 108 (1), p. 374.
¹⁴²See footnote 103 (7), p. 374.
¹⁴³See footnote 107 (1), p. 374.
¹⁴⁴See footnote 103 (7), p. 374.
¹⁴⁵See footnote 103 (7), p. 374, and footnote 114, p. 375.
¹⁴⁶Stokes, J., Jr., and Neefe, J. R.: Prevention and Attenuation of Infectious Hepatitis by Gamma Globulin; Preliminary Note. J.A.M.A. 127: 144-145, 20 Jan. 1945.
¹⁴⁷Havens, W. P., Jr., and Paul, J. R.: Prevention of Infectious Hepatitis With Gamma Globulin. J.A.M.A. 129: 270-272, 22 Sept. 1945.
¹⁴⁸See footnote 100 (2), p. 372.
¹⁴⁹Havens, W. P., Jr.: Properties of the Etiologic Agent of Infectious Hepatitis. Proc. Soc. Exper. Biol. & Med. 58: 203-204, March 1945.
¹⁵⁰See footnote 99 (1), p. 371, and footnote 128, p. 376.
¹⁵¹(1) See footnote 81, p. 361. (2) Stokes, J., Jr.: Unpublished observations.

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TABLE 71.-Results of administration, to volunteers, of materials obtained from patients in the acute phase of infectious hepatitis

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TABLE 72.-Results of administration, to volunteers, of materials obtained from patients in various stages of the incubation period and convalescence of infectious hepatitis

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

¹Havens, W. P., Jr.: 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. 1: 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.

TABLE 73.-Results of attempts to demonstrate immunity and cross-immunity in volunteers convalescent from experimentally induced infectious hepatitis, in 1946

[In the "Challenge virus" column, IH = infectious hepatitis, and SH = serum hepatitis]

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.

Relationship of Serum Hepatitis to Infectious Hepatitis

The exact relationship between infectious hepatitis and homologous serum hepatitis eluded solution, and, indeed, an appellative dilemma was created by the arbitrary definition of the latter form of the disease on the basis of probable route of transmission. Whether homologous serum hepatitis merely represented the artificial transmission of the naturally occur-

383

ring disease was the subject of frequent discussion. While this may have occurred more frequently then was suspected, there was no evidence to indicate that it explained the relationship between the two.

The results of epidemiologic, clinical, and experimental studies revealed that certain similarities and differences existed between the two conditions and their causative agents. Although these two forms of hepatitis are clinically and pathologically indistinguishable after the onset of disease, attention was early directed to the fact that in infectious hepatitis the onset was more apt to be abrupt, with an elevated temperature of over 100° F. (37.8° C.).¹⁵² In addition, serum hepatitis was described as being at times more severe as it occurred in debilitated patients. The causative agents of both diseases were found to be filtrable, resistant to a temperature of 56° C. for at least 30 minutes, and transmissible to man in serial passage, evoking homologous immunity. They were regarded as viruses; however, they were not successfully transmitted to laboratory animals or embryonated eggs.

In contrast to these similarities were certain differences that were consistently reproducible by two different groups of investigators, members of the Commission on Neurotropic Virus Diseases and of the Commission on Measles and Mumps, working under the auspices of the Army Epidemiological Board. In table 74 is recorded a comparison of the behavior of two apparently different strains of virus, summarized from the results of Paul and Havens and of Stokes and Neefe in experiments with volunteers described earlier in this section.

The incubation period of infectious hepatitis was short, ranging from 20 to 40 days, in contrast to the long period (40 to 160 days) of homologous serum hepatitis. That the prolonged incubation period of the latter disease was determined by the parenteral inoculation of virus partially

TABLE 74.-Comparison of behavior of viruses of infectious hepatitis and serum hepatitis in experimentally infected volunteers

¹⁵²See footnote 26, p. 340.

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neutralized by antibody in the serum was considered. However, the short incubation periods following both parenteral and oral inoculation of volunteers with serum containing the same strain of infectious hepatitis virus suggested that such a mechanism was not the complete explanation of difference in time interval.¹⁵³ Prolonged incubation periods were indeed reported in experimentally induced infectious hepatitis when the inoculation was by the parenteral route,¹⁵⁴ but the failure to test the same inoculums for infectivity by the oral route denied any comparison of the effect of route of inoculation on length of incubation.

The virus of serum jaundice was found in the circulating blood during the long incubation period as well as in the active stage of the disease. Experimentally, it appeared to be infectious only when inoculated parenterally, with two possible exceptions. The disease thus produced was not as contagious as infectious hepatitis, evidence of contact infection was rare, and the virus was not found in the feces. This fact, in combination with the failure to produce this disease in volunteers by the oral administration of serum known to contain virus, suggested that the intestinal-oral route was not important in its spread, differentiating it in some degree from infectious hepatitis. Of interest in this regard was the comparison of the elimination of two strains of virus in the feces after parenteral inoculation.¹⁵⁵ A strain of infectious hepatitis virus was readily detected in the feces during the acute phase of the disease produced by parenteral inoculation. In contrast, a strain of serum hepatitis virus also inoculated parenterally in other volunteers was not found in the feces during the acute phase. In addition, studies on the immunity of volunteers corroborate the epidemiologic experience that patients who have had either infectious hepatitis or homologous serum hepatitis were susceptible when exposed to the other disease. Lastly, the long period of viremia in patients with serum hepatitis, in contrast to the much shorter period of viremia in infectious hepatitis, was adduced to explain the difference in the prophylactic effect of normal human gamma globulin in the two conditions. In the former, questionably favorable results followed the administration of two doses a month apart, while no protection was demonstrable when only one dose was given. This suggested that the efficacy might have a quantitative relationship with the amount of circulating virus. It was not determined by the end of the war whether the differences in route of inoculation, length of incubation period, onset of disease, distribution of virus, period of infectivity, and lack of cross-immunity represented the activities of actually different viruses or of antigenic differences of various strains of one virus.¹⁵⁶

¹⁵³Havens, W. P., Jr.: Elimination in Human Feces of Infectious Hepatitis Virus Parenterally Introduced. Proc. Soc. Exper. Biol. & Med. 61: 210-212, March 1946.
¹⁵⁴See footnote 116, p. 375, and footnote 126, p. 376.
¹⁵⁵See footnote 153.
¹⁵⁶It is pertinent to point out that many of these unknowns still persist at the time of writing this chapter in 1963.-W. P. H., Jr.

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