CHAPTER XIII
Viral Hepatitis
W. Paul Havens, Jr., M.D.
The emergence of viral hepatitis as one of the most importantcauses of loss of time among U.S. troops during World War II was as unexpectedas it was dramatic. Conditioned largely by memories and descriptions of themedical experiences in World War I in which this disease played an almostunnoticed role in our forces both here and abroad, it is no wonder that thosecharged with the preparation of programs for the control and treatment ofinfectious diseases turned their attention first to respiratory infections.Records of the bitter ravages of influenza and secondary bacterial pneumoniasdoubtless prompted the Preventive Medicine Service of the Surgeon General'sOffice to establish early in 1941 the Board for the Investigation and Control ofInfluenza and Other Epidemic Diseases in the Army. This board was approved bythe Secretary of War in January 1941 and, eventually, became known as the ArmyEpidemiological 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 noconsideration 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 inour Civil War,1 as well as the oft repeated story of the military importanceof this disease among foreign troops in Germany,2 in the Mediterranean littoral,3in 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 readilyunderstandable in view of the remoteness of these experiences both temporallyand spatially. In addition, it is curious but true that our concept of thenature of viral hepatitis was generally somewhat more naive than that of certainof 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 MostFrequent in British Military Hospitals in Germany, From January 1761 to theReturn of the Troops to England in March 1763. London: Millar, Wilson, andDurham, 1764.
3Larrey, D. J.: Relation Historique et Chirurgical de l'Exp?ditionde l'Arm?e d'Orient en Egypte et en Syrie. Paris: Demonville et Soeurs,1803.
4Sarrailh?, A., and Clunet, J.: La "Jaunisse descamps" et l'?pid?mie de paratypho?de des Dardanelles. Bull. et m?n.Soc. m?d. d. h?p. de Paris, 3 s?r., 40: 563-567, 1916.
5Cantacuz?ne, J.: Sur une ?pid?mie d'ict?re observ?e en Roumanie pendant la campagne de 1917. Presse m?d. 26: 541-543, 24 Oct.1918.
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that occasional pioneers in this country, including Blumer6and Rich,7 had pointed the way to a better understanding of thedisease.
It is particularly ironic that the concern about anotheracute infection producing necrosis of the liver-yellow fever-and theaggressive efforts made to expedite the production of enormous supplies ofvaccine against it did not potentiate our awareness of the importance of viralhepatitis. Our introduction, in 1942, was a rude one and was marked by the greatepidemic of homologous serum hepatitis transmitted by the injection of yellowfever vaccine stabilized with human serum containing a strain of hepatitisvirus. Unfortunately, this catastrophe was not to be the last. Subsequently, in1942-45, as our troops appeared in the Middle East, in North Africa, in theFar East, in Europe, and in the Pacific Ocean Areas, they were riddled by thenaturally occurring epidemic disease, infectious hepatitis. It is pertinent topoint out here that recognition of the differences between the transmitteddisease and the naturally occurring one was not immediate, and, indeed, it wasnot until 1944-45 that two separate entities, serum hepatitis and infectioushepatitis, were generally recognized. However, it is a tribute to the vigor andsagacity of a number of military medical officers and their civilian consultantsthat many of the problems associated with this unexpected and unwelcomesituation were quickly recognized and that many of the etiologic, clinical, andepidemiologic unknowns were solved.
Viral hepatitis, with close to 200,000 cases, erupted in theperiod between 1942 and 1945 as a matter of prime importance to ourArmed Forces. It is the purpose of this account to set down theexperiences of the Army with serum hepatitis and infectious hepatitis during theperiod of World War II (table 65).
[Rate expressed as number of admissions per annum per 1,000average strength]
Area | 1942-45 | 1942 | 1943 | 1944 | 1945 | |||||
Number | Rate |
| Rate | Number | Rate | Number | Rate | Number | Rate | |
Continental United States | 46,750 | 3.17 | 33,569 | 12.63 | 3,906 | 0.75 | 3,175 | 0.80 | 6,100 | 2.08 |
Overseas | 135,633 | 12.63 | 15,664 | 26.74 | 24,966 | 14.79 | 24,608 | 6.44 | 70,395 | 15.16 |
|
| 182,383 | 7.16 | 49,233 | 15.18 | 28,872 | 4.20 | 27,783 | 3.57 | 76,495 | 10.10 |
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 reportby L?rman8 of an outbreak of jaundice occurring in shipworkers severalweeks after vaccination with human glycerinized lymph. Stokes and his coworkers,9in the United States, and Ruge,10 in Germany, subsequently reported theoccurrence of jaundice in patients undergoing antisyphilitic therapy, althoughthey apparently considered its cause to be infectious jaundice occurring inpatients made more susceptible either by their syphilitic infection or by thetreatment given for it. It was reserved for Flaum and his associates,11in 1926, to point out that, in a clinic caring for persons with diabetes, thosepatients who acquired hepatitis were doubtless infected by contaminated needlesor syringes; further, they suggested that the long incubation period of thisdisease distinguished it from the shorter incubation period of infectioushepatitis and raised the question whether two viruses might not exist. Theprescience of these workers merits special mention, particularly in view of theconsiderable period of time that elapsed before their speculations were provedto be true.
In the late 1930's, Findlay and his associates12 describedthe occurrence of jaundice in Africa in persons who had been immunized againstyellow fever with a vaccine containing human serum and suggested the viralnature of the icterogenic agent. During the same period, Soper and Smith13 andFox 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 andMcNalty16 also incriminated human serum as the probable medium oftransmission
8L?rman, A.: Eine Icterusepidemie. Berl. kiln. Wchnschr. 22:20-23, 1885.
9Stokes, J. H., Ruedemann, R., Jr., and Lemon, W. S.: EpidemicInfectious 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 F?llen. 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 AcuteHepatitis and Yellow Fever Immunization. Tr. Roy. Soc. Trop. Med. & Hyg. 31: 297-308, November1937. (2) Findlay, G. M., and MacCallum, F. O.: Hepatitis and Jaundice Associated With Immunization AgainstCertain 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-CalledEpidemic Catarrhal Jaundice). Tr. Roy. Soc. Trop. Med. & Hyg, 32: 575-586, February 1939.
13Soper, F. L., and Smith, H. H.: Yellow Fever VaccinationWith 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 AgainstYellow 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 andAdministration of Measles Serum. In Great Britain, Ministry of Health. On the State of the Public Health. Annual Report of the Chief MedicalOfficer 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 inchildren, following the injection of pooled measles immune serum.
Thus, it would appear that by 1940 serum hepatitis was eithersuspected or regarded in some parts of the world as a disease potentiallytransmissible by human serum containing an icterogenic agent. Despite thisrecognition in certain circles, the subject received little attention in theUnited States, and although an account of it had already been published here in1939,17 the concept of the true nature of serum hepatitis, and indeed ofinfectious hepatitis, had not yet reached a level of widespread generalawareness in our medical profession. This, combined with the facts that (1)serum hepatitis had never been recognized as a military disease and (2) thehuman serum used in the vaccine had been heated to 56?C., for at least 30minutes, apparently lulled any suspicion that might have arisen. It is easy tosee, then, how the pressure created by the decision to immunize large numbers oftroops that might be going into areas where yellow fever was highly endemic orepidemic made defensible the acceptance of the calculated risk of producing andinoculating millions of doses of yellow fever vaccine stabilized with humanserum. That this would end in a catastrophe that evoked unjustly criticaleditorials18 in certain segments of our press and outraged demands forcongressional investigation by a member of the House of Representatives19 wasnot anticipated.
The Epidemic and Its Characteristics
Although the exact number of cases of serum hepatitis thatoccurred in 1942 is not known, it is presumed that most of the 49,233 admissionsto hospitals for hepatitis reported for the total U.S. Army were caused by theinjection of yellow fever vaccine stabilized by human serum containing anicterogenic virus. Of these total Army figures, 33,569 cases were reported fromthe continental United States and 15,664 from theaters outside the continentalUnited States.
Late in the autumn of 1941, the immunization of U.S. troopsagainst yellow fever was initiated on a large scale. This program had beenrecommended by the Subcommittee on Tropical Diseases of the National ResearchCouncil in 1940 primarily because of the epidemic of yellow fever that year inthe 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.), rankingminority member of the House Military Affairs Committee, on 30 July 1942, urgedcongressional investigation of the cause of the 28,585 cases of yellow jaundicein the Army, apparently from the use of yellow fever vaccine. "Thedisclosures on the number of cases of jaundice are a national disgrace and thecountry is entitled to know what happened." Thomas continued: "I amsure that the parents of the stricken youths whose life expectation may havebeen reduced by the attack are not satisfied with the report that the Army hopesthe situation has been cleaned up. The Nation is entitled to know what happenedand who is to blame."
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the East. The decision to immunize large numbers of mencreated a huge demand for yellow fever vaccine, and the burden for itsproduction was undertaken, late in 1940, by the International Health Division ofthe Rockefeller Foundation, New York, N.Y. It is not the purpose of this paperto discuss the various aspects of this immunization program or the decisionsthat led to its adoption, but this whole subject has been carefully reviewed anddocumented by Long20 and by Paul and Gardner.21
The first cases of hepatitis that were subsequently to beidentified as serum hepatitis caused by yellow fever vaccine appeared inFebruary 1942, and by the end of the first week in March of that year, it becameclear from reports emanating from widely separated areas that an epidemicdisease associated with jaundice had appeared in the Army. Although earlysuspicions were directed toward the possibility that yellow fever itself orepidemic catarrhal jaundice might be involved, it was rather quickly recognizedthat the occurence of jaundice in men throughout this country and in far-flungplaces abroad was associated with the previous injection of yellow fever vaccineand, indeed, with certain specific lots of it.
The possibility was early considered that the administrationof the vaccine might have activated a virus latent in the host, causinghepatitis; however, the true nature of the situation was soon appreciated, andthe human serum used to stabilize the vaccine was indicated as carrying anicterogenic agent that produced hepatitis. A speedy solution of this aspect ofthe problem was made possible by the work of a number of different groups andindividuals working together and independently. The history of this indictmentand the fascinating tale of the incrimination of certain lots of human serumthat came from the Johns Hopkins University School of Medicine, Baltimore, Md.,were well recorded by Sawyer and his associates.22 Suffice it to saythat Dr. Kenneth F. Maxcy, of the Army Epidemiological Board, and Dr. Karl F.Meyer, of the George Williams Hooper Foundation, were among those who furnishedthe penetrating and incisive epidemiologic evidence that made the solutionpossible. As a result, The Surgeon General, Maj. Gen. James C. Magee, on 14April 1942, approved the recommendation to suspend the use of the yellow fevervaccine made by the International Health Division of the Rockefeller Foundationfor 2 months, and to use the U.S. Public Health Service vaccine produced in itsRocky Mountain Laboratory, Hamilton, Mont. Subsequently,
20Long, Arthur P.: The Army Immunization Program. In MedicalDepartment, 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 workedclosely from 1943 to 1946 in Egypt and in New Haven, Conn. Many of the points ofview expressed in this history were derived from this association and fromsubsequent ones over the years. His concepts concerning hepatitis and itsmilitary importance were eventually set down in the following document: Paul,John R., and Gardner, Horace T.: Viral Hepatitis. In Medical Department, UnitedStates Army. Preventive Medicine in World War II. Volume V. CommunicableDiseases. 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 theUnited 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 ofserum hepatitis following immunization with yellow fever vaccine failed tooccur.
From its point of recognition in the week ending on 7 March1942, the epidemic in the United States progressed rapidly and reached its peakof 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.-Weeklyadmissions for jaundice (essentially serum hepatitis) in the U.S. Army incontinental United States, January-December 1942
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CHART 3.-Weekly admissions for jaundice (essentiallyserum hepatitis) in the U.S. Army
overseas, January-December 1942
separated localities abroad during the first 2 weeks inMarch, but the peak of incidence of the disease appeared to occur 1 or 2 weekslater than in the continental United States. The decline of incidence abroad wasalso similar to that in this country (chart 3).
The first information about jaundice on board American troopships came by way of a telephone message from Dr. Andrew Davidson, Chief MedicalOfficer of Health for Scotland, on Wednesday, 13 May 1942, advising that therewere 26 cases among approximately 20,000 troops. These men continued to theirdestination in Northern Ireland, and during the ensuing weeks, the number ofcases increased. Almost all these patients were sent to the 5th GeneralHospital, near Belfast. By 20 May 1942, 83 patients had been admitted to thewards, and by the end of the next week, 231 patients had been admitted. A numberof clinical and laboratory investigations were initiated, and the relationshipof the epidemic with the previous injection of yellow fever vaccine stabilizedwith human serum was established. A total of 1,915 cases occurred, of which1,591 were in Northern Ireland and 324 in Great Britain.
In the course of the inquiry made in Northern Ireland duringthe period of 20-27 May 1942, repeated reference was made to "Honoluludisease" by a number of the medical officers who had accompanied theaffected troops from the United States, and the statement was made that thejaundice 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 staffmembers of the Rockefeller Foundation who were said to have come to theconclusion that the jaundice there was due to the ingestion of infected pork andthat the infectious agent was a filtrable virus. It was regarded ascommunicable, and the incubation period was fixed at about 10 to 14 days.Subsequently, troops from this post moved to Fort Ord, Calif., for embarkationto 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 on30 March and arrived on 3 April, carrying about 5,800 men. During the passage toHawaii, 1 case of jaundice developed in the first convoy and 11 in the secondconvoy. On arrival in Honolulu, additional cases began to appear at about 2-weekintervals, tending to occur in crops. By 3 April 1942, there were 500 patientsin hospitals in Honolulu with jaundice. Although it was the belief of some ofthe physicians in Hawaii that the condition was unrelated to the administrationof yellow fever vaccine, it indeed seemed to represent the same situation asoccurred in the Zone of Interior, in Northern Ireland and Great Britain, and inother parts of the world. Its appearance, in January 1942, suggested that lotsof vaccine inoculated as early as October 1941 were probably involved.23
An epidemic of serum hepatitis with approximately 1,520 casesoccurred in Iceland in 1942, beginning with troops arriving there during Marchand April. Most of these men had been vaccinated against yellow fever with lotNo. 368. In Canada, U.S. troops had the first case of serum hepatitis in themiddle of May 1942, with an increasing number of new cases until a peak wasreached around the first or second week of July. A few new cases appeared afterthis in August, but none thereafter. In the Central Pacific Area, serumhepatitis made its advent in troops arriving at Oahu between 10 and 16 March1942, 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 patientswere hospitalized.
23At the time of the Pearl Harbor raid and subsequentthereto, 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 alltroop convoys before they docked. The occurrence of one case of jaundice ofundetermined origin in the first convoy of troops cited above did not appear towarrant 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 itwas then thought that they represented mild cases of yellow fever contractedfrom the yellow fever inoculations. This introduced an immediate problem sincethe mosquito vector of yellow fever, Aedes aegypti, was present inHawaii. Emergency measures were set in motion by quickly erecting a tent campnext to the Honolulu docks and surrounding it by a fence for quarantinepurposes. The debarked troops were returned to dockside, placed in thisquarantine, and mosquito control measures instituted. Daily inspections of thetroops 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 directlyinto it when they arrived. Of course, many more cases developed subsequently,and the affected personnel were hospitalized. Finally, the number of casessubsided, 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 outbreakof serum hepatitis. Six of these lots were highly icterogenic, and to three ofthem (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 werescheduled for duty overseas were immunized with yellow fever vaccine in thelatter part of 1941. Among the lots used were three highly icterogenic ones. Thesecond phase of immunization occurred between 20 January and 15 April 1942 whenall the personnel in the Army were vaccinated. The remaining icterogenic lots ofvaccine were used during this time. The first peak of the epidemic, occurring inMarch-May 1942, represented cases occurring in men immunized in the previousautumn; the second peak, occurring from late May through July, was made up ofcases occurring in men immunized during the second period of vaccination.
It was early appreciated that the incubation period of thisdisease was unusually long and, in addition, highly variable, ranging from 60 to150 days. This variability was emphasized by Parr,24 who studied alarge 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 amongthese men. The differences in incubation period were interpreted as the resultof variations in the state of health of the hosts.
A striking characteristic of the outbreaks that occurred bothin the continental United States and abroad was the apparent failure of thedisease to spread to persons who had not been similarly immunized. Occasionalincidents were reported, however, in which the wives of men with postvaccinalhepatitis acquired hepatitis. This lack of communicability by personal contactexcept possibly under most intimate terms was a matter of great interest,particularly to those charged with the responsibility of attempting to determinethe relationship between serum hepatitis and the naturally occurring epidemicdisease.
There were those, however, who felt that actually aconsiderably greater communicability existed, and postulated the concept thatthe immunization with the yellow fever vaccine had not been directly responsiblefor the occurrence of hepatitis but rather that it rendered the men moresusceptible to the naturally occurring disease. Freeman25 describedoutbreaks at Fort Belvoir, Va., Fort Sill, Okla., and Fort Lewis, Wash., inwhich an increase in incidence of hepatitis among unvaccinated troops occurredduring outbreaks in men who had been immunized with icterogenic lots. It seemsfair to say that this concept was probably not valid in view of the vast amountof evidence incriminating certain lots of serum
24Parr, L. W.: Host Variation in the Manifestation ofDisease, With Particular Reference to Homologous Serum Jaundice in the Army ofthe United States. M. Ann. District of Columbia 14: 443-449, October 1945.
25Freeman, G.: Epidemiology and Incubation Period ofJaundice Following Yellow Fever Vaccination. Am. J. Trop. Med. 26: 15-32,January 1946.
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as icterogenic. However, complete unanimity of opinion onthis subject was not attained.
Among the curious strokes of fate was the statisticalimprobability that allowed the absence of postvaccinal hepatitis in the Navy.They had received only two lots of icterogenic vaccine (Nos. 334 and 369) andhad used them sparingly. Thus, at the meeting, on 14 April 1942, at which therecommendation to discontinue yellow fever vaccine produced by the InternationalHealth Division of the Rockefeller Foundation was approved by Surgeon GeneralMagee, Capt. (later Rear Adm.) Charles S. Stephenson, MC, of the Navy, was ableto state that there had been no jaundice among Navy personnel followingimmunization with this vaccine. About half a million men had been immunizedbefore 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 onsetof the disease, the clinical course was indistinguishable from that of epidemichepatitis or so-called catarrhal jaundice. For this reason, the major discussionof the clinical aspects will be reserved for inclusion in the section dealingwith infectious hepatitis.
Certain special features were observed, however, that servedto differentiate serum hepatitis from the epidemic disease. Important amongthese was the type of onset that was described as insidious in contrast to themore abrupt beginning of infectious hepatitis. Fever of any significance wasunusual in patients with serum hepatitis in contrast to the common occurrence offever, often of considerable degree, in patients at the onset of the epidemicdisease. In addition, arthralgia, urticaria, and itching were common enough inpatients at the onset of serum hepatitis to mark these symptoms as clinicaldifferences between the two conditions.
Among the best clinical accounts was that of Turner and hiscolleagues26 who described an outbreak at Camp Polk among men who hadbeen immunized with yellow fever vaccine lot No. 369. The epidemic was heraldedby a sharp increase in admissions of patients with jaundice to the hospitalduring the first week in May, progressing to its peak during the week of 20June, and declining thereafter with a low level attained in the first week inSeptember. The incubation periods ranged from 8 to 23 weeks. During the periodof 1 May-12 September 1942, 4,083 patients were observed and, of these, 14died. It was of interest that those who died had their first symptoms in theearly part of the outbreak, from 15 May to 10 June, and the disease appeared tobe 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 inSoldiers After Inoculation With Yellow Fever Vaccine, With EspecialConsideration of Severe Attacks. Ann. Int. Med. 20: 193-218, February 1944.
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admitted after the incidence was declining. Since these menwere inoculated at the same time, the question may be raised whetherprolongation of the incubation period might have been another manifestation ofthe mildness of the disease.
Because every effort was made to get patients into thehospital promptly, it was possible to study a goodly percentage of these menearly in the course of disease. Fifty-two percent were admitted during theirfirst week of illness and 41 percent during their second or third week ofillness. The remaining 7 percent straggled in thereafter. The onset of diseasewas usually vague and insidious, with mild afternoon fatigue and malaise,followed subsequently by the appearance of anorexia, weakness, nausea, abdominalpain 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 tothe fact that a fair number of patients with jaundice were completelyasymptomatic. Fever was not common and, if it occurred, lasted only 2 or 3 days.Diurnal variations of anorexia, abdominal distress, and even enlargement of theliver were described, with an increase in signs and symptoms at the end of theday. In a certain number of patients, sudden attacks of severe weakness andsweating occurred, suggesting hypoglycemia, and relief was afforded by theingestion of a meal of carbohydrates. A small percentage of patients had actualpain in the right upper quadrant of the abdomen or the lower part of the rightside of the chest, radiating up to the neck and the right shoulder. This wasoften made worse by walking or deep breathing. Although suggestive ofdiaphragmatic irritation, no report was made of hearing a friction rub. Onoccasion, pain in the right lower quadrant of the abdomen simulated acuteappendicitis, and it was sometimes not possible to make a differential diagnosiswithout laparotomy.
Aside from jaundice, enlargement and tenderness of the liverwere the two most striking findings, occurring in 40 percent (hepatomegaly) and20 percent (hepatic tenderness) of patients. Petechial hemorrhages in the skinand mucous membranes were frequently observed in the seriously sick patients butalso, on occasion, in the mildly sick. They extended over the lateral aspects ofthe chest and arms and were often widespread. Occasional patients had spidernevi that disappeared during convalescence.
Classification of cases in relation to degree of severity wasmade on the basis of three different criteria-the intensity and the durationof jaundice and the maximum loss of weight. Under these terms, 81 percent wereregarded as mildly sick, 17 percent moderately severely sick, and 2 percentseverely sick. Included in those regarded as mildly sick was a group of patientswith so-called "trivial illness." The diagnosis of hepatitis in thesepatients was made not infrequently on the basis of symptoms and the presence ofbilirubinuria 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 havebeen made so early in this clinical experience. However, it is obvious that theepidemiologic pattern of disease in men who had been inoculated with a highlyicterogenic lot of yellow fever vaccine (No. 369) supported the validity of thisconcept. Of even greater interest, however, was the suggestion that, althoughthere was little unequivocal evidence of a subclinical form of the disease, themedical officers involved in this study felt that there was sufficient to causethem to believe in the existence of this entity also.
It was appreciated that worsening of the course of thedisease could occur quite subtly and quickly, and certain guides in prognosiscame to be used. Considerable confidence was placed in the capacity of patientsto respond vigorously to the parenteral administration of vitamin K as afavorable sign. Frequent measurements of the degree of bilirubinuria, the gainor loss of weight, and the amount of food consumed were made, and continuedanorexia and loss of weight with deepening jaundice were regarded as ominous.
Among the fatal cases, death occurred from 24 to 101 daysafter onset of the disease. In a goodly percentage of them, death came laterrather than earlier in the course of the disease, and attention was called tothe fact that, in patients who lived for a longer period, alterations in type ofhepatic involvement occurred as well as changes in other organs. Thus, it wasbelieved that, during the more prolonged course of the disease that eventuallyterminated fatally, the continuing necrosis and regeneration brought aboutstructural changes in the liver, resulting in (1) certain manifestations ofintrahepatic obstructive jaundice and (2) changes in vascular patterns, withincrease of portal pressure. Portal hypertension with congestive splenomegalydid occur and, on occasion, with excessive hemolysis and rupture of esophagealvarices.
Luck?27 described in detail the findings at necropsy of alarger group of fatal cases, and they will be dealt with more fully in thesection on "Infectious Hepatitis." At this point, they may besummarized as ranging from massive acute hepatic necrosis in those dying earlyto varying degrees of hepatic necrosis and regeneration with alterations of thelobular 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 diseaseincluded neurologic disturbances, gastrointestinal hemorrhage, ascites,
27Luck?, B.: Pathology of FatalEpidemic Hepatitis. II. Structureof 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, hemorrhagesinto the skin and mucous membrane, and morbilliform rashes. Most of them wereevidence of increased severity of the disease, although on occasion milder casesdid have numerous petechial hemorrhages in the skin and mucous membranes.Neurologic disturbances were often bizarre. Severe emotional and mental disarraywere followed often by tremor and coma. Gastrointestinal hemorrhage occurred notonly from rupture of esophageal varices but also from direct bleeding into thegastrointestinal tract from multiple small points. In fatal cases, hemorrhageinto the mesentery was observed, and in at least one patient, this wasassociated 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 seriouslysick patients or fatal cases azotemia occurred. Of particular interest was thedescription of the so-called tremor syndrome. It was observed duringconvalescence or even after apparent recovery and consisted of a slow, coarsetremor of the extremities at rest, made worse by movement. This, at times,appeared to be associated with weakness, and one patient was described as havinghis knees "buckle under him" so that he fell down. There was noapparent association of this with hypoglycemia, and the ingestion of food gaveno relief.
Delayed recovery occurred in a small percentage of patients,whose complaints were primarily concerned with easy fatigue and disorders of thegastrointestinal tract. Anorexia, intolerance for fatty foods, pain in the rightupper quadrant of the abdomen after exercise, anxiety, and tremor were commonsymptoms. They appeared to reflect, in most instances, what was subsequentlytermed the "posthepatitis" syndrome.28 In a survey of 200soldiers who had been sent back to the United States from overseas after severalmonths of hospitalization because of such delayed recovery, Col. Julien E.Benjamin, MC, and Maj. Ralph C. Hoyt, MC,29 found that most of thesoldiers were without objective evidence of hepatic disease and required only anadequate diet, physical reconditioning, and indoctrination to restore them tohealth. In many instances, the cause of disability was a neurosis that had beenlatent but reactivated by the advent of hepatitis. Of 127 of these soldierswhose capacity to excrete intravenously administered Bromsulphalein (sulfobromophthalein)was measured, only 11 (8.7 percent) had abnormal tests and most of theseeventually returned to normal.
Treatment
Treatment was concerned with rest and frequent feedings ofcarbohydrates. 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 FollowingPostvaccinal (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 variousvitamin supplements, methionine and choline, apparently did not expediterecovery. In seriously sick patients, it was believed that the course of theirdisease was not favorably altered by administration of vitamins, transfusions ofblood or plasma, or intravenous infusions of dextrose in saline. However, it ishard to believe that the provision of adequate amounts of fluid and electrolyteswith 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 serumhepatitis was terminated by the omission of human serum from yellow fevervaccine, 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 ofeffective methods of ridding these materials of viable hepatitis viruses madeserum hepatitis a continuing problem.30 Maj. Paul B. Beeson, MC,31in England, predicted early in 1943 the hazards attending the use of suchtransfusions, and on 1 June 1945, in a survey of 1,762 cases of hepatitis undertreatment in general hospitals in the United States, Sartwell32 justifiedthis prophecy. Of these patients, 500 gave a history of receiving transfusionsof blood or its products before the onset of hepatitis, and of the 500, a largeproportion appeared to have been infected by this means. There is every reasonto believe that the early awareness of this hazard in the minds of British andUnited States medical officers in England was important in the education of ourmedical officers in the Zone of Interior in the recognition of this disease.
The pooling of plasma from large numbers of persons augmentedthe risk of infection, and the course of the disease was often much more severein patients debilitated by trauma and exhaustion. Because of these problems,efforts were made in 1944-45 to determine whether the prophylactic effect ofnormal human gamma globulin that had been recently demonstrated in infectioushepatitis might also be true for serum hepatitis. Grossman and his associates33were successful in demonstrating protection when two intramuscular injections of10 ml. each were given 1 month
30(1) Morgan, H. V., and Williamson, D. A. J.: JaundiceFollowing Administration of Human Blood Products. Brit. M.J. 1: 750-753,19 June 1943. (2) Homologous Serum Jaundice. (Memorandum prepared by medicalofficers 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 AfterTransfusion 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 BloodTransfusion. 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 byMeans 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 associates34failed to find any protective effect when a single injection was given.33
The painfully won awareness of other methods of artificialtransmission of hepatitis also emerged during these years of World War II.Inadequately sterilized syringes and needles were indicated in its transmissionin procedures involving withdrawal of blood for laboratory determinations orinjection of medications.36 Clinics for the care of patients with syphilis,diabetes, and arthritis achieved recognition as areas of high risk for theaccidental transmission of hepatitis, and ample proof of the role of the needleand the syringe was afforded by a sharp reduction in the incidence of thedisease following the institution of adequate sterilization of theseinstruments. It can truly be said that the widespread recognition of thesevarious hazards constituted a major advance in medical knowledge, initiatedlargely by military experience but penetrating deeply into civilian practice.
INFECTIOUS HEPATITIS
Historical Background
The importance of infectious hepatitis in medical militaryhistory has long been recognized. Troops concentrated during war appear to havebeen particularly vulnerable, and in this country and abroad the militaryhistory of the last two centuries is replete with accounts of epidemics ofjaundice, many of which doubtless represented this disease. During World War I,British37 and French troops38 in the Mediterranean areaand in the Dardanelles suffered serious outbreaks, and during World War II, itwas 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 thenature of infectious hepatitis generally held in this country was somewhat naiveat the beginning of World War II. The term "catarrhal jaundice" waswidely 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 AgentAgainst Homologous Serum Hepatitis. Am. J.M. Sc. 213: 53-57, January 1947.
35The discrepancy in these results became a matter ofdiscussion intermittently during the ensuing years and, eventually, prompted the studies of Mirick and his coworkers who, in 1962, reportedthat the intramuscular administration of 10 ml. of gamma globulin on twooccasions, 1 month apart, to recipients of transfusions of whole bloodsignificantly reduced the incidence of hepatitis with jaundice, although theattack rate of anicteric hepatitis was similar to that in transfused patientswho 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 InfectionDuring Withdrawal of Blood. Brit. M.J. 1: 625-626, 5 May 1945.
37Martin, C. J.: Concerning the Pathology and Etiology of theInfectious 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 longsince described diffuse hepatocellular necrosis in patients with this disease atnecropsy, the early concept of Virchow42 that catarrhal jaundice resulted fromthe obstruction caused by a plug of mucus in the ampulla of Vater was widelyaccepted, resisting even the reports of later investigators, including Roholmand Iversen,43 who described inflammatory and degenerative changes inthe hepatic parenchymal cells in specimens of the liver obtained by biopsy frompatients with infectious hepatitis. It was actually not until we were well alongin World War II that the true nature of this infection was generally appreciatedby our civilian physicians and medical officers in this country and abroad.
Knowledge of the causative organism of this disease was slowto develop, and recognition of its viral etiology, although suspected somewhatearlier, was largely a product of studies carried on during World War II. Priorinvestigations were concerned with the possible role of Leptospira icterohemorrhagiae,and during World War I, the recovery of certain strains of salmonellae fromthe blood or feces of patients with jaundice, as well as the development ofantibodies in their blood to certain strains of salmonellae, suggested thatthese organisms might be etiologically involved.44 In view ofinformation made available during World War II, it is likely that these latterobservations reflected the simultaneous occurrence of two diseases whose mannerof spread (the intestinal-oral route) was the same.45
It would appear that infectious hepatitis enjoyed littleprominence in the U.S. Army during the decade before World War II. Up until1939, it was reportable not as an entity but under such entries as "spirochetalhemorrhagic jaundice," "other protozoal diseases," or "otherdisease of the gallbladder and biliary passages"; after that, and until1943 when the term "hepatitis" was used, it was variously reported orcoded as "spirochetal jaundice," "cholangitis," or"other disease of the gallbladder and biliary ducts." During theperiod from 1938 to 1941, the incidence ranged from 1.2 to 1.93 per annum per1,000 average strength. This was not unlike the incidence recorded from 1931through 1937 when a few cases of disease specifically involving the gallbladderor ducts were also included with cholangitis. Similar figures characterized thesituation in the British Army in England; however, in contrast to both was theexperience of the British garrison in Malta in which there was a steady increasein 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 desHepatogenen, Insbesondere des Katarrhalischen Icterus. Virchows Arch. f.path. Anat. 32: 117-125, 1865.
43Roholm, K., and Iversen, P.: Changes in Liver in AcuteEpidemic Hepatits (Catarrhal Jaundice) Based on 38 Aspiration Biopsies. Actapath. et microbiol. Scandinav. 16: 427-442, 1939.
44See footnote 4, p. 331.
45Havens, W. P., Jr., and Wenner, H. A.: Infectious HepatitisComplicated 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 13.9per 1,000.46 In retrospect, it should not have been surprising that ourimmunologically naive troops sustained tremendous casualties from this diseaseafter they entered the Mediterranean area that was to serve as the scene of agreat outbreak as well as the seeding place of the disease in troops who wereeventually to go to the European theater and act as a reservoir for its spreadthere. In the vast Pacific area as well, infectious hepatitis was to loom as oneof the most important causes of morbidity (table 66).
[Preliminary data based on tabulations of individual medicalrecords and summaries of statistical health reports]
[date expressed as number of cases per 1,000 average strengthper annum]
| | | | |
|
| 1942-45 | 7.16 | 3.17 | 27.50 | 6.89 |
| 1942 | 15.18 | 12.63 | 26.51 | 23.49 |
| 1943 | 4.20 | .75 | 3.40 | 7.81 |
| 1944 | 3.57 | .80 | 9.21 | 2.58 |
| 1945 | 10.10 | 2.08 | 45.97 | 9.46 |
Although a number of interesting observations were made,particularly from the epidemiologic standpoint in the latter two areas, themajor studies that eventually reached publication were carried on in theMediterranean area, and it is with these activities that this section is largelyconcerned.
Mediterranean Area and Middle East Theater
Relatively small numbers of U.S. troops went into Egypt inthe early autumn before the subsequent major landings in North Africa inNovember 1942. It became known very shortly that French, British Commonwealth,and Axis troops had had a bitter experience with epidemic hepatitis at varioustimes during the period from 1939 to 1942 in the North African desert. TheFrench stationed large bodies of troops in southern Tunisia during the springand 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 Germantroops near Sirte and Benghazi during the fall of 1940, rapidly became a seriousproblem among
46Dixon, H. B. F.: Notes on Infective Hepatitis inMalta, 1938-1942. J. Roy. Army M. Corps 82: 44-48, January 1944.
47Essential Technical Medical Data, North AfricanTheater 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 airforce. Thousands of cases occurred but the Germans appeared more vulnerable thanthe Italians, with a ratio of three to one cases. In May 1943, the closing ofthe Tunisian campaign revealed that large numbers of German and Italianprisoners were jaundiced.48 Australian troops were involved late in1941 while attempting to hold Tobruk, and in the following year they, the NewZealanders, and the British Eighth Army were caught up in a great epidemicduring and after the campaign for El Alamein.
In 1942, the epidemic was well on its way in August andreached a peak in November. In U.S. troops in Egypt during that autumn andwinter, the disease first occurred in the fliers and ground troops of the NinthAir Force, as these men operated between Alexandria, Benghazi, and Tobruk.Despite the fact the U.S. troops in Egypt had an appreciable amount of hepatitisamong the small numbers of men there, the incidence among U.S. forces in NorthAfrica (Algeria and Tunisia) was low during the autumn and winter of 1942-43and remained so into the summer of 1943.
This security was not to last for long, however, and in thelate summer of 1943 began the volcanic experience that was to erupt into themost expensive and devastating problem that we were to encounter in relation toinfectious hepatitis. It came to be, during 1943-45, the most important causeof man-days lost due to illness among U.S. forces in the Mediterranean-NorthAfrican 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 shouldhave occurred coincident with the invasion of Sicily and should involve BritishCommonwealth and American troops in Egypt, in North Africa, and subsequently inSicily and Italy was a hindrance of inestimable magnitude to military activityand strained the medical facilities almost beyond their capabilities. It is noexaggeration to say that the hospitals from Cairo to Palermo were filled withpatients with hepatitis, with beds occupying the corridors and every otheravailable space. The task of caring for all these patients in addition to themounting numbers of battle casualties was indeed a formidable one.
Thus, for the second time within a short period, U.S. forcesand their medical officers and civilian consultants were confronted with a greatepidemic of hepatitis, this time, however, the naturally occurring disease. Ourfirst major experience with hepatitis in the North African theater started whenthe 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 andguarding Axis prisoners. A severe outbreak of diarrhea occurred among them inMay, June, and the first half of July, and hepatitis began to appear at theend 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 Hepatitisin MTOUSA.
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sharply in this division and the disease spread rapidly toothers.49 This was to harass us during the next 18 months in the longand bitter campaign in Italy where the incidence rose astronomically in theautumn and winter of 1943-44 and again, although in lesser magnitude, in 1944-45(table 67).
[Preliminary data based on summaries of statistical healthreports]
[Rate expressed as number of cases per annum per 1,000 averagestrength]
Year | Mediterranean theater | Africa-Middle East theater | |||||
|
|
|
|
|
| ||
1942 | 21,328 | 33 | 1.5 | 5,764 | 81 | 14.1 | |
1943 | 423,114 | 15,865 | 36.8 | 52,349 | 257 | 4.8 | |
1944 | 659,661 | 14,980 | 22.7 | 47,376 | 294 | 6.2 | |
1945 | 331,325 | 7,584 | 22.9 | 40,884 | 351 | 8.6 | |
It was quite natural that those interested in and chargedwith the responsibility of solving the many problems associated with thissituation should be influenced by their recent experiences with the outbreak ofthe artificially transmitted disease, serum hepatitis. However, it wasimpossible to apply some of the information previously gained without confusingthe present circumstances. As might be expected, attempts were made early tothink in terms of the long incubation period of homologous serum hepatitis inconsidering certain epidemiologic problems confronting us in North Africa. Thatthis was untenable was soon appreciated, and our awareness of this was expeditedby consultation with British medical officers who marked the incubation periodof the epidemic disease as between 30 and 40 days. That this or possibly an evenshorter period was indeed true was borne out by experiences encountered later infresh U.S. troops who contracted hepatitis 1 month after arrival in Italy andonly 6 weeks after leaving the Zone of Interior.
Outstanding among the problems associated with this vastepidemic was the lack of knowledge of how the disease was transmitted. In thedesert campaigns in 1940-42, British, German, and Italian forces had beenravaged by infectious hepatitis. In early October 1942, just as the Britishlaunched their counteroffensive at El Alamein, the disease again became aproblem, and as the battle progressed, the acquisition of hepatitis by troopsbecame clearly associated with their exposure to unsanitary conditions that werealmost 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 humanexcrement and incompletely buried corpses of German and Italian troops. Myriadsof flies were present, and Lt. Col. Raymond Kirk,50 of the NewZealand General Hospital, reported the occurrence of 1,060 cases among 7,000troops in the area. He suggested that the disease might well be flyborne on thebasis of the rapid spread of disease among troops living and fighting underthese unsanitary conditions in contrast to the failure to spread in hospitalsand prisoner-of-war camps where hygiene was good and fly abatement wassuccessful. Others hypothesized that the method of spread of disease was by (1)droplet infection among contacts; (2) vectors, such as rodents, insects, orpigs; and (3) man, as a manifestation of bacterial warfare. The possibility thatit was due to or made worse by malnutrition and inadequate diets was alsomentioned.
An early proponent of the importance of feces in the spreadof epidemic hepatitis was Maj. C. E. van Rooyen, RAMC, who was stationed at the15th Scottish General Hospital in Cairo. Major van Rooyen who was interested intesting this hypothesis in volunteers expressed this view on more than oneoccasion to certain members of the Commission on Neurotropic Virus Diseases,Army Epidemiological Board.51 This group had been in Cairo sinceearly 1943, sent by the Preventive Medicine Service of the Office of The SurgeonGeneral to work on certain diseases of military importance in the Middle East,and sandfly fever and poliomyelitis had engaged their efforts during the firstpart 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, certainmembers of the Commission on Neurotropic Virus Diseases directed their attentionto the epidemiologic and etiologic aspects of infectious hepatitis and, amongother 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, certainconcepts were elaborated concerning the length of the incubation period ofepidemic hepatitis, its age distribution, and its relationship to serumhepatitis. The incubation period appeared to range from 18 to 25 days; thepaucity of cases among adult natives suggested it was a disease of childhood,with immunity acquired early; and U.S. soldiers recovered from serum hepatitiswere not immune to epidemic hepatitis when exposed in the Mediterranean theater.The vulnerability of air forces personnel was particularly noticeable, and itwas 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 andhepatitis 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. (laterLt. 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 timebetween 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 UnitedStates and established under the auspices of the Army Epidemiological Board alaboratory for the study of acute hepatitis in the Section of PreventiveMedicine of the Yale University School of Medicine, at New Haven, Conn. Theexperiments conducted there employing human volunteers will be discussed in alater section.
The whole epidemiologic pattern of hepatitis in theMediterranean theater was described by Gauld.52 He depicted thedrawn-out progress of an infectious disease among large numbers of susceptibleyoung adults thrust into an area where it was widely endemic and where theconditions for spread were highly favorable. In general, the highest morbidityoccurred in the immunologically more naive troops from the United States andEurope in contrast to a lower incidence among troops from civilizations of lesswell established sanitary practices, although there were exceptions to this.Gauld was particularly interested in the respiratory route as a possible way ofspread of hepatitis, and the sharp increase in incidence among American troopsin 1943 and 1944, both in August and in November and December, respectively,suggested to him that this might be important, although he took cognizance ofthe evidence that the disease could be spread by filth through the medium ofpersonal contact. Explosive outbreaks were rare, and of the two observed onlyone was well enough documented to warrant mention. This occurred in the 86thMountain Infantry Regiment and appeared to have resulted from the drinking ofcontaminated well water.
In some groups of U.S. troops, the incidence of the diseasewas significantly greater among officers than among enlisted men. The incidencedecreased as the age of the individual soldiers advanced, and a certain degreeof immunity to hepatitis was manifested in the seasoned troops. The attack rateamong seasoned U.S. troops in 1944-45 was 42 per 1,000 compared with amorbidity of 109 per 1,000 among fresh reinforcements. Men who had beenvaccinated against yellow fever in 1941-42 and who had acquired serumhepatitis at that time were not protected from acquiring infectious hepatitislater. Indeed, the attack rate among such men was significantly higher thanamong others.53
European Theater of Operations
Infectious hepatitis was unimportant in the European theateruntil the winter and spring of 1944-45. True, there had been a brief flurry of
52Gauld, R. L.: Epidemiological Field Studies ofInfectiousHepatitis in the Mediterranean Theater of Operations. Am. J. Hyg. 43: 248-313,May 1946.
53Gauld, R. L.: Field Studies Relating to Immunity inInfectious 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 1943-44among 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 troopsbecame a part, was not involved in any widespread epidemic until the winter andspring of 1945 when the incidence rose to 12 per 1,000 per annum.54
During the winter of 1944-45, the incidence of the diseasein the European theater rose sharply to 17 per 1,000 per annum, potentiatedlargely by the entry of troops who had served in Italy and Africa. The SeventhU.S. Army invaded southern France, on 15 August 1944, from Italy and wasinitially made up of three infantry divisions from the Fifth U.S. Army. It wasapparently thoroughly seeded with infectious hepatitis, and as it advancednorthward, it contacted troops from the Normandy beachhead and received directlyinto its ranks units that had just come from the United States. The story of therole of the Seventh U.S. Army in the introduction and spread of hepatitis amongits 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 theirimpression that localized outbreaks again were rare and that the disease had awidespread distribution, with its manner of spread by some form ofperson-to-person contact.
Pacific Area
In the vast Pacific area, infectious hepatitis also assumed atremendous importance, and actually its morbidity in the Southwest Pacificincreased from 1943 to 1945 when it and the number of troops involved exceededthat of any other theater; 39,277 cases were treated in 1945, causing anincalculable loss of time. Likewise in the Western Pacific Area, hepatitisproved to be a leading cause of disability.
The epidemiology of the disease, as it made its appearance invarious far-flung islands, presented different problems from those involved inthe Mediterranean and European theaters. Occasional outbreaks were investigated,including one on Biak Island by Maj. James L. Borland, MC,57 and another onHollandia by Maj. Ray E. Trussell, MC,58 in October 1944. The formerwas concerned about the possibility of spread by a vector such as a night-bitingPhlebotomus or common fly, while the latter attributed the spread ofdisease 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 diseasesubsequently when these troops were in combat in Europe was questioned later byPaul and Gardner (see footnote 21, p. 335).
55Gauld, R. L.: Epidemiology of Hepatitis-MilitaryExperience. [Unpublished manuscript.]
56Gowen, G. H.: Observations on Infectious Hepatitisin Seventh Army, 1944-45. Bull. U.S. Army M. Dept. 6: 456-461, October 1946.
57Essential Technical Medical Data, U.S. Army Forces in theFar East (Southwest Pacific Area), for December 1944, dated 15 Feb. 1945,Appendix H thereto.
58Trussell, R. E.: Epidemiologic Aspects of an Outbreak ofInfectious 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 byCol. Henry M. Thomas, Jr., MC.59
China-Burma-India and Latin American Theaters
The incidence of infectious hepatitis in theChina-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 ofthese areas and yet there was no correlation between them and the attack ratesfor infectious hepatitis.
Clinical Pattern
Clinical descriptions of the course of the disease in two largegroups of U.S. troops were made by Havens60 in 1944 from the 38thGeneral Hospital in Egypt and by Barker, Capps, and Allen,61in1945, from the 12th General Hospital in Naples. The former outlined the initialexperience of U.S. troops in the Middle East with infectious hepatitis in theautumn and winter of 1942-43 and again in 1943-44.
The latter in association with the 15th Medical GeneralLaboratory set up a center for the care and study of patients with infectioushepatitis in the Mediterranean theater. This came about as the result of asuggestion made, in December 1943, to the Surgeon, Peninsular Base Section, byCol. Perrin H. Long, MC, Consultant in Medicine, Mediterranean theater. ColonelLong had suggested that, when the 12th General Hospital arrived from NorthAfrica, Lt. Col. (later Col.) Marion H. Barker, MC, be assigned the problem offinding out what he could about infectious hepatitis. The suggestion was carriedout 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 GeneralLaboratory 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 theirtechnical advice and skill toward the solution of the numerous problems. Anumber of clinical studies were described, and the correlation of histologicalterations of the liver obtained by biopsy with clinical status
59Technical Memorandum No. 16, Office of the ChiefSurgeon, U.S. Army Forces in the Far East, 1 Oct. 1944.
60Havens, W. P., Jr.: Infectious Hepatitis inMiddle 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.: AcuteInfectious Hepatitis in the Mediterranean Theater, Including Acute HepatitisWithout 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 thedevelopment of chronic disease, and the need for adequate rest was emphasized.62
Nonicteric hepatitis
Although hepatitis without jaundice was a recognized entityamong our Allied military medical colleagues and despite the fact that attentionhad been called to its existence in the clinical descriptions of serum hepatitisfollowing the reception of yellow fever vaccine by our troops, there were manyof our medical officers who at first were reluctant to accept its recognition asa part of the broad clinical spectrum of infectious hepatitis. However, it wasnot long before educational progress was made along this line, and its existencewas generally admitted. Nonicteric hepatitis was regarded as a milder form ofthe disease, with a shorter duration. How often it occurred could not bedetermined owing to the lack of specific serologic diagnostic tests; however,that it occurred far more frequently than suspected is doubtless true. Gowen63suggested that its ratio to hepatitis with jaundice was as much as 8:1 inTunisia, on the basis of epidemiologic and clinical evidence. The occurrence ofmalaise, anorexia, easy fatigue, nausea, and vomiting, with evidence of hepaticdysfunction, in soldiers who, although not jaundiced, were stationed in epidemicareas was enough to suggest the diagnosis of nonicteric hepatitis. In many ofthese patients, the liver was palpable and tender. Although recovery was usuallyprompt, relapse with jaundice on occasion occurred.
Icteric hepatitis
When jaundice was present, the disease could usually bedivided into two phases-preicteric and icteric. Among the troops studied inEgypt and Italy, approximately 83 percent had a well-defined preicteric phaseand about 17 percent presented themselves with jaundice as the first evidence ofthe 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 ofsigns and symptoms from 4 to 5 days after onset followed by their recurrence andeventually jaundice. All grades of severity of constitutional reaction occurred;however, it was not possible to predict the degree of severity of the totalcourse of disease from the character of its beginning. Anorexia, beginninginsidiously, was the most common initial symptom and, indeed, often directed thegroup medical officer's attention to the diagnosis. That this was a moresensitive indicator of hepatitis in the field, where rations were less thanappealing to a capricious appetite, is understandable. Easy
62(1) Circular Letter No. 19, Office of theSurgeon,Headquarters, North African Theater of Operations, U.S. Army, 28 Mar. 1944. (2)Circular Letter No. 37, Office of the Surgeon, Headquarters, North AfricanTheater 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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fatigability and disinterest in occupation, with nausea aftermeals, soon occurred, and toward the end of the preicteric phase, vomiting wasnot uncommon. Actual abdominal pain was unusual, although on occasion it didoccur in the right upper or lower quadrant, and acute cholecystitis or acuteappendicitis was at times suspected and unwarranted operations performed. Undersuch circumstances, the gallbladder or appendix was normal, and enlargedmesenteric lymph nodes were found. Discomfort in the upper quadrant of theabdomen occurred early in a goodly percentage of patients and was described asdistress or fullness in the epigastrium and right upper quadrant, made worse byeating and activity. Riding in a jeep was particularly aggravating and notinfrequently was the event that precipitated sufficient discomfort to cause asoldier to go to sick call. Constipation, flatulence, and diarrhea were presentin a small percentage of patients, as were symptoms of infection of the upperrespiratory tract.
Among the patients having a definite preicteric phase, theonset was abrupt in 53 percent of those described by Havens64 and in 80 percent ofthose described by Barker and his associates.65 It was ushered in with fever,chilliness (rarely frank chills), malaise, headache, and generalized muscularaches. Prostration was not uncommon, and aching eyes with pain of the eyeballswere associated complaints. Fever was usually remittent, with a daily maximumtemperature 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 afrank chill daily, followed by fever with a temperature of 104? F., for thefirst few days. Symptoms directing attention to the gastrointestinal tract,including anorexia, nausea, vomiting, and upper abdominal distress, developed inthese patients as they did in those without fever. Within 48 hours after thetemperature reached normal, clinical jaundice was evident.
Palpation of the abdomen often elicited tendernessparticularly in the right upper quadrant and epigastrium where pressure evoked asense of nausea. The liver and spleen were uncommonly palpable in this earlyphase of the disease; however, percussion with the first over the right lowerribs frequently caused discomfort or pain in the area of the liver. Barker andhis associates called attention to the rather constant early appearance ofcervical adenopathy occurring as "a soft, slightly tender, lima bean sizedgland * * * found along the posterior border of thesternocleidomastoid muscle low in the neck." It was often easy todemonstrate this visually by having the patient bend his neck away from theinvolved side. Also of particular importance was the occurrence of bilirubinuriathat usually appeared later in the preicteric phase but from 48 to 72 hoursbefore clinical jaundice. More than one soldier made his own diagnosis ofinfectious hepatitis by noting a change in the color of his urine.
Icteric phase
The duration of the icteric phase ranged from as short a timeas 4 days to as long a period as 4 months, with an average of 2 to 4 weeks, indifferent groups of patients. Fever was uncommon; when present, it lasted ashort time. Jaundice reached its maximum within 3 to 10 days in most patients.As it increased, the malaise and gastrointestinal symptoms worsened, and duringthis period, nausea and vomiting were at times severe enough to require theadministration of fluid parenterally. It was not unusual for patients to havereasonable appetites in the morning but to complain of a sense of fullness afterlunch that progressed to the point of such discomfort after the evening mealthat vomiting, either spontaneous or self-induced, occurred. In the mildly sickpatients, these symptoms were slight and of short duration, but in those whowere seriously sick, they persisted as long as 3 to 4 weeks. In such seriouslysick patients, lassitude, emotional instability, and depression occurred.Increasing jaundice was accompanied by diminishing amounts of pigment in thefeces, and among the sicker patients, acholic stools were found. Disorder ofbowel 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 ofpatients by the time jaundice was evident, and although their presence did notalways 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 smallpercentage. Bradycardia was unusual and occurred during the first 2 weeks oficterus.
Jaundice usually reached its maximum in 10 days, and at thispoint, a remarkable clinical change occurred, with sharp regression of symptomsand return of sense of well-being. Appetite improved and was frequentlyvoracious. Hepatic tenderness subsided, and the liver diminished in size so thatit was usually no longer palpable 2 weeks after the appearance of jaundice. Lossof weight in amounts of 5 to 10 or even 20 pounds in the more seriously sickpatients was usual, but strength was regained fairly promptly in the mildly ormoderately sick patients. Even in this group, however, activity was oftenfollowed by upper abdominal fullness and discomfort for several days after thedisappearance of all other symptoms.
The duration of hospitalization became a matter ofconsiderable importance and discussion. The first documented experience of U.S.soldiers with infectious hepatitis in World War II was in the Middle East in1942-43. In this group, described by Havens,66 the duration ofhospitalization ranged from 7 to 87 days, with an average of 29.8 days. Somewhatlater, in 1944, Barker and his associates67 described the course of thedisease in another large group of soldiers in Italy and pointed out that theaverage duration of hospitalization ranged between 6 and 8 weeks. It is likelythat the exhaustion and physical disability caused by battle conditions that thelatter group had sustained before acquiring hepatitis prolonged the course oftheir 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 exercisebefore returning to duty. It was emphasized that patients who had apparentlyclinically recovered and who were without jaundice while at rest in bed notinfrequently developed signs and symptoms of the disease, with or withoutjaundice, following increased activity. Because of this, an exercise tolerancetest was devised to select those patients who required further hospitalization.Using these criteria, about 10 percent of patients with icteric hepatitis hadnot made complete recovery after 3 months of hospitalization.
Infectious hepatitis, in spite of its high morbidity andfrequently 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 andincluded pneumonia, myelitis, and aseptic meningitis. Seborrheic dermatitis andlabial herpes occurred in a small percentage of patients.
Relapse
Although the vast majority of patients made an uneventfulrecovery, there were those who suffered an interruption of convalescence, with areturn 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 1? to 10 percent, and the factorsthat caused it were not completely defined. Indulgence in alcoholic beveragesand excessive activity before recovery were incriminated in some cases; however,a certain number of patients relapsed in spite of what appeared to be idealtreatment. Patients who did sustain relapse made eventual complete recovery inalmost all cases, but Barker and his associates68 felt strongly thatthis could only be defined by the capacity of the patient to perform gradedexercise tolerance tests without having a return of symptoms, signs, orlaboratory evidence of hepatitis.
Chronic Hepatitis
A small percentage of patients with acute hepatitis hadevidence of hepatic disease long after the expected time of recovery. Barker andhis associates69 found 18 percent in one group of 431 soldiers in thiscategory, 4 months after the onset of disease, and emphasized the prolongedtreatment required to effect recovery. These patients had a characteristichistory of hepatitis, with or without jaundice, followed by partial recovery andsubsequent return of weakness, anorexia, and epigastric discomfort. The liverwas often enlarged and tender, and while jaundice was not always present, theresults of the Bromsulphalein excretion test and thymol turbidity test wereabnormal. Unfortunately, adequate followup of these patients was not possible inall instances; however, it was the impression that recovery was complete in mostcases. That evidence of continuing hepatic disease could exist for many months,culminating in complete recovery, was well established by these observations. Itwas postulated that the development of cirrhosis was rare, although serialbiopsies of the livers of civilian patients in various stages of hepatitis hadpreviously suggested that it did occur.70
Two other groups of patients were distinguished from thosejust described with persistent activity of the disease: (1) those withsubjective complaints but without any objective evidence of hepatic disease, and(2) those with vague mild complaints and slight stable abnormality of serumbilirubin and Bromsulphalein excretion, with or without enlargement of theliver. The former group fell in the same category as those patients describedpreviously in the section on serum hepatitis as having "posthepatitissyndrome."71 The latter when tested by exercise tolerance manifested noclinical worsening and were regarded as having an inactive disease with mildresidual 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 GeneralHospital and the 15th Medical General Laboratory, in Naples, biopsies of theliver were performed on patients in various phases of nonfatal infectioushepatitis.72 During the acute icteric period, the following were found:Periportal cellular infiltration, predominantly mononuclear; swelling of thereticuloendothelial cells and intralobular infiltration; focal necrosis withacidophilic degeneration of hepatic cells; lobular disarray; numerous mitoticfigures and multinucleate cells; and biliary thrombi in dilated canaliculi. Thepattern of the lobular reticular framework was usually intact, although onoccasion it was distorted with areas of condensation apparent. Similar changeswere found in the preicteric phase or in nonicteric hepatitis except thatbiliary stasis was rarely seen. Of particular interest was the demonstration ofthe wide variation in time of recovery, as manifested by the histologicappearance of the liver. Although complete regeneration was found after 1 or 2months in some patients, in others evidence of activity persisted for severalmonths. No evidence of cirrhosis was found in 89 nonfatal cases.
The possibility that the severe progressive chronic hepaticdisease described earlier among civilians73 might eventuate in some soldiersprompted biopsy of the livers of men whose recovery had been long delayed.74Of 40 such patients examined from 100 to 500 days after onset, the specimens ofliver studied were normal in 15; doubtful in 10; and in 15 therewere periportal and lobular inflammation and focal hyaline necrosis.Unfortunately, these patients were lost to followup examinations so that nothingcould be said about their eventual outcome. Thus, it was suggested that,although the incidence of continuing disease was indeed low, the possibility ofits rare occurrence demanded recognition. Opinion in this regard was notunanimous, and Luck?75 was impressed with the concept that nonfatal viralhepatitis was followed by complete recovery and restitution of normal hepaticstructure. At all events, the preponderance of evidence indicated that theoccurrence of cirrhosis in soldiers following nonfatal epidemic hepatitis wasrare.76
In fatal cases, the pathologic changes were described in twogroups by Luck?77 and by Luck? and Mallory:78 (1) the fulminant form inwhich death occurred within 10 days after onset, and (2) the subacute form inwhich 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) someinvestigators 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.
78Luck?, B., and Mallory, T.: Fulminant Form of EpidemicHepatitis. Am. J. Path. 22: 867-945, September 1946.
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than normal, soft and smooth, and massive central necrosiscompletely destroyed the parenchyma in the fulminant form. There was no evidenceof regenerative hyperplasia, and mononuclear cellular infiltration was found atthe periphery of the lobule. In the subacute form, the liver was also oftenreduced in size but not infrequently the surface was irregular, with reddepressed areas surrounded by yellow-green nodules. Parenchymal destruction wasirregular and associated with areas of regeneration. Destruction of lobulararchitecture 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 andsplenomegaly were frequently present. Ascites was common, and hemorrhage, edema,and inflammation of the gastrointestinal tract were often found. The kidneyswere enlarged with fat storage in the fulminant cases, and bile nephrosis inthose of longer duration. Alterations in the central nervous system includedswelling of ganglion cells, distortion of nuclei, meningeal lymphocyticinfiltration, and perivascular lymphocytic cuffing in the basal ganglions.
The pathologic changes which have been briefly described hereare well illustrated by the authors; selected plates, from the publishedliterature, are reproduced here as plates I through VI, through the courtesy ofthe American Journal of Pathology.
Clinical Laboratory Studies
The laboratory tests that could be performed were often quitelimited by the exigencies of the situation; however, in some areas, aconsiderable amount of data was accumulated. The number of erythrocytes and theamount of hemoglobin were normal except in certain patients who had prolongeddebilitating disease. Of particular interest, however, was the pattern ofleukocytic response that occurred, characterized by the appearance of leukopeniawith both neutropenia and lymphopenia early in the acute febrile phase of thedisease. Relative lymphocytosis subsequently occurred, and numerous atypicallymphocytes identical with those commonly associated with infectiousmononucleosis made their appearance. In general, the hematologic pattern hadreturned to normal by the end of the second week of the disease.79Determinations of the coagulation and bleeding time and the fragility oferythrocytes were found to be normal in small groups of patients.80Prolongation of the prothrombin time in severe degree was regarded as an ominoussign, particularly if there was no favorable response to the parenteraladministration of vitamin K. The
79(1) Havens, W. P., Jr., and Marck, R. E.: LeukocyticResponse 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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sedimentation rate of erythrocytes was usually normal early in the acutephase, increasing after the appearance of jaundice.81
Numerous attempts were made to develop specific serologic tests, but none ofthese was successful. Saline extracts of normal liver and liver from fatal casesof hepatitis were used as antigens in complement fixation82 and precipitintests.83 Although positive tests were found in as many as one-thirdof the patients, they were of no practical value. A heterophile antibodyabsorbable on boiled guinea pig kidney and human liver was found in the acutephase serums of some patients,84 and falsely positive Wassermann andKahn85 reactions were also described in as many as 20 percent of some groups ofpatients.86
81Unpublished personal observations.-W. P. H., Jr.
82Eaton, M. D., Murphy, W. D., and Hanford, V. L.: Heterogenetic Antibodiesin 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 positiveWassermann and Kahn reactions were unsuccessful, with rare exceptions. SeeHavens, W. P., Jr., Gambescia, J. M., and Knowlton, M.: Results of Heterophile Antibody Agglutination and Kahn Tests in PatientsWith Viral Hepatitis. Proc. Soc. Exper. Biol. & Med. 67: 437-440, April 1948.
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The desirability of early diagnosis, before jaundiceappeared, or in patients with nonicteric hepatitis, as well as the need todetermine when recovery had occurred, focused attention on certain laboratorydeterminations. Doubtless, the most commonly used test in the field was thedetermination of bilirubin in the urine. Bilirubinuria appeared in the latterpart of the preicteric phase and, as mentioned before, often served as adiagnostic aid to the soldier himself. The icterus index was widely used as ameasure of the amount of jaundice where facilities were not available fordetermining the serum bilirubin. After jaundice had disappeared, theBromsulphalein excretion test was used, when possible, to determine if activityof hepatitis persisted. In small groups of volunteers87 under controlledconditions, it was shown that the excretion of intravenously administeredBromsulphalein was impaired on the third day of the disease, with bilirubinuriaappearing the following day. The cephalin-cholesterol flocculation test waspositive by the fifth day, when the 1-minute direct serum bilirubin wasincreased above normal. By the seventh day, the total serum bilirubin and theurinary urobilinogen were above normal. The thymol turbidity and colloidal goldtests were positive in the early part of the icteric phase. Bilirubinuriadisappeared before clinical jaundice, and the serum bilirubin usually was normalin the fifth or sixth week of the disease. Bromsulphalein excretion testsperformed shortly thereafter were usually normal. The cephalin-cholesterolflocculation and thymol turbidity tests became negative in 6 to 10 weeks and in8 to 12 weeks, respectively. The persistence of a strongly positive thymolturbidity test was regarded as indicating persisting activity of the disease.88
Among the interesting phenomena encountered were tiny motilespirochetal-like filaments visualized by dark-field microscopy in the serums ofpatients with hepatitis.89 More than 1 hour was spent convincing their
87See footnote 81, p. 361.
88Serums obtained from volunteers with experimentallyinduced infectious hepatitis were subsequently subjected to determinationsof serum proteins. The characteristic pattern of change was a sharp, earlydecline in serum albumin with a rise in globulins, largely gamma globulin. Thealbumin returned to normal levels by the fifth week, but the globulins remainedsomewhat elevated often for a few weeks thereafter. Persistence of largeamounts of serum gamma globulin was associated with activity of the disease. SeeHavens, W. P., Jr., and Williams, T. L.: Changes in Serum Proteins inPatients With Experimentally Induced Infectious Hepatitis. J. Clin. Invest. 27:340-345, May 1948.
89Kuzell, W. C.: "Artifact Spirochetes" inInfectious Hepatitis. Bull. U.S. Army M. Dept. 89: 112-114, June 1945.
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observers that they were artifacts and not the causativeorganisms of hepatitis.
Roentgenographic evidence of gastroduodenitis andgastroscopic evidence of acute gastritis were demonstrated in volunteers90 withexperimentally induced hepatitis, corroborating the clinical and pathologic datathat emphasized the involvement of the gastrointestinal tract in this disease.
Differential Diagnosis
The elevated temperatures and often severe constitutionalsymptoms in the preicteric phase made diagnosis difficult, particularly in areassuch as Sicily, North Africa, the Middle and Far East, and the Pacific where anumber of other acute infections, largely unfamiliar to our medical officers,were present. Thus, it should not be surprising that this disease was animportant cause of "fever of undetermined origin" in its preictericphase. Our British medical colleagues pointed out that in this phase pressureover the epigastrium frequently caused nausea, and this proved to be a valuablesign. 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 someassistance, but the appearance of bilirubinuria was doubtless the most importantevidence pointing to the diagnosis. During the febrile preicteric period, thediseases 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 ofjaundice, the diagnostic dilemma was less, although on occasion poisoning due tocarbon 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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chloride, Weil's disease, acute cholangitis, or even yellowfever had to be considered. Jaundice due to excessive hemolysis or extrahepaticobstruction rarely occurred and did not constitute a problem in diagnosis.Epidemiologic evidence, the subsequent course of the disease, the number andtype of leukocytes in the blood, the results of tests of hepatic function, andthe demonstration of specific causative agents or their antibodies furnished thecorrect diagnosis in most instances. Confusion with infectious mononucleosiswith jaundice was resolved by the heterophile antibody test, which is negativein infectious hepatitis.
Treatment
Treatment was supportive and symptomatic. The administrationof methionine, choline, crude liver extract, normal human gamma globulin,92and 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 thatthere was not complete agreement on their exact specifications with some of ourAllied medical colleagues or even among our own medical officers. Actually, mostof the precepts of therapy that emerged by the end of the war were derived fromthe principles set down by Barker and his associates93 whose experiencewas largely with troops who had been exhausted by physical hardship beforeacquiring hepatitis. In addition, these patients were frequently hospitalizedunder conditions in which it was not easy to furnish a diet that would bewelcome to men whose appetites at best were capricious. It is doubtless truethat their therapeutic regimen could have been modified with impunity for menwho started their disease in relatively good physical condition and who werehospitalized under circumstances favorable for obtaining attractive food. Thatthis was the case was substantiated by the experience in Egypt94 atthe 38th General Hospital where the therapeutic regimen was more relaxed withoutprolonging 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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ent medical officers, most of whom actually had littlecomprehension of the disease or of its therapeutic requirements. It was indeedthe frequency of relapse in patients sent back to duty too soon that promptedthe emphasis on prolonged rest in bed (3-5 weeks), followed by a gradualexercise tolerance test (7-10 days) when jaundice disappeared and theexcretion of intravenously injected Bromsulphalein measured 10 percent or less.Only after a convalescent was able to pass such a test was he regarded as fitfor duty.95
The dietary regimen recommended by Barker and his colleagues96was high in carbohydrates (350 gm.) and protein (250 gm.) and low in fat (40gm.). The reason for reduction in fat was far from clear; however, restrictionof this foodstuff had long been practiced in the therapy of catarrhal jaundiceand doubtless this influenced the recommendation. Actually, it was shown inother patients97 that the ingestion of a diet rich in protein and carbohydratewithout restriction of fats was well tolerated and associated with equallyspeedy recovery.98
95Over the years after World War II, the duration ofhospitalization for hepatitis increased until it became as long as 89days in certain groups during the Korean War. This was doubtless a naturaloutcome of the failure to discern the reason for the occurrence of relapseor prolonged disease and the belief that more rest would prevent them. Thepoint was finally reached when this concept was questioned, and it was subsequentlyshown by Chalmers and his associates that men could be sent back to duty quitesafely in shorter periods. In addition, they demonstrated that allowing men outof bed around the room or ward except for an hour's rest after each meal didnot prolong the course of the disease but actually hastened an earlierreturn 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. Advantagesof 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 particularin providing such a diet were considerable, and it was often not easy to make asolution of powdered milk in water palatable as a source of protein. It was notunusual that dietary excesses should have evolved, and, on occasion, regimensincluding as much as 350 gm. of protein were advised. This in combination withlarge amounts of carbohydrate and little fat was far from appealing to jadedappetites. However, as with the duration of rest in bed, a more realisticdietary approach eventually emerged, recommending well-balanced, high-caloricmeals similar to those described in the early experience with hepatitis in Egypt(see footnote 60, p. 353). Of importance in this evolution was thedemonstration of the advantage of a diet of 2,000 to 3,000 calories, made up of19 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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Early in the course of the disease when anorexia, nausea, orvomiting were problems, the intravenous administration of 2,000 to 3,000 ml. of5 percent dextrose in isotonic solution of sodium chloride was of value. Whenoral feedings could be taken, they were better tolerated in the early phase ofthe disease in small, frequently administered amounts.
As recovery progressed, the caloric intake was maintained at3,000-4,000 calories per day. There was no reason to believe thatsupplemental vitamins were of any value; however, the administration of vitaminK parenterally (Hykinone, 2.4 mg. (1/28 gr.)) daily for several days frequentlybrought about an increase of plasma prothrombin when it was low. The danger ofusing opiates and barbiturates was stressed. Alcoholic beverages wereinterdicted throughout the course of the disease and for 6 months afterrecovery, although there was no evidence that modest amounts were harmful afterrecovery and it is likely that the injurious effects of small amounts werestressed without adequate evidence.
Prophylaxis and Control
The association of epidemics with poor sanitation and thesubsequent incrimination of the intestinal-oral route as a way of spread of thedisease directed measures toward (1) improvement of the general sanitation ofcamps, (2) fly abatement, (3) sterilization of food receptacles, (4) eliminationof possibly infected foodhandlers, and (5) prevention of fecal contamination offood, water, and milk. Under conditions of battle, these measures were obviouslyimpossible to carry out, and reference has been made to the frightful sanitarysituation prevailing in certain sectors of the Alamein Line, and early site ofthe great epidemic in North Africa. An important problem appeared, althoughlate, with the realization that the Lyster bag technique of treatment of waterthat was ordinarily practical was not effective in destroying the hepatitisvirus.90
90(1) Neefe, J. R., Stokes, J., Jr.,Baty, J. B., andReinhold, 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 ofwater before treating it with chlorine made possible the inactivation ofhepatitis virus. See Neefe, J. R., Baty, J. B., Reinhold, J. G., andStokes, J., Jr.: Inactivation of the Virus of Infectious Hepatitis in DrinkingWater. Am. J. Pub. Health 37: 365-372, April 1947.
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Specifically, some success was achieved in the prevention ofthe disease in certain groups of heavily exposed troops in the campaign in Italyby the intramuscular administration of normal human gamma globulin.100
EXPERIMENTAL STUDIES WITH HEPATITIS VIRUSES
The enormity of the problem created by the outbreaks of serumhepatitis and infectious hepatitis in both Allied and Axis troops, in additionto the failure to propagate the causative agents by the various laboratorytechniques known at that time, urged the use of human volunteers as the means ofacquiring necessary information. Experimental studies were carried on inGermany, in the Middle East, in England, and in the United States, and althoughthe natural limitations of this method of investigation were great, an imposingamount of knowledge was accumulated in the period of World War II. In reviewingthese data, it is evident that the positive results were of greater value thanthe negative ones, although it is also apparent that there was sufficientconsistency among the negative results reported by various investigators to givethem considerable worth. The prolonged course of disease in viral hepatitis madeit an undesirable candidate for investigation in volunteers; however, itsextremely low mortality made defensible the acceptance of the challenge createdby the exigencies of the times. Much is owed to the relatively small number ofvolunteers who contributed so generously of themselves, and their roles cannever be forgotten. To those who shared these experiences, they were frequentlyharrowing, 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 werewidely separated-in Philadelphia, Pa., New Haven, Conn., and Ann Arbor, Mich.-and to facilitate a ready exchange of ideas without loss of individualindependence, the Army Epidemiological Board established the "HepatitisStudy Group" in July 1944. The respective field and laboratory work wascarried 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 Schoolof Medicine, University of Pennsylvania; (2) Dr. John R. Paul and Maj. W. PaulHavens, Jr., MC, of the Section of Preventive Medicine of the Yale UniversitySchool of Medicine, New Haven; and (3) Dr. Thomas Francis, Jr., at the School ofPublic Health, University of Michigan, Ann Arbor.
The Commission on Measles and Mumps worked with a number ofdifferent units of volunteers, including inmates of the New Jersey State Prisonat Trenton, N.J., and groups of conscientious objectors from a specialorganization for this purpose known as the Civilian Public Service Unit No. 140of Philadelphia, Pa. The Commission on Neurotropic Virus Diseases foundvolunteers in various groups of conscientious objectors working in Stateinstitutions in the vicinity of New Haven, including Civilian Public ServiceUnit No. 81 at the Connecticut State Hospital, Middletown, Conn., CivilianPublic Service Unit No. 68 at the Norwich State Hospital at Norwich, Conn., andsubsequently a special Branch of Civilian Public Service Unit No. 140 of NewHaven, Conn., housed in a fraternity house at Yale University. Volunteers werealso found among prisoners at the Federal Correctional Institution in Danbury,Conn., and at the State Prison in Wethersfield, Conn. The Commission onInfluenza found volunteers in the State Prison of Southern Michigan, Jackson,Mich.
The results of the various studies carried on by these groupsas well as by certain other investigators abroad are described in the sectionson "Serum Hepatitis" and "Infectious Hepatitis," whichfollow.
Serum Hepatitis
The pioneer experiments of Oliphant and his colleagues101were reported in 1943 and described the transmission of hepatitis tovolunteers by the parenteral inoculation of serum obtained from patients in theacute phase of homologous serum hepatitis, resulting from the administration ofknown icterogenic yellow fever vaccine. Cameron,102 working in theMiddle 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.
374
to volunteers by inoculating blood obtained from patientsacutely sick with the disease. These results were corroborated and extended byothers.103
In contrast, attempts to demonstrate virus in the feces ofpatients in the acute phase of the disease by oral or parenteral inoculationwere unsuccessful,104 as were, with two possible exceptions105attempts to transmit the disease experimentally by feeding serum ornasopharyngeal washings. Limited attempts to detect virus in nasopharyngealwashings and urine were unsuccessful, with the possible exception of a singlereport by Findlay and Martin,106 who described the occurrence ofjaundice in a volunteer 50 days after intranasal inoculation of nasopharyngealwashings from a patient in the acute phase of hepatitis caused by theadministration of yellow fever vaccine. Unfortunately, the number of experimentsperformed were insufficient to offer conclusive evidence whether serum hepatitisvirus was in the urine, the nasopharyngeal washings, or the feces, or whetherthe disease could be produced by the ingestion of infectious material. In regardto the latter, however, Havens and his colleagues107 and Neefe and hisassociates108 were unable to transmit serum hepatitis to volunteers byfeeding infectious serum that produced the disease regularly when inoculatedparenterally.
The accidental contamination of pools of serum or plasma bythe blood of apparently healthy persons carrying virus suggested that a carrierstate might exist more often than was hitherto suspected. The importance of thiswas augmented by the tremendous use of human blood and plasma and stimulated theinvestigation of the period of infectivity of patients with this disease. Only alimited number of experiments were done; however, virus was found in the bloodof volunteers during the
103(1) MacCallum, F. O., and Bauer, D. J.: Homologous SerumJaundice: Transmission Experiments With Human Volunteers. Lancet 1: 622-627,13 May 1944. (2) Neefe, J. R., Miller, T. G., and Chornock, F. W.: HomologousSerum 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 HumanVolunteers. J. Clin. Invest. 23: 836-855, September 1944. (4) MacCallum, F. O.: Transmission of Arsenotherapy Jaundiceby Blood; Failure With Faeces and Nasopharyngeal Washings. Lancet 1: 342, 17Mar. 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., andStokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis;Studies in Volunteers Bearing on Immunological and Other Characteristics ofthe 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 HomologousSerum Hepatitis and Infectious (Epidemic) Hepatitis. Am. J.M. Sc. 210: 29-32, July 1945. (2) See footnote103 (4). (3) Havens, W.P., Jr.: The Period of Infectivity of Patients With Homologous Serum Jaundiceand Routes of Infection in This Disease. J. Exper. Med. 83: 441-447, June1946.
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., andPaul, J. R.: Experimental Production of Hepatitis by Feeding IcterogenicMaterials. 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; ExperimentalStudy of Immunity and Cross Immunity in Volunteers; Preliminary Report. Am.J.M. Sc. 210: 561-575, November 1945. (2) See footnote 103 (7).
375
incubation period as well as in the acute phase of thedisease by Neefe and his coworkers109 (87 days before the onset ofhepatitis), by Paul and his associates110 (60 days before the appearanceof 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,112similar attempts to recover virus were unsuccessful. It was not determinedwhether a carrier state might exist after recovery or whether patients withrelapse or chronic hepatitis were infectious.
Evidence suggesting that serum hepatitis virus evokedhomologous immunity was furnished by Neefe and his group,113 whoreinoculated nine volunteers convalescent 6 to 9 months from experimentallyinduced homologous serum hepatitis. None of the convalescents became sick, whileeight out of nine controls contracted serum hepatitis, with incubation periodsranging from 60 to 110 days. However, there was no apparent cross-immunitybetween homologous serum hepatitis and infectious hepatitis as far as could bedetermined from the studies of Havens114 and of Neefe and hiscolleagues.115 Volunteers convalescent from the former diseasecontracted the latter when reinoculated with a strain of infectious hepatitisvirus. The report of Oliphant,116 who described complete protection in 10volunteers convalescent from serum hepatitis when they were reinoculated with astrain of virus presumed to be infectious hepatitis, requires consideration inthis regard. Although the strain of virus he used to challenge his convalescentswas obtained in Italy where infectious hepatitis was epidemic, it is importantto note that it produced hepatitis in the controls after a long incubationperiod of 85 to 106 days, suggestive of the behavior usually associated withserum hepatitis virus. The geographic coexistence of serum hepatitis andinfectious hepatitis viruses that produce disease with long and short incubationperiods, respectively, was evident from the reports of Paul and Havens117and of Cameron118 in the Middle East, and it would appear that Oliphant'sexperience reflected a similar situation.
As a result of such studies in volunteers, it was shown thatthe serum hepatitis virus was (1) filterable through Berkefeld N and Seitz E Kfilters, (2) resistant to temperatures of 56? to 60? C. for at least 30minutes, and (3) transmissible to man in serial passage by parenteralinoculation of infectious material. The studies also showed that the virussurvived 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 BetweenInfectious 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: ExperimentalStudy of Immunity. Pub. Health Rep. 59: 1614-1616, 15 Dec. 1944.
117See footnote 103 (6), p. 374.
118See footnote 102, p. 373.
376
temperature of 4? C. for a long period;119 at atemperature of -10? to -20? C. for 4? years, but apparently became inactiveafter 5 years at this temperature;120 in a desiccated state at roomtemperature for at least a year;121 and in serum containing Merthiolate inconcentration 1 : 2,000,122 in a mixture of equal parts of phenol and etherin 0.5 percent concentration,123 and in an 0.2-percentconcentration of tricresol124 (tables 68, 69, and 70).
Infectious Hepatitis
The first successful transmission of infectious hepatitis tovolunteers was described in Germany in 1942 in a short report by Voegt,125 whofed them duodenal fluid and blood obtained from patients in the acute phase ofthe disease. In 1944, MacCallum and Bradley,126 in England, andmembers of the Commission on Neurotropic Virus Diseases of the ArmyEpidemiological Board, in the United States,127 were independentlyand almost simultaneously successful in producing the disease in volunteers byfeeding feces and serum obtained from a patient in the acute phase of infectioushepatitis. The source of this strain of hepatitis virus was a soldier who hadsickened on the Anzio beachhead in 1943. Because of pain in the right lowerquadrant of the abdomen, an appendectomy was performed. The appendix was normal,but mesenteric adenitis was found. The patient was transferred back to the 38thGeneral Hospital in Egypt where he subsequently became jaundiced and had atypical course of infectious hepatitis. The role of feces and theintestinal-oral route in the transmission of the disease was thus wellestablished.
Also of epidemiologic importance was the subsequent recoveryof the hepatitis virus in 1945 by Neefe and Stokes128 from water drawnfrom
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. M?nchen. med. Wchnschr. 89: 76, 23 Jan. 1942.
126MacCallum, F. O., and Bradley, W. H.: Transmission ofInfective 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 ofInfectious Hepatitis Apparently Due to a Water Borne Agent. J.A.M.A. 128: 1063-1075,11 Aug. 1945.
377
a well in a children's camp in Pennsylvania during an epidemic of thedisease. The volunteers who ingested this water that was proved to have fecalcontamination and the volunteers who ingested feces obtained from children withinfectious hepatitis in the camp contracted the disease, giv-
378
[The minus sign = before onset of the disease;the plus sign = after appearance of jaundice]
Author | Year | Day material was obtained |
| |
| Jaundiced | |||
|
|
| Number |
|
Neefe et al1 | 1944 | -87 | 2 | 22 |
Paul et al3 | 1945 | -60 | 8 | 3 |
Havens4 | 1946 | -16 | 4 | 1 |
Havens4 | 1946 | 28 to 32 | 5 | 0 |
MacCallum & Bauer5 | 1944 | 66+ | 5 | 0 |
MacCallum & Bauer5 | 1944 | 141+ | 5 | 0 |
Oliphant et al6 | 1943 | 75 postjaundice | 15 | 0 |
1Neefe, J. R., Stokes, J., Jr., Reinhold, J. G., and Lukens, F. D.W.:Hepatitis Due to the Injection of Homologous Blood Products in Human Volunteers.J. Clin. 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 HomologousSerum 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; TransmissionExperiments With Human Volunteers. Lancet 1: 622-627, 13 May 1944.
6Oliphant, J. W., Gilliam, A. G., and Larson, C. L.: Jaundice FollowingAdministration of Human Serum. Pub. Health Rep. 58: 1233-1242, 13 Aug. 1943.
[In the "Challenge virus" column, IH = infectious hepatitis and SH =serum hepatitis]
| | | | | | |||||
| | | | | | | ||||
|
|
|
|
|
|
|
|
|
| |
| Oliphant1 | 1944 | IH | 10 | 0 | --- | 11 | 4 | 85-106 | |
| Havens2 | 1945 | IH | 3 | 3 | 20-25 | 11 | 5 | 23-31 | |
| Neefe et al3 | 1946 | IH | 5 | 4 | 28-37 | 6 | 5 | 28-32 | |
| Neefe et al3 | 1946 | SH | 9 | 0 | --- | 9 | 8 | 60-100 | |
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 InfectiousHepatitis 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 ofthe Etiological Agents. Am. J. Med. 1: 3-22, July 1946.
ing unequivocal proof to the concept previously based on epidemiologicevidence, that common source waterborne outbreaks could and did occur.
Attempts were also made to determine the infectivity of urine andnasopharyngeal washings in limited experiments. The results following
379
the ingestion of urine were contradictory, and although Voegt129 and Findlay and Willcox130 reported success, MacCallum and Bradley,131 Havens,132and 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.135However, 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 bloodand feces of patients in the acute phase of the disease, attention was directedto determining when the virus appeared in these materials and how long itremained there. This was of particular concern in relation to the possibilitythat patients with relapse or chronic hepatitis might be infectious or thatthose who had made a complete recovery might remain carriers of the virus. Theperiod of infectivity of patients with infectious hepatitis was thereforeinvestigated in a few experiments. Virus was found in the blood 3 days beforethe onset of symptoms.136 However, a single attempt to detect it inthe blood halfway through the incubation period of experimentally inducedinfectious hepatitis was unsuccessful, as were attempts to recover the virusfrom the blood and feces 1 month137 after onset, and from the feces 3 months138after the disappearance of jaundice.139 The whole question of whethera "carrier state" existed either in the blood or in the feces remainedunanswered, although there was epidemiologic evidence, particularly fromcivilian experience, to suggest that it did.
129See footnote 125, p. 376.
130(1) Findlay, G. M., and Willcox, R. R.: Transmission ofInfective Hepatitis by Faeces and Urine. Lancet 1: 212, 17 Feb. 1945. (2)Findlay later suggested that the apparent infectivity of urine in his experimentwas due to the presence of erythrocytes associated with urinary bilharziasis.However, recent experiments by Krugman (personal communication) and hisassociates indicate that the virus is excreted in the urine in the acute phaseof the disease and may be transmitted to volunteers by feeding,
131See footnote 126, p. 376.
132Havens, W. P., Jr.: Period of Infectivity of PatientsWith 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 9months after the onset of hepatitis, Neefe and his associates obtainedspecimens of liver (by biopsy), blood, and feces, and fed them to volunteers whodeveloped certain vague symptoms and slight alterations of tests of hepatic function. The results, however, were not clearly defined, and no conclusionwas 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 PersistentSymptoms, Disability, and Hepatic Disturbance ("Chronic HepatitisSyndrome") Following Acute Infectious Hepatitis. J. Clin, Invest. 26: 329-338,March 1947.
380
Experimentally, a limited amount of data indicated thatimmunity develops during recovery from hepatitis. Both Havens140and Neefe andhis associates141 showed that volunteers convalescent 6 to 9 months fromexperimentallyinduced infectious hepatitis were immune when reinoculated with the homologousstrain. In addition, Neefe and his group142 showed that volunteers recovered fromhepatitis experimentally induced by a strain of virus obtained from the stoolsof children with the disease in Pennsylvania were immune when inoculated with astrain of hepatitis virus obtained from the stool of a soldier who contractedthe disease in Sicily.143
Evidence thus became available that more than one strain ofhepatitis virus might cause hepatitis in man, and at least two strains of viruswere described as being immunologically distinct.144These strainsof virus were termed "infectious hepatitis" and "homologous serumhepatitis," and the similarities and differences between them will bediscussed more fully at the end of this section. However, it may be mentionedhere that, in a limited number of experiments, volunteers convalescent fromhepatitis produced by one strain of virus were not immune when reinoculated withthe other strain of virus.145 In regard to immunity, it was shown by Stokesand Neefe146 and by Havens and Paul147 that normal human gamma globulin inamounts of 0.06 to 0.12 ml. per pound of body weight, administeredintramuscularly, prevented the epidemic disease.148
As a result of these studies and others in volunteers, it wasalso demonstrated that the etiologic agent of infectious hepatitis wasfilterable through an L2 Chamberland or Seitz E K filter, that it was resistantto a temperature of 56? C. for at least 30 minutes, and that it wastransmissible to man in serial passage by feeding or parenteral inoculation ofinfectious material.149 The virus withstood chlorination, namely,one part chlorine residual per million for 30 minutes,150 and remained activein materials frozen for 1 to 1? years, but not for 3 years, at -10? to -20?C. Another strain of virus was inactive after storage at Dry Ice temperature for32 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.
381
TABLE 71.-Results of administration, tovolunteers, of materials obtained from patients in the acute phase of infectious hepatitis
382
[F = feces; S = serum; the minus sign = beforeonset; the plus sign = after onset]
Author | Year | Inoculum | Day material was obtained |
| |
| Jaundiced | ||||
|
|
|
|
| Number |
Havens1 | 1946 | F | -15 | 3 | 0 |
Francis et al2 | 1945 | S | -3 | 8 | 4 |
Havens1 | 1946 | F&S | 25+ to 31+ | 10 | 0 |
Neefe et al3 | 1945 | F | 21 post jaundice | 7 | 0 |
Neefe et al4 | 1947 | Liver | 180+ | 5 | 0 |
Neefe et al4 | 1947 | S | 106+ to 367+ | 5 | 0 |
Neefe et al4 | 1947 | F | 92+ to 342+ | 5 | 0 |
1Havens, W. P., Jr.: Period of Infectivity ofPatients With Experimentally Induced Infectious Hepatitis. J. Exper.Med. 83: 251-258, March 1946.
2Francis, T., Jr., Frisch, A. W., and Quilligan, J. J., Jr.: Demonstrationof Infectious Hepatitis Virus in Presymptomatic Period After Transfer byTransfusion. 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 HomologousSerum Hepatitis and Infectious (Epidemic) Hepatitis. Am. J.M. Sc. 210:29-32, July 1945.
4Neefe, J. R., Stokes, J., Jr., Garber, R. S., andGellis, S. S.: Studies on the Relationship of the Hepatitis Virus to PersistentSymptoms, Disability, and Hepatic Disturbance ("Chronic HepatitisSyndrome") Following Acute Infectious Hepatitis. J. Clin. Invest. 26: 329-338,March 1947.
[In the "Challenge virus" column, IH =infectious hepatitis, and SH = serum hepatitis]
Author | Challenge virus |
| Controls | ||||
Inoculated | Jaundiced |
| Inoculated | Jaundiced | Incubation period | ||
|
| Number | Number |
| Number | Number | Days |
Havens1 | IH | 9 | 0 | --- | 12 | 8 | 21-30 |
Neefe et al2 | IH | 17 | 0 | --- | 14 | 6 | 25-37 |
Neefe et al2 | SH | 4 | 2 | 101, 102 | 9 | 8 | 60-110 |
1Havens, W. P., Jr.: Immunity in Experimentally Induced Infectious Hepatitis. J. Exper. Med. 84: 403-406, November 1946.
2Neefe, J. R., Gellis, S. S., and Stokes, J., Jr.: Homologous Serum Hepatitis and Infectious (Epidemic) Hepatitis; Studies in Volunteers Bearing on Immunological and Other Characteristics of the Etiological Agents. Am. J. Med. 1: 3-22, July 1946.
Relationship of Serum Hepatitis to Infectious Hepatitis
The exact relationship between infectious hepatitis andhomologous serum hepatitis eluded solution, and, indeed, an appellative dilemmawas created by the arbitrary definition of the latter form of the disease on thebasis of probable route of transmission. Whether homologous serum hepatitismerely represented the artificial transmission of the naturally occur-
383
ring disease was the subject of frequent discussion. Whilethis may have occurred more frequently then was suspected, there was no evidenceto indicate that it explained the relationship between the two.
The results of epidemiologic, clinical, and experimentalstudies revealed that certain similarities and differences existed between thetwo conditions and their causative agents. Although these two forms of hepatitisare clinically and pathologically indistinguishable after the onset of disease,attention was early directed to the fact that in infectious hepatitis the onsetwas 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 timesmore severe as it occurred in debilitated patients. The causative agents of bothdiseases were found to be filtrable, resistant to a temperature of 56? C. forat least 30 minutes, and transmissible to man in serial passage, evokinghomologous immunity. They were regarded as viruses; however, they were notsuccessfully transmitted to laboratory animals or embryonated eggs.
In contrast to these similarities were certain differencesthat were consistently reproducible by two different groups of investigators,members of the Commission on Neurotropic Virus Diseases and of the Commission onMeasles and Mumps, working under the auspices of the Army Epidemiological Board.In table 74 is recorded a comparison of the behavior of two apparently differentstrains of virus, summarized from the results of Paul and Havens and of Stokesand 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) ofhomologous serum hepatitis. That the prolonged incubation period of the latterdisease was determined by the parenteral inoculation of virus partially
| | | |
| 1. Filtrable | Seitz E. K | Seitz E K. |
| 2. Resistance to heat | 56? C., 30 minutes | 56? C., 60 minutes. |
| 3. Susceptible host | Man | Man. |
| 4. Incubation period (days) | 15 to 34 | 56 to 134. |
| 5. Route of infection (experimental) | Parenteral or oral inoculation. | Parenteral inoculation. |
| 6.Virus in stool | Acute phase | Not demonstrated. |
| 7.Virus in serum | do | Incubation period and acute phase. |
| 8. Immunity: | ||
| a. Homologous | Present | Present. |
| b. Heterologous | None apparent | None apparent. |
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 ofvolunteers with serum containing the same strain of infectious hepatitis virussuggested that such a mechanism was not the complete explanation of differencein time interval.153 Prolonged incubation periods were indeedreported in experimentally induced infectious hepatitis when the inoculation wasby the parenteral route,154 but the failure to test the sameinoculums for infectivity by the oral route denied any comparison of the effectof route of inoculation on length of incubation.
The virus of serum jaundice was found in the circulatingblood during the long incubation period as well as in the active stage of thedisease. Experimentally, it appeared to be infectious only when inoculatedparenterally, with two possible exceptions. The disease thus produced was not ascontagious as infectious hepatitis, evidence of contact infection was rare, andthe virus was not found in the feces. This fact, in combination with the failureto produce this disease in volunteers by the oral administration of serum knownto contain virus, suggested that the intestinal-oral route was not importantin its spread, differentiating it in some degree from infectious hepatitis. Ofinterest in this regard was the comparison of the elimination of two strains ofvirus in the feces after parenteral inoculation.155 A strain ofinfectious hepatitis virus was readily detected in the feces during the acutephase of the disease produced by parenteral inoculation. In contrast, a strainof serum hepatitis virus also inoculated parenterally in other volunteers wasnot found in the feces during the acute phase. In addition, studies on theimmunity of volunteers corroborate the epidemiologic experience that patientswho have had either infectious hepatitis or homologous serum hepatitis weresusceptible when exposed to the other disease. Lastly, the long period ofviremia in patients with serum hepatitis, in contrast to the much shorter periodof viremia in infectious hepatitis, was adduced to explain the difference in theprophylactic effect of normal human gamma globulin in the two conditions. In theformer, questionably favorable results followed the administration of two dosesa month apart, while no protection was demonstrable when only one dose wasgiven. This suggested that the efficacy might have a quantitative relationshipwith the amount of circulating virus. It was not determined by the end of thewar whether the differences in route of inoculation, length of incubationperiod, onset of disease, distribution of virus, period of infectivity, and lackof cross-immunity represented the activities of actually different viruses or ofantigenic differences of various strains of one virus.156
153Havens, W. P., Jr.: Elimination in Human Feces ofInfectious 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 theseunknowns still persist at the time of writing this chapter in 1963.-W.P. H., Jr.
