POSTGRAD. MED. J ( 963), 39, 212

VIRAL HEPATITISW. PAUL HAVENS, JR., M.D.

Departments of Microbiology and Medicine, The Jefferson Medical College of Philadelphia,Philadelphia, Pennsylvania

INSIGHT in the importance of viral hepatitis isfurnished by the degree to which it has occupiedthe time of numerous workers throughout theworld. Attesting to this during the past decadeare approximately 2,600 papers, published in 23languages. About one-third of these are in English.A review of a representative segment of the workdone during the past 20 years reveals that whilemany have been attracted to the field, only asmall number of faithful followers have survived.Lavish at times and at others parsimonious havebeen the rewards of their efforts. Impetuousclaims have been followed by the slow, erosivedenials of time, and more than one eager devoteehas been crushed by the failure of his colleaguesto repeat his reported success. After two decadesthe often-cited major problems are as crucialnow as they were in 1942, i.e. (a) the failure topropagate human hepatitis viruses in any hostexcept man and (b) the consequent lack of aspecific serologic test for their identification.Over the years many claims of successful trans-mission of human hepatitis viruses to a variety oflaboratory animals, embryonated eggs, and culturesof cells of various species were made but notcorroborated by others. However, recent reportsof the isolation of strains of viruses from patientswith hepatitis in cultures of human cells haveagain stimulated new hope and the outcome ofthese interesting studies is eagerly awaited,although it is easy to appreciate that the longdismal record of unrequited claims tends to bediscouraging.The real rewards throughout the years have

come from studies in volunteers, and ever sincethe initial successful transmission of infectioushepatitis in Germany (Voegt, I942) and serumhepatitis in the United States (Oliphant, Gilliamand Larson, 1943) there has been a progressionof investigations that have resulted in an imposingmass of information. During World War II and

Some of the investigations on which this report isbased and in which the author participated were carriedout under the sponsorship of the Commission on ViralInfections of the Armed Forces Epidemiological Board,and were supported by the Office of The SurgeonGeneral, Department of the Army.

for a short time thereafter, studies with volunteerswere carried on in the Middle East, England,and the United States. All of this work and theclinical and epidemiologic observations thenavailable were reviewed by Havens (I948, I954a).During the past eight years, further studies withserum hepatitis and infectious hepatitis have beenhighly productive. It is the purpose of this paperto pick up the threads of the information presentedin the review of I954 (Havens I954a), relatingwhat has happened since that time to certainfacts or concepts that had been previously eluci-dated.

INFECTIOUS HEPATITISVirus A

Because of the high incidence of infectioushepatitis among children in the WillowbrookState School in New York and its importance asa cause of loss of time among nursing personnelwhen they contracted the disease, Dr. RobertWard and Dr. Saul Krugman were invited by theschool authorities to assist them in epidemiologicstudies and control of the disease. As a result ofthe investigations subsequently carried out,important information, either new or supple-menting previously known facts, became available.Early studies in volunteers had revealed viremiathree days before the onset of disease, during thepreicteric phase, and in the early icteric phase ofdisease (Havens, I948). These findings werecorroborated (Ward, Krugman, Giles, Jacobs andBodansky, 1958) and it was also shown thatviremia was present 25 days after experimentalinfection and 2-3 weeks before the appearance ofjaundice, although attempts to recover virus fromthe blood a week earlier (18 days after experi-mental inoculation) were unsuccessful (Krugman,Ward, Giles, Bodansky and Jacobs, 1959). Theduration of viremia has been a matter of interestand concern from the beginning of the studies onhepatitis, and the work at Willowbrook corrobor-ated in part studies made in the I940'S when anumber of unsuccessful attempts were made torecover virus at intervals from I-13 months afterthe onset of disease (Havens, 1948). Because ofthis, the concept had developed and appears

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still valid that the average patient could be regardedas no longer infectious as far as blood was con-cerned one month after the onset of disease,although it was indeed suspected early that thiswas probably not true for all patients. That thisdoubt was justified was proved by the demon-stration of Virus A in the blood of a patient,completely recovered, eight months after theonset of infectious hepatitis (Murray, Diefenbach,Geller, Leone and Ratner, I955).

Similar temporal relationships have been foundto characterize the duration of presence of Virus Ain the faeces. That it was present in the stools ofpatients during the acute phase of disease wasdemonstrated independently and almost simul-taneously in England (MacCallum and Bradley)and in the United States (Havens, Ward, Drill andPaul) in 1944. This has been repeated in otherstudies, including those done at Willowbrookduring recent years. Here, also, it was shownthat virus may be excreted in the fieces 25 daysafter experimental inoculation (when viremia, asstated above, was also present) and two to threeweeks before the appearance ofjaundice. Howeveran attempt to recover virus from faces obtainedtwo weeks earlier (eleven days after experimentalinoculation) was unsuccessful (Ward and Krugman1961). Just as the duration of viremia was, fromthe beginning, a matter of interest, so was theduration of persistence of virus in the faeces. Theearly attempts in the 1940's failed to recovervirus from the faeces of adult patients one, three,and eleven months after the onset of illness, andsimilar attempts among children at Willowbrookone month after onset were also unsuccessful.Because of the results of the early studies, it wasgenerally believed that patients were no longerinfectious as far as the faeces were concerned onemonth after onset, although again, as with viremia,it was suspected that this need not always betrue. The detection of virus in the stools of twoinfants with chronic hepatitis five and fifteenmonths, respectively, after the onset of theirdisease justified this suspicion (Capps, Bennettand Stokes, 1950). The evidence that has accumu-lated over the past two decades supports theconcept that the infectivity of blood and facesoccupies a period of at least three to four weeksin the incubation period and acute phase of diseasein a large percentage of patients. That viremia orfaecal excretion of virus may continue for pro-longed periods under certain circumstances is alsoquite clear, supporting the concept long appreci-ated on epidemiologic grounds that the carrier isan important medium for the maintenance andtransmission of infection.The possibility of more subtle relationships

between virus and host, though long suspected,

was not placed on a firm footing until the detectionof viremia by Krugman and his associates (I959)in a subject 37 days after experimental inoculationwhen the subject was clinically well and withoutany evidence of hepatic dysfunction except for amild increase in serum glutamic oxalacetictransaminase. Thus, it would appear that viremiamay exist in asymptomatic persons for a consider-able period of the incubation period when tests ofhepatic function are normal and also at a timeappropriate for the onset of disease when theonly evidence of hepatic involvement is a minorabnormality of one test of hepatic function. Thefrequency of occurrence of such an apparentlybenign relationship is unknown, although it isquite likely that it is far more common, particularlyamong children, than previously suspected.

In the course of innumerable attempts toisolate hepatitis virus from man, a number ofknown human viruses, including strains ofECHO and adenoviruses (unpublished), Coxsackievirus (Morris, Elisberg, Pond and Webb, 1962),and herpes simplex viruses, as well as a numberof enzootic viruses (Morris and Nakamura, 1959),have been recovered but regarded as commensalsunrelated to hepatitis. The long history offailures (or successes that were eventually regardedas failures because of inability of others to repro-duce them) was reviewed in 1954 (Havens,I954b) in relation to the many attempts topropagate hepatitis Virus A in a wide variety oflaboratory animals and birds, embryonated eggs,and cultures of various human and animaltissues. Since then, similar failures and successeshave been reported from many widely separatedplaces in the world; however, a review of thesupporting evidence for the alleged successreveals nothing that is convincing (Havens, I963).The new wave of enthusiasm engendered

recently in the United States by reports of theisolation of several strains of viruses from patientswith hepatitis by American workers is based onclaims of success in cultures of (a) monkey kidneytissue (McKee, 1962); (b) human embryoniclung tissue (Davis, 1961); (c) chimpanzee kidneycells (Hillis, 1961); and (d) human cells (Chang,I96I). The last mentioned is an interestingimmunologically nonreactive virus called lipovirus.Whether any one of these strains of virus willeventually be shown to have a causative rolein human hepatitis remains to be seen, and muchmore needs to be done before this informationbecomes available.The most prominent candidate strains of

hepatitis-associated viruses as far as the publicitythey have received are the strains first describedby Rightsel, Keltsch, Tekushan and McLean(I956). They were isolated on cultures of human

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cells and, as might be expected, provoked tremen-dous interest. Although the efforts of a number ofother laboratories to reproduce these initialresults were unsuccessful, the original investi-gators can only be complimented on their persis-tence, and in the past two years they havemodified certain cumbersome aspects of theirtechniques and have again described success.Three strains of virus were allegedly propagatedon cultures of similar cells and, in addition,the inoculation of tissue culture material intovolunteers produced hepatitis after an incubationperiod of 30 to 42 days (Taylor, Rightsel, Boggsand McLean, I962). The serologic evidenceadduced to support the causative role of theseviruses in the disease sustained by the volunteersis less than orthodox; however, certain of theirphysical properties are indeed compatible withwhat is known about hepatitis viruses, i.e. (a)relative stability when exposed to heat and ether,and (b) size of about 15 m[V in diameter as definedby electron microscopy and ultrafiltration. Again,it can only be hoped that these results will bereproduced in other laboratories; however, thismay not be as simple as might be desired since thetechniques used still present problems and thelikelihood of further difficulties with them is good.Many years ago, Essen and Lembke (I944)

described polyhedral particles with a diameter ofthe order of I8o m[± when visualized by electronmicroscopy in duodenal secretions of patientswith hepatitis. Since then a number of studieshave been made and enthusiastic reports havecome from Austria (Braunsteiner, Fellinger,Pakesch, Beyreder, Grabner and Neumayr, I957),the United States (Gueft, 1961), and Nigeria(Bearcroft, I962). Particles of variable size, someof them compatible with what is suspected ofhepatitis Virus A, have been described occurringas dense cytoplasmic inclusions with a darkcentral granule in duodenal secretions andhepatic cells. Whether these actually representhepatitis virus is, as yet, unknown.

EpidemiologyInfectious hepatitis has emerged as a common

disease of the mid-part of the twentieth century,and in 1952 cognizance was taken of its importanceas well.as that of serum hepatitis in a meeting ofthe World Health Organization at Liege, Belgium.During recent years, the incidence of infectioushepatitis has increased in both hemispheres innorthern and southern latitudes. Among theseveral similarities that exist between this diseaseand poliomyelitis, McCollum (1962) included theevolution of their epidemiologic patterns, bothdiseases having emerged into a phase of long-term widespread epidemicity after obscure begin-

nings with brief periods of localized outbreaks. InHungary and Czechoslovakia where reporting iscompulsory, hepatitis has reached pandemicproportions, and in Australia and Denmark therates have been high. In contrast are the relativelylow rates reported for Greece and Italy, raisingthe question that the available figures mayrepresent less than accurate notification in theseareas (McCollum, 1962). In the United Stateswhere viral hepatitis was not generally notifieduntil 1952, early records of the incidence ofinfectious hepatitis were better kept in Californiathan in most places, and the major increase thereoccurred during the past decade (Clark, Beck,Edwards and Drake, I960). The same appears tohave been true throughout the country, and twolarge outbreaks occurred in 1954 and 1961. Atpresent, the morbidity is declining in the UnitedStates, completing a cycle of seven years that israther like the six to ten year cycles commonlyseen in other countries. Mortality has not fluctu-ated significantly in the United States, and theoccurrence of 550 to 900 deaths per year duringthe past eleven years provided a constancy thatwas in contrast to the variability in morbidityduring this period. One possible explanation ofthis situation was provided by Dauer (1961) whoattributed the former to deaths from serumhepatitis, while infectious hepatitis provided thesharp fluctuations in morbidity. Of interestin this regard is the experience in Denmark wheretwo severe outbreaks with high mortality occurredin I933 and I943. Since the latter, the highlyfatal form of hepatitis has practically disappearedand there has been a fairly steady decline inmorbidity to a level of 31.6 per Ioo,ooo perannum in I96I, the lowest figure ever recorded inDenmark. However, this is considerably higherthan the maximum incidence notified in theUnited States in the same year, and the questioncan be hsked again whether the reporting in thelatter country has, as yet, attained maximumeffectiveness. The notification of infectioushepatitis has been highly irregular in variousparts of the world, ranging from the extremes ofnone to the enviable records of Denmark andSweden where accurate statistics are availableconcerning morbidity and mortality since I928.From such records and from the descriptions oflocalized outbreaks in areas where reporting isless well done has sprung a tremendous amount ofinformation. While much of this has come fromcivilian sources, the high incidence of diseaseamong the military of many nations during thepast two decades has also furnished valuableknowledge and indeed has been a stimulus tocloser study of the disease among civilians. Muchof this was reviewed in 1954 (Havens), and since

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then outbreaks among the military and civilianshave continued to provide experience thatcorroborated and, at times, extended previouslyavailable knowledge.The concept that the most important way of

transmission of disease is by direct contactappears still to hold, although several interestingaccounts of common-source outbreaks continue toappear. A huge water-borne epidemic due tofaecal contamination of a river was described inIndia (Melnick, I957) as well as other smalloutbreaks in the United States due to faecalcontamination of streams (Mosley, I959), wells(Poskanzer and Beadenkopf, I96I), and municipalwater supplies that had been inadequately precipit-ated before chlorination (Wilcox, Davenport,Coohan, Papsdorf and Johnson, I96I). Food wasalso implicated, and the personnel of certainships of the Sixth Fleet, U.S. Navy, were involvedin an outbreak while based in the MediterraneanSea (McCollum, I96I). Contaminated foodbought from family vendors on the docks inNaples was regarded as the likely source ofinfection. A fascinating tale of epidemiologicdetective work was spun by Mason and McLean(I962) who discovered raw oysters as the sourceof one outbreak in the United States, andDougherty and Altman (I962) similarly incrimin-ated raw clams in another. In both instances, theshellfish were obtained from faecally contaminatedwater; however, their role would doubtless nothave been suspected if the investigating epidemi-ologists had not been struck by the unusuallyhigh incidence of disease among adults, partic-ularly adult males. The suspicion that an unusualsituation might be involved directed attention tothe possibility of a common source of infection. Itserves to point up the importance of increasingmarine activities in small boats as well as theoverloading of sanitary facilities at water resortsas sources of pollution of water harboring shellfish.

Epidemiologic evidence has long emphasizedthe probable importance of the carrier as a mediumfor maintenance of virus and its transmission.How frequently the carrier state persists forprolonged periods and whether it exists as anintermittent or constant phenomenon in theindividual carrier is not known. The recentexperiments of Krugman and his associates (1959)have added to previously known data concerningthe duration of viremia and excretion of virus inthe feces so that now it is appreciated that thesephenomena may exist for at least three to fourweeks in infected persons, regardless of whetherthere is any evidence of clinical disease. The factthat virus was present in the faeces (and the blood)of asymptomatic experimentally infected subjects18 days after inoculation and two to three weeks

before the onset ofjaundice confirms the long heldsuspicions that such a situation doubtless existedand was important in the spread of disease.Of particular interest in this regard was the

recent report of an outbreak of hepatitis amonghandlers of chimpanzees newly arrived in theUnited States from Africa (Hillis, I961). Followingthis, the Communicable Disease Center, inAtlanta, Georgia, began the collection of otherdata, and, to date, 73 human cases of a disease:clinically indistinguishable from infectious.hepatitis have occurred in persons having closecontact with chimpanzees, monkeys or gorillasthree to six weeks before the onset of illness(CDC Report No. I3, 1962). The majority werechimpanzee-associated, although this cannot beinterpreted as any unusual susceptibility of thechimpanzee to infection or the carrier state. Thesignificance of these observations awaits definition;however, it would seem likely that the route ofinfection was man to subhuman primate to man,with infection occurring in the subhumanprimate shortly after arriving in this country or,indeed, in Africa in the period following trappingand awaiting shipment. Without developingclinically recognizable hepatitis, these animalsapparently excreted virus for variable periods inthe faeces, making infection of the handlerspossible.Clinical Course of DiseaseThe descriptions of clinically apparent hepatitis

that came out of the experience of World War IIhave not been supplemented in any significantway during the past few years since the lastreview in 1954 (Havens, I954a) with the exceptionof the interesting report of an outbreak ofcholestatic hepatitis among U.S. soldiers (Dubin,Sullivan, Legolvan and Murphy, I960). Ward,Krugman and Giles (1960) in their studiesincluded clinical descriptions of a mild disease inchildren from which complete recovery was therule. Whether the second attacks that occurred inapproximately 5% of their cases represented theeffect of inadequate immunologic response or theimpact of another strain of virus is not known. Itis doubtless pertinent to point out that theincubation period of 34-50 days that they describedin their experimentally transmitted disease isactually not particularly different from theshorter incubation periods of 16-42 days describedby others years ago for experimentally transmittedinfectious hepatitis (Havens, 1948). The formerincubation periods were calculated from inocula-tion to day of appearance of jaundice, while thelatter were calculated from inoculation to thefirst appearance of symptoms that usually occur7-10 days before clinical jaundice is evident.

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Although the ratio of inapparent to clinicallydiagnosed infections has long been thought tobe variable but high, Ward and Krugman (I96I)stressed the frequency of inapparent infections inchildren and suggested that the ratio might be ashigh as twelve to one. Their role epidemiologicallywas emphasized, and interest in it led to studiesthat resulted in a new insight into the naturalhistory of the disease. The discovery of hepatitisVirus A in the blood and fmces of children in theincubation period of experimentally transmittedhepatitis two to three weeks before recognition ofjaundice, when there was no evidence of clinicaldisease or hepatic dysfunction, provided thenecessary data to establish the fact that analimentary phase, long recognized on epidemio-logic, clinical, and pathologic grounds, is anintegral part of the natural history of disease.This plus the fact that viremia was found in anasymptomatic subject 37 days after the ingestionof Virus A, when the diagnosis of infectioushepatitis was made solely on the basis of a slightincrease in serum glutamic oxalacetic transaminase,urged the acceptance of a 'wide spectrum ofseverity of infection with Virus A. The questioncould well be asked whether infectious hepatitisis indeed a good name for this disease, since thespectrum might range from (a) an asymptomaticalimentary form without demonstrable hepaticdamage, to (b) asymptomatic infection withminimal hepatic dysfunction, to (c) clinicalhepatitis, with or without jaundice (Havens, I962).Only the development of specific virologic andimmunologic techniques can establish the validityof this concept.Sequelae

As a result of certain experiences in World WarII among U.S. troops in the MediterraneanTheater (Barker, Capps and Allen, I945), a greatfear of chronic hepatitis developed amongphysicians and laity, particularly in the UnitedStates, even though there was at no time sufficientevidence to prove that it actually was an importanthazard. During the past decade the situation hasbeen viewed more realistically by some, (Martini,I96I) but there are others who have taken theopposite extreme. For the latter, the persistencefor several months of mild hepatic dysfunction,with or without clinical evidence of disease, is theonly acceptable residual of acute hepatitis, andcirrhosis of the liver apparently has no place inthe natural history of this disease. The genesis ofthis belief lies in the failure to find evidence ofsignificant residual hepatic disease in groups ofU.S. (Zieve, Hill, Nesbitt and Zieve, I953) (Neefe,Gambescia, Kurtz, Smith, Beebe, Jablon, Rein-hold and Williams, I955) (Chalmers, I96I) and

British veterans (Cullinan, King and Rivers, 1958)several years after they had acquired epidemichepatitis or serum hepatitis. The lack of a historyof preceding hepatitis in a considerable percentageof patients who came to clinical awareness onlywhen they established chronic liver disease iscited in support of this concept. However,competent observers in England (Sherlock, 1948),the United States (Ratnoff and Patek, 1955), andGermany (Kalk and Wildhirt, 1960) have describedchronic progressive hepatitis and cirrhosisfollowing a disease that is clinically indistin-guishable from acute viral hepatitis and, indeed,the increase in mortality from chronic liverdisease in Denmark during the past 15 years isregarded as an aftermath of the great epidemic ofinfectious hepatitis in the mid-I940's (Bjorneboe,1957). In addition, the frequency of undiagnosedinfections makes it impossible to say that chronichepatic disease is unrelated to preceding infection.

In spite of interest in inadequate diet,insufficient rest, intercurrent infections, and othernonspecific factors as possible conditioninginfluences in the development of chronic hepatitis,the two major unanswered questions are whetherit is due to (a) the persistent activity of virus or

\ (b) some inherent defect in the host. There is noreason to believe that the nonspecific factors areoperative, and there is no practical way to deter-mine whether hepatitis virus persists in patientswith chronic hepatitis, although it has beendemonstrated to do so on occasion. However,whether it is implicated in the production ofchronic disease under this circumstance isunknown, since it has also been found in perfectlyhealthy persons.

In an effort to explain the development ofchronic hepatic disease, Gear (1946) suggestedthat it might be the result of autoimmune mechan-isms. He postulated that any noxious material,including chemicals, bacterial toxins, or viruses,might function as the initiating injurious forcesubsequently combining with products of cellulardestruction that in certain patients evoked anantibody, which in its union with antigen provokedfurther cellular injury, thereby establishing aself-perpetuating progressive disease. This wasnot seized upon at once with enthusiasm, althoughit is of interest that a good bit of nonspecificserologic evidence accumulated before and afterGear's initial suggestion lent some support to it(Havens 1948, i954b). However, in the past fewyears a great deal of interest has been manifestedin this idea, particularly in Australia and theUnited States. Mackay, Taft and Cowling (1956)in Australia coined the term 'lupoid hepatitis,'and since then a number of papers recentlyreviewed by Mackay (1961) have appeared from

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both continents. The results of earlier serologicstudies were extended and materials were found inthe serums of patients with chronic hepatitis thatbound nuclear and cytoplasmic substances(Deicher, Holman and Kunkel, I960) (Paronetto,Schaffner and Popper, 1961). Fluorescencemicroscopy was employed to demonstrate gammaglobulin in the livers of patients with chronichepatitis (Cohen, Ohta, Singer and Popper, 1960).Although the concept is attractive and, indeed, itis quite clear that chronic hepatitis may flourishin a biologic environment that contains many ofthe phenomena associated with auto-immunedisease, the final proof is not yet available thatauto-immune mechanisms produce chronic hepaticdisease in man (Havens, 1959). Most of thoseconcerned with the possibility that it might betrue believe that cellular rather than circulatingantibodies are important in continuing the damage.Since the latter are generally regarded, however,,as reflecting the presence of cells that might beinvolved in production of cellular antibody, thereport of Good and Page (1960) of the occurrenceof acute yellow atrophy and postnecrotic scarringof the liver, respectively, in two patients withagammaglobulinemia who contracted acutehepatitis casts some doubt on the importance ofauto-immune mechanisms in their evolution.

Laboratory StudiesThe numerous attempts to devise serologic

tests for the diagnosis of viral hepatitis resulted inthe description of a series of nonspecific reactionsthat have been interesting in many instances butof little value except possibly for a recentlydeveloped hemagglutination test. Many of thesewere reviewed (Havens, I954b), but since then anumber of others have been described, includingthe use of (a) suspensions of Bacillus prodigiosustreated with acute-phase serums for agglutinationtests (Infectious Hepatitis Report, 1960), and (b)the Schultz-Dale reaction in guinea pigs to detectsoluble antigens in serum (Makari, 1960). Twosorts of crude neutralization tests were alsodescribed, utilizing convalescent-phase serumsto neutralize the inflammatory effects of injectingacute-phase serum into (a) the allantoic fluid ofembryonated hens' eggs (Pollard and Diserens,1956), and (b) the anterior chamber of the rabbit'seye (Infectious Hepatitis Report, 1960). Althoughclaims of specificity were made, others wereunsuccessful in reproducing them.Over the years, hope has repeatedly been

engendered that some sort of tests employinghemagglutination might be as valuable in viralhepatitis as it has in infectious mononucleosis.Despite the detection of agglutinins for theerythrocytes of a number of species including man

in a small but variable percentage of sera ofpatients with acute hepatitis, neither specificitynor value could be ascribed to them. The descrip-tion of hemagglutinins for day-old chick erythro-cytes in acute-phase serums of monkeys withyellow fever suggested the possibility that theymight also be found in acute-phase sera of patientswith viral hepatitis. This was indeed found to betrue in 70% of patients (Morris, 1957) (Havens,1958, 1960) (McCollum, Bech, Isacson andRiordan, 1959). The hemagglutinins appearedearly, frequently before the onset of disease, anddisappeared after two to three weeks. That theywere intimately related to the acquisition ofhepatitis was well demonstrated; however, thereappeared to be no specificity to the reaction as faras hepatitis virus was concerned. Of importanceis the fact that the test is uniformly negative inpatients with obstructive and hemolytic jaundice,lending it value in differential diagnosis (Havens,1962).

Descriptions of numerous metabolic and bio-chemical changes occurring during the course ofhepatitis have been reviewed or noted elsewhere(Iber and Mendeloff, 1962) (Havens, 1963). Amongthe most important was the measurement ofcertain serum enzymes and, from the diagnosticand prognostic standpoints, the measurement ofthe serum glutamic oxalacetic transaminase hasdoubtless achieved the greatest use (Wr6blewski,Jervis and LaDue, 1956). It is of particulardiagnostic value in hepatitis without jaundice orin the preicteric phase of disease and later whenthere may be difficulty in differentiating obstruc-tive jaundice. During convalescence, it serves asa guide to prognosis (Bodansky, Schwartz,Krugman, Giles and Jacobs, 1960).TreatmentThe treatment of viral hepatitis is concerned

with the provision of rest and a well-balanceddiet. Over the years, certain extremes in manage-ment have evolved only to reverse themselves to amore realistic position in the middle of the road.The nonspecific and supportive nature of themeasures available has been reviewed recently(Iber and Mendeloff, 1962), summing up thesituation quite adequately. Attention has beencalled to the fear of development of chronichepatitis that plagued both medical profession andlaity during the 1940's and early 1950's and thenaturally resulting prolonged hospitalization orconfinement to bed that in some areas attained theridiculous (Havens, 1962). Indeed it was rebellionagainst this that prompted a study in U.S. occupa-tion troops in Germany (Swift, Gardner,Moore, Streitfeld and Havens, I950) and subse-quently in U.S. troops in Japan (Chalmers,

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Reynolds, Eckhardt, Cigarroa, Deane, Reifenstein,Smith and Davidson, 1955). The observationsmade indicated what many already knew but werereluctant to express, that patients convalescentfrom hepatitis could tolerate more activity thangenerally believed and, more concretely, thatpatients allowed up in their rooms or wardfollowing a period of one hour's rest after eachmeal did just as well as those kept strictly at restin bed. Actually, by such gradually increasingactivity, they were able to return to duty oneweek sooner.

Dietary regimens went through similar excesses,and the sharp reduction in fats, for no justifiedreason, resulted frequently in large, unattractiveamounts of carbohydrate and protein being offeredto patients whose appetites were at best notvigorous. The recommendation of a well-balanceddiet containing 2,000-3,000 calories, with I9%in protein, Ioo-I20g. of fat, and the remainderin carbohydrate, was welcomed by most (Chalmersand associates, I955).The question when a patient is ready to return

to active life has been the subject of numerousdiscussions. A realistic approach appears to bethat this is possible when the serum bilirubinmeasures less than 1.5 mg., Iooml, the brom-sulphalein retention io% or less (5 mg./kg. bodyweight, 45 minutes), the patient is asymptomatic,and the liver no longer tender.

In the absence of specific treatment, it is nowonder that the use of adrenal steroids shouldhave occupied the efforts of many. Althoughfavorable changes following their administrationhave been widely described and reviewed (Iberand Mendeloff, I962), their use has been recom-mended for only seriously sick patients or forthose with prolonged illness. The use of thesematerials has doubtless been wider among patientswith cholangiolitic hepatitis or chronic hepatitis,and the benefits that have been observed in someof these patients, particularly among the formergroup, have caused the recommendation of a trialof therapy in all such patients (Sherlock, 1958)(Havens, I962). In patients with cholangiolitichepatitis, itching has been relieved by the use of aresin sequestering bile salts in the intestinaltract (Havens, I963). Attention must be paid tothe level of prothrombin in the blood since it maybe sharply reduced during treatment, requiringthe use of vitamin'K parenterally.PreventionThe prolonged duration of viremia and excretion

of virus in the faeces makes it difficult to preventthe spread of infectious hepatitis, particularlywhen a large percentage, as among children,never develop clinically recognized disease. In

those in whom the diagnosis is made, it has beenrecommended that the stools be regarded asinfectious for at least four weeks, and adequatesterilization of instruments coming in contact withthe blood of such patients has been re-emphasized.Normal human gamma globulin, previouslythought to prevent infection, has more recentlybeen shown to modify it. Krugman and Ward(I96I-I962) found the incidence of nonictericinfection as great in children who had receivedgamma globulin. The amounts used have rangedwidely, and from o.oI-o.o6 ml./lb. of bodyweight, intramuscularly, have been effective.Amounts of 0.01-0.02 have frequently beenreported as effective in children, althoughKrugman and Ward (I96I-I962) have questionedwhether this might be enough in adults. Ofparticular importance in answering this questionis the presumed amount of exposure that theadult might encounter. Thus, larger doses mightbe recommended for persons going to live inareas where the disease is highly endemic andwhere control of hygienic facilities, particularlyfood-handlers, might be less than desirable. Undersuch circumstances, repeated adminstration ofgamma globulin at stated intervals might beconsidered. The duration of partial protection soderived depends on the dosage and has beenestimated to range from four to eight weeks. Ifexposure is heavy, however, it has been shown inchildren that protection persists for many months(Ward and Krugman, I96I), and this has beenregarded as strong support for the concept thatunder such conditions partial passive protectionmight be supplemented by active immunity. Thatthis might also occur for adults living underconditions of high exposure would justify therepeated adminstration ofgamma globulin to them.

SERUM HEPATITISThe importance of serum -hepatitis today

emerges as a civilian problem and stems largelyfrom its mortality. Although the over-all deathrate from this form of hepatitis in previouslyhealthy young adult males, as experienced in thegreat epidemic following the administration ofyellow fever vaccine to U.S. troops in 1941-1942,was low and similar to that of the epidemicdisease in similar groups (<2/o000), Parr (I945)pointed out that differences in incubation periodand possibly severity of disease were related todifferences in fitness of the host. This was borneout by the increased mortality in wounded menwho acquired hepatitis from transfusions ofplasma or blood; and subsequently in civilianlife the mortality of hepatitis so acquired by olderand debilitated persons, who were most likely to.receive transfusions, has been a. matter of great

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concern. That variations in strains of virus mightbe partially operative in conditioning thesedifferences has also been suspected. Unfortunately,the diagnosis of serum hepatitis must be made onthe basis of a preceding history of circumstancesallowing the parenteral transmission of virus,although in occasional situations ofcommon-sourceinfection the epidemiologic background has been ofcrucial assistance. Without more specific measures,the true incidence of the disease cannot be defined.The sharp diminution in the use of plasma incertain parts of the world during the past fifteenyears has greatly reduced common-source out-breaks attributable to it, althougfi they still occuron occasion (CDC Report No. 12, I962). Serumhepatitis exists now as a clinical entity largely onthe basis of infections transmitted by transfusionsof whole blood and by inadequately sterilizedinstruments. Varying estimates have been madeof the carrier rates of hepatitis viruses amongadults, depending on the time and place of survey.A recent estimate of Stokes (1962) in the UnitedStates placed the figure at 2 to 4%. Amongrecipients of whole blood, the risk of serumhepatitis has also been reported as highlyvariable, ranging from 0.3 to 4.13%. Of interestand importance has been the suggestion thatprofessional donors carry a greater hazard (Allen,Dawson, Sayman, Humphreys, Benham andHavens, I959). The role of inadequately sterilizedinstruments doubtless is far more important intransmitting disease than is generally suspected.Attention has been drawn to this possibility incertain areas where parenteral therapy is commonin general practice, and the frequently describedoutbreaks of jaundice in clinics and their cessationfollowing appropriate sterilization of instrumentsare a matter of medical history (Havens, 1948,1954a). That individual physicians might beimplicated in such situations was reported in 1948(Correspondence-Naples) following the occurr-ence of an outbreak among the practice of aphysician in Italy, and more recently outbreakswere ascribed to the use of inadequately sterilizedequipment in the offices of two physicians in theUnited States (Dull, I96I) (CDC Report No. I2,I962). In this regard, attention was called again tothe possibilities of infection in certain dentalprocedures (Knighton, I96I).

Hepatitis Virus BEarly studies in experimentally infected

volunteers, reviewed elsewhere (Havens, 1948,I954a), revealed viremia to be present in theacute phase of disease and during the prolongedincubation period 87 days before the onset ofdisease, 60 days before the appearance of jaundice,and I6 days before the appearance of jaundice.

Similar attempts to recover virus from the bloodduring convalescence from one to five months afteronset were unsuccessful (Havens, 1948).Subsequent studies (Stokes, Berk, Malamut,Drake, Barondess, Bashe, Wolman, Farquhar,Bevan, Drummond, Maycock, Capps and Bennett,1954) (Neefe, Norris, Reinhold, Mitchell andHowell, I954) (Murray, Diefenbach, Ratner,Leone and Oliphant, 1954) were designed tofurnish evidence of the carrier state that wasalready well accepted on clinical and epidemio-logic grounds. As a result of these studies, it wasshown that certain persons with or withouthepatic disease might remain carriers for as longas five years. In addition, Virus B was found inthe blood of a donor I35 days after he gave atransfusion that was believed to have producedhepatitis in the recipient. The same donorsubsequently developed hepatitis and was againproven to have viremia six months after recovery(Murray and associates, 1954).As in infectious hepatitis, claims have been

made over the years of successful transmissionof Virus B to a variety of laboratory animals,embryonated eggs, and cultures of tissues of avariety of species. These have been reviewedpreviously (Havens, 1948, I954b) and attentionhas been called to the failure to substantiate anyof these claims. More recently, reports weremade of the isolation of hepatitis Virus B oncultures of embryonic human lung (Bolin,Alsever, Barger and Jarvis, 1961) and on culturesof a variety of cells by O'Malley, Meyer andSmadel (I96I). The former experiments havenot been reproduced by others; the latter are ofparticular interest since the virus isolated wasobtained from a pool of plasma known to containhepatitis Virus B, and patients convalescent fromserum hepatitis were found to have neutralizingantibodies against this agent. The results offurther studies are awaited with interest.As in infectious hepatitis, attempts have been

made to visualize hepatitis Virus B by means ofelectron microscopy. During recent years, reportshave come from Austria (Braunsteiner andassociates, 1957) and the United States (Gueft,1961) describing oval cytoplasmic particles 400 x600 A in size in sections of the liver from patientswith serum hepatitis. Again, as with Virus A ininfectious hepatitis, there is inadequate evidenceto prove that they actually represent hepatitisVirus B.

EpidemiologyIt has long been suspected that the epidemiology

of serum hepatitis and infectious hepatitis hasinterrelationships, although they have never beendefined. From the clinical standpoint, the

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coexistence of these two diseases became apparentwith the first known outbreak of serum hepatitisdescribed by Liirman (1885). Since then,numerous descriptions of the occurrence of bothdiseases in the same geographic areas have beenrecorded. This subject was reviewed in I957(Havens), and it was emphasized that strains ofVirus A and Virus B had been shown to coexist inseveral parts of the world. For example, duringWorld War II, strains of Virus B were found inthe Middle East and Italy during epidemics ofinfectious hepatitis and in the United States andEngland where infectious hepatitis was endemicand of low incidence. In the period of Occupationof Germany when infectious hepatitis wasappatently widespread, a strain of Virus B wasalso found (Evans, 1950). The differences andsimilarities between them are familiar to all, andthe former, in particular, have been the subjectof speculation. It has been suggested that theprolonged incubation period of serum hepatitisis a function of the route of inoculation, yet thedemonstration years ago that Virus A fed orally orinjected parenterally produced hepatitis withsimilar short incubation periods negates thisconcept. The fact that Virus A is excreted in thefaeces following parenteral inoculation (Havens,1946) has always appeared to be in strikingcontrast to the failures to recover Virus B from thefaeces of patients with serum hepatitis. That theremay be occasional exceptions to the latter, however,has been hinted by the rare occurrence of hepatitisin the wives of soldiers with serum hepatitis andthe description of contact cases in one outbreakof serum hepatitis reported by Mirick and Shank(1959). Attention was called recently (Havens,I961-1962) to the possibility that Virus B need notdepend on the needle for its survival but rather onthe emergence of new strains derived from VirusA that had undergone alterations in certainproperites during prolonged residence in thehost with alimentary disease and viremia. Thus,biologic survival might be guaranteed despite thefact that alterations in properties would maketransmission dependent on parenteral inoculation.Whether such speculations may be removed fromthe realm of fantasy and given a solid basis offact depends on the development of specificimmunologic techniques. Without them, we canalso do little more than think in terms of twostrains of hepatitis viruses, A and B, although thehistory of multiple attacks of hepatitis in personsat high risk of parenteral infection such as narcoticaddicts (Havens, 1956) has suggested that several

strains may exist. Stokes (1962) has recentlyre-emphasized this possibility, citing in supportof it the apparent differences in modifying effectsof normal human gamma globulin.PreventionThe inability to detect the presence of hepatitis

virus in human blood or its products and the lackof practical effective means to rid most of them ofiviable virus remain the major problems in theiprevention of parenterally transmitted disease.At present, human albumin and gamma globulinprepared by ethanol fractionation are the onlycomponents know to be free of the danger of'transmitting hepatitis. The attempts to utilize a'number of so-called hepatic functional studies,with special emphasis on those reflecting alterationsin serum proteins (Alsever, Barger, Priest andLove, 196I) and enzymes (Bang, Ruegsegger,Ley and Ladue, 1959), to detect carriers ofhepatitis virus among donors have been described;however, it is obvious that they are sharplylimited in effectiveness, since viremia may existin the presence of normal results. Following thedisappointment in the early failures of ultra-violet radiation of plasma, further efforts weremade to combine treatment with ultravioletradiation and beta-propiolactine, and preliminarypromising results with other viruses warrantfurther study of this approach (Stokes, I962).Storage of plasma at approximately go°F. for sixmonths, as recommended by Allen (1960), appearsto be effective in general although not always; itcannot, however, be said to be a practical way ofsolving the problem of stockpiling plasma forlarge-scale emergencies.The prevention of the artificial transmission of

hepatitis viruses at present depends largely onthe physician and his assistants. It is his responsi-(bility (a) to reserve the use of potentially infectiousmaterials to patients who actually need them, and(b) to use disposable equipment or be sure thatnondisposable equipment is thoroughly washedbefore autoclaving (15 to 20 pounds pressure for

\20 minutes) or boiling (30 minutes). Mirick,Ward and McCollum (1962) have found that theintramuscular injection of io ml. of normalhuman gamma globulin on two occasions a monthapart after receiving transfusions of blood signi-ficantly reduced the incidence of hepatitis withjaundice, although nonicteric infection occurredas frequently. The procurement of sufficientgamma globulin to have this practiced generallywould doubtless be a difficult problem to solve.

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the General Population of Three Counties in California, Amer. J. trop. Med. Hyg., 9, 639.COHEN, S., OHTA, G., SINGER, E. J., and POPPER, H. (1960): Immunocytochemical Study of Gamma Globulin inLiver in Hepatitis and Postnecrotic Cirrhosis, J. exp. Med., IIl, 285.

Correspondence-Naples (1948): Epidemic of Homologous Serum Hepatitis, J. Amer. med. Ass., 136, 209.CULLINAN, E. R., KING, R. C., and RIVERS, J. S. (1958): The Prognosis of Infective Hepatitis; a Preliminary Account of

a Long Term Follow-up Period, Brit. med. J., i, 1315.DAUER, C. C. (1961): Mortality from Infectious Hepatitis, Publ. Hlth. Rep. (Wash.), 76, oo6.DAVIS, E. V. (I96I): Isolation of Viruses from Children with Infectious Hepatitis, Science, 133, 2059.DEICHER, H. R. G., HOLMAN, H. R., and KUNKEL. H. G. (I960): Anticytoplasmic Factors in the Sera of Patients with

Systemic Lupus Erythematosus and Certain Other Diseases, Arthr. and Rheum., 3, I.DOUGHERTY, W. J., and ALTMAN, R. (1962): Viral Hepatitis in New Jersey 1960-1961, Amer. J. Med., 32, 704.DUBIN, I. N., SULLIVAN, B. H., Jr., LEGOLVAN, P. C., and MURPHY, L. C. (1960): The Cholestatic Form of Viral

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DULL, H. B. (1961): Syringe-transmitted Hepatitis: a Recent Epidemic in Historical Perspective, J. Amer. med. Ass.,176, 4I3.ESSEN, K. W., and LEMBKE, A. (I944): Zur Aetiologie der Hepatitis epidemica, Med. Ztschr., I, 99.EVANS, A. S. (I950): Serum Hepatitis in U.S. Troops in Germany, Proc. Soc. exp. Biol., 75, 809.GEAR, J. (1946): Autoantigens and Autoantibodies in the Pathogenesis of Disease with Special Reference to Blackwater

Fever, Trans. roy. Soc. trop. Med. Hyg., 39, 301.GOOD, R. A., and PAGE, A. R. (I960): Fatal Complications of Viral Hepatitis in Two Patients with Agammaglobulinemia,Amer. J. Med., 29, 804.GUEFT, B. (I96I): Viral Hepatitis under the Electron Microscope, Arch. Path., 72, 61.HAVENS, W. P., Jr. (1946): Elimination in Human Feces of Infectious Hepatitis Virus Parenterally Introduced, Proc.

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