The Willowbrook Hepatitis Studies Revisited: Ethical Aspects

SPECIAL ARTICLE

The Willowbrook Hepatitis Studies Revisited:Ethical Aspects

Saul Krugman From the Departmentof Pediatrics,New YorkUniversity School of Medicine,New York,New York

Studies of the natural history and prevention of viral hepatitis were initiated at Willow- brook State School in 1955. During the subsequent two decades there was considerable controversyregarding the ethical aspects of these studies. The background of these studies is described in detail in historical context. This report should provide the reader with in- formation needed to make an independent objective judgement of the ethics of the Wil- lowbrook hepatitis studies.

Duringthe first half of this century,outbreaks of were perceived by some critics to be unethical. As various infectious diseases were prevalentin or- a matter of fact, in recent years the name "Willow- phanages, military barracks,and institutionsfor brook" has become synonymous with medical re- mentallyretarded children. These outbreaks involved searchgone astray.With time, facts have become dis- highly susceptiblepopulations living in conditions torted or forgotten, leaving only emotions. of overcrowdingand poor hygiene. Certain infectious Thirty years have elapsed since the Willowbrook diseases,such as influenzaand measles,occurred as hepatitis studies were initiated in the mid-1950s. I epidemicsat variableintervals. Other infections, such am as convinced today as I was at that time that our as shigellosisand hepatitis,were generally endemic studies were ethical and justifiable. This judgement in nature. is based on knowledge of the extraordinary condi- Duringthe mid-1950smy colleague,Dr. Robert tions that existed in the institution as well as on an Ward,and I wereinvited to join the staff of Willow- assessment of the potential risks and benefits for the brookState School as consultantsin infectiousdis- participants. The purpose of this article is to discuss eases.This institution for mentallyretarded children the ethical aspects of our studies, within their ap- hadbeen plagued by the occurrenceof suchepidemic propriate historical context. It is hoped that this in- and endemicdiseases as measlesand hepatitis.Our formation will enable the readerto make an indepen- efforts duringthe nexttwo decadeswere devoted to dent, objective judgement as to the ethics of the the control of these infectious diseases. Willowbrook studies. In 1960an epidemicof measlesswept through Wil- lowbrook, 60 childrendead. The studiesthat leaving Establishment of the Willowbrook we initiatedwith the liveattenuated measles vaccine State School developedby Dr. JohnEnders and his colleaguescul- In 1938 the New York state legislature perceived the minatedin the eradicationof measlesfrom the in- need for an additional institution for the care of men- stitution by the end of 1963. tally retardedchildren. It allocated funds to purchase Hepatitis,which affected virtually every child in 375 acres of land located at Willowbrook on Staten Willowbrookas well as manyemployees, proved to Island and authorized the construction of facilities be a more difficult problem.It was essentialto ac- to care for 3,000 mentally retardedchildren from the quirenew knowledgeabout the naturalhistory of greater-NewYork metropolitan area. The institution, this disease- knowledgethat mightlead to its ulti- completed in 1942and designatedWillowbrook State mate control. School, was taken over by the federal government The studies duringthe subsequenttwo decades to meet an urgent need for an army hospital to care for disabled military personnel from World War II. The U.S. Army Medical Corps renamed it the Hal- Receivedfor publicationSeptember 10, 1985,and in revised loran General in honor of the late Colonel form October22, 1985. Hospital Paul a Pleaseaddress requests for reprintsto Dr.Saul Krugman, New Stacey Halloran, U.S. Army medical YorkUniversity School of Medicine,550 First Avenue, New York, corpsman. New York,10016 After the war ended-in 1945, there was consider-

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able political pressure to retain Halloran General State School and LetchworthVillage wereintroduced Hospital as a VeteransAdministration hospital. The into Willowbrook by patients who were transferred conflict between the needs of the VeteransAdminis- from these institutions. tration and the needs of the New York State Depart- ment of Mental Hygiene was described in the fol- Recognition of Hepatitis as an Endemic Disease lowing letter sent by Governor Thomas Dewey to General Omar Bradley,who was director of the Vet- The occurrence of so-called infectious hepatitis was erans Administration at that time. first observed in 1949. Later, in response to extraor- from the Everyyear in the Stateof New York,thousands dinary pressure many parents, patient popu- of childrencome into this worldwho arementally lation increased rapidly in subsequent years; it ex- and physicallydefective and feeble minded,who ceeded 3,000 in 1953, 4,000 in 1955, and eventually nevercan becomemembers of society.They require it exceeded 6,000. In his report to a joint legislative constantcare, both medicallyand physically,and committee on mental and physical handicap, the late in many cases, for social, psychologicaland eco- Dr. Jack Hammond, director of Willowbrook State nomicreasons, few parents can afford to placethem School stated: in privateinstitutions. Even if suchinstitutions existedin sufficientquantity, the resultis thatthe state The overcrowdedconditions in the buildingsmake must take responsibilityfor the careof these chil- care,treatment, supervision and possibletraining drenand do so witha highdegree of tendernessand of the patientsdifficult, if not impossible.When attention. the patientsare up and in the day rooms,they are At present,the Stateof New Yorkoperates two crowdedtogether, soiling, attackingeach other, downstateinstitutions for the careof such infants abusingthemselves and destroyingtheir clothing. and children.One is the WassaicState School in At nightin manyof the dormitoriesthe beds must Duchess and the other is LetchworthVillage in be placed togetherin order to providesufficient Rockland County. There are severalother state spacefor all patients.Therefore, except for one nar- schoolsfor mentaldefectives but theyare too over- rowaisle, it is virtuallynecessary to climbover beds crowdedand none is or can be equippedfor the ad- in orderto reachthe children. ditonal care of infants. Hundredsof infantsand childrenunable to care The residents of Willowbrook State School were for themselvesare sleeping on mattresseson floors the most severely retarded, the most handicapped, of these institutions.What is more seriousis that and the most helpless of those being cared for in the thereare to nine hundredinfants eight on the wait- New York state system. The population of about list for admissionand the StateCommission of ing 6,000 included 77%7who were severelyor profoundly MentalHygiene daily must deal with distracted par- retarded,60% who were not toilet trained, 39% who ents who seek to havetheir children placed in state institutions.The mail of the Commissionerof Men- were not ambulatory, 30% who had convulsive sei- and 64% who were of tal Hygieneis filledwith lettersfrom suchparents, zures, incapable feeding them- many of whom are veterans. selves. Thus, the conditions were optimal for the It seemsto me that we are now confrontedwith transmission of hepatitis, shigellosis, respiratoryin- these two conflictingobligations at Willowbrook. fections, and parasitic infections. The firstis that of the FederalGovernment to pro- By the early 1950s the director of Willowbrook vide hospitalcare for its veteransafter they are dis- and his staff were convinced that serious overcrowd- chargedfrom service.The secondis the obligation ing and an inadequatestaff werein great part respon- of the Stateof NewYork to carefor provide perma- sible for the increasing hepatitis problem. Their nently helpless infants. Obviously,Willowbrook statisticsindicated that the annual attack rate of cannot be used for both. hepatitis with jaundice was 25 per 1,000 among the chil- Finally, on October 24, 1947, after a delay of five dren and 40 per 1,000 among the adults. Efforts to years, 10 patients from Wassaic State School and 10 correct this intolerable situation were unsuccessful. patients from Letchworth Village were transferred Society had created a problem, but it provided no to Willowbrook State School. Initially, patients were solution. It was during that period that my colleague, both transferredfrom other institutions and admit- the late Dr. Robert Ward, and I were asked to join ted from the community. In retrospect, it is appar- the staff of Willowbrook as consultants in infectious ent that the infectious diseases endemic in Wassaic diseases. We were not qualified to deal with the so- WillowbrookRevisited 159

cietalproblems, but we believedthat we could help abilityof removingmy child from Willowbrook State control the existingmedical problemof hepatitis. School so that he/she can live at home."A total of 24 parentsresponded, and only two childrenwere taken home at that time! Identificationof the HepatitisProblem in Willowbrook The WillowbrookHepatitis Studies Our first objectivein 1955was to carryout an ex- tensiveepidemiologic survey. We were fortunate be- After one yearof carefulobservation and study in cause new tests to detect hepaticdysfunction were 1955,we concludedthat the controlof hepatitisin describedthat year,namely, serum glutamic oxaloa- Willowbrookcould be achievedif it werepossible cetic transaminase(SGOT) and serumglutamic py- to deviseand conductwell-designed studies to shed ruvic transaminase(SGPT). These sensitiveassays new light on the naturalhistory and preventionof enabledus to detectthe presenceof hepatitiswith- the disease- new knowledgethat couldconceivably out jaundice (anicterichepatitis). Today, SGOT is lead to the developmentof a vaccine.Thus, our de- called alanine aspartatetransaminase (AST), and cision to proposethe exposureof a small number SGPT is called alanine aminotransferase(ALT). of newlyadmitted children to the endemicWillow- Our colleague,the late Dr. Joan P. Giles, joined brookstrain of hepatitisvirus was reachedafter se- us during this period. During the course of our riousconsideration of the'followingfactors and as- epidemiologicsurveys and the performanceof rou- sumptions: tine physicalexaminations, she collectedmany thou- (I) As indicatedpreviously, under the conditions sands of serum specimens.Instead of discarding existingin the institution,most newlyadmitted chil- them - the usual practice in most laboratories - we drenwould contract hepatitis. This empiricimpres- storedthem in an increasingnumber of deepfreezers. sion was confirmedin the 1970swhen newlydevel- The scientificdividends of this serumbank proved oped serologic tests revealedthat >907o of the to be incalculablein later years. residentsof the institutionhad hepatitisA and B After the resultsof the SGOTand SGPT assays markersof past infection. werereviewed, it wasobvious that the detectedcases (2) Hepatitiswas knownto be especiallymild in of icterichepatitis represented the tip of a hepatitis the three-to 10-yearage groupthat would partici- iceberg.The resultsof these highlysensitive tests of pate in the studies.Our extensivesurvey confirmed liverdysfunction convinced us that most newlyad- that most infectionswere inapparent or benignand mittedchildren were destined to contracthepatitis there wereno deaths. infectionunder the conditionsthat existedin the in- (3) Theartificially induced infection would induce stitution.The occurrenceof hepatitisamong Wil- immunityto the endemicstrain of hepatitisvirus lowbrookchildren was as predictableand inevitable and, we hoped,to otherstrains that mightbe intro- as the occurrenceof respiratoryinfections among duced by new admissionsor transfersto Willow- childrenin day care centers. brook. Studiesin the 1940shad revealedthat hepa- Duringthe courseof our epidemiologicsurvey in titis A infection was followed by homologous 1955,all of the evidenceindicated that the endemic immunity.Therefore, the artificiallyinduced infec- diseasewas so-calledinfectious or type A hepatitis, tion would be prophylactic. an infectionthat spreadvia the fecal-oralroute. The (4) The childrenwould be admittedto a specially diseasewas mild and there were no deaths.Although equipped,specially staffed unit wherethey would the samedisease was more severe and more debilitat- be isolated from exposureto other endemicinfec- ing in the adultemployees, they, too, recoveredcom- tious diseasesoccurring in the institution- namely, pletely.Previous experience of variousinvestigators shigellosis,respiratory infections, and parasiticin- had revealedthat hepatitisA was much milderin fections. childrenthan in adults.Efforts to reducethe over- (5) Only children whose parents gave consent crowdedconditions at Willowbrookcontinued to be would be included. Our method of obtainingin- unsuccessful.In a desperateattempt the director formed consent changed progressivelyduring the mailedletters to about5,000 parents, requesting that courseof the studies.In 1956the informationwas theyreturn a questionnairethat containedthe state- conveyedto individualparents by letteror personal ment, "I wish to discussthe possibilityand advis- interview.Later, we adopteda group techniqueof 160 Krugman

obtainingconsent. First, a psychiatricsocial worker Duringthe period1956-1967, we believedthat we discussedthe projectwith parentsduring a prelimi- weredealing with endemicityof hepatitisA, an in- nary interview.Those who wereinterested were infectionthat shouldbe followedby lastingimmunity. vited to attenda groupsession at the institutionto However,by 1967it wasobvious that manychildren discussthe projectin greaterdetail. These sessions had had two attacksof hepatitis.Our studies of this wereconducted by our staff responsiblefor the pro- phenomenonrevealed that one attackwas caused by gram,including Dr. Giles, the supervisingnurse, staff the so-calledMS-1 strain of hepatitisvirus and the attendants,and psychiatricsocial workers. Meetings secondattack, by the MS-2 strain.Thus, it became wereoften attendedby outsidephysicians who had apparentthat two types of hepatitiswere endemic expressedinterest. Parents, in groupsof six to eight, in Willowbrook-MS-1,resembling hepatitis A, and were given a tour of the facilities. The purposes, MS-2,resembling hepatitis B. By 1969,after Blum- potentialbenefits, and potentialhazards of the pro- bergdiscovered the Australiaantigen, the newtech- gramwere discussed with them, and they wereen- nologyenabled us to confirmthat Willowbrook MS- couragedto ask questions.Thus, all parentscould 2 serumcontained hepatitis B antigen. hear the responseto questionsposed by the more Our serum bank containedspecimens obtained articulatemembers of the group.After leavingthis from most patients who contractednaturally ac- briefingsession, parents had an opportunityto talk quiredhepatitis during the period1956-1969. When withtheir private physicians, who couldcall Dr. Giles we testedthese serumspecimens in the 1970s,using for moreinformation. Approximately two weeksaf- the newlydeveloped serologic assays, it wasobvious ter the visit, the psychiatricsocial workercontacted that both hepatitisA (MS-1)and hepatitisB (MS-2) the parentsfor theirdecision. If the decisionwas in had been endemicin the institutionsince 1956. It the affirmative,the consentwas signed,but parents was also apparentthat hepatitisB, like hepatitisA, wereinformed that consentcould be withdrawnat wasgenerally a mild or inapparentinfection in Wil- anytime. It wasclear that the groupmethod enabled lowbrook children.A retrospectivediagnosis was us to obtain a more thorough informed consent. madeby testingthe serafor the presenceof hepati- Childrenwho were wardsof the state or children tis B antigen and abnormal serum transaminase withoutparents were never included in our studies. values. During the course of this new survey,we From 1956the protocolswere reviewed and sanc- foundthat most childrenhad markersof presentor tioned by variouslocal, state,and federalagencies. past hepatitisB infection. Thus, it was likely that Thesestudies were reviewed and approved by the New newlyadmitted children would be intenselyexposed YorkUniversity and Willowbrook State School com- to both types of hepatitis.When this new informa- mitteeson humanexperimentation after their for- tion was presentedto the membersof the Commis- mationin February1967. Prior to thisdate, the func- sion on ViralInfections of the ArmedForces Epi- tions of the presentInstitutional Review Board were demiologicalBoard in 1969, they agreedthat the performedby the ExecutiveFaculty of the School studies should be continued. of Medicinefor studiesof this type.The initialpro- It shouldbe emphasizedthat the studieswere con- posal in 1956was reviewed and approvedby the fol- ductedin WillowbrookState School becausehepa- lowinggroups: Executive Faculty, New York Univer- titis wasa severeproblem in this institutionand not, sitySchool of Medicine;New York State Department as somecharged, because we werelooking for a fac- of MentalHygiene; New YorkState Department of ile "guineapig" population. The fact that the chil- Health;and ArmedForces Epidemiological Board. drenwere mentally retarded was relevant only to the It is of interestthat the guidelinesthat wereadopted extent that society placed them in an institution for the hepatitisstudies at their inceptionin 1956 wherehepatitis was prevalent.The primaryobjec- conformedto the WorldMedical Association's draft tive of our studies was to protectthe childrenand Code of Ethicson HumanExperimentation, which employeeswhile acquiringnew knowledgein the was presentedto its generalassembly in September process. 1961,five yearslater. It is also of interestthat our established of informedconsent was instituted policy of Contributionsof Willowbrook at least 10 beforeit was mandated most re- Summary years by Studies searchinstitutes and medicalcenters in the United Hepatitis States. The accomplishmentsof the Willowbrookstudies WillowbrookRevisited 161

are well documentedin the medicalliterature (see for childrenin ourspecial isolation unit was less than Bibliography,below). They include: the risk for other childrenwho were admittedto (1) Identification of two distinctive clinical, buildingsin the institutionwhere shigellosis and re- epidemiologic,and immunologictypes of hepatitis, spiratoryinfections, as well as hepatitis,were en- MS-1(type A) andMS-2 (typeB). The serumspec- demic. imenscollected from patientswith MS-1and MS-2 A centuryago ClaudeBernard defined the limits infection providedmany investigatorswith "pedi- of human experimentation.He statedthat A or greed"sera knownto be specificfor hepatitis it is our and our to an Blum- duty right perform experi- B. Afterthe discoveryof Australiaantigen by ment on man wheneverit can save life, curehim, berg and colleagues,the use of these clinicalsam- or gainsome potential benefit. The principle of med- ples by variousinvestigators established the associ- icaland surgical morality, therefore, consists in never ation between Australia antigen and hepatitis B performingon man an experimentwhich might be virus. harmfulto him to any extent,even though the re- (2) Demonstrationthat hepatitisB infection is sult may be highly advantageousto scienceor to transmittedby intimatecontact and oral as well as the health of others.But performingexperiments parenteralexposure. Previously,it wasbelieved that and operationsexclusively from the point of view inoculationwith contaminatednee- of thepatient's own advantage does not preventtheir percutaneous out to science. dles, blood, or blood productswas essentialfor the turning profitably transmissionof hepatitisB. It is well recognizedto- My colleague,the lateDr. JoanP. Giles,expressed day that hepatitisB is a sexuallytransmitted infec- it beautifullyand succinctlyin herletter to the Lan- tion andit is spreadby intimatephysical contact and cet, publishedMay 29, 1971,in which she said, "A transferof body fluids. farmermay pull up corn seedlingsto destroythem (3)Demonstration that hepatitis B immuneglobu- or he may pull them up to set them in betterhills lin is effectivefor theprevention of type B hepati- for better growing.How then does one judge the tis. The resultsof this study led to the initiation deed withoutthe motive?"This describesthe moti- of severallarge multicentertrials to determinethe vationfor our studiesat WillowbrookState School. efficacy of HBIG in preventinghepatitis B among I am greatlyindebted to manycollaborators, col- suchhigh-risk individuals as hemodialysisstaff and leagues, and organizationsfor support and en- patients,newborns of HBsAg-positivemothers, sex- couragementduring the courseof our Willowbrook ual contactsof patientswith acute hepatitisB, and hepatitisstudies: personsaccidentally inoculated with HBsAg-positive To the late Dr. RobertWard, who was the prin- blood by needle-stickexposures. cipal investigatorof our studiesfrom 1956to 1958. (4) Developmentof thefirst prototype inactivated He was an outstandinginvestigator and a colleague hepatitis B vaccine. It was demonstratedthat a who had exceptionalhuman qualities. boiled 1:10dilution of MS-2 serumin distilledwa- To the late Dr. Joan P. Giles, who died of cancer ter was not infectious,but it was immunogenicand in 1973after devoting 17 years of herlife to the care protective.These studies, published in 1970,clearly of the childrenin our hepatitisunit. Shewas a highly demonstratedthe feasibilityof developinga hepati- ethicalphysician and a personof greathumanity and tis B vaccineand stimulatedvarious investigators to integrity. prepareinactivated vaccines from the plasma of ToHarriet Friedman and CassLattimer, research chronichepatitis B carriers. associates,for morethan 25 yearsof competentand meticulouswork in our laboratory. To the late Dr. Jack directorof Wil- Conclusion Hammond, lowbrookState School. He and his dedicatedstaff WhileI agreewith the criticsof medicalresearch who laboredunder the most difficultcircumstances. They statethat the ends (successfulaccomplishments) do weresubjected to incredibleabuse by certainrepre- not justify the means,I believethat this generaliza- sentativesof the newsmedia and by publicity-seeking tion does not applyto our Willowbrookstudies. Un- legislatorswho criticizedthem for the horriblecon- derthe conditionsthat existedin the institution,all ditions in the institution. Their morale was childrenwere constantly exposed to the naturallyac- devastatedbecause they knewthat the pressuresof quiredhepatitis viruses. Moreover, the overallrisk society(distraught parents and their legislators) were 162 Krugman

responsiblefor increasingthe census to more than Giles JP, LiebhaberH, KrugmanS, LattimerC. Earlyviremia 6,000in a 3,000-bedinstitution. It was"society" that andviruria in infectioushepatitis. Virology 1964;24:107-8 was for the con- KrugmanS, GilesJP, Hammond J. Infectioushepatitis: evidence responsible overcrowded,unhygienic for twodistinctive clinical, epidemiological, and immuno- ditions in Willowbrook,not the dedicatedpeople logical types of infection. JAMA 1967;200:365-73(re- who workedthere under stressfulconditions. printedas a LandmarkArticle; JAMA 1984; 252:393-401) To the late Dr. John R. Paul and Dr. Robert GilesJP, KrugmanS. Viralhepatitis: immunoglobulin response McCollumof YaleUniversity for their encourage- duringthe courseof the disease.JAMA 1969;208:497-503 ment and wise counsel the 1950sand 1960s. Giles JP, McCollumRW, Berndtson LW Jr, KrugmanS. Viral during hepatitis:relation of Australia/SHantigen to the Willow- Tothe ArmedForces Epidemiological Board and brook MS-2 strain.N Engl J Med 1969;281:119-22 the U.S. ArmyMedical Research and Development KrugmanS, GilesJP, Hammond J. Hepatitisvirus: effect of heat Command for 25 consecutiveyears of financial on the infectivityand antigenicityof the MS-1and MS-2 support. strains.J Infect Dis 1970;122:432-6 to anddevoted KrugmanS, GilesJP. Viral hepatitis: new light on an old disease. And, finally, manyloyal colleagues JAMA 1970;212:1019-29 and friendswhose supporthelped ease the pain in- LanderJJ, GilesJP, Purcell RH, KrugmanS. Viralhepatitis, type flictedby manyvicious attacks during the late 1960s B (MS-2strain): detection of antibodyafter primary in- and early 1970s.We wereespecially grateful to the fection. N Engl J Med 1971;285:303-7 parentsof the Willowbrookchapter of the Benevo- KrugmanS, GilesJP, Hammond J. Viralhepatitis, type B (MS-2 strain):studies on active immunization.JAMA 1971; lent Societyof RetardedChildren for the plaquethat 217:41-5 they presentedto us at their 1967annual meeting. KrugmanS, GilesJP, Hammond J. Viralhepatitis, type B (MS-2 The inscriptionon the plaque stated, "In recogni- strain):prevention with specifichepatitis B immunese- tion of distinguished,pioneering, humanitarian re- rum globulin.JAMA 1971;218:1665-70 searchin the preventionof infectiousdiseases and Le BouvierGL, McCollumRW, Hierholzer WJ Jr, IrwinGT, their resultant in born and KrugmanS, GilesJP. Subtypesof Australiaantigen and complication children, hepatitis-Bvirus. JAMA 1972;222:928-30 unborn." KrugmanS, GilesJP. Viralhepatitis, type B (MS-2-strain).Fur- ther observationson natural history and prevention. N Engl J Med 1973;288:755-60 GerinJL. Bibliography(in chronologicorder) KrugmanS, HoofnagleJH, GeretyRJ, KaplanPM, Viralhepatitis, type B: DNA polymeraseactivity and an- WardR, KrugmanS, GilesJP, JacobsAM, Bodansky0. Infec- tibody to hepatitis B core antigen. N Engl J Med tious hepatitis:studies of its naturalhistory and preven- 1974;290:1331-5 tion. N Engl J Med 1958;258:407-16 KrugmanS, BirdRG, Zuckerman AJ. Characterizationof MS-2 KrugmanS, WardR. Clinicaland experimentalstudies of infec- (hepatitisB) serumby electronmicroscopy. J InfectDis tious hepatitis.Pediatrics 1958;22:1016-22 1974;130:416-8 KrugmanS, WardR, GilesJP, Bodansky0, JacobsAM. Infec- KrugmanS, FriedmanH, LattimerC. Viralhepatitis, type A: tioushepatitis: detection of virusduring incubation period identificationby specificcomplement fixation and immune and in clinicallyinapparent infection. N Engl J Med adherencetests. N Engl J Med 1975;292:1141-3 1959;261:729-34 KrugmanS. Effect of humanimmune serum globulin on infec- Bodansky0, KrugmanS, WardR, SchwartzMK, Giles JP, Jacobs tivity of hepatitisA virus. J Infect Dis 1976;134:70-4 AM. Infectioushepatitis: correlation of clinicaland lab- DienstagJL, KrugmanS, WongDC, PurcellRH. Comparison oratoryfindings, including serum enzyme changes. Am of serologicaltests for antibodyto hepatitisA antigen, J Dis Child 1959;98:166-86 usingcoded specimens from individuals infected with the KrugmanS, WardR, GilesJP, JacobsAM. Infectioushepatitis: MS-1 strain of hepatitis A virus. Infect Immun studieson the effect of gammaglobulin and on the inci- 1976;14:1000-3 dence of inapparentinfection. JAMA 1960;174:823-30 KrugmanS, FriedmanH, LattimerC. HepatitisA and B: sero- KrugmanS, WardR. Infectioushepatitis: current status of preven- logic surveyof variouspopulation groups. Am J MedSci tion with gamma globulin. Yale J Biol Med 1961/2; 1978;275:249-55 34:329-39 KrugmanS, OverbyLR, Mushahwar IK, Ling C-M, Fr6sner GG, KrugmanS, WardR, GilesJP. The naturalhistory of infectious DeinhardtF Viralhepatitis, type B: studieson naturalhis- hepatitis.Am J Med 1962;32:717-28 tory and preventionre-examined. N Engl J Med 1979; GilesJP, Krugman S, ZiringP, JacobsAM, LattimerC. Leucine 300:101-6 aminopeptidaseactivity in infectioushepatitis. Am J Dis KrugmanS. Incubationperiod of typeB hepatitis[letter]. N Engl Child 1963;105:256-60 J Med 1979;300:625