THE YALE JOURNAL OF BIOLOGY AND MEDICINE 49, 199-203 (1976)
Viral Hepatitis: Overview and Historical Perspectives' SAUL KRUGMAN Department of Pediatrics, New York University School of Medicine, New York, New York 10016 Received December 15, 1975
It is a privilege and an honor to be asked to present a general overview and a historical perspective of a subject that has occupied the last 20 years of my medical career. I can assure you that when I accepted this assignment, I did not regard it with a "jaundiced eye." It is particularly appropriate to discuss viral hepatitis with military consultants to the Armed Forces because it is well known that this disease has had a profound effect on military as well as civilian populations throughout the world. During the past three or more centuries "epidemic jaundice" (viral hepatitis, type A) has been recognized as an important military disease, especially during periods of war. Outbreaks were recorded in Germany in 1629 and in the British Army in Flanders in 1743. Epidemics occurred in military and civilian populations at the time of the siege of Paris during the Franco-Prussian war in 1870. Other epidemics occurred during the Boer War in South Africa and in the Japanese Navy during the war with Russia in 1904. This trend continued during the course of all subsequent conflicts: World Wars I and II, the Middle East Wars in 1948, 1956, and 1967, and more recently the Korean and Vietnamese Wars. During the past 50 years the term "epidemic jaundice" referred to a disease that had other names in various parts of the world: jaunice des camps in France, Soldatengelbsucht in Germany, infective hepatitis in England, Botkin's disease in Russia, and acute catarrhal jaundice, epidemic hepatitis, and infectious hepatitis in the United States and other parts of the world. More recently the term proposed by MacCallum in the 1940's, "viral hepatitis, type A," has been adopted. Unlike epidemic jaundice, an ancient disease, serum hepatitis (type B hepatitis) has a more recent history. The first outbreak was described less than 100 years ago by Liirman (1). The occurrence of smallpox in Bremen in 1883 was followed by an extensive vaccination program. The vaccine at that time was prepared from glycerinated lymph of human origin. Of 1289 vaccinated shipyard workers, 191 (15%) developed jaundice after intervals of several weeks to 6 months. In contrast, of 500 unvaccinated new employees, none became jaundiced. In retrospect, it is obvious today that Liirman's report of an epidemic of icterus in 1883 represented the first recognition of an epidemic of viral hepatitis, type B. During the first half of this century it became obvious that epidemics of jaundice were occurring in patients attending venereal disease clinics, diabetic clinics, and tuberculosis clinics, and in children who received inoculations of measles and mumps human convalescent serum, in patients who received blood transfusions, and in 'Supported in part by the U.S. Army Medical Research and Development Command (Contract No. DAMD 17-76-C-6012). Presented at the Annual Meeting of the Society of Medical Consultants to the Armed Forces, Shoreham Hotel, Washington, D.C., December 10, 1975.
199 Copyright © 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.
200
SAUL KRUGMAN
military personnel who received yellow fever vaccine. Epidemiological investigations incriminated contaminated needles and syringes, contaminated blood and blood products, and the infectious human serum component of the vaccine as the source of hepatitis virus. The disease that has been designated as viral hepatitis, type B, today, accumulated more than 20 aliases during the past 50 years. A few of the more common former names include serum hepatitis, long-incubation hepatitis, post-transfusion hepatitis, homologous serum hepatitis or jaundice, yellow fever vaccine hepatitis, and post-salvarsan or arsphenamine hepatitis or jaundice. In his discussion of historical perspectives at an international symposium on viral hepatitis that was held in Toronto, Canada, in 1971, Dr. F. 0. MacCallum cited two important events related to hepatitis that undoubtedly had an impact on both the history of medicine and the history of the world (2). The first event occurred in Sweden in 1925 and the second in England in 1942. A report by Flaum and colleagues (3) from Sweden described an epidemic ofjaundice that occurred among diabetics attending a laboratory for blood tests. This episode occurred shortly after Banting and Best in Toronto isolated insulin. Fortunately, the Swedish patients did not receive insulin. As stated by Dr. MacCallum, "one can imagine the consternation that might have been caused if their hepatitis had occurred after injection of the new wonder drug and the present world-wide rapid dissemination of information in the lay and medical press had prevailed at that time." The episode that occurred in England is best described in Dr. MacCallum's own words: "One day in 1942, I received a message to go to Whitehall to see one of the senior medical advisers and when I arrived I was asked 'What is this yellow fever vaccine and how dangerous is it?' After explaining its constitution and the possibility of a mild reaction four to five days after inoculation, I was told that the Cabinet was at that moment debating whether or not Mr. Churchill should be allowed to go to Moscow, which he wished to do in a few days' time. The yellow fever vaccine was theoretically essential before he could fly through the Middle East, but I explained that no antibody would be produced before seven to ten days so that there would be little point in giving the vaccine. It was finally decided that the vaccine would not be used, and the administrators would take care of the situation. Several months later I received an irate call from the Director of Medical Services of the R.A.F. who had been inoculated with the same batch of vaccine which would have been used for Mr. Churchill, and was informed that the D. G. had spent a very mouldy Christmas with hepatitis about 66 days after his inoculation.... I will leave it to you to speculate on what might possibly have been the effect on the liver of our famous statesman and our ultimate fate if he had received the icterogenic vaccine." The importance of hepatitis as a military and civilian disease provided the motivation for many investigators in the 1940's to search for a suitable animal model for the propagation of the causative agent or agents. With the advent of tissue culture technology in the 1950's it was hoped that hepatitis virus, like poliovirus and other viruses, would be successfully cultivated in cell culture. On March 31, 1954, a symposium on the laboratory propagation and detection of the agent of hepatitis was sponsored by the National Academy of Sciences and the Armed Forces Epidemiological Board. The participants, several of whom are present at this meeting, reviewed the extensive studies by many investigators who described negative results of their attempts to propagate hepatitis virus in cell cultures, in guinea pigs, in hamsters, in rabbits, in various strains of mice and rats, in newborn swine, and in such nonhuman primates as baboons, chimpanzees, marmosets, and various species of monkeys. At the conclusion of this meeting Dr. Sabin who was
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201
present stated that he considered the meeting unique in presenting such an encouraging display of perseverance and patience in the face of frustrating experimentation. Two and a half years later another symposium, sponsored by Henry Ford Hospital, was held in Detroit, Michigan. The participants of this symposium reviewed the current status of knowledge of the etiology of viral hepatitis. At this meeting McLean, Rightsell, and their colleagues (4) described their studies suggesting that they had cultured hepatitis virus in Detroit: six cell cultures. In their conclusion they stated that, "On the basis of these data we cannot be sure that the virus of hepatitis is being cultivated, but it is not unlikely and certainly further work is indicated." Nearly 20 years have elapsed since this meeting and as of the present time no one has successfully cultivated hepatitis virus A or B in cell culture. Evidence for the viral etiology of hepatitis stemmed in great part from the results of experiments with human volunteers in the 1940's. Type A hepatitis was studied by Voeght (5), by Cameron (6), by MacCallum and Bradley (7), by Havens (8), by Paul, Havens, Sabin, and Philip (9), and by Stokes and Neefe (10). These investigators also studied type B hepatitis (9,1 1). These studies identified two immunologically distinct types of hepatitis. Type A hepatitis was characterized by an incubation period of approximately 15 to 34 days as compared with 56 to 134 days for type B. Type A hepatitis occurred after oral and parenteral exposure. Type B hepatitis, however, was transmitted by inoculation but not orally. Homologous immunity was present, and there was no evidence of heterologous immunity. Hepatitis A virus was present in stools and serum during the acute phase of the disease; it was not detected during convalescence. Hepatitis B virus was demonstrated in blood during the incubation period as well as the acute phase of the disease. These studies were extended by Stokes and colleagues (12) in the 1950's when they demonstrated a carrier state. It was in 1945 that Stokes and Neefe (13) and Havens and Paul (14) reported that type A hepatitis could be prevented or attenuated by the use of 'y-globulin. These studies were subsequently confirmed and extended by many other investigators. Passive immunization will be discussed in detail by Major Gilbert Irwin during the course of this symposium. Our studies at the Willowbrook State School in the late 1950's and 1960's further confirmed and extended previous observations of the natural history, epidemiology, and prevention of viral hepatitis. The background of our studies and the justification for carrying them out were described in detail in various publications (15-18). The new findings may be summarized as follows. (i) Hepatitis A virus was demonstrated in stools and serum during the latter part of the incubation period as well as during the acute phase; it was not detected during convalescence. (ii) Serum containing hepatitis B virus was shown to be infective by mouth as well as by inoculation. (iii) Hepatitis B was shown to spread under the conditions of prolonged, intimate physical contact. (iv) Two immunologically distinct types of hepatitis were identified in an institution where hepatitis was highly endemic. One type, designated MS-1, resembled type A hepatitis, and the other, designated MS-2, resembled type B hepatitis. (v) A series of controlled studies with immune serum globulin confirmed and extended previous reports (19,20). These studies provided the basis for recommendations for the use and dosage schedule of y-globulin for military personnel assigned to areas where hepatitis was highly endemic. They were subsequently confirmed by the Korean studies to be discussed by Major Irwin.
202
SAUL KRUGMAN
The discovery of Australia antigen by Blumberg and his colleagues (21,22) during the latter part of the 1960's and its association with hepatitis B virus provided the technology needed to further clarify the natural history of type B hepatitis. During a seminar on viral hepatitis in Paris in 1971 Dr. John F. Enders highlighted this important development when he said: "After a long and arid period, a new and exhilarating phase in the study of hepatitis has begun. The discovery of Australia antigen came like an unexpected shower on desert soil." In the wake of this discovery, many investigators from many disciplines, virology, epidemiology, immunology, biochemistry, hematology, and others, were attracted to the field of hepatitis research. The result has been a virtual explosion of new knowledge. The exciting new developments in both hepatitis B and hepatitis A research were discussed in March of this year during a 3-day symposium sponsored by the National Academy of Sciences (23). Briefly, the highlights of this symposium included: (i) Visualization by electron microscopy and partial characterization of hepatitis A virus, its successful transmission to marmoset monkeys and chimpanzees, and the development of a practical, sensitive immune adherence test to detect hepatitis A antibody by Dr. Hilleman and his colleagues. (ii) Visualization by electron microscopy and characterization of hepatitis B virus and its antigens, its successful transmission to chimpanzees, the development of sensitive tests to detect hepatitis B surface and core antigens and their respective antibodies, the development of an inactivated hepatitis B vaccine from purified hepatitis B surface antigen, and the development of hepatitis B immune serum globulin from plasma containing high levels of antibody to hepatitis B surface antigen. These new developments will be summarized and updated by the participants of this symposium. I should like to conclude this overview and historical perspective of viral hepatitis on a note of serendipity. It is well known that Blumberg's study that led to the discovery of Australia antigen was not designed to discover the causative agent of type B hepatitis. If he had included this objective in his grant application, the study section would have considered him either naive or out of his mind. Yet, the chance inclusion of one serum specimen from an Australian aborigine in a panel of 24 sera that was used in his study of polymorphisms of serum proteins and the development of isoprecipitins in transfused patients led to detection of an antigen that subsequently proved to be the hepatitis B surface antigen. In retrospect, it was obvious that the Australian aborigine was a hepatitis B carrier. Our development of a heat-inactivated hepatitis B vaccine in 1970 also resulted from pure serendipity. Our study was designed to determine the effect of heat (boiling for 1 min) on the infectivity of hepatitis A virus. The results indicated that this treatment of a 1:10 dilution of MS- I serum in distilled water destroyed the infectivity of the hepatitis A virus that was present (24). These findings indicated that it was not necessary to boil water for 15 to 20 min under field conditions where hepatitis contamination was suspected. Later when the same study was repeated using a 1:10 dilution of MS-2 serum in distilled water, it became obvious that the 1-min boil destroyed the infectivity of the hepatitis B virus, but much to our surprise the material was antigenic. In subsequent studies it was shown that this heat-inactivated serum was antigenic, protective, and not infectious and that it behaved like an inactivated hepatitis B vaccine (25,26). During the past 5 years progress achieved in hepatitis research has been truly phenomenal. However, as we shall learn during the course of this symposium much remains to be done. Unlike the difficult problem of cancer the technology is available, in great part, to solve many problems related to hepatitis. At least two important ingredients are essential: money and time. We who have been involved in hepatitis re-
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search during the past three decades have been keenly aware that until recent years the major support came from the Armed Forces. Our studies on the natural history and prevention of viral hepatitis have been funded by the Army for 21 consecutive years. A recent survey by Dr. Sabin revealed that in 1974 the National Institutes of Health provided the major support to most investigators in the field. Additional funds have been provided by other governmental as well as private agencies. I feel confident that in his closing remarks Dr. Sabin will highlight the urgent need for continuation of adequate support at this crucial period when so many problems need solution. REFERENCES 1. Lurman, A., Eine Icterusepidemie. Berlin Klin. Wochenschr. 22, 207 (1885). 2. MacCallum, F. O., Historical perspectives. Canadian Med. Assoc. J. 106,423 (1972). 3. Flaum, A., Malmros, H., and Persson, E., Eine nosocomiale ikterus Epidemic. Acta Med. Scand. (Suppl.) 16, 544 (1926). 4. Rightsel, W. A., Keltsch, R. A., Tekushan, F. M., and McLean, I. W., Tissue culture cultivation of cytopathic agents from patients with clinical hepatitis. Science 124, 226 (1956). 5. Voeght, H., Zur Aetiologie der Hepatitis epidemica. Munchen Med. Wochenschr. 89, 76 (1942). 6. Cameron, J. D. A., Infective hepatitis. Quart J. Med. 12, 139 (1943). 7. MacCallum, F. O., and Bradley, W. H., Transmission of infective hepatitis to human volunteers. Lancet 2, 228 (1944). 8. Havens, W. P., et al., Experimental production of hepatitis by feeding icterogenic materials. Proc. Soc. Exp. Biol. Med. 57, 206 (1944). 9. Paul, J. R., Havens, W. P., Sabin, A. B., and Philip, C. B., Transmission experiments in serum jaundice and infectious hepatitis. J. Amer. Med. Ass. 128, 911 (1945). 10. Neefe, J. R., Gellis, S. S., and Stokes, J., Jr., Homologous serum hepatitis and infectious (epidemic) hepatitis: Studies in volunteers bearing on immunological and other characteristics of the etiological agents. Amer. J. Med. 1, 3 (1946). 11. MacCallum, F. O., Transmission of arsenotherapy jaundice by blood: Failure with feces and nasopharyngeal washings. Lancet 1, 342 (1945). 12. Stokes, J. Jr., et al., The carrier state in viral hepatitis. J. Amer. Med. Ass. 154, 1059 (1954). 13. Stokes, J. Jr., and Neefe, J. R., Prevention and attenuation of infectious hepatitis by gamma globulin: Preliminary note. J. Amer. Med. Ass. 127, 144 (1945). 14. Havens, W. P., Jr., and Paul, J. R., Prevention of infectious hepatitis with gamma globulin. J. Amer. Med. Ass. 129, 270-272 (1945). 15. Ward, R., et al., Studies on its natural history and prevention. N. Engi. J. Med. 258, 407 (1958). 16. Krugman, S., Ward, R., and Giles, J. P., The natural history of infectious hepatitis. Amer. J. Med. 32, 717 (1962). 17. Krugman, S., Giles, J. P., and Hammond, J., Infectious hepatitis: Evidence for two distinctive clinical, epidemiological, and immunological types of infection. J. Amer. Med. Ass. 200, 365 (1967). 18. Krugman, S., and Giles, J. P., Viral hepatitis: New light on an old disease. J. Amer. Med. Ass. 212, 1019-1029 (1970). 19. Krugman, S., et al., Infectious hepatitis: Studies on the effect of gamma globulin and on the incidence of inapparent infection. J. Amer. Med. Ass. 174, 823 (1960). 20. Krugman, S., and Ward, R., Infectious hepatitis: Current status of prevention with gamma globulin. Yale J. Biol. Med. 34, 329-339 (1961-62). 21. Blumberg, B. S., Alter, H. J., and Visnich, S., A 'new' antigen in leukemia sera. J. Amer. Med. Ass. 191, 541-546 (1965). 22. Blumberg, B. S., et al., A serum antigen (Australia antigen) in Down's syndrome, leukemia and hepatitis. Ann. Intern. Med. 66,924 (1967). 23. Proceedings of a symposium on viral hepatitis held at the National Academy of Sciences, Washington, D.C., March 17-19, 1975. Amer. J. Med. Sci. 270, No. 1 and 2 (1975). 24. Krugman, S., Giles, J. P., and Hammond, J., Hepatitis virus: Effect of heat on the infectivity and antigenicity of the MS- I and MS-2 strains. J. Infect. Dis. 122, 432 (1970). 25. Krugman, S., Giles, J. P., and Hammond, J., Viral hepatitis, type B: Studies on active immunization. J. Amer. Med. Ass. 217, 41 (1971). 26. Krugman, S., and Giles, J. P., Viral hepatitis, type B (MS-2 strain): Further observations on natural history and prevention. N. Engl. J. Med. 288,755 (1973).
Viral Hepatitis: Overview and Historical Perspectives' SAUL KRUGMAN Department of Pediatrics, New York University School of Medicine, New York, New York 10016 Received December 15, 1975
It is a privilege and an honor to be asked to present a general overview and a historical perspective of a subject that has occupied the last 20 years of my medical career. I can assure you that when I accepted this assignment, I did not regard it with a "jaundiced eye." It is particularly appropriate to discuss viral hepatitis with military consultants to the Armed Forces because it is well known that this disease has had a profound effect on military as well as civilian populations throughout the world. During the past three or more centuries "epidemic jaundice" (viral hepatitis, type A) has been recognized as an important military disease, especially during periods of war. Outbreaks were recorded in Germany in 1629 and in the British Army in Flanders in 1743. Epidemics occurred in military and civilian populations at the time of the siege of Paris during the Franco-Prussian war in 1870. Other epidemics occurred during the Boer War in South Africa and in the Japanese Navy during the war with Russia in 1904. This trend continued during the course of all subsequent conflicts: World Wars I and II, the Middle East Wars in 1948, 1956, and 1967, and more recently the Korean and Vietnamese Wars. During the past 50 years the term "epidemic jaundice" referred to a disease that had other names in various parts of the world: jaunice des camps in France, Soldatengelbsucht in Germany, infective hepatitis in England, Botkin's disease in Russia, and acute catarrhal jaundice, epidemic hepatitis, and infectious hepatitis in the United States and other parts of the world. More recently the term proposed by MacCallum in the 1940's, "viral hepatitis, type A," has been adopted. Unlike epidemic jaundice, an ancient disease, serum hepatitis (type B hepatitis) has a more recent history. The first outbreak was described less than 100 years ago by Liirman (1). The occurrence of smallpox in Bremen in 1883 was followed by an extensive vaccination program. The vaccine at that time was prepared from glycerinated lymph of human origin. Of 1289 vaccinated shipyard workers, 191 (15%) developed jaundice after intervals of several weeks to 6 months. In contrast, of 500 unvaccinated new employees, none became jaundiced. In retrospect, it is obvious today that Liirman's report of an epidemic of icterus in 1883 represented the first recognition of an epidemic of viral hepatitis, type B. During the first half of this century it became obvious that epidemics of jaundice were occurring in patients attending venereal disease clinics, diabetic clinics, and tuberculosis clinics, and in children who received inoculations of measles and mumps human convalescent serum, in patients who received blood transfusions, and in 'Supported in part by the U.S. Army Medical Research and Development Command (Contract No. DAMD 17-76-C-6012). Presented at the Annual Meeting of the Society of Medical Consultants to the Armed Forces, Shoreham Hotel, Washington, D.C., December 10, 1975.
199 Copyright © 1976 by Academic Press, Inc. All rights of reproduction in any form reserved.
200
SAUL KRUGMAN
military personnel who received yellow fever vaccine. Epidemiological investigations incriminated contaminated needles and syringes, contaminated blood and blood products, and the infectious human serum component of the vaccine as the source of hepatitis virus. The disease that has been designated as viral hepatitis, type B, today, accumulated more than 20 aliases during the past 50 years. A few of the more common former names include serum hepatitis, long-incubation hepatitis, post-transfusion hepatitis, homologous serum hepatitis or jaundice, yellow fever vaccine hepatitis, and post-salvarsan or arsphenamine hepatitis or jaundice. In his discussion of historical perspectives at an international symposium on viral hepatitis that was held in Toronto, Canada, in 1971, Dr. F. 0. MacCallum cited two important events related to hepatitis that undoubtedly had an impact on both the history of medicine and the history of the world (2). The first event occurred in Sweden in 1925 and the second in England in 1942. A report by Flaum and colleagues (3) from Sweden described an epidemic ofjaundice that occurred among diabetics attending a laboratory for blood tests. This episode occurred shortly after Banting and Best in Toronto isolated insulin. Fortunately, the Swedish patients did not receive insulin. As stated by Dr. MacCallum, "one can imagine the consternation that might have been caused if their hepatitis had occurred after injection of the new wonder drug and the present world-wide rapid dissemination of information in the lay and medical press had prevailed at that time." The episode that occurred in England is best described in Dr. MacCallum's own words: "One day in 1942, I received a message to go to Whitehall to see one of the senior medical advisers and when I arrived I was asked 'What is this yellow fever vaccine and how dangerous is it?' After explaining its constitution and the possibility of a mild reaction four to five days after inoculation, I was told that the Cabinet was at that moment debating whether or not Mr. Churchill should be allowed to go to Moscow, which he wished to do in a few days' time. The yellow fever vaccine was theoretically essential before he could fly through the Middle East, but I explained that no antibody would be produced before seven to ten days so that there would be little point in giving the vaccine. It was finally decided that the vaccine would not be used, and the administrators would take care of the situation. Several months later I received an irate call from the Director of Medical Services of the R.A.F. who had been inoculated with the same batch of vaccine which would have been used for Mr. Churchill, and was informed that the D. G. had spent a very mouldy Christmas with hepatitis about 66 days after his inoculation.... I will leave it to you to speculate on what might possibly have been the effect on the liver of our famous statesman and our ultimate fate if he had received the icterogenic vaccine." The importance of hepatitis as a military and civilian disease provided the motivation for many investigators in the 1940's to search for a suitable animal model for the propagation of the causative agent or agents. With the advent of tissue culture technology in the 1950's it was hoped that hepatitis virus, like poliovirus and other viruses, would be successfully cultivated in cell culture. On March 31, 1954, a symposium on the laboratory propagation and detection of the agent of hepatitis was sponsored by the National Academy of Sciences and the Armed Forces Epidemiological Board. The participants, several of whom are present at this meeting, reviewed the extensive studies by many investigators who described negative results of their attempts to propagate hepatitis virus in cell cultures, in guinea pigs, in hamsters, in rabbits, in various strains of mice and rats, in newborn swine, and in such nonhuman primates as baboons, chimpanzees, marmosets, and various species of monkeys. At the conclusion of this meeting Dr. Sabin who was
VIRAL HEPATITIS: OVERVIEW AND PERSPECTIVES
201
present stated that he considered the meeting unique in presenting such an encouraging display of perseverance and patience in the face of frustrating experimentation. Two and a half years later another symposium, sponsored by Henry Ford Hospital, was held in Detroit, Michigan. The participants of this symposium reviewed the current status of knowledge of the etiology of viral hepatitis. At this meeting McLean, Rightsell, and their colleagues (4) described their studies suggesting that they had cultured hepatitis virus in Detroit: six cell cultures. In their conclusion they stated that, "On the basis of these data we cannot be sure that the virus of hepatitis is being cultivated, but it is not unlikely and certainly further work is indicated." Nearly 20 years have elapsed since this meeting and as of the present time no one has successfully cultivated hepatitis virus A or B in cell culture. Evidence for the viral etiology of hepatitis stemmed in great part from the results of experiments with human volunteers in the 1940's. Type A hepatitis was studied by Voeght (5), by Cameron (6), by MacCallum and Bradley (7), by Havens (8), by Paul, Havens, Sabin, and Philip (9), and by Stokes and Neefe (10). These investigators also studied type B hepatitis (9,1 1). These studies identified two immunologically distinct types of hepatitis. Type A hepatitis was characterized by an incubation period of approximately 15 to 34 days as compared with 56 to 134 days for type B. Type A hepatitis occurred after oral and parenteral exposure. Type B hepatitis, however, was transmitted by inoculation but not orally. Homologous immunity was present, and there was no evidence of heterologous immunity. Hepatitis A virus was present in stools and serum during the acute phase of the disease; it was not detected during convalescence. Hepatitis B virus was demonstrated in blood during the incubation period as well as the acute phase of the disease. These studies were extended by Stokes and colleagues (12) in the 1950's when they demonstrated a carrier state. It was in 1945 that Stokes and Neefe (13) and Havens and Paul (14) reported that type A hepatitis could be prevented or attenuated by the use of 'y-globulin. These studies were subsequently confirmed and extended by many other investigators. Passive immunization will be discussed in detail by Major Gilbert Irwin during the course of this symposium. Our studies at the Willowbrook State School in the late 1950's and 1960's further confirmed and extended previous observations of the natural history, epidemiology, and prevention of viral hepatitis. The background of our studies and the justification for carrying them out were described in detail in various publications (15-18). The new findings may be summarized as follows. (i) Hepatitis A virus was demonstrated in stools and serum during the latter part of the incubation period as well as during the acute phase; it was not detected during convalescence. (ii) Serum containing hepatitis B virus was shown to be infective by mouth as well as by inoculation. (iii) Hepatitis B was shown to spread under the conditions of prolonged, intimate physical contact. (iv) Two immunologically distinct types of hepatitis were identified in an institution where hepatitis was highly endemic. One type, designated MS-1, resembled type A hepatitis, and the other, designated MS-2, resembled type B hepatitis. (v) A series of controlled studies with immune serum globulin confirmed and extended previous reports (19,20). These studies provided the basis for recommendations for the use and dosage schedule of y-globulin for military personnel assigned to areas where hepatitis was highly endemic. They were subsequently confirmed by the Korean studies to be discussed by Major Irwin.
202
SAUL KRUGMAN
The discovery of Australia antigen by Blumberg and his colleagues (21,22) during the latter part of the 1960's and its association with hepatitis B virus provided the technology needed to further clarify the natural history of type B hepatitis. During a seminar on viral hepatitis in Paris in 1971 Dr. John F. Enders highlighted this important development when he said: "After a long and arid period, a new and exhilarating phase in the study of hepatitis has begun. The discovery of Australia antigen came like an unexpected shower on desert soil." In the wake of this discovery, many investigators from many disciplines, virology, epidemiology, immunology, biochemistry, hematology, and others, were attracted to the field of hepatitis research. The result has been a virtual explosion of new knowledge. The exciting new developments in both hepatitis B and hepatitis A research were discussed in March of this year during a 3-day symposium sponsored by the National Academy of Sciences (23). Briefly, the highlights of this symposium included: (i) Visualization by electron microscopy and partial characterization of hepatitis A virus, its successful transmission to marmoset monkeys and chimpanzees, and the development of a practical, sensitive immune adherence test to detect hepatitis A antibody by Dr. Hilleman and his colleagues. (ii) Visualization by electron microscopy and characterization of hepatitis B virus and its antigens, its successful transmission to chimpanzees, the development of sensitive tests to detect hepatitis B surface and core antigens and their respective antibodies, the development of an inactivated hepatitis B vaccine from purified hepatitis B surface antigen, and the development of hepatitis B immune serum globulin from plasma containing high levels of antibody to hepatitis B surface antigen. These new developments will be summarized and updated by the participants of this symposium. I should like to conclude this overview and historical perspective of viral hepatitis on a note of serendipity. It is well known that Blumberg's study that led to the discovery of Australia antigen was not designed to discover the causative agent of type B hepatitis. If he had included this objective in his grant application, the study section would have considered him either naive or out of his mind. Yet, the chance inclusion of one serum specimen from an Australian aborigine in a panel of 24 sera that was used in his study of polymorphisms of serum proteins and the development of isoprecipitins in transfused patients led to detection of an antigen that subsequently proved to be the hepatitis B surface antigen. In retrospect, it was obvious that the Australian aborigine was a hepatitis B carrier. Our development of a heat-inactivated hepatitis B vaccine in 1970 also resulted from pure serendipity. Our study was designed to determine the effect of heat (boiling for 1 min) on the infectivity of hepatitis A virus. The results indicated that this treatment of a 1:10 dilution of MS- I serum in distilled water destroyed the infectivity of the hepatitis A virus that was present (24). These findings indicated that it was not necessary to boil water for 15 to 20 min under field conditions where hepatitis contamination was suspected. Later when the same study was repeated using a 1:10 dilution of MS-2 serum in distilled water, it became obvious that the 1-min boil destroyed the infectivity of the hepatitis B virus, but much to our surprise the material was antigenic. In subsequent studies it was shown that this heat-inactivated serum was antigenic, protective, and not infectious and that it behaved like an inactivated hepatitis B vaccine (25,26). During the past 5 years progress achieved in hepatitis research has been truly phenomenal. However, as we shall learn during the course of this symposium much remains to be done. Unlike the difficult problem of cancer the technology is available, in great part, to solve many problems related to hepatitis. At least two important ingredients are essential: money and time. We who have been involved in hepatitis re-
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search during the past three decades have been keenly aware that until recent years the major support came from the Armed Forces. Our studies on the natural history and prevention of viral hepatitis have been funded by the Army for 21 consecutive years. A recent survey by Dr. Sabin revealed that in 1974 the National Institutes of Health provided the major support to most investigators in the field. Additional funds have been provided by other governmental as well as private agencies. I feel confident that in his closing remarks Dr. Sabin will highlight the urgent need for continuation of adequate support at this crucial period when so many problems need solution. REFERENCES 1. Lurman, A., Eine Icterusepidemie. Berlin Klin. Wochenschr. 22, 207 (1885). 2. MacCallum, F. O., Historical perspectives. Canadian Med. Assoc. J. 106,423 (1972). 3. Flaum, A., Malmros, H., and Persson, E., Eine nosocomiale ikterus Epidemic. Acta Med. Scand. (Suppl.) 16, 544 (1926). 4. Rightsel, W. A., Keltsch, R. A., Tekushan, F. M., and McLean, I. W., Tissue culture cultivation of cytopathic agents from patients with clinical hepatitis. Science 124, 226 (1956). 5. Voeght, H., Zur Aetiologie der Hepatitis epidemica. Munchen Med. Wochenschr. 89, 76 (1942). 6. Cameron, J. D. A., Infective hepatitis. Quart J. Med. 12, 139 (1943). 7. MacCallum, F. O., and Bradley, W. H., Transmission of infective hepatitis to human volunteers. Lancet 2, 228 (1944). 8. Havens, W. P., et al., Experimental production of hepatitis by feeding icterogenic materials. Proc. Soc. Exp. Biol. Med. 57, 206 (1944). 9. Paul, J. R., Havens, W. P., Sabin, A. B., and Philip, C. B., Transmission experiments in serum jaundice and infectious hepatitis. J. Amer. Med. Ass. 128, 911 (1945). 10. Neefe, J. R., Gellis, S. S., and Stokes, J., Jr., Homologous serum hepatitis and infectious (epidemic) hepatitis: Studies in volunteers bearing on immunological and other characteristics of the etiological agents. Amer. J. Med. 1, 3 (1946). 11. MacCallum, F. O., Transmission of arsenotherapy jaundice by blood: Failure with feces and nasopharyngeal washings. Lancet 1, 342 (1945). 12. Stokes, J. Jr., et al., The carrier state in viral hepatitis. J. Amer. Med. Ass. 154, 1059 (1954). 13. Stokes, J. Jr., and Neefe, J. R., Prevention and attenuation of infectious hepatitis by gamma globulin: Preliminary note. J. Amer. Med. Ass. 127, 144 (1945). 14. Havens, W. P., Jr., and Paul, J. R., Prevention of infectious hepatitis with gamma globulin. J. Amer. Med. Ass. 129, 270-272 (1945). 15. Ward, R., et al., Studies on its natural history and prevention. N. Engi. J. Med. 258, 407 (1958). 16. Krugman, S., Ward, R., and Giles, J. P., The natural history of infectious hepatitis. Amer. J. Med. 32, 717 (1962). 17. Krugman, S., Giles, J. P., and Hammond, J., Infectious hepatitis: Evidence for two distinctive clinical, epidemiological, and immunological types of infection. J. Amer. Med. Ass. 200, 365 (1967). 18. Krugman, S., and Giles, J. P., Viral hepatitis: New light on an old disease. J. Amer. Med. Ass. 212, 1019-1029 (1970). 19. Krugman, S., et al., Infectious hepatitis: Studies on the effect of gamma globulin and on the incidence of inapparent infection. J. Amer. Med. Ass. 174, 823 (1960). 20. Krugman, S., and Ward, R., Infectious hepatitis: Current status of prevention with gamma globulin. Yale J. Biol. Med. 34, 329-339 (1961-62). 21. Blumberg, B. S., Alter, H. J., and Visnich, S., A 'new' antigen in leukemia sera. J. Amer. Med. Ass. 191, 541-546 (1965). 22. Blumberg, B. S., et al., A serum antigen (Australia antigen) in Down's syndrome, leukemia and hepatitis. Ann. Intern. Med. 66,924 (1967). 23. Proceedings of a symposium on viral hepatitis held at the National Academy of Sciences, Washington, D.C., March 17-19, 1975. Amer. J. Med. Sci. 270, No. 1 and 2 (1975). 24. Krugman, S., Giles, J. P., and Hammond, J., Hepatitis virus: Effect of heat on the infectivity and antigenicity of the MS- I and MS-2 strains. J. Infect. Dis. 122, 432 (1970). 25. Krugman, S., Giles, J. P., and Hammond, J., Viral hepatitis, type B: Studies on active immunization. J. Amer. Med. Ass. 217, 41 (1971). 26. Krugman, S., and Giles, J. P., Viral hepatitis, type B (MS-2 strain): Further observations on natural history and prevention. N. Engl. J. Med. 288,755 (1973).
