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• W1977797400 abstract "In this article, I am discussing selected aspects of the history of viral hepatitis. I believe that those who are unable or unwilling to learn from history are compelled to repeat it. The history of viral hepatitis is a telling example of the reticence and tenacious resistance that acceptance of new scientific findings and concepts may encounter when faced by ingrained orthodoxy and authoritarian dogmatism. It is very likely that viral hepatitis is a disease of antiquity, mentioned already by Hippocrates 2400 years ago when he wrote of infectious icterus.1 We do not know, of course, whether this might have been hepatitis A, hepatitis E or some other acquired form of liver disease. But it is beyond doubt that in the Middle Ages, outbreaks of what was then called ‘campaign or epidemic jaundice’ frequently were associated with, or followed by, major human catastrophes, such as wars, famines or earthquakes. And in World War I, the military forces on either side of the Western Front were heavily plagued by hepatitis, as was the German army in World War II, particularly at the Russian front. These dramatic epidemic outbreaks undoubtedly were caused by hepatitis A virus, but at the time of World War II, it still was an unfamiliar concept that such epidemics could be the result of viral infections transmitted by contaminated food or water. In contrast to hepatitis A, transferred by the fecal–oral route, ‘serum hepatitis’ (now equated with hepatitis B or C) was first observed in 1885, but at that time it was of course not recognized as an infectious disease. In that year, Lürman witnessed an almost explosive outbreak of ‘catarrhal jaundice’ in several hundred workers of a large shipyard in the Hansastadt Bremen.2 And in the same year, Jehn reported a similar outbreak among the inmates of an insane asylum in Merzig in the Saarland.3 These workers and inmates recently had been vaccinated against smallpox. The illness appeared 2–8 months following administration of a glycerinated human lymph preparation; it usually presented with systemic manifestations of fatigue, anorexia and gastrointestinal complaints, followed by progressive jaundice and pruritus. After exclusion of all other possibilities, Lürman deductively concluded that the vaccine was the putative cause of the disease, but he cautiously added ‘I am not in a position to supply an explanation for this curious chain of cause and effect’.2 This was hardly surprising, as the concept of filtrable subcellular agents as the cause of human infection emerged only at the beginning of the 20th century,4 and positive identification of a self-replicating crystalline virus did not occur until 50 years later.5 It is remarkable, therefore, that already in 1908, McDonald with refined foresight had prophesized that fulminant hepatitis may be an infectious disease transmitted by a pathogenic virus.6 It took several decades and countless misinterpretations before this novel, even revolutionary concept had gained acceptance in the English-speaking world, and it took even longer to convince the medical establishment of Continental Europe. Subsequent to Lürman and Jehn's striking reports, unexplained jaundice occurred with increasing frequency in groups of patients treated with commonly used medications such as the antisyphilitic Salvarsan7 or insulin. Salvarsan, in particular, was considered a hepatotoxic drug, an erroneous belief which in Continental Europe obstinately survived beyond World War II,8 despite an earlier report by the Medical Research Council of Great Britain that demonstrated convincingly that organic arsenicals do not harm the liver. After the introduction of insulin in 1922, jaundice also appeared with increasing frequency in diabetic hospital wards and clinics. However, it took several decades to realize that this was produced not by insulin, but by the multiple use of blood-contaminated injection needles.8 One of the most illustrative happenings was the so-called Schnepper Ikterus reported in 1926 by Flaum et al. from the Diabetes Clinic in Göteborg, Sweden.9 Here, jaundice developed in a large number of diabetic patients who regularly visited the clinic's laboratory for blood–sugar determinations. The blood samples were drawn by piercing the earlobe with a small spring-loaded lancet that was cleaned only perfunctorily between uses. Flaum et al. astutely concluded that this epidemic of jaundice was caused by a viral infection transmitted from patient-to-patient by the contaminated Schnepper.9 This and similar reports that appeared during the last decade before the outbreak of World War II,10 gradually furnished very strong evidence for parenteral transmission of serum hepatitis by blood-contaminated needles or through administration of human-derived vaccines or blood products. Irrefutable evidence eventually was provided in 1942 by the catastrophic outbreak of infectious hepatitis in 28 585 USA servicemen who had been inoculated with yellow fever vaccine, 62 of whom died.11 Alarmed by this report, the British Cabinet decided against the yellow fever vaccination of Prime Minister Winston Churchill in preparation for his historic visit with Stalin in 1942.12 The transmission of this viral infection also became an increasing problem in war casualties and civilians transfused with whole blood, plasma or other human blood products. As a consequence, major hepatitis research projects were initiated during the latter part of World War II in the USA and England. These included deliberate transmission of infectious hepatitis to human volunteers under strictly controlled conditions. The results of these and other studies appeared towards the end of World War II in several classical publications,13-16 which for the first time permitted a clear distinction between acute infectious (epidemic) hepatitis A and the more drawn out (serum) hepatitis B. The former appeared to be an acute, self-limited disease with an incubation time of 15–43 days. By contrast, the incubation time of hepatitis B was several months, and its course seemed to be more protracted and often chronic. These studies also showed that infectious (epidemic) hepatitis A is usually transmitted by virus-infected human excreta that had contaminated drinking water or food, whereas serum hepatitis B seemed to be transferred by direct exposure to virus-containing blood or blood products or through intimate body contact. And last, it was demonstrated that a filtrate of fecal material obtained from patients with hepatitis A was infective, thus confirming that the pathogenic agent is a subcellular viral particle, as had been prophesized almost 40 years earlier by McDonald.6 It is worth noting that the first successful deliberate transmission of viral hepatitis to human volunteers was reported in 1942 by Voegt who was a member of Eppinger's Clinic at the University Hospital in Vienna; he used controlled oral administration of duodenal aspirate or parenteral injection of blood collected from patients with ‘catarrhal jaundice’.17 Voegt's findings, for obvious reasons, escaped attention in the English-speaking countries and his chief, Professor Hans Eppinger, never accepted the validity of his observations. It is surprising and ironic that when faced with such overwhelming scientific evidence, the medical establishment of Continental Europe until well after the end of World War II8 obstinately refused to accept ‘catarrhal jaundice’ as a viral infection of the liver parenchyma. Instead, it tenaciously believed in the time-honored dogma of an inflammatory mucous plug obstructing biliary drainage in the region of the papilla of Vater. Although an analogy with obstructive bronchitis may have been alluring, such a mucous plug in the biliary tree never had been observed or clearly documented at autopsy stage. I tried, but failed to discover where this century-old myth of the biliary mucous plug might have originated; it had appeared in the literature already in the 18th century. It was fully endorsed in the 19th century by the elite of Europe's hierarchical academic medicine, including such luminaries as the pathologist Rokitansky and the clinical liver specialists Laënnec, Hanot, Budd and particularly Frerichs whose textbook ‘Klinik der Leberkrankheiten’ was such a success that it was translated into English and French within 2 years of its appearance in 1858. What undoubtedly provided the ultimate dogmatic imprimatur of the mucous plug misconception was its endorsement by Virchow in 1865.18 Such was Virchow's magistral authority that even after World War II, students at Continental medical schools still were taught the fallacy of the mucous plug, while needle-transmitted viral infection remained unappreciated as the cause for the high incidence of catarrhal jaundice in diabetic wards.8 And as late as 1940, Lainer who was Eppinger's Oberarzt at Vienna's University Hospital, published what he called the crucial experiment to rule out an infectious etiology of catarrhal jaundice. His evidence consisted of the observation that healthy medical students, given blood or duodenal aspirate from jaundiced patients failed to develop icterus.19 Eppinger, who probably was the most brilliant hepatologist of the first half of the twentieth century, never accepted an infectious etiology of catarrhal jaundice;20 it has been suggested that realization of this scientific error may have contributed to his progressive depression and eventual suicide in 1945. During the first two decades after the end of World War II, major efforts were undertaken to identify, isolate and propagate hepatitis viruses in vitro in the hope of eventually developing protective vaccines. In the USA, most of these investigations were funded by the U.S. Army Medical Research Subcommittee on Liver, which was chaired by Professor Hans Popper. But despite major efforts, all attempts failed to detect putative hepatitis viruses by morphologic or culture techniques.8 An international symposium, organized by the National Academy of Sciences and the Armed Forced Epidemiological Board in New York in 1954 reviewed and analyzed this frustrating experience.21 But despite the inability to discover the viruses causing hepatitis A and B, a few noteworthy and important advances were made during the 1950s and 1960s. These included the demonstration that Marmosets (dwarf monkeys) are susceptible to transmission of hepatitis A.22 Another very significant contribution was made by a long-term epidemiological research project based in the Willowbrook New York State School under the direction of Paul Krugman.23 These investigations demonstrated immunologic distinction between the two known types of viral hepatitis, and provided crucial information on their mode of transmission, incubation times and duration of viremia and viral shedding in naturally or deliberately infected patients. But, as identification of the hepatitis viruses had remained elusive, the only means available for identification of infectious material was controlled transmission of the infection to susceptible humans or subhuman primates, a procedure that met with considerable polemic.8 The long-awaited breakthrough came in the late 1960s from an unexpected source, and as is frequently the case, the full significance of the initial observation was not immediately recognized. In studies of genetic polymorphism of serum proteins, Blumberg, Alter and Visnich detected a novel antigen in plasma of patients with leukemia or thalassemia and of some apparently healthy individuals living in tropical or subtropical regions.24 But subsequent observations by several investigators25-27 unmistakably linked the new antigen to hepatitis B, and it also was identified by Krugman's group in serum samples from Willowbrook patients suffering from ‘long-incubation-period serum hepatitis’.28 And in 1970, Dane et al. detected spherical virus-like 42 nm particles in the serum of patients with antigen-associated viral hepatitis,29 which eventually turned out to be the hepatitis B virus. These momentous discoveries gave enormous impetus to hepatitis research, both in the USA and in the re-emerging European and Japanese research establishments. Within a few years, the hepatitis B virus was structurally characterized as a DNA virus, its immunogenic determinants were defined and its biological and pathogenic properties recognized.30, 31 And after little more than 10 years since the identification of the hepatitis B virus, an effective hepatitis B vaccine became available.32 Once the hepatitis B virus had been identified and characterized, the discovery of the hepatitis A virus followed suit in short time. Moreover, additional viruses were detected in patients with acute or chronic hepatitis who had tested negative for hepatitis A or B virus; initially these illnesses collectively were called non-A, non-B hepatitis.33 The hepatitis A virus was first described in 1973 by Feinstone et al.,34 when they detected virus-like particles in feces of patients experimentally infected with hepatitis A virus-contaminated material. The particles, measuring 27 nm were immunoprecipitated by serum collected from patients during convalescence, but not during the acute phase of the infection. Provost and Hilleman subsequently succeeded in propagating hepatitis A virus in cell culture,35 which greatly facilitated its identification as a single-stranded RNA virus and allowed analysis of its genome. A form of acute self-limited viral hepatitis, similar to hepatitis A, but serologically distinct, had been observed since the 1980s in South-East Asia and other tropical regions. It was designated hepatitis E, and evidently was transmitted by the fecal–oral route and perhaps also by sexual contact, but its epidemiology still is poorly understood. It differs clinically from hepatitis A in that it tends to cause fulminant and frequently fatal hepatitis in women in the third trimester of pregnancy. The virus causing hepatitis E has been identified as a single-stranded RNA virus, which by means of PCR, was detected in feces, serum and bile samples of hepatitis E patients or experimentally infected primates.36 A hepatitis E vaccine is being developed and currently is undergoing clinical trials. By the mid-1970s, blood banks had started to test their blood supplies for antibodies to hepatitis A and B and to discard positive blood units. As a consequence, the incidence of transfusion-transmitted hepatitis dropped, but it did so far less than expected.37 In fact, after transfusion of multiple blood units, occurrence of hepatitis at times was as high as 20%, and most of these patients were serologically negative for hepatitis A and B.33, 37 Although this form of transfusion-associated non-A, non-B hepatitis initially was regarded as a mild illness, it soon was recognized as a slowly progressive chronic liver disease, eventually proceeding to cirrhosis38 and frequently causing primary hepatocellular carcinoma.39 Many attempts were made to identify the virus of this non-A, non-B hepatitis, but all methods failed which had been successful in other similar instances.37 However, in the late 1970s, the infection was successfully transmitted to chimpanzees.40 With this new experimental approach, it was observed that when sequentially challenged with different inocula, chimpanzees developed a series of individual episodes of non-A, non-B hepatitis.41 This strongly suggested that there existed more than one non-A, non-B virus. Because of the continuing failure to identify and isolate the putative hepatitis C virus, Houghton et al. resorted to recombinant DNA cloning technology, which in 1989 allowed the preparation of a non-A, non-B hepatitis-specific DNA clone.42 Bacterial expression of this clone produced a protein that was recognized by specific antibodies present in serum of patients with hepatitis C or of chimpanzees challenged with the virus. The cDNA clone had been derived from a single-stranded RNA molecule of approximately 9500 nucleotides that was exclusively present in infectious material. Moreover, the single-stranded RNA was found to encode an antigen that was specifically associated with non-A, non-B hepatitis in chimpanzees and humans.42 The identification of a single-stranded RNA molecule as the infective agent of hepatitis C was a dramatic breakthrough. In rapid sequence, the virus' genome and genetic diversity were defined,43, 44 virus replication was reported in human T-cell culture,45 and preliminary observations were reported with a vaccine protecting chimpanzees against experimental hepatitis C infection.46 With the elimination of hepatitis C-infected blood from blood banks, the incidence of transfusion-transmitted hepatitis sharply dropped, but it did not completely vanish. This may suggest that there are additional blood-borne agents causing hepatic infection that remain to be discovered. The use of sensitive tests for the assay of circulating antibodies to hepatitis C virus revealed that the disease occurs world-wide with an incidence ranging from 0.1 to 2.0% in different populations.47 Most of these cases represent chronic hepatitis and many are clinically asymptomatic. The epidemiology is understood incompletely, but blood-borne transmission appears to be predominant, including legitimate and illegitimate use of virus- contaminated needles. The origin of the hepatitis C virus remains obscure, but its geographically based genetic heterogeneity and world-wide distribution suggest that it is a virus that has been around for a long time.48 This selective review of the history of viral hepatitis offers an impressive illustration of how relatively crude but perceptive epidemiological observations, made more than 100 years ago, eventually led to the development of effective vaccines for several types of viral hepatitis. But the path was a long and circuitous one, strewn with unappreciated observations, lack of imaginative interpretations and dogmatic rigidity. To be sure, in 1885, Lürman2 and Jehn3 were in no position to suspect that the human lymph used for preparing small pox vaccine could have been contaminated with hepatitis virus. But it was only a few years later that a filtrable, subcellular agent was identified as the cause of bovine foot-and-mouth disease.49 And around the turn of the last century, yellow fever was the first human infection shown to be transmitted by a filtrable, submicroscopic agent.4 McDonald, therefore, was very much in step with his time when in 1908, he speculated that fulminant hepatitis may be an infectious disease caused by a virus (at that time, virus meant an infective, filtrable, subcellular agent).6 And by 1926, Flaum et al. were convinced that the epidemic of jaundice, observed in diabetics who had their ears pierced by a Schnepper, was transmitted from human-to-human by a virus.9 It is astounding, therefore, that it took another 15 years until the English-speaking world accepted the idea that hepatitis is a human-transmitted viral disease. And in Continental Europe, the war-related breakdown of communication and ingrained dogmatism were delaying this realization for another decade. Hippocrates undoubtedly was correct when he said ‘In medicine, one must pay attention not to plausible theorizing, but to experience and reason’.50" @default.
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• W1977797400 title "History of viral hepatitis: A tale of dogmas and misinterpretations1" @default.
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