Before the precise recognition of what we now define as viruses, bacteria, fungi, and protozoa, all infectious agents were referred to as viruses, from the Latin for poison. The work of scientists such as Pasteur, Lister, and Koch in the 1800s led to the isolation of pure cultures of bacteria and the demonstration of their causal role in infectious diseases. By the turn of the century, experimental evidence was accumulating that culture-sterile, filtered preparations could transmit infection 151, 185. For example, Walter Reed published his observations on the transmission of yellow fever by inoculation of human volunteers with filtered serum isolated from patients with clinical disease in 1902. He commented "Yellow fever, like the foot and mouth disease of cattle, is caused by a micro-organism so minute in size that it might be designated as ultra-microscopic" 206. Transmission of foot-and-mouth disease observed in cattle followed earlier reports that tobacco mosaic disease could be transmitted with a filtered inoculum 151, 185. In contrast, the viral etiology of epidemic jaundice was not widely accepted by physicians until the mid-20th century. Indeed, an editorial in the Journal of the American Medical Association used the term "catarrhal jaundice" as late as 1943 15. The basic science of viruses and the clinical science of their associated diseases have made enormous progress this century. The Nobel laureate Peter Medawar succinctly put it when he said that "No virus is known to do good; it has been well said that a virus is `a piece of bad news wrapped up in protein' " 169.
Historical Epidemic Jaundice
According to Cockayne, catarrhal jaundice was recognized in ancient Greece and Rome 46. The ancient Chinese were also apparently aware of its existence. Cockayne accepts the first reference to epidemic jaundice as that occurring in Minorca in 1745, recorded by Cleghorn in Epidemic Diseases of Minorca 1744 to 1749, and he reports numerous other instances in the 1700s and 1800s. Clearly, by the time of his review in 1912, there was ample evidence of its occurrence.
Infectious Agent of Epidemic Jaundice
McDonald is credited 115, 272 as the first person to implicate a virus as the etiologic agent of what we now call hepatitis A 166. However, in his report of acute yellow atrophy of the liver being "produced when some special virus acts on a previously damaged liver," he may have used the term in the sense of any infectious agent, not the filterable agent of Reed and other investigators. Similarly, Cockayne in his treatise on the relationship between epidemic and catarrhal (sporadic) jaundice writes "due to virus remaining active" and "a virulent condition" 46. Cockayne considered that many of the features of epidemic and sporadic cases of jaundice were like those of mumps, another disease of uncertain etiology at that time; he concluded that both epidemic and sporadic jaundice was caused by a specific organism of unknown nature.
Viral Etiology of Epidemic Hepatitis
In 1931, Findlay, Dunlop, and Brown presented a paper entitled "Observations on Epidemic Catarrhal Jaundice" at the Royal Society of Tropical Medicine and Hygiene 81. After reviewing the history of epidemic jaundice, current knowledge, and a contemporary outbreak in Surrey, they concluded that it was likely due to an "ultra-microscopic virus which is pathogenic only to man," similar to varicella, herpes zoster, rubella, and dengue. Deliberate experimental transmission to human volunteers was first reported from Germany in 1942 255 and the Middle East in 1943 42, more than 25 years before successful transmission in an animal model 116. H. C. Brown, one of the authors of the 1931 paper ascribing the etiology of epidemic jaundice to a virus, developed an illness with the characteristics of a sporadic case of epidemic jaundice. He became ill in Yorkshire described by Pickles 196. The timing of Brown's symptoms was consistent with what we now know is the incubation period of hepatitis A and perhaps the first documentation of viremic serum transmitting epidemic hepatitis 81.
All viruses are classified by their virion properties (morphology, physicochemical and physical properties, genome, proteins, lipids, carbohydrates, genome organization, and replication), antigenic properties, and biologic properties (Table 1). The viral genome is either RNA or DNA and double stranded or single stranded. In addition, the viral particle may be enveloped (host-derived lipid envelope) or nonenveloped. Each of the five major hepatitis viruses (Table 1)hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), delta hepatitis virus (HDV), and hepatitis E virus (HEV)belongs to a separate family (the taxonomy of viruses includes family, genus, and species).