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Viral Hepatitis in 1963
Viral Hepatitis in I963 From the Department of Medicine, Sinai Hospital, Baltimore, Maryland
ALBERT 1. MENDELOFF, M.D. Associate Profes.~or of Medicine, J ohns H opkins University School of Medicine; P hysician-in-Chief, Sinai Hospital
As OF 1963 the viral etiology for the two diseases we call IH and SH hepatitis is heavily documented,2-5, 7,15,17 and it is probable that there are more than two viruses involved. It may be that the tissue response we call viral hepatitis can be induced by a large number of viruses, some of which may be endemic in the blood of apparently healthy persons. It is impossible at present to discredit the mass of epidemiologic evidence which suggests that most hepatitis seen in the populations of the Western World occurs as the result of viral invasion of the intestinal tract at a definite point in time, requires incubation periods of three to six weeks to develop into a clinical disorder involving the liver almost exclusively, and is characterized by excretion of the virus into the stools, presumably via the bile, for a period of several weeks following the hepatic invasion.
PATHOLOGY By light microscopy biopsy material from the liver in the usual case shows within each hepatic lobule necrosis of parenchymal cells, cellular infiltration in the portal triads and throughout the lobule, and variable proliferation and swelling of Kupffer cells. Regenerative activity is usually marked, and there are evident variation in size and shape of parenchymal cells, mitotic figures, and binucleate cells. At any given point in the evolution of this picture the intralobular patterns are disrupted, inflammatory cells may be seen in clumps around degenerating parenchymal cells, and pigments, both bilirubin and the lipofuscin supposedly derived from parenchymal cells, may be distributed irregularly. Reticulin stains show that the supporting framework of each lobule is preserved; if more than single lobules are involved in a very severe necrotic process, the reticulin may be broken down, and the groundwork for a postnecrotic scarring is thus established. The greater the amount
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of reticulin involved in such a destructive process, the wider the collagen bands which develop, and the more necessary is the development of a regenerative process of disorderly pattern to replace the normal liver. Unless reticulin stains, connective tissue stains, and hematoxylin-eosin stains are used simultaneously on the same tissue preparation, it is easy to miss these postnecrotic changes. Most often the scarring is less marked, and small focal scars and even chronic lymphocytic inflammatory responses may be noted in biopsies for months after all signs of clinical activity have disappeared. CLINICAL SYNDROMES
There are now in the literature many excellent articles 8 , 11 dealing with the clinical features of all forms of hepatitis, their differential diagnosis, course and prognosis. This article is too limited by space considerations to cover this material in any detail, and the author asks the reader's indulgence if he attempts to summarize in the paragraphs that follow the salient clinical points. Classical Acute Viral Hepatitis
The classical form of acute viral hepatitis usually has characteristic symptoms and signs and accounts for about 80 per cent of the recognized cases of the disease. The deviant syndromes may very well be due to host variants (age, sex, other diseases) rather than to variations in strains of virus, pathological responses or antibody production. The disease ordinarily is ushered in by a definite feeling of malaise, often with slight fever, coryza or joint stiffness; after a few days lassitude, soreness of muscles and chilly sensations without shaking chills dominate the picture. These are succeeded by definite anorexia, nausea and dull upper abdominal pain. Rarely diarrhea and severe right upper quadrant pain occur for a day or two. Cigarette smokers notice a marked distaste for cigarettes; nonsmokers have severe anorexia. Cigar smokers have not been characterized on this point. The fever is usually less than 103 0 F., and fluctuates irregularly. At this point pressure over the liver, especially fist percussion, produces definite vvincing, even when the organ is not palpably enlarged. Generalized lymphadenopathy is usually not striking, although a palpable spleen in younger subjects is noted in about 2,5 per cent of cases at some time during the disease. Usually the liver enlargement becomes clinically evident at about the time the urine darkens, and the bilirubinuria usually precedes scleral and dermal icterus by 24 to 48 hours. During these first few days of jaundice the intensity of the discoloration mounts rapidly, the patient feels very sorry for himself, and then rather suddenly his appetite begins to improve and his muscle strength increases, even while his icterus is still deepening. The serum bilirubin continues to increase for about a
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week, and begins to descend slowly while the patient is already making an obvious clinical recovery. A sudden increase in urinary output often heralds the recovery early in the icteric period. During this period of relative well-being, the liver remains tender to percussion, and the patient soon finds that he is readily fatigued by minimal activity. The period of jaundice lasts from one to six weeks, during which time liver biopsy is definitely abnormal, liver function tests are deranged, and the patient is usually overoptimistic as to his ability to get up and about in his normal fashion. The next six week period usually sees a return to normalcy with respect to signs and symptoms, and by four months 80 per cent of cases occurring in previously healthy subjects under 30 years of age show neither clinical nor biochemical stigmata of liver damage. The most important differential considerations, once jaundice has occurred, concern the presence of extrahepatic obstruction, toxic hepatitis due to drugs or protoplasmic poisons, infectious mononucleosis, leptospirosis, or acute exacerbations of chronic liver disease. Atypical features of history, clinical findings or course should alert the physician to question his original diagnosis of viral hepatitis and carry out the appropriate measures for establishing a more accurate label for the process. Variants of the Classical Form
In the 20 per cent of patients who present features markedly differing from the classical case, some differ in the severity of the disease at the onset, and others differ by an unusually prolonged or complicated course. Acute fulminant hepatitis is a term given to a violent form of hepatitis, progressing to death within two weeks of the onset of illness. These patients, fortunately few in number, begin with symptoms not unlike those of the classical type, but progress rapidly into severe hepatic decompensation or into hepatic coma and other evidences of severe central nervous system disorder. Nausea and vomiting are common and intractable bleeding from the gut and into the skin usually usher in the final few hours of life, and oliguria and ascites are usually present. At the present time there is no way to predict which patients will manifest this form of the disease. Even more important, the diagnosis must be thought of whenever a violent illness with some, if not all, of these symptoms is encountered. The term subacute hepatitis is applied to an illness lasting one or t\VO years, often beginning with a classical onset, but occasionally having no recognizable hepatitic symptoms at the onset of a vague illness which only later manifests aspects of hepatic insufficiency, and/or portal hypertension. Liver biopsy is the best way to show that collapse of reticulum has occurred; the liver itself is often small rather than large; splenomegaly and angiomata may be noted; anemia, leukocytosis and
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progressive hypoalbuminemia and hyperglobulinemia may characterize the laboratory findings. The case fatality rate is high, probably around 60 per cent; those who recover go on to develop postnecrotic cirrhosis, but this may heal or remain latent. A nicteric hepatitis refers either to a mild case of classical hepatitis or to a generalized disorder without signs localizing in any organ. Liver function tests are usually mildly abnormal, and bile may appear in the urine. It is obvious that this diagnosis is missed more often than it is made; most of our information about it has come from careful follow-up studies on volunteers infected with virus-laden stool or blood, who may manifest the abnormal function studies without any clinical features suggestive of hepatitis. That there is a large reservoir of such cases in the population at all times is thought likely because of the presence in gamma globulin obtained from healthy adults of specific protective substances against the virus, and of the widespread immunity to IH infections seen clinically. Demonstration of viremia in otherwise healthy subjects has been discussed above. Cholestatic hepatitis is the name given to those patients with obvious classical hepatitis who in the course of their disease present mainly signs, symptoms and laboratory evidence of biliary tract obstruction. The pathological findings are not very specific; usually by the time pruritus and prolonged jaundice have become established most of the lesions of acute patchy hepatic necrosis have healed, and only bile thrombi and some increase in periportal inflammatory cells may be noted. Most of these patients have few complaints other than the jaundice and itching; it is the physician who becomes uneasy after weeks of watching what he had thought to be a commonplace hepatitis develop these obstructive symptoms. The liver function tests show early the usual abnormalities of parenchymal cell function seen in classical hepatitis; as these come back to normal, the serum alkaline phosphatase rises, the bilirubin remains elevated, the cholesterol in serum is abnormally high and the serum globulin concentration tends to increase slowly. The differentiation of this disease from surgically correctable extrahepatic biliary obstruction is often impossible without exploration of the abdomen; fortunately, hepatocellular function in these cases is usually quite good, and there are no serious contraindications to exploration. Sequelae of Acute Hepatitis
In general, these consist of (1) recurrences of the original symptoms (usually less severe), (2) prolonged convalescence with mild symptoms lasting as long as three years but without serious complication and with eventual complete healing, and finally (3) the development of cirrhosis. The cholestatic form of hepatitis is thought to serve in a few instances as the precursor of biliary cirrhosis; the usual form of cirrhosis developing after classical hepatitis, when it does do so, has the features of post-
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necrotic scarring as its base. Differentiation of these chronic forms from a prolonged hepatitis without evidence of necrosis can be made only from biopsy material. There are no good statistical data on the frequency \vith which hepatitis does go on to cirrhosis, since in many cases it must be the anicteric form of hepatitis which is the precursor, and we have no idea whatever as to its frequency.1 Lupoid Hepatitis
Lupoid hepatitis refers to a peculiar form of chronic liver disease occurring in young women, characterized by features of progressive liver dysfunction, marked rise in serum gamma globulin concentrations, and the more or less constant finding of a positive L.E. phenomenon in the blood. Some of the features of disseminated lupus erythematosus may be present but they are characteristically not sustained, and at autopsy none of the characteristic lupus lesions have been demonstrated in other organs. Conversely, the liver in classical cases of lupus erythematosus usually does not show any characteristic stigmata. The exact relationships of this entity, if it be one, to known forms of viral hepatitis are entirely unclear. EPIDEMIOLOGY
The Population at Risk
Only since both IH and SH forms of hepatitis became reportable in the United States have data defining the number of cases and methods of spread of these diseases been assessable. In most parts of the country there has been a steady rise in the incidence of reported cases, beginning about 1954, and reaching a peak of 72,000 cases in 1961. As a cause of death (less than 1000 per year) it is not a major disease, but even so only influenza exceeds it as a cause of mortality from viral diseases. As befits an infection which is oral-anal in its transmission, IH virus has always seemed to occur more frequently among the young. 13 Most of the documented epidemics in the continental D.S. have been in those under 25, and secondary cases occurring in the affected families have been noteworthy. In fact, the usual assumption, based on laboratory studies of nonjaundiced siblings of jaundiced patients, is that at least half of the cases are anicteric. The analogy with poliomyelitis in this regard, as in many others, is quite obvious, and much has been written recently about these similarities, although it is probable that the usually described ratio of 100 nonparalytic to one paralytic case of poliomyelitis is much higher than the possible 2- or 3-to-l ratio of anicteric to icteric cases of infectious hepatitis. At any rate, the behavior of a population exposed to IH virus will depend upon the previous exposure of that group to this virus or viruses,
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and the factors, whatever they may be, which govern immune responses of the host on the one hand, and on the other hand those which permit strain variations in the viruses. Suffice it to say that somewhat less than half the recognized cases of hepatitis at present being reported are in subjects under 20 years of age; hospitalized cases are showing a steadily rising incidence in adults, so that even in the D.S. nationally in 1961 about 65 per cent of the reported cases were in adults. There is no question that at least part of this trend is due to the fact that IH infections in adults are likely to be more severe and more easily identified as requiring hospitalization for treatment or for differential diagnosis, but nevertheless it is likely that the disease is affecting proportionately more older persons as the childhood experience with the virus lessens, presumably as a result of better sanitation. Pathogenesis
Exposure to a common source of infection is the classic form of epidemic hepatitis, and the identification of cases as due to such a source depends largely on the acumen of the physicians and public health authorities involved in the care of such patients. Dramatic identifications of infected water supplies at summer camps, of poor sanitation at schools, in hospital wards and in state hospitals, and the 1961 Atlantic Coast clam and oyster infestation should serve to remind physicians that every case of suspected hepatitis should be reported and basic epidemiologic data gathered pertaining to it. l l Most cases will probably prove to arise on endemic backgrounds, without recognizable single sources to explain a succession of patients falling ill at regular intervals over a period of several months, but common sources will be 'missed regularly if each physician does not try to establish such a focus in each case. It has been pointed out by McCollum13 that the national incidence pattern for hepatitis over the past six or seven years indicates that, despite the rather striking rise in the total number of cases reported, the crude mortality rate has been stable. He suggests that this may represent a mixed population of cases, most of which are of high incidence and low mortality, the others being of low incidence and high case fatality rate. A natural assumption would be that the latter group consist of serum hepatitis, but there are difficulties in the way of accepting this suggestion. This disease is no longer occurring in epidemics traceable to wide-scale immunization procedures or to the receiving of plasma derived from very large numbers of blood donors. Most cases occur following injections of medications, intravenous fluids, blood and local anestheticagents in hospitals and private offices of dentists, physicians and surgeons. Since there is still no practical method of identifying the patient with serum hepatitis clinically or by biopsy, and the incubation period varies from 56 to 180 days, some confusion of the diagnosis of
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IH with SH viral hepatitis must be occurring at all times. The risk of serum hepatitis in recipients of whole blood lies somewhere between 0.2 and 5 per cent as a nationwide figure; the number of patients carrying IH virus in their serum without clinical symptoms is unknown, but might be high even without the evidence alluded to above that a significant proportion of the normal population is chronically viremic. The inoculation of blood and blood products may definitely tran~mit both IH and SH viruses. Io Of the common blood derivatives, plasma, thrombin and fibrinogen have definitely been shown to transmit hepatitis viruses; serum albumin, gamma globulin, fibrinolysin and probably antihemophilic globulin have not been so incriminated as of this writing. The high incidence of serum hepatitis in tattooed men and in drug addicts, attributable to poor sterilization of needles and syringes, also brings out the extraordinarily small doses of blood necessary to infectestimated as 0.0004 m!. in the case of SH, and 0.01 m!. in the case of IH. Thus human subjects of any age are potentially susceptible to both these virus groups, but many persons develop immunity to one or both groups as they live out their lives. As better sanitation eliminates or diminishes the free traffic in fecal contamination among children, the susceptibles will probably continue to be relatively older than has been the case in the past. SH viral immunity is much more limited in extent in the population at large, since it seems to be, in this country, associated almost exclusively with iatrogenic procedures which fortunately are not everyman's lot. The prospect is dim that the disease will spontaneously cease to be a major cause of morbidity without strenuous efforts to perfect a vaccine and sterilize blood and blood products. IMMUNITY
Recent studies of continuous hepatitis attacks in a closed institution have provided additional information to supplement the previous concepts that persons fed or inoculated with IH virus develop a disease, icteric or nonicteric, and some degree of immunity to a second challenge with the virus. In this closed population of children, Krugman et al. noted 4.6 per cent of second attacks of icteric hepatitis, presumably to the same strain of virus in approximately the the same dose. 12 Similar studies elsewhere and the behavior of the naturally occurring disease in countries where widespread immunity is thought to exist on the basis of childhood infections also suggest that immunity to IH infections, although definite, may not be adequate to protect against subsequent massive dosage of virus, and certainly not to other strains of virus, if these can be demonstrated. In addition, techniques of prevention using gamma globulin will often modify icteric hepatitis to nonicteric mild disease after a much-lengthened incubation period; during this prolonged period in the anicteric and often mildly ill patient the serum may still
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be infectious. Melnick has reported a remarkable epidemic occurring in New Delhi, India, where nearly 6 per cent of a total urban population of 1.6 million persons came down with hepatitis within two months of exposure to water heavily infected with hepatitis virus. 14 Such an event in a population usually thought to have been exposed to the virus in childhood, and thus as immune as one could expect a total population to become, suggests either that the virus was an entirely different strain, or that the immunity was breached by the massive amount of virus ingested. The Parke-Davis group, in their recent studies of neutralizing antibody titers to the tissue-culture-grown virus strains, have certainly demonstrated specificity of antibody two months or more after the challenge doses of virus were given. 17 On the other hand, this circulating antibody seems to disappear much more rapidly than is the case with naturally occurring cases of hepatitis, in whom high levels of homologous antibody have been maintained for three years or more. The entire problem of the mechanism of antibody-viral interactions is still under study, and the recent demonstration by Herriott that the free nucleic acids of viral particles can be infectious even in the presence of antisera casts a misty light on the meaning of circulating antibody in these diseases in which cell invasion occurs early. 9 Bound up with the problem of immunity and the persistence of virus in,blood is the use of gamma globulin parenterally to modify or prevent hepatitis. It was early demonstrated that, assuming a 10 per cent secondary attack rate in families with one kno\vn case of hepatitis, the immediate inoculation of the family members with gamma globulin reduced the incidence of secondary cases to less than 1 per cent, or tenfold. The dose required to produce this protection is still not precisely known, and of course must be demonstrated on a statistical basis. Originally, it was demonstrated that 0.01 ml. gamma globulin per pound of body weight was sufficient to stop epidemics of hepatitis in young adults; Krugman et al. believe this is too little, and suggest, on the basis of their work with children, that 0.06 ml. per pound, given prior to development of symptoms, will prevent the appearance of icteric hepatitis for periods as long as nine months. Other workers have shown that gamma globulin will suppress clinical evidences of hepatitis even after the prodromal symptoms have begun, but not after the seventh day of such symptoms. There is no evidence that gamma globulin will modify chronic hepatitis or relapsing hepatitis. If, as McLean and his co-workers believe, serum hepatitis may be an infection by a strain of virus which, purely because it is more prone to latency, may linger longer in the blood which becomes the infective vehicle, then perhaps gamma globulin may also protect against this disorder. Drake was unable to demonstrate protection against serum hepatitis by gamma globulin in 1953,6 but more recent studies have
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demonstrated definite protection by the administration of the protein just before or after transfusion and one month later. More than a threefold protection "vas demonstrated in one of these studies carried out in older persons undergoing thoracic surgery, and a seven-fold reduction in hepatitis was shown among otherwise healthy soldiers given transfusions of' blood or plasma. lo If these studies are confirmed, a unifying concept regarding the various viruses now being demonstrated may emerge, sinee it is difficult under present schemes of thinking to imagine how antibodies to SR virus can be formed in persons never before having received blood or blood products. The implication of variations in Red Cross gamma globulin antibody concentrations against measles has been stressed by Stokes16 in considering the probably even greater variation one might anticipate in concentrations of antibody against the less ubiquitous hepatitis viruses. Thus, results of protection when using material so variable in its antibody concentration must be weighed cautiously, and the best results be accorded the most weight. Stokes has also been the principal spokesman for the description of the natural immunity to hepatitis as a "passive-active immunization," a situation analogous to that in which the natural decline of circulating gamma globulin injected parenterally does not result in a disappearance of immunity when the patient is continuously exposed to the infective agent. Utilizing the results of Krugman et aI., he suggests that the use of orally administered serum from cases of early hepatitis plus parenterally administered gamma globulin given almost simultaneously would result in prolonged immunity and a much milder clinical disorder. TREATMENT OF THE CLINICAL DISEASE
In their recent article dealing with prevention and treatment of hepatitis, Iber and Mendelofflo state: "At the present time there is no definite evidence that known agents directly attack the virus of hepatitis once it has invaded the liver. This serious limitation forces the physician to direct his efforts toward prevention of the disease, keeping the patient alive, arresting the damage, and encouraging regeneration of normal liver cells in every way possible. Since the disease tends to be self-limited and mild in children and young adults, evaluation of therapeutic measures in this, the largest group of sufferers, is extremely difficult. In the treatment of severe chronic or relapsing hepatitis the number of patients is small and multiple therapeutic programs common. Thus good statistical grounds for preferring one or another regimen are lacking." Since the above was written, Stokesl6 has reintroduced his concept that severe liver necrosis in hepatitis may be the result of symbiotic activity of virus and enteric bacterial pathogens. He has pointed out previously that many severe outbreaks of epidemic hepatitis are indeed preceded by bacterial enterocolitis, and that subjects who were chronic carriers of
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Salmonella choleraesuis developed unusually severe hepatitis when infected experimentally with IH virus. Early attempts by other investigators to confirm this work were inconclusive. A program for testing this hypothesis is now under way. The cornerstones of therapy in the average case of hepatitis, especially when the subject is a child or a male under 25, is rest in bed during the febrile phase of the disease, and the provision of a balanced and calorically adequate diet when the patient feels like eating it. Despite demonstrations among armed forces personnel in the Orient that strict bed rest was not more beneficial than lounging about, and that 4000 calories a day was not more beneficial than 3000 calories (to patients whose needs were probably 2500 calories), most physicians will err on the side of caution with regard to rest, although strict bed rest for most patients is not necessary. A sensible plan is to allow the patient to walk to the bathroom or to his meals, when he begins to want to do so, but to get off his feet after each meal for about an hour until the day when his serum bilirubin drops to about 1.5 mg. per 100 ml. or the sulfobromophthalein retention to 5 per cent at 45 minutes. If gradual ambulation is not accompanied by evening temperature rises, dye retention, or elevations of serum transaminase or bilirubin, it is continued to the point at which the patient is allowed to carry out his usual activities for the mornings of a given week, coming home for lunch, taking a short walk before supper, and getting into bed after supper. At the end of one week of such a regimen, the above tests are repeated; if normal, a return to full activity is indicated for the next week. If these criteria are not met, or if the patient has a return of anorexia or malaise, a return to partial bed rest is indicated. The diet in hepatitis should be a normally balanced one, containing one gram of protein per kilogram of body weight, fat of 60 to 80 gm., and carbohydrate sufficient to make up daily c~loric needs, generally about 3000 calories for an adult. It is important to divide the diet in such a way that the patient receives nearly half of his daily calories at breakfast, and the remainder in small attractive feedings every three hours during the day. Intravenous glucose infusions are needed if the patient cannot ingest more than 1000 calories orally per day, and under such circumstances vitamin supplementation is required. Diet supplements under the usual circumstances are unnecessary. Intravenous fat emulsions for as many as six days are probably without harm. The measurement of urinary output and fluid intake is useful in the first two weeks of the disease, when marked disturbances in water and sodium metabolism occur; a diuresis usually heralds clinical improvement. Critical discussions of these matters of diet and rest may be found else,vhere. 8 , 10, 11 Of all the other adjuvants to the therapy of hepatitis, only one deserves thoughtful mention. The adrenal steroids should be used in the treatment of the more severe cases, or those which represent the begin-
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ning of a relapsing or chronic course. Older persons with hepatitis and adolescent girls seem to do especially poorly when treated conservatively; despite the well-known disadvantages of full steroid therapy, it is my feeling that such a regimen is of obvious benefit in most of these cases, and life-saving in a fair proportion. Prednisone in doses of 60 mg. per day for the first four or five days, and at levels of 30 mg. per day thereafter for ten or more days usually makes appetite return, mental acuity increase, and spontaneous voluntary muscular activity purposeful. Pruritus, if present, is greatly relieved.; patients are more active during the day, and sleep better at night. The use of nonabsorbable antacids is mandatory one hour after each feeding, and at bedtime, when steroids are being administered. The withdrawal of steroids must be very slow, as hepatic coma has often been precipitated by too rapid tapering of this therapy. It is unlikely that doses of prednisone greater than 60 mg. per day will reverse fulminant hepatitis, a rare and almost universally fatal form of the disease, but the few reported patients who have survived have received at least 60 mg. of prednisone daily. PREVENTION OF SPREAD AND METHODS OF PROTECTING CONTACTS
Despite the present confusion as to the identity of a number of viruses isolated from the serum of hepatitis cases and from asymptomatic human subjects, all the viruses so far studied have shown similar resistance to heat, ether and chlorination at levels usually obtaining in \vater supplies. The main reliance in preventing spread of infection from the intestinal tract of the patient to the mouth of a contact or to food prepared by the contact is careful and meticulous hand \vashing, \vith soap, on the part of the latter. Stokes 16 has stressed that in institutions a single toilet is often constantly contaminated, and this, plus inadequate hand washing, may serve as the source of a continuing outbreak. If this be the case, then the toilet seat should be cleaned after each use, preferably with a 1 per cent aqueous iodine solution, and each person using the toilet should have a separate packet of toilet paper rather than a few pieces from a common roll of toilet tissue. All feces-contaminated fomites, particularly bedclothing and bedpans, should be autoclaved; other fomites coming in contact with the patient's hands, such as books, pencils, radios etc., should be considered as contaminated and not allowed to leave the patient's room. The patient should not receive gifts which cannot stand autoclaving or iodine sterilization. Enteric precautions employing a covering gown which remains in the patient's room, careful handwashing technique, and restriction of the number of persons visiting the patient seem able to control most outbreaks. That this is effective is the best answer to the possibility that respiratory spread of the disease is of importance. Despite the catarrhal nature of the prodromal symptoms,
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respiratory transmission has never been demonstrated in IH infections. For patients with probable serum hepatitis, as much disposable equipment as possible should be provided for the collection of blood or the infusing of parenteral solutions. All nondisposable pieces of apparatus should be sterilized by autoclaving at 15 pounds per square inch at 1240 F. for 20 minutes; boiling for 30 minutes is probably also adequate. Large and expensive pieces of hospital equipment which are constantly exposed to blood-e.g. the artificial kidney dialyzers, heart-lung pumps, continuous oxygen analyzers-have been shown to be rendered virusfree by gaseous sterilization with ethylene oxide. IQ Blood and blood derivatives which can stand ten hours of heating at 60 0 C. will be free of virus, but only albumin can withstand such treatment. It appears to be possible to sterilize fluid blood or plasma by the addition of 1.5 gm. of beta propiolactone per liter, especially if the amounts treated are not very large; large-scale sterilization is also effective provided that the mechanisms governing the mixing of the materials always function efficiently. In the final analysis, the control of these viral diseases which can produce so much morbidity and a significant mortality must lie in measures to increase immunity and lessen the risk of massive exposure. These surely mean the development of a vaccine for all persons to receive as children, with boosters from time to time, and the limitation by physicians of blood transfusions which are not absolutely necessary. The inactivation of the virus in processed blood is also necessary. Fortunately, although none of these measures is at hand at this writing, there is every reason to believe that the next decade will see gratifying fulfillment of these needs. REFERENCES 1. Baggenstoss, A. H.: Postnecrotic cirrhosis: Morphology, etiology, and pathogenesis. In Progress in Liver Disease, Chap. 2 (H. Popper and F. Schaffner, Eds.). New York, Grune & Stratton, 1962. 2. Bearcroft, W. G. C.: Cytological and cytochemical studies on the liver cells of yellow-fever infected rhesus monkeys. J. Path. & Bact. 80: 19, 1960. 3. Bearcroft, W. G. C.: Electron-microscope studies on the liver in infective hepatitis. J. Path. & Bact. 83: 383, 1962. 4. Braunsteiner, H., Fellinger, K., Pakesch, F., Beyreder, Jr., Grabner, G. and Neumayr, A.: Elektromimikroskopische Beobachtungen an Leberzellen bei Serumhepatitis und Hepatitis epidemica. Klin. Wchnschr. 35: 901, 1957. 5. Davis, E. V.: Isolation of viruses from children with infectious hepatitis. Science 133: 2059, 1961. 6. Drake, M. E. and others: Failure of convalescent gamma globulin to protect against homologous serum hepatitis. J.A.M.A. 152: 690, 1953. 7. Eichenwald, H. F. and Mosley, J. W.: Viral Hepatitis-Clinical and Public Health Aspects. U. S. Public Health Service, Publication No. 435, 1959. 8. Havens, W. P., Jr.: Viral hepatitis: Clinical patterns and diagnosis. Am. J. Med. 32: 665, 1962. 9. Herriott, R. M.: Infectious nucleic acids, a new dimension in virology. Science 13J,.: 256, 1961.
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10. Iber, F. L. and Mendeloff, A.!.: Prevention and treatment of viral hepatitis. Arch. Int. Med. 109: 310, 1962. 11. Klatskin, G.: In Principles of Internal Medicine (T. R. Harrison et al., Eds.). 4th Ed., Chap. 280. New York, Blakiston Co. 1962. 12. Krugman, S., Ward, R. and Giles, J. P.: The natural history of infectious hepatitis. Am. J. Med. 32: 717, 1962. 13. McCollum, R. W.: Epidemiologic patterns of viral hepatitis. Am. J. Med. 32: 657, 1962. 14. Melnick, J. L.: A water-borne urban epidemic of hepatitis. In Hepatitis Frontiers (F. Hartman et aI., Eds.). Boston, Little, Brown & Co., 1957, pp. 287-295. 15. O'Malley, J. P., Mayer, H. M., Jr. and Smadel, J. E.: Antibody in hepatitis patients against a newly isolated virus. Proc. Soc. Exper. BioI. & Med. 108: 200,1961. 16. Stokes, J., Jr.: The control of viral hepatitis. Am. J. Med. 32: 729, 1962. 17. Taylor, A. R., Rightsel, W. A., Boggs, J. D. and McLean, I. W., Jr.: Tissue culture of hepatitis virus. Am. J. Med. 32: 679, 1962. Sinai Hospital of Baltimore Baltimore 15, Maryland
ALBERT 1. MENDELOFF, M.D. Associate Profes.~or of Medicine, J ohns H opkins University School of Medicine; P hysician-in-Chief, Sinai Hospital
As OF 1963 the viral etiology for the two diseases we call IH and SH hepatitis is heavily documented,2-5, 7,15,17 and it is probable that there are more than two viruses involved. It may be that the tissue response we call viral hepatitis can be induced by a large number of viruses, some of which may be endemic in the blood of apparently healthy persons. It is impossible at present to discredit the mass of epidemiologic evidence which suggests that most hepatitis seen in the populations of the Western World occurs as the result of viral invasion of the intestinal tract at a definite point in time, requires incubation periods of three to six weeks to develop into a clinical disorder involving the liver almost exclusively, and is characterized by excretion of the virus into the stools, presumably via the bile, for a period of several weeks following the hepatic invasion.
PATHOLOGY By light microscopy biopsy material from the liver in the usual case shows within each hepatic lobule necrosis of parenchymal cells, cellular infiltration in the portal triads and throughout the lobule, and variable proliferation and swelling of Kupffer cells. Regenerative activity is usually marked, and there are evident variation in size and shape of parenchymal cells, mitotic figures, and binucleate cells. At any given point in the evolution of this picture the intralobular patterns are disrupted, inflammatory cells may be seen in clumps around degenerating parenchymal cells, and pigments, both bilirubin and the lipofuscin supposedly derived from parenchymal cells, may be distributed irregularly. Reticulin stains show that the supporting framework of each lobule is preserved; if more than single lobules are involved in a very severe necrotic process, the reticulin may be broken down, and the groundwork for a postnecrotic scarring is thus established. The greater the amount
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of reticulin involved in such a destructive process, the wider the collagen bands which develop, and the more necessary is the development of a regenerative process of disorderly pattern to replace the normal liver. Unless reticulin stains, connective tissue stains, and hematoxylin-eosin stains are used simultaneously on the same tissue preparation, it is easy to miss these postnecrotic changes. Most often the scarring is less marked, and small focal scars and even chronic lymphocytic inflammatory responses may be noted in biopsies for months after all signs of clinical activity have disappeared. CLINICAL SYNDROMES
There are now in the literature many excellent articles 8 , 11 dealing with the clinical features of all forms of hepatitis, their differential diagnosis, course and prognosis. This article is too limited by space considerations to cover this material in any detail, and the author asks the reader's indulgence if he attempts to summarize in the paragraphs that follow the salient clinical points. Classical Acute Viral Hepatitis
The classical form of acute viral hepatitis usually has characteristic symptoms and signs and accounts for about 80 per cent of the recognized cases of the disease. The deviant syndromes may very well be due to host variants (age, sex, other diseases) rather than to variations in strains of virus, pathological responses or antibody production. The disease ordinarily is ushered in by a definite feeling of malaise, often with slight fever, coryza or joint stiffness; after a few days lassitude, soreness of muscles and chilly sensations without shaking chills dominate the picture. These are succeeded by definite anorexia, nausea and dull upper abdominal pain. Rarely diarrhea and severe right upper quadrant pain occur for a day or two. Cigarette smokers notice a marked distaste for cigarettes; nonsmokers have severe anorexia. Cigar smokers have not been characterized on this point. The fever is usually less than 103 0 F., and fluctuates irregularly. At this point pressure over the liver, especially fist percussion, produces definite vvincing, even when the organ is not palpably enlarged. Generalized lymphadenopathy is usually not striking, although a palpable spleen in younger subjects is noted in about 2,5 per cent of cases at some time during the disease. Usually the liver enlargement becomes clinically evident at about the time the urine darkens, and the bilirubinuria usually precedes scleral and dermal icterus by 24 to 48 hours. During these first few days of jaundice the intensity of the discoloration mounts rapidly, the patient feels very sorry for himself, and then rather suddenly his appetite begins to improve and his muscle strength increases, even while his icterus is still deepening. The serum bilirubin continues to increase for about a
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week, and begins to descend slowly while the patient is already making an obvious clinical recovery. A sudden increase in urinary output often heralds the recovery early in the icteric period. During this period of relative well-being, the liver remains tender to percussion, and the patient soon finds that he is readily fatigued by minimal activity. The period of jaundice lasts from one to six weeks, during which time liver biopsy is definitely abnormal, liver function tests are deranged, and the patient is usually overoptimistic as to his ability to get up and about in his normal fashion. The next six week period usually sees a return to normalcy with respect to signs and symptoms, and by four months 80 per cent of cases occurring in previously healthy subjects under 30 years of age show neither clinical nor biochemical stigmata of liver damage. The most important differential considerations, once jaundice has occurred, concern the presence of extrahepatic obstruction, toxic hepatitis due to drugs or protoplasmic poisons, infectious mononucleosis, leptospirosis, or acute exacerbations of chronic liver disease. Atypical features of history, clinical findings or course should alert the physician to question his original diagnosis of viral hepatitis and carry out the appropriate measures for establishing a more accurate label for the process. Variants of the Classical Form
In the 20 per cent of patients who present features markedly differing from the classical case, some differ in the severity of the disease at the onset, and others differ by an unusually prolonged or complicated course. Acute fulminant hepatitis is a term given to a violent form of hepatitis, progressing to death within two weeks of the onset of illness. These patients, fortunately few in number, begin with symptoms not unlike those of the classical type, but progress rapidly into severe hepatic decompensation or into hepatic coma and other evidences of severe central nervous system disorder. Nausea and vomiting are common and intractable bleeding from the gut and into the skin usually usher in the final few hours of life, and oliguria and ascites are usually present. At the present time there is no way to predict which patients will manifest this form of the disease. Even more important, the diagnosis must be thought of whenever a violent illness with some, if not all, of these symptoms is encountered. The term subacute hepatitis is applied to an illness lasting one or t\VO years, often beginning with a classical onset, but occasionally having no recognizable hepatitic symptoms at the onset of a vague illness which only later manifests aspects of hepatic insufficiency, and/or portal hypertension. Liver biopsy is the best way to show that collapse of reticulum has occurred; the liver itself is often small rather than large; splenomegaly and angiomata may be noted; anemia, leukocytosis and
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progressive hypoalbuminemia and hyperglobulinemia may characterize the laboratory findings. The case fatality rate is high, probably around 60 per cent; those who recover go on to develop postnecrotic cirrhosis, but this may heal or remain latent. A nicteric hepatitis refers either to a mild case of classical hepatitis or to a generalized disorder without signs localizing in any organ. Liver function tests are usually mildly abnormal, and bile may appear in the urine. It is obvious that this diagnosis is missed more often than it is made; most of our information about it has come from careful follow-up studies on volunteers infected with virus-laden stool or blood, who may manifest the abnormal function studies without any clinical features suggestive of hepatitis. That there is a large reservoir of such cases in the population at all times is thought likely because of the presence in gamma globulin obtained from healthy adults of specific protective substances against the virus, and of the widespread immunity to IH infections seen clinically. Demonstration of viremia in otherwise healthy subjects has been discussed above. Cholestatic hepatitis is the name given to those patients with obvious classical hepatitis who in the course of their disease present mainly signs, symptoms and laboratory evidence of biliary tract obstruction. The pathological findings are not very specific; usually by the time pruritus and prolonged jaundice have become established most of the lesions of acute patchy hepatic necrosis have healed, and only bile thrombi and some increase in periportal inflammatory cells may be noted. Most of these patients have few complaints other than the jaundice and itching; it is the physician who becomes uneasy after weeks of watching what he had thought to be a commonplace hepatitis develop these obstructive symptoms. The liver function tests show early the usual abnormalities of parenchymal cell function seen in classical hepatitis; as these come back to normal, the serum alkaline phosphatase rises, the bilirubin remains elevated, the cholesterol in serum is abnormally high and the serum globulin concentration tends to increase slowly. The differentiation of this disease from surgically correctable extrahepatic biliary obstruction is often impossible without exploration of the abdomen; fortunately, hepatocellular function in these cases is usually quite good, and there are no serious contraindications to exploration. Sequelae of Acute Hepatitis
In general, these consist of (1) recurrences of the original symptoms (usually less severe), (2) prolonged convalescence with mild symptoms lasting as long as three years but without serious complication and with eventual complete healing, and finally (3) the development of cirrhosis. The cholestatic form of hepatitis is thought to serve in a few instances as the precursor of biliary cirrhosis; the usual form of cirrhosis developing after classical hepatitis, when it does do so, has the features of post-
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necrotic scarring as its base. Differentiation of these chronic forms from a prolonged hepatitis without evidence of necrosis can be made only from biopsy material. There are no good statistical data on the frequency \vith which hepatitis does go on to cirrhosis, since in many cases it must be the anicteric form of hepatitis which is the precursor, and we have no idea whatever as to its frequency.1 Lupoid Hepatitis
Lupoid hepatitis refers to a peculiar form of chronic liver disease occurring in young women, characterized by features of progressive liver dysfunction, marked rise in serum gamma globulin concentrations, and the more or less constant finding of a positive L.E. phenomenon in the blood. Some of the features of disseminated lupus erythematosus may be present but they are characteristically not sustained, and at autopsy none of the characteristic lupus lesions have been demonstrated in other organs. Conversely, the liver in classical cases of lupus erythematosus usually does not show any characteristic stigmata. The exact relationships of this entity, if it be one, to known forms of viral hepatitis are entirely unclear. EPIDEMIOLOGY
The Population at Risk
Only since both IH and SH forms of hepatitis became reportable in the United States have data defining the number of cases and methods of spread of these diseases been assessable. In most parts of the country there has been a steady rise in the incidence of reported cases, beginning about 1954, and reaching a peak of 72,000 cases in 1961. As a cause of death (less than 1000 per year) it is not a major disease, but even so only influenza exceeds it as a cause of mortality from viral diseases. As befits an infection which is oral-anal in its transmission, IH virus has always seemed to occur more frequently among the young. 13 Most of the documented epidemics in the continental D.S. have been in those under 25, and secondary cases occurring in the affected families have been noteworthy. In fact, the usual assumption, based on laboratory studies of nonjaundiced siblings of jaundiced patients, is that at least half of the cases are anicteric. The analogy with poliomyelitis in this regard, as in many others, is quite obvious, and much has been written recently about these similarities, although it is probable that the usually described ratio of 100 nonparalytic to one paralytic case of poliomyelitis is much higher than the possible 2- or 3-to-l ratio of anicteric to icteric cases of infectious hepatitis. At any rate, the behavior of a population exposed to IH virus will depend upon the previous exposure of that group to this virus or viruses,
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and the factors, whatever they may be, which govern immune responses of the host on the one hand, and on the other hand those which permit strain variations in the viruses. Suffice it to say that somewhat less than half the recognized cases of hepatitis at present being reported are in subjects under 20 years of age; hospitalized cases are showing a steadily rising incidence in adults, so that even in the D.S. nationally in 1961 about 65 per cent of the reported cases were in adults. There is no question that at least part of this trend is due to the fact that IH infections in adults are likely to be more severe and more easily identified as requiring hospitalization for treatment or for differential diagnosis, but nevertheless it is likely that the disease is affecting proportionately more older persons as the childhood experience with the virus lessens, presumably as a result of better sanitation. Pathogenesis
Exposure to a common source of infection is the classic form of epidemic hepatitis, and the identification of cases as due to such a source depends largely on the acumen of the physicians and public health authorities involved in the care of such patients. Dramatic identifications of infected water supplies at summer camps, of poor sanitation at schools, in hospital wards and in state hospitals, and the 1961 Atlantic Coast clam and oyster infestation should serve to remind physicians that every case of suspected hepatitis should be reported and basic epidemiologic data gathered pertaining to it. l l Most cases will probably prove to arise on endemic backgrounds, without recognizable single sources to explain a succession of patients falling ill at regular intervals over a period of several months, but common sources will be 'missed regularly if each physician does not try to establish such a focus in each case. It has been pointed out by McCollum13 that the national incidence pattern for hepatitis over the past six or seven years indicates that, despite the rather striking rise in the total number of cases reported, the crude mortality rate has been stable. He suggests that this may represent a mixed population of cases, most of which are of high incidence and low mortality, the others being of low incidence and high case fatality rate. A natural assumption would be that the latter group consist of serum hepatitis, but there are difficulties in the way of accepting this suggestion. This disease is no longer occurring in epidemics traceable to wide-scale immunization procedures or to the receiving of plasma derived from very large numbers of blood donors. Most cases occur following injections of medications, intravenous fluids, blood and local anestheticagents in hospitals and private offices of dentists, physicians and surgeons. Since there is still no practical method of identifying the patient with serum hepatitis clinically or by biopsy, and the incubation period varies from 56 to 180 days, some confusion of the diagnosis of
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IH with SH viral hepatitis must be occurring at all times. The risk of serum hepatitis in recipients of whole blood lies somewhere between 0.2 and 5 per cent as a nationwide figure; the number of patients carrying IH virus in their serum without clinical symptoms is unknown, but might be high even without the evidence alluded to above that a significant proportion of the normal population is chronically viremic. The inoculation of blood and blood products may definitely tran~mit both IH and SH viruses. Io Of the common blood derivatives, plasma, thrombin and fibrinogen have definitely been shown to transmit hepatitis viruses; serum albumin, gamma globulin, fibrinolysin and probably antihemophilic globulin have not been so incriminated as of this writing. The high incidence of serum hepatitis in tattooed men and in drug addicts, attributable to poor sterilization of needles and syringes, also brings out the extraordinarily small doses of blood necessary to infectestimated as 0.0004 m!. in the case of SH, and 0.01 m!. in the case of IH. Thus human subjects of any age are potentially susceptible to both these virus groups, but many persons develop immunity to one or both groups as they live out their lives. As better sanitation eliminates or diminishes the free traffic in fecal contamination among children, the susceptibles will probably continue to be relatively older than has been the case in the past. SH viral immunity is much more limited in extent in the population at large, since it seems to be, in this country, associated almost exclusively with iatrogenic procedures which fortunately are not everyman's lot. The prospect is dim that the disease will spontaneously cease to be a major cause of morbidity without strenuous efforts to perfect a vaccine and sterilize blood and blood products. IMMUNITY
Recent studies of continuous hepatitis attacks in a closed institution have provided additional information to supplement the previous concepts that persons fed or inoculated with IH virus develop a disease, icteric or nonicteric, and some degree of immunity to a second challenge with the virus. In this closed population of children, Krugman et al. noted 4.6 per cent of second attacks of icteric hepatitis, presumably to the same strain of virus in approximately the the same dose. 12 Similar studies elsewhere and the behavior of the naturally occurring disease in countries where widespread immunity is thought to exist on the basis of childhood infections also suggest that immunity to IH infections, although definite, may not be adequate to protect against subsequent massive dosage of virus, and certainly not to other strains of virus, if these can be demonstrated. In addition, techniques of prevention using gamma globulin will often modify icteric hepatitis to nonicteric mild disease after a much-lengthened incubation period; during this prolonged period in the anicteric and often mildly ill patient the serum may still
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be infectious. Melnick has reported a remarkable epidemic occurring in New Delhi, India, where nearly 6 per cent of a total urban population of 1.6 million persons came down with hepatitis within two months of exposure to water heavily infected with hepatitis virus. 14 Such an event in a population usually thought to have been exposed to the virus in childhood, and thus as immune as one could expect a total population to become, suggests either that the virus was an entirely different strain, or that the immunity was breached by the massive amount of virus ingested. The Parke-Davis group, in their recent studies of neutralizing antibody titers to the tissue-culture-grown virus strains, have certainly demonstrated specificity of antibody two months or more after the challenge doses of virus were given. 17 On the other hand, this circulating antibody seems to disappear much more rapidly than is the case with naturally occurring cases of hepatitis, in whom high levels of homologous antibody have been maintained for three years or more. The entire problem of the mechanism of antibody-viral interactions is still under study, and the recent demonstration by Herriott that the free nucleic acids of viral particles can be infectious even in the presence of antisera casts a misty light on the meaning of circulating antibody in these diseases in which cell invasion occurs early. 9 Bound up with the problem of immunity and the persistence of virus in,blood is the use of gamma globulin parenterally to modify or prevent hepatitis. It was early demonstrated that, assuming a 10 per cent secondary attack rate in families with one kno\vn case of hepatitis, the immediate inoculation of the family members with gamma globulin reduced the incidence of secondary cases to less than 1 per cent, or tenfold. The dose required to produce this protection is still not precisely known, and of course must be demonstrated on a statistical basis. Originally, it was demonstrated that 0.01 ml. gamma globulin per pound of body weight was sufficient to stop epidemics of hepatitis in young adults; Krugman et al. believe this is too little, and suggest, on the basis of their work with children, that 0.06 ml. per pound, given prior to development of symptoms, will prevent the appearance of icteric hepatitis for periods as long as nine months. Other workers have shown that gamma globulin will suppress clinical evidences of hepatitis even after the prodromal symptoms have begun, but not after the seventh day of such symptoms. There is no evidence that gamma globulin will modify chronic hepatitis or relapsing hepatitis. If, as McLean and his co-workers believe, serum hepatitis may be an infection by a strain of virus which, purely because it is more prone to latency, may linger longer in the blood which becomes the infective vehicle, then perhaps gamma globulin may also protect against this disorder. Drake was unable to demonstrate protection against serum hepatitis by gamma globulin in 1953,6 but more recent studies have
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demonstrated definite protection by the administration of the protein just before or after transfusion and one month later. More than a threefold protection "vas demonstrated in one of these studies carried out in older persons undergoing thoracic surgery, and a seven-fold reduction in hepatitis was shown among otherwise healthy soldiers given transfusions of' blood or plasma. lo If these studies are confirmed, a unifying concept regarding the various viruses now being demonstrated may emerge, sinee it is difficult under present schemes of thinking to imagine how antibodies to SR virus can be formed in persons never before having received blood or blood products. The implication of variations in Red Cross gamma globulin antibody concentrations against measles has been stressed by Stokes16 in considering the probably even greater variation one might anticipate in concentrations of antibody against the less ubiquitous hepatitis viruses. Thus, results of protection when using material so variable in its antibody concentration must be weighed cautiously, and the best results be accorded the most weight. Stokes has also been the principal spokesman for the description of the natural immunity to hepatitis as a "passive-active immunization," a situation analogous to that in which the natural decline of circulating gamma globulin injected parenterally does not result in a disappearance of immunity when the patient is continuously exposed to the infective agent. Utilizing the results of Krugman et aI., he suggests that the use of orally administered serum from cases of early hepatitis plus parenterally administered gamma globulin given almost simultaneously would result in prolonged immunity and a much milder clinical disorder. TREATMENT OF THE CLINICAL DISEASE
In their recent article dealing with prevention and treatment of hepatitis, Iber and Mendelofflo state: "At the present time there is no definite evidence that known agents directly attack the virus of hepatitis once it has invaded the liver. This serious limitation forces the physician to direct his efforts toward prevention of the disease, keeping the patient alive, arresting the damage, and encouraging regeneration of normal liver cells in every way possible. Since the disease tends to be self-limited and mild in children and young adults, evaluation of therapeutic measures in this, the largest group of sufferers, is extremely difficult. In the treatment of severe chronic or relapsing hepatitis the number of patients is small and multiple therapeutic programs common. Thus good statistical grounds for preferring one or another regimen are lacking." Since the above was written, Stokesl6 has reintroduced his concept that severe liver necrosis in hepatitis may be the result of symbiotic activity of virus and enteric bacterial pathogens. He has pointed out previously that many severe outbreaks of epidemic hepatitis are indeed preceded by bacterial enterocolitis, and that subjects who were chronic carriers of
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Salmonella choleraesuis developed unusually severe hepatitis when infected experimentally with IH virus. Early attempts by other investigators to confirm this work were inconclusive. A program for testing this hypothesis is now under way. The cornerstones of therapy in the average case of hepatitis, especially when the subject is a child or a male under 25, is rest in bed during the febrile phase of the disease, and the provision of a balanced and calorically adequate diet when the patient feels like eating it. Despite demonstrations among armed forces personnel in the Orient that strict bed rest was not more beneficial than lounging about, and that 4000 calories a day was not more beneficial than 3000 calories (to patients whose needs were probably 2500 calories), most physicians will err on the side of caution with regard to rest, although strict bed rest for most patients is not necessary. A sensible plan is to allow the patient to walk to the bathroom or to his meals, when he begins to want to do so, but to get off his feet after each meal for about an hour until the day when his serum bilirubin drops to about 1.5 mg. per 100 ml. or the sulfobromophthalein retention to 5 per cent at 45 minutes. If gradual ambulation is not accompanied by evening temperature rises, dye retention, or elevations of serum transaminase or bilirubin, it is continued to the point at which the patient is allowed to carry out his usual activities for the mornings of a given week, coming home for lunch, taking a short walk before supper, and getting into bed after supper. At the end of one week of such a regimen, the above tests are repeated; if normal, a return to full activity is indicated for the next week. If these criteria are not met, or if the patient has a return of anorexia or malaise, a return to partial bed rest is indicated. The diet in hepatitis should be a normally balanced one, containing one gram of protein per kilogram of body weight, fat of 60 to 80 gm., and carbohydrate sufficient to make up daily c~loric needs, generally about 3000 calories for an adult. It is important to divide the diet in such a way that the patient receives nearly half of his daily calories at breakfast, and the remainder in small attractive feedings every three hours during the day. Intravenous glucose infusions are needed if the patient cannot ingest more than 1000 calories orally per day, and under such circumstances vitamin supplementation is required. Diet supplements under the usual circumstances are unnecessary. Intravenous fat emulsions for as many as six days are probably without harm. The measurement of urinary output and fluid intake is useful in the first two weeks of the disease, when marked disturbances in water and sodium metabolism occur; a diuresis usually heralds clinical improvement. Critical discussions of these matters of diet and rest may be found else,vhere. 8 , 10, 11 Of all the other adjuvants to the therapy of hepatitis, only one deserves thoughtful mention. The adrenal steroids should be used in the treatment of the more severe cases, or those which represent the begin-
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ning of a relapsing or chronic course. Older persons with hepatitis and adolescent girls seem to do especially poorly when treated conservatively; despite the well-known disadvantages of full steroid therapy, it is my feeling that such a regimen is of obvious benefit in most of these cases, and life-saving in a fair proportion. Prednisone in doses of 60 mg. per day for the first four or five days, and at levels of 30 mg. per day thereafter for ten or more days usually makes appetite return, mental acuity increase, and spontaneous voluntary muscular activity purposeful. Pruritus, if present, is greatly relieved.; patients are more active during the day, and sleep better at night. The use of nonabsorbable antacids is mandatory one hour after each feeding, and at bedtime, when steroids are being administered. The withdrawal of steroids must be very slow, as hepatic coma has often been precipitated by too rapid tapering of this therapy. It is unlikely that doses of prednisone greater than 60 mg. per day will reverse fulminant hepatitis, a rare and almost universally fatal form of the disease, but the few reported patients who have survived have received at least 60 mg. of prednisone daily. PREVENTION OF SPREAD AND METHODS OF PROTECTING CONTACTS
Despite the present confusion as to the identity of a number of viruses isolated from the serum of hepatitis cases and from asymptomatic human subjects, all the viruses so far studied have shown similar resistance to heat, ether and chlorination at levels usually obtaining in \vater supplies. The main reliance in preventing spread of infection from the intestinal tract of the patient to the mouth of a contact or to food prepared by the contact is careful and meticulous hand \vashing, \vith soap, on the part of the latter. Stokes 16 has stressed that in institutions a single toilet is often constantly contaminated, and this, plus inadequate hand washing, may serve as the source of a continuing outbreak. If this be the case, then the toilet seat should be cleaned after each use, preferably with a 1 per cent aqueous iodine solution, and each person using the toilet should have a separate packet of toilet paper rather than a few pieces from a common roll of toilet tissue. All feces-contaminated fomites, particularly bedclothing and bedpans, should be autoclaved; other fomites coming in contact with the patient's hands, such as books, pencils, radios etc., should be considered as contaminated and not allowed to leave the patient's room. The patient should not receive gifts which cannot stand autoclaving or iodine sterilization. Enteric precautions employing a covering gown which remains in the patient's room, careful handwashing technique, and restriction of the number of persons visiting the patient seem able to control most outbreaks. That this is effective is the best answer to the possibility that respiratory spread of the disease is of importance. Despite the catarrhal nature of the prodromal symptoms,
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respiratory transmission has never been demonstrated in IH infections. For patients with probable serum hepatitis, as much disposable equipment as possible should be provided for the collection of blood or the infusing of parenteral solutions. All nondisposable pieces of apparatus should be sterilized by autoclaving at 15 pounds per square inch at 1240 F. for 20 minutes; boiling for 30 minutes is probably also adequate. Large and expensive pieces of hospital equipment which are constantly exposed to blood-e.g. the artificial kidney dialyzers, heart-lung pumps, continuous oxygen analyzers-have been shown to be rendered virusfree by gaseous sterilization with ethylene oxide. IQ Blood and blood derivatives which can stand ten hours of heating at 60 0 C. will be free of virus, but only albumin can withstand such treatment. It appears to be possible to sterilize fluid blood or plasma by the addition of 1.5 gm. of beta propiolactone per liter, especially if the amounts treated are not very large; large-scale sterilization is also effective provided that the mechanisms governing the mixing of the materials always function efficiently. In the final analysis, the control of these viral diseases which can produce so much morbidity and a significant mortality must lie in measures to increase immunity and lessen the risk of massive exposure. These surely mean the development of a vaccine for all persons to receive as children, with boosters from time to time, and the limitation by physicians of blood transfusions which are not absolutely necessary. The inactivation of the virus in processed blood is also necessary. Fortunately, although none of these measures is at hand at this writing, there is every reason to believe that the next decade will see gratifying fulfillment of these needs. REFERENCES 1. Baggenstoss, A. H.: Postnecrotic cirrhosis: Morphology, etiology, and pathogenesis. In Progress in Liver Disease, Chap. 2 (H. Popper and F. Schaffner, Eds.). New York, Grune & Stratton, 1962. 2. Bearcroft, W. G. C.: Cytological and cytochemical studies on the liver cells of yellow-fever infected rhesus monkeys. J. Path. & Bact. 80: 19, 1960. 3. Bearcroft, W. G. C.: Electron-microscope studies on the liver in infective hepatitis. J. Path. & Bact. 83: 383, 1962. 4. Braunsteiner, H., Fellinger, K., Pakesch, F., Beyreder, Jr., Grabner, G. and Neumayr, A.: Elektromimikroskopische Beobachtungen an Leberzellen bei Serumhepatitis und Hepatitis epidemica. Klin. Wchnschr. 35: 901, 1957. 5. Davis, E. V.: Isolation of viruses from children with infectious hepatitis. Science 133: 2059, 1961. 6. Drake, M. E. and others: Failure of convalescent gamma globulin to protect against homologous serum hepatitis. J.A.M.A. 152: 690, 1953. 7. Eichenwald, H. F. and Mosley, J. W.: Viral Hepatitis-Clinical and Public Health Aspects. U. S. Public Health Service, Publication No. 435, 1959. 8. Havens, W. P., Jr.: Viral hepatitis: Clinical patterns and diagnosis. Am. J. Med. 32: 665, 1962. 9. Herriott, R. M.: Infectious nucleic acids, a new dimension in virology. Science 13J,.: 256, 1961.
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10. Iber, F. L. and Mendeloff, A.!.: Prevention and treatment of viral hepatitis. Arch. Int. Med. 109: 310, 1962. 11. Klatskin, G.: In Principles of Internal Medicine (T. R. Harrison et al., Eds.). 4th Ed., Chap. 280. New York, Blakiston Co. 1962. 12. Krugman, S., Ward, R. and Giles, J. P.: The natural history of infectious hepatitis. Am. J. Med. 32: 717, 1962. 13. McCollum, R. W.: Epidemiologic patterns of viral hepatitis. Am. J. Med. 32: 657, 1962. 14. Melnick, J. L.: A water-borne urban epidemic of hepatitis. In Hepatitis Frontiers (F. Hartman et aI., Eds.). Boston, Little, Brown & Co., 1957, pp. 287-295. 15. O'Malley, J. P., Mayer, H. M., Jr. and Smadel, J. E.: Antibody in hepatitis patients against a newly isolated virus. Proc. Soc. Exper. BioI. & Med. 108: 200,1961. 16. Stokes, J., Jr.: The control of viral hepatitis. Am. J. Med. 32: 729, 1962. 17. Taylor, A. R., Rightsel, W. A., Boggs, J. D. and McLean, I. W., Jr.: Tissue culture of hepatitis virus. Am. J. Med. 32: 679, 1962. Sinai Hospital of Baltimore Baltimore 15, Maryland