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Chapter 18

Table of Contents

Chapter 18

Hepatitis

Joe A. Dean, M.D., and Brigadier General Andre J. Ognibene, MC, USA

Viral hepatitis has been described as "an acute infectious illness in which hepatic cell necrosis is responsible for the most frequent, prominent, and characteristic symptoms" (Mosley and Galambos 1969). Certainly there are other causes of "infectious hepatitis," such as yellow fever, leptospirosis, louseborne relapsing fever, EBV (Epstein-Barr virus), rubella, and cytomegalovirus. This chapter will deal with the more classical "viral hepatitis" in the military setting.

HISTORY

Zuckerman (1976b) has written a fine review of the history of hepatitis, from which much of this historical background is drawn. Descriptions of liver diseases, jaundice in particular, can be found in Babylonian talmud of the 5th century B.C. During this early period, Hippocrates described "epidemic" jaundice as "the fourth kind of jaundice" (yellow bile) (Cockayne 1912). The first recorded reference to the contagious nature of jaundice appears to have been in the 8th century A.D., in a letter from Pope Zacharias to St. Boniface, Archbishop of Mainz.       

That jaundice was a common disorder was especially evident in the Middle Ages when, during the many wars, "campaign jaundice" was described as following cholera and bubonic plague in importance as a cause of pandemics in Europe. An excellent historical account of campaign jaundice was given by Von Bormann et al. (1943), who described an outbreak occurring in Germany in 1629. The first definitive description of a jaundice epidemic in civilians was recorded in Germany in 1791 by Herlitz, who introduced the term "icterus epidemicus." Sydenham, in London, had already recorded some observations of epidemic jaundice (1624 to 1689).

The pathology of jaundice was described by Virchow (1865), after an examination of a single case in which mucus from the duodenum had blocked the terminal portion of the common bile duct. Frõhlich, in a review of jaundice out breaks (1879), suggested that an infectious process might be responsible for only 1 of the 30 outbreaks studied.

Jaundice apparently afflicted Napoleon's army in Egypt, but whether this outbreak was caused by infectious hepatitis is questionable, especially because of the high mortality rate. During the American Civil War, the Union Army suf-


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fered a reported 71,691 cases of jaundice. Epidemic jaundice was also present in the Franco-Prussian War in 1870, the French referring to infectious hepatitis as "jaunisse des camps" and the Germans as "Soldatengelbsucht." In South Africa during the Boer War, 5,648 cases of jaundice were recorded with typically low mortality. The Japanese Navy experienced epidemics during Japan's war with Russia in 1904 and 1905, and huge epidemics occurred during World War I.

The epidemic of 1942 caused by use of batches of yellow fever vaccine contaminated with hepatitis virus, coupled with the eruption of 200,000 cases of viral hepatitis between 1942 and 1945, identified the disease as a matter of prime importance to our Armed Forces during World War II (MD-IM3, p. 332). It became evident during this conflict that effective methods to treat or prevent hepatitis in soldiers were urgently required.

ETIOLOGY

The clinical features and etiologies of viral hepatitis may be divided into Types A, B, and C. Type A hepatitis or "catarrhal jaundice" was described by Hirsch (1886, p. 418) as first occurring in epidemic form in 1745. More recently, the syndrome has been called "infectious hepatitis." Type B hepatitis refers to "serum" (posttransfusion) hepatitis, the earliest known epidemic of which, as described by Lurman (1885), occurred in 1883 after inoculation of shipyard workers with smallpox vaccine containing human serum. When Types A and B hepatitis have been excluded from the diagnosis, other viral types become apparent; these have been designated as Types C, D, etc. EBV, rubella, and cytomegalovirus are the three most commonly described Type C etiologic agents (Sherlock 1976).

Type A Hepatitis

Type A hepatitis may have been described in De internis affectionibus by Hippocrates (Mosley and Galambos 1969, p. 410):

This type of jaundice is called epidemic because it occurs in all seasons. It is caused above all else by overindulgence, excesses of wine, and after a chill. From the first moment the body changes color and becomes yellow; the eyes become markedly jaundiced; the disease appears under the hair and under the nails. There are chills and low-grade fever. The patient is weak. The head aches; the urine is yellow and thick. This form of jaundice is less dangerous * * * and is cured if quickly treated.

eparation of Type A from Type B hepatitis did not occur until the 1940's, however, when volunteer studies demonstrated that the two were distinct entities (Yoshibumi and Shigemoto 1941; Voegt 1942; Havens 1946a & b; MacCallum and Bauer 1944; Neefe, Gellis, and Stokes 1946; MacCallum 1945; Neefe, Stokes, and Reinhold 1945; Paul et al. 1945). With the discovery of hepatitis B surface antigen (Australian antigen, HBs Ag) in 1963 (Blumberg, Alter, and Visnich 1965) and the demonstration of hepatitis A antigen 10 years later (Feinstone, Kapikian, and Purcell 1973; Mascoli et al. 1973), the two major types of viral hepatitis could be differentiated.

The antigen of Type A hepatitis is a viruslike particle, 27 nm in diameter, which is present in the feces of patients in both the late incubation and early


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acute phases of illness. The virus is resistant to heat, ether, and acid but sensitive to ultraviolet radiation, formalin, and chlorine. The antigen can be separated into "empty," "light," and "heavy" particles, but infectivity has not been associated with any one population of particles. The agent has been classified as an RNA virus (Purcell 1976; Provost et al. 1975; Dienstag and Purcell 1976; Sherlock 1976). Recovery of viruslike particles from the liver suggests that this organ is a site of viral replication. The fecal-oral transmission cycle of Type A hepatitis suggests that an intestinal phase of virus replication may also occur.

To date, only one serological type of hepatitis A virus has been identified. It is antigenically indistinguishable from the MS-1 strain which Krugman, Giles, and Hammond (1967) investigated at Willowbrook State School in New York. In fection with this virus has been demonstrated throughout the world (Dienstag 1976).

Serologic diagnosis of Type A hepatitis is presently confined to research laboratories because of the difficulty in obtaining hepatitis A virus for use as an antigen. Techniques include immune electron microscopy, immune adherence hemagglutination, complement fixation, and radioimmunoassay. Such serologic tests have confirmed that hepatitis A virus is the etiologic agent in almost all epidemics of hepatitis as well as in a significant number of sporadic cases (Purcell 1976). The prevalence of hepatitis A virus antibody in the population is directly proportional to age and inversely proportional to socioeconomic class. Approximately 45 percent of Americans studied have a positive antihepatitis A virus antibody (Szmuness et al. 1976).

Type B Hepatitis

As noted earlier, Type B hepatitis can be traced with certainty only from the late 1800's. The relatively late emergence of the illness seems to be compatible with the notion that its propagation depends primarily upon parenteral transmission. However, because barber venesection, scarification, and tattooing have been practiced throughout much of the world for centuries and are alternate routes of "parenteral" transmission, and because the virus is prevalent in culturally isolated populations (Mosley 1975), this theory of evolution must be viewed with skepticism.   

The Type B hepatitis virus is an antigenically complex 42 nm ("Dane") particle (fig. 76). Its surface antigen (HBS Ag), is, of course, the distinguishing characteristic of the infection. HBS Ag has antigenic heterogeneity with approximately 12 different genotype variants (a, y, w, l, d, r, x, t, g, q, n, j). In combination, these genotypes form four principal phenotypic expressions (adw, adr, ayw, ayr) and a variety of less common phenotypes. There is no apparent clinical difference among the phenotypes, and they are of epidemiological interest only. At the center of the Dane particle is an antigenically distinct core which is synthesized in the hepatic parenchymal cell nucleus. Serum antibodies to the core antigen (HBC Ag) can be detected in infected individuals, and DNA-dependent DNA polymerase activity has been described. A third antigen, the "e" antigen, may represent the DNA polymerase protein. The "e" antigen is found only with cir-


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FIGURE 76.-The Dane particle. (Sherlock, S. 1976. Introduction: A bird's eye view. Paper, postgraduate course on viral hepatitis, American Association for the Study of Liver Disease, Nov. 76, pp. 1-1-1-10.)

culating HBS Ag and is related to liver damage. Each antigen (HBS Ag, HB, Ag, "e" antigen) has corresponding antibodies, that is, anti-HBSAb, anti-HBS Ab, and anti "e" Ab (Zuckerman 1976a; Sherlock 1976).

EPIDEMIOLOGY

Type A hepatitis is endemic among school age children and young adults in the United States. There is no known reservoir for the virus, and propagation of the disease is by person-to-person transmission. Transmission is usually by the fecal-oral route since sufficiently large concentrations of the virus are present only in stool. The communicable period is short during the prodrome and diminishes with the onset of jaundice. Viremia is similarly short; therefore, only a few cases of instrument- or transfusion-related illness have been reported. Percutaneous introductions can occur (Mosley 1975; 1976).

Type B hepatitis is endemic among all age groups in the United States. A large reservoir of chronically infected humans can be established in any population in which it is introduced. Maintenance is, therefore, not dependent on chains of person-to-person infection as with Type A hepatitis. The major mode of transmission is parenteral, but other mechanisms are important, such as personal contact involving exchange of saliva, sexual contact, and vertical transmission (prepartal, intrapartum, and postpartum). By far the most common mode of transmission recently has been illicit self-injection of drugs using shared equipment (Mosley 1976, Szmuness 1975).


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CLINICAL FEATURES

On 17 March 1975, the National Academy of Sciences convened a symposium on viral hepatitis, which represents the most complete single compilation of data on viral hepatitis to date. The opening remarks by Dr. Allan Redeker (1975) introduced the clinical aspects of viral hepatitis as follows:

Acute viral hepatitis is a relatively common illness caused by infection with one of two or more viral agents. Both the acute and the chronic phases may be either totally silent or clinically manifest. The acute infection can be abruptly fatal; chronic infection can result in the development of cirrhosis and is probably one of the leading causes of cirrhosis throughout the world. Fortunately, in the majority of instances, acute hepatitis resolves totally without sequelae. [See chart 26.]

Acute viral hepatitis is characterized by a prodromal phase of vague gastrointestinal and constitutional symptoms, including fatigue, malaise, lassitude, diarrhea, nausea, vomiting, and anorexia. Taste and olfactor disturb ances may enhance the loss of appetite. Distaste for tobacco may occur but is an inconstant symptom. Especially in Type A hepatitis, fever (100° to 104° F), cough, coryza, myalgias, pharyngitis, and photophobia may be present. One to 4 days before the onset of jaundice, the urine darkens and the stool becomes lighter in color. Transient pruritus may occur.

The icteric phase of acute hepatitis usually lasts less than 6 to 8 weeks. There is no difference between types of viral agent in this phase. Mild weight loss (5 to 10 pounds) is common. The prodromal symptoms decrease in the first few days of jaundice. The jaundice usually peaks between 1 and 2 weeks after onset. Hepatic enlargement and tenderness occur initially but decrease after the first 2 weeks. A recovery phase of 2 to 6 weeks follows the icteric phase in which serum abnormalities may continue. The patient usually feels well (Koff and Isselbacher 1974).

Laboratory findings in acute viral hepatitis include a normal leukocyte count or mild leukopenia (transient), atypical lymphocytes (2 to 20 percent), and mild hemolysis with reticulocytosis (uncommon). The SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic-pyruvic transaminase) may be abnormal 7 to 14 days before onset of jaundice, and peak typically between 400 and 3,000 units. The serum bilirubin is usually above 3 mg/100 ml at onset of icteric phase with a peak of 5 to 20 mg/100 ml. Patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency or sickle-cell disease may have more significant hemolysis, and profound hyperbilirubinemia may occur. (In Vietnam, there was no apparent alteration of the clinical course of the disease in troops with G6PD deficiency.) The serum alkaline phosphatase is usually only mildly elevated (5 to 15 Bodansky units), although "cholestatic hepatitis" may occur with peak alkaline phosphatase levels greater than 15 Bodansky units. In these cases, infectious mononucleosis or other causes of obstructive jaundice require consideration. In uncomplicated acute viral hepatitis, the prothrombin time remains normal (Koff and Isselbacher 1974). An abnormal prothrombin time often heralds the onset of acute fulminant hepatitis; thus, in any combat theater where hepatitis is expected, this laboratory test must be made available.


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CHART 26.-Courses of acute viral hepatitis1

The characteristic pathologic changes in acute viral hepatitis involve the portal, periportal, and lobular areas of the liver (fig. 77). The portal tracts are enlarged by accumulation of inflammatory cells and edema. The inflammatory cells are predominantly mononuclear cells with some polymorphonuclear leukocytes. Ductular proliferation may be seen, as may necrosis of periportal hepatocytes and loss of a definite "limiting plate." The characteristic lesion is single cell injury and "spotty" necrosis. Affected areas are randomly scattered throughout the lobule but are most prominent around the efferent vein (Koff and Isselbacher 1974, pp. 1529-31; Boyer and Klatskin 1970).

COMPLICATIONS

Extrahepatic manifestations of viral hepatitis have been described as "Immune Complex Syndromes" (Alpert 1976; Gocke 1975). Usually these occur with hepatitis B virus infection, but non-B hepatitis viruses may also produce them. Three major syndromes are recognized. First and most commonly, a prodrome similar to serum sickness may occur, with rash, urticaria, polyarthralgia, and, in 10 to 20 percent of patients, acute arthritis. This syndrome usually occurs a few days to 6 weeks before the onset of hepatitis and is transient, lasting only 2 to 7


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days. Circulating immune complexes (HBS Ag-IgM, IgG) have been demonstrated. Components of serum complement (C'H5o, C'3, C'4) are low in both serum and joint fluid.

The second syndrome is that of polyarteritis nodosa, which occurs with hepatitis B infection. The onset involves fever, myalgia, polyarthralgia, rash, and urticaria. Peripheral neuropathies, hypertension, eosinophilia, hematuria, and azotemia may ensue. Fibrinoid necrosis and perivascular inflammation in the walls of small arteries and arterioles can be demonstrated. HBS Ag persists throughout the illness. In the early acute phase, serum C'H50 is decreased and circulating complexes of HBS Ag/anti-HBS Ab are present. HBS Ag, IgM, IgG, and C'3 deposit in vessels (Gocke 1975).

The third syndrome is that of hepatitis B-associated glomerulonephritis, which usually presents in chronic form but may be acute. It is associated with chronic hepatitis in adults and may be responsible for over 30 percent of glomerulonephritis in children. Most often, it is membranous or membranoproliferative. Nodular deposits of HBS Ag, IgG, IgM, and C'3 occur on the glomerular basement membrane (Gocke 1975).

Fulminant hepatitis is an uncommon complication of acute viral hepatitis (fig. 78). Approximately 1.0 to 2.4 percent of patients hospitalized with acute viral hepatitis will develop this complication regardless of virus type. The term "fulminant" applies when abrupt hepatic failure occurs during the course of the illness. "Subacute (fatal) hepatitis" refers to a course of acute viral hepatitis with hepatic failure of more gradual onset. Fulminant hepatitis occurs infrequently in children and does not occur in anicteric hepatitis. The mortality rate increases with age, with the highest survival in the 0- to 14-year age group (37 to 47 percent) and the lowest in patients over 44 years (0.0 to 6.5 percent). In the active-duty military age group (15 to 44 years), the survival rate is 20 to 25 percent. These percentages are from two studies of patients with presumed fulminant viral hepatitis and stage IV portal-systemic encephalopathy ("hepatic coma") (Redeker 1975, pp. 9-11). It should be emphasized that the overall mortality for acute viral hepatitis is under 1 percent. It is theorized that the increased survival rate in younger individuals with fulminant hepatitis is related to their greater capacity for rapid hepatocyte regeneration. This concept derives support from the finding of high concentrations of serum alpha-fetoprotein, which indicates regeneration, in patients surviving fulminant viral hepatitis (Redeker 1975, p. 10; Karvountzis and Redeker 1974).

Preexistent cirrhosis or malignancy produces an unusually high mortality rate. Other than supportive measures, to date no mode of therapy is of established benefit. Exchange transfusion, extracorporeal hemoperfusion through heterologous liver, plasmapheresis, and corticosteroids are the most commonly considered therapies. Previous studies (Boyer and Klatskin 1970) have suggested that cirrhosis develops following severe necrosis; however, recent studies (Karvountzis, Redeker, and Peters 1974) demonstrate that patients recovering from fulminant hepatitis seldom develop cirrhosis, although liver biopsies that resemble chronic active hepatitis may persist. Following uncomplicated acute viral hepatitis, however, the majority of patients recover completely (Redeker 1975, p. 9).


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FIGURE 77.-High power microscopic views of hepatic parenchyma in acute viral hepatitis demonstrating (top) mononuclear leukocyte infiltration and edema (hematoxylin-eosin), and (bottom) prominent reaction about efferent vein (Masson)


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FIGURE 78.-Top: Liver of patient dying of fulminant viral hepatitis, showing massive hemorrhagic necrosis and fat deposition. Bottom: High power microscopic view (hematoxylin-eosin) of hepatic parenchyma in late fulminant hepatitis showing massive necrosis and fibrosis.


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CHRONIC HEPATITIS

Approximately 10 percent of hepatitis B patients develop chronic hepatitis. Type A hepatitis rarely becomes chronic. The majority of patients found to have chronic hepatitis do not have a recognizable acute illness. The two basic types of chronic hepatitis are the chronic persistent and chronic active forms.

Chronic persistent hepatitis is the more common type, occurring 10 times more frequently than chronic active hepatitis. It is characterized by persistent elevations of the serum transaminase (100 to 300 unit range), with a gradual yearly decrease toward normal in an asymptomatic patient. Progression to cirrhosis is rare. HBS Ag titers are normally high in Type B cases. Recurrent jaundice is not a feature of the illness. Some cases will resolve spontaneously, including disappearance of HBS Ag (Redeker 1975, p.12). The morphologic picture (fig. 79) is that of mild histopathologic changes with "cobblestone" hepatocyte architecture, minimal necrosis, and round cell reaction (Edmondson and Schiff 1975, pp. 256-57).

Chronic active hepatitis may be viral or nonviral. About 1 to 3 percent of patients with acute icteric viral hepatitis develop it (Redeker 1975, pp. 13-15). The range and pattern of hepatic distortion are broad. Many patients are totally asymptomatic. Recurrent or intermittent episodes of jaundice may occur, which are usually associated with impressive elevations of the serum transaminases. As Boyer and Klatskin (1970) have demonstrated, extensive necrosis ("submassive necrosis") during the initial acute hepatitis is a predisposing factor to development of chronic active hepatitis, as well as (questionably) to development of cirrhosis, and (unequivocally) to a poorer prognosis.

The pathologic changes which have been described as active juvenile cirrhosis, lupoid hepatitis, subacute hepatitis, autoimmune hepatitis, chronic viral hepatitis, plasma cell hepatitis, liver disease in young women with hyperglobu linemia, subacute hepatitis necrosis, chronic liver disease in young people, and numerous other synonyms are those of chronic active hepatitis. On biopsy (fig. 80), one observes cellular infiltration, including plasma cells, lymphocytes, and macrophages, a continuing type of hepatocyte injury indicated by ballooning (hydropic degeneration), active necrosis, eosinophilic degeneration, and dropout of liver cells. The periportal areas, particularly, are involved. The degree of collapse and fibrosis is variable. In early disease, collapse and necrosis may not be present, but "piecemeal" necrosis is. As the disease progresses, fibrous tissue entraps islands of parenchyma, frequently connecting the portal and centrolobular areas by the septa (bridges) which it forms. Lobular architecture is destroyed by these septa. Plasma cell infiltration is abundant. The end stage (fig. 81) is marked by regenerative pseudolobules with ongoing necrosis and chronic infiltration (postnecrotic or macronodular cirrhosis) (Edmondson and Schiff 1975, pp. 257-58).

Therapy of chronic active hepatitis usually consists of corticosteroids and possibly immunosuppressive agents (Sherlock 1974). A limited number of controlled studies have been done, and understanding of the natural history of


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FIGURE 79.-Top: High power microscopic view (hematoxylin-eosin) of hepatic parenchyma in chronic persistent hepatitis showing minimal necrosis, preservation of limiting plate, and round cell infiltration. Bottom: Same, with Masson stain.


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FIGURE 80.-Top: High power microscopic view (hematoxylin-eosin) of hepatic parenchyma in chronic active hepatitis showing piecemeal necrosis, limiting plate loss, periportal hepatocyte entrapment, and bridging necrosis. Bottom: Low power view (Masson) of same.


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FIGURE 81.-Low power microscopic view (hematoxylin-eosin) of postnecrotic (macronodular) cirrhosis demonstrating large bands of fibrous tissue encircling regenerating macronodules.

resolution of this form of hepatitis is poor; thus, these nonspecific treatment modalities are difficult to assess. They have been shown to have beneficial effects on survival, hepatic histology, and laboratory tests in non-B hepatitis patients, but such evidence is lacking for Type B chronic active hepatitis (Cook, Mulligan, and Sherlock 1971; Soloway et al. 1972).

VIETNAM EXPERIENCE

Organized study of the large numbers of troops afflicted with hepatitis was not undertaken in Vietnam; attention was focused on prevention and therapy. As early as the 1940's, Stokes and Neefe (1945) reported that epidemic icteric hepatitis could be either prevented or attenuated by the parenteral administration of human serum gamma globulin. In 1964, a program designed to protect all military personnel stationed in Asia against hepatitis was instituted. A 16-percent solution of human serum gamma globulin in a dose of 0.05 ml/lb was used. The gamma globulin was prepared from blood donated in the United States. A significant decrease in the prevalence of hepatitis during that year as compared to the previous year was seen in preliminary observations in both Korea and Vietnam. However, close examination of monthly hepatitis rates revealed that the decrease had begun 4 months before the gamma globulin prophylaxis program was initiated. Thus it was impossible to determine whether


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the incidence of icteric hepatitis in American troops hospitalized in Southeast Asia was significantly affected by the administration of gamma globulin from the United States (Conrad 1972).

With the increasing involvement in Vietnam after 1965, national stockpiles of gamma globulin were significantly depleted and a reassessment of the prophylactic program was necessary. The dose of gamma globulin administered to soldiers was reduced to 5 ml of a 16-percent solution after arrival overseas, with a second injection 5 months later (DA Circ). It was decided, in 1966, that only persons under high risk of exposure to infectious hepatitis would receive the inoculations of gamma globulin. A continuing incidence greater than five cases per 1,000 per year in particular units was suggested as a guideline for this high risk group.

No significant increases in the incidence of hepatitis during the next year were associated with the decreased utilization and dosage of gamma globulin. In Vietnam, the case rates for viral hepatitis ranged between 4 and 10 per 1,000 troops per annum (HOA). A systematic study of the policy of prophylactic gamma globulin administration in high risk patients was never accomplished in Vietnam.

However, a large body of data was available from the Korean era (Conrad 1969). Conrad (1972) did a study of all soldiers arriving in Korea through a single airport. Between May 1967 and August 1969, 107,803 troops were given, upon arrival, either a 10-ml injection containing 2 ml, 5 ml, or 10 ml of a 16-percent human serum gamma globulin or a 10-ml albumin-sucrose-potassium glutamate solution. A second injection of the same material was given to 65 percent of these soldiers 5 to 7 months later. Soldiers having symptoms or physical findings of hepatitis were hospitalized and examined. A liver biopsy specimen was obtained fom 82 percent of the patients. Results showed 467 documented cases of icteric viral hepatitis in the subjects studied. The calculated incidence was 5.67 cases per 1,000 among the control subjects, who received the albumin, while among soldiers given various amounts of gamma globulin it was 4.04 (2 ml group), 3.39 (10 ml group), and 2.90 (5 ml group) cases per 1,000. Significant protection was provided to those receiving 2 ml of gamma globulin but slightly less than that which was observed with 5 ml. The larger dose of 10 ml did not produce a further reduction in the incidence of viral hepatitis.

In addition, there was no significant difference between the incidence of other infectious diseases in the gamma globulin-protected group and in the control group. Conrad also compared the hospital records of patients who received the 5- or 10-ml dose of gamma globulin with those of patients injected with placebo, to determine whether gamma globulin affected the severity of the illness. Again, no significant differences appeared between the groups. Since almost none of the patients studied had had blood transfusions, it was believed that most were infected orally. The availability of data showing minimal differences between treated and untreated groups in mass prophylaxis reinforced the policy in Vietnam of providing only 2 ml of gamma globulin to individuals in whose units a significant epidemic exposure was manifest. There is no evidence that this policy had any effect on the incidence or severity of disease.


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As the number of troops, and consequently the number of cases of hepatitis, increased and the necessity for air evacuation of these patients from Vietnam became apparent, the prolonged period of treatment and hospitalization not only caused a loss of duty time but also produced a logistical problem of evacuation and replacement. The opening of the 6th Convalescent Center at Cam Ranh Bay, Vietnam, on 16 May 1966, provided a way station to which hepatitis patients could be evacuated for convalescence. However, the prolonged recovery phase was still a major factor contributing to the number of man-days lost to combat units.   

In examining the problem of treating hundreds of patients with infectious hepatitis at the 6th Convalescent Center, Repsher and Freebern (1969) were impressed by the benignity of the clinical course in most of the patients, the occur rence of relapses despite adherence to a bed rest regimen, and the uneventful clinical course of patients who engaged in physical activity contrary to advice. Based on these observations, they performed a pilot study on the effect of vigorous reconditioning on patients whose liver function tests had not completely returned to normal values. The effect of exercise on recovery from viral hepatitis had been reviewed earlier by Chalmers et al. (1955) and Nefzger and Chalmers (1963), whose extensive studies led to the conclusion that patients allowed ad libitum activity improved just as rapidly as those kept on strict bed rest. In addition, patients who returned to active physical rehabilitation as soon as the results of their liver function tests were relatively normal were found to have an uncomplicated convalescence similar to that of patients returned to duty much more gradually. Nelson and coworkers (1954) had reexamined, 2 to 3 years after onset of disease, patients who had had ad libitum exercise. Their studies included hepatic biopsies in 40 of the 80 patients, all of which showed no evidence of residual liver disease. Furthermore, Repsher and Freebern's review of existing literature indicated an absence of controlled or prospective studies demonstrating any benefit from the traditional enforced bed rest regimen.

Repsher and Freebern (1969) then undertook a prospective study of 398 American servicemen at the 6th Convalescent Center. Inclusion in the study required elevations of serum bilirubin concentration and SGOT. Patients were examined to preclude the presence of malaria, infectious mononucleosis, pneumonia, or other illnesses. They were required to have been asymptomatic with return of appetite for less than 5 days despite the persistence of abnormal liver function. Evidence of previous hepatitis or history of blood transfusion in the preceding year excluded patients from the study. Patients were divided randomly into rest and exercise groups. The rest group's activity was restricted to a 100-yard walk to the messhall and a walk to the theater or post exchange; they were otherwise confined to the ward. The exercise group participated in a 1-hour session of calisthenics 6 mornings a week, including a 1-mile run and, for 4 afternoons a week, a 2-hour work detail filling sandbags, painting buildings, and constructing bunkers. This group also participated in supervised athletics including softball, swimming, volleyball, and basketball. During the period of study, all groups were under the direct observation of the assigned physicians.


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Comparison of these groups showed no difference in duration of illness. In one-third of the cases, the SGOT was still elevated when the serum bilirubin had returned to normal, a situation no more frequent in the exercise group than in the rest group. While recovery time was unchanged in the two groups, the time to return to duty was shorter for the exercise group. The exercise group was shown to be fit for return to combat duty immediately on completion of hospitalization. The rest group, however, required conditioning and observation before discharge and appropriate disposition could be made. As a result of this study, individuals recovered from hepatitis were returned to combat duty earlier than had been possible in the past. Repsher and Freebern cautioned against making generalizations about infectious hepatitis in all adults from studies of the disease in this military population of otherwise healthy young men. Furthermore, the origin of the disease may differ in different parts of the world. They also warned against applying their findings to Type B hepatitis, inasmuch as presumably their cases were caused by Type A virus.  

The studies of Krugman, Ward, and Giles (1962) indicated that in most cases virus is excreted from about 16 days before icterus to about 8 days after its appearance. Based on this information, no attempt was made to separate the exer cise group from the other patients at the 6th Convalescent Center. Most patients had been hospitalized primarily at an evacuation or field hospital before transfer to the convalescent center, with an average of 8 days' delay before arrival there. Normal hygiene was maintained but isolation procedures for hepatitis patients were not practiced. They shared common dining facilities with the staff and with other patients. During the 6 months of the study, none of the patient contacts developed hepatitis; only one case was identified in a staff member in the year that followed, but it could be attributed to eating in a local village. Thus, this study was responsible for simplifying hospital care for hepatitis patients in addition to significantly reducing combat man-days lost. Returning the individual to his parent unit reduced the need for out-of-country evacuation and replacement from the continental United States.

Table 81 lists the number of cases of hepatitis, by month, in Vietnam for 1965-72 and the numbers of noneffective days for 1965-70. While the number of cases per year remained fairly constant, the noneffective days decreased by 65,986 between 1968 and 1970. The average time lost from duty per individual thus decreased from 35.7 days to 18.6 days during that period.

While an exercise program for the patient with uncomplicated hepatitis was shown to be appropriate in a combat theater, considerable concern arose regarding those patients who might have chronic active hepatitis. Studies by Anand, Tamburo, and Leevy (1971) had shown some detrimental effect of exercise on hepatic function in patients with chronic active hepatitis. At the 6th Convalescent Center, Jolson and Blailock (1970) studied 26 patients with a clinical diagnosis of viral hepatitis, randomly selected for aspiration liver biopsy by the Menghini technique. Six of these patients were noted to have some increase in portal collagen and minimal fibrous interconnecting bridging. Three of the six had evidence of focal, piecemeal necrosis at the limiting plate compatible with chronic active hepatitis. Followup of these three patients was obtained with


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TABLE 81.-New cases of hepatitis, by month, among active-duty Army personnel in Vietnam, 1965-72

biopsies 30 to 90 days later. The pathological changes in each case progressively decreased in severity as fibrous interportal bands disappeared. Results were inconclusive, though they suggested that additional studies on larger numbers of patients might be considered.

The success of the 6th Convalescent Center's programs in returning hepatitis patients to duty resulted in publication of an official fact sheet on management and evacuation policy by Col. Philip J. Noel, Jr., MC, USARV (U.S. Army, Vietnam) surgeon (1970). The text of the fact sheet follows:

The projected possibility of a shortage of convalescent beds has not materialized. Therefore, the following management practices for viral hepatitis patients are being established.  

All patients with viral hepatitis will be admitted to an acute treatment facility. When subjective symptomatology improves, the patient will be transferred to the 6th Convalescent Center.

Patients contracting viral hepatitis with over ten months in-country will be evacuated directly from the acute treatment facility to CONUS. Their clinical status should be stable prior to disposition.   

Those patients transferred to the 6th Convalescent Center will undergo a program of treatment and graded physical exercise and reconditioning. This program will allow most of the affected individuals to be returned to full duty.   Those patients whose clinical states do not warrant return to full duty within the limits of the established evacuation policies will be returned to CONUS.

The important point is the requirement for a physical activity program. However, with American withdrawal and the increase in hepatitis related to drug abuse, definitive conclusions about the long-term followup of patients treated with daily exercise could not be reached. Many questions remain for future study in large troop populations with hepatitis, especially if therapy continues to include early ambulation, exercise, and early return to duty.

It was indeed fortunate that the major complications of hepatitis were infrequently seen in Vietnam. Although a limited number of patients developed fulminant hepatitis, as a general rule most patients had uncomplicated


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recoveries without significant sequelae. Problems with hepatitis in drug abusers will be discussed in volume III of this series on internal medicine in Vietnam.    

Following the discovery of hepatitis B antigen, viral hepatitis could be divided into two major groups based on the antigen's presence or absence. To determine the importance of HBS Ag positive hepatitis in Vietnam, Neumann and Benenson (1974) studied patients admitted to four U.S. military hospitals with a diagnosis of acute viral hepatitis. From August to December 1970, 175 American servicemen with acute viral hepatitis were studied and information was gathered on possible exposure to other persons with hepatitis and other epidemiological variables. HBS Ag was detected in the serum of 71 of these soldiers. There appeared to be no relationship between the presence of the antigen and race, sex, location, eating habits, drug use, or contact with other hepatitis cases. The signs and symptoms of disease among all patients are noted in table 82.

The epidemiology of Type B hepatitis was studied only late in the conflict and includes Thai and Cambodian population samples as well as American. Table 83 demonstrates the prevalence of antigenic markers of hepatitis B subgroups in varied populations. The antigenic subtypes of Americans stationed in Southeast Asia were unlike those of the indigenous populations and those of Americans in the United States (Snitbhan et al. 1975). The adr subtype, present in 85 percent of asymptomatic Asians, is noted in only 2.5 percent of Americans in the United States. However, it is found in 40 percent of American asymptomatic carriers in Asia. Such differences indicate that Americans acquire HBS Ag of subtype adr in Asia. Subtypes are region-dependent and not solely related to national origin. The presence of adr in Americans with hepatitis suggests transmission from the local population and the frequency of ayw confirms passage of infection from one American to another. The future study of subtypes can offer an effective epidemiological tool in review of large populations.

Epidemics related to Type A hepatitis were documented in units in Vietnam (Kunkel 1967). An episode of 71 cases of viral hepatitis among 1st Infantry Division personnel occurred between 3 April and 1 June 1967, while they were engaged in Operation JUNCTION CITY in War Zone C near the Cambodian border. All of the afflicted individuals had been in the field during the estimated time of the exposure; 92 percent were found to have been in one of the villages in the operations area, and 94 percent had been assigned duties at a single bridge site. Further investigation incriminated nonpotable ice supplies. Waterborne Type A hepatitis was well documented as far back as the 1930's and 1940's; however, it did not become part of everyday epidemiological consideration until the Delhi epidemic of 1955-56, which involved 29,300 cases (Mosley 1972). Scattered reports of epidemic outbreaks most likely related to iceborne or waterborne routes were characteristic of the Vietnam experience.

An analysis of hepatitis rates (chart 27) for the Vietnam war reflects three major phases. The first years, when activities were limited, were characterized by a low incidence rate. This was soon followed by rising rates as more troops became exposed to the environment and as established principles of hygiene and discipline were less effectively enforced. In 1968-69, however, personal hygiene


437

TABLE 82.-Clinical findings among 175 American servicemen in Vietnam with acute viral hepatitis, August-December 1970

CHART 27.-Hepatitis incidence rates during the Vietnam war


438

was emphasized and unit awareness was aroused. This was followed by a drop in the incidence rate. However, as the problem of drug abuse developed, rates again rose. Studies at that time (Neumann and Benenson 1974) revealed 41 percent of the patients were afflicted with type B hepatitis; this was the first time such data were available in Vietnam and reflected a shift in the epidemiology of the disease. With U.S. withdrawal, further study was aborted.

TABLE 83.-Prevalence of hepatitis B surface antigen1 and relative frequency of HBs Ag subtypes in various populations in Southeast Asia

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