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Chapter 3, Part 3

Medical Science Publication No. 4, Volume II

VIRAL HEPATITIS: INFORMATION OBTAINED DURING THE KOREAN WAR*

CAPTAIN THOMAS C. CHALMERS, MC

During the recent Korean conflict infectious hepatitis was a prominent and serious cause of medical disability. In the absence of a specific chemotherapeutic agent the treatment of the disease has continued to be symptomatic, and a conservative approach, relying primarily on prolonged bed rest in the hospital, had been adopted by the Army Medical Corps during the period following World War II.

FIGURE 1.

SOURCE: Reprinted with permission "Health of the Army," January, February, and March 1953.

This resulted in a prolongation of the total period of disability from around 50 days in World War II to around 80 days during the recent hepatitis epidemic among troops fighting in Korea. As a result of controlled studies conducted at the Army Hepatitis Center in Kyoto, Japan, summarized below, it has become apparent that the "routine" treatment has been too conservative, and that from 2 to 3 weeks can, with safety, be eliminated from the average duration of disability.


*Presented 27 April 1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical Servive Graduate School, Walter Reed Army Medical Center, Washington,
D. C.


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The incidence of acute infectious hepatitis among American troops in Korea (1) is shown in figure 1. It is of interest that there was a 3-month lag period between the first peak in incidence and the time at which sanitation was at its worst and the dysentery rate highest, during the defense of the Pusan perimeter in August 1950. The first peak of 31 per thousand was reached in November 1950, while the United Nations troops were advancing to the Yalu River. During the next 3 months the rate fell off in spite of the retreat southward, and then rose to its highest levels, 33 to 35 per thousand, during February, March and April of 1951. There was again a sharp fall, and for the last year of the war the rate was no higher than it had been during the peacetime occupation.

These rates are partially explained by the epidemiological observations on hepatitis made during World War II. The incidence is highest during the spring and fall and at times when, owing to rigorous fighting conditions, the ordinary principles of sanitation are difficult to follow. It seems probable that the rather steady rates during the occupation and after the major campaigns of the war had ended are more associated, as in post-war Germany, with contact with the native population, while the peaks in incidence were principally due to breakdown in sanitation contingent on the fighting and unstable front line.

It is assumed that most of the patients discussed above had infectious, or epidemic, rather than homologous serum hepatitis. Those whose illness followed plasma or blood transfusions have been tabulated separately and averaged 0.2 per thousand. This figure, however, is undoubtedly low. Eighty-eight percent of the patients diagnosed as having infectious hepatitis had had some kind of parenteral injections in the 6 months before onset, and therefore may have had "needle" hepatitis. Only in the last half of the war was the multiple-dose syringe technic, known to transmit the hepatitis virus, abandoned completely.

A surprisingly high incidence of homologous serum hepatitis among wounded men was revealed in a survey conducted by Sborov, et al. (2) in three Army hospitals during 1950 and 1951. Patients on surgical and orthopedic wards who had received plasma and blood transfusions at the time of wounding were followed closely at weekly intervals and liver function tests were performed when clinically indicated. The results are summarized in table 1. This rate was higher than any previously reported following plasma or whole blood transfusions. The most important contribution of the study, however, lies in its comparison of the rates before and after the introduction of ultraviolet


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Table 1. The Incidence of Hepatitis Among Patients Transfused with Plasma and Blood (From Sborov, et al. (2))

 

Plasma and blood

Blood alone

Total number of patients

255

322

Average units per patient

1.4 (plasma)
5.3 (blood)

5.6

Number with hepatitis

56

12

Percent of patients

22

4

irradiated plasma. There was no difference. Thus it was clearly demonstrated during the Korean War that irradiation of plasma as practiced commercially was ineffective.

When it became apparent that the incidence of infectious hepatitis had reached epidemic proportions among the troops in Korea, it was decided to assign the patients to one hospital where the treatment could be standardized and the disease studied. The 35th Station Hospital in Kyoto, Japan, later the U. S. Army Hospital, 8164th Army Unit, was therefore designated as a hepatitis center. Patients were transferred there by air from the various hospitals in Korea as soon as the diagnosis of hepatitis was made. In the first 2 years that the Hepatitis Center was in operation over 4,000 patients were admitted and much useful knowledge of the natural history and treatment of the disease was acquired.

The usefulness of needle biopsy of the liver in the management of patients presenting problems in diagnosis or disposition was established (3). For the first time it was noted that significant amounts of fat could appear in the livers of patients convalescent from acute infectious hepatitis.

Several studies on the efficacy of vitamin B12 early in the course of the disease were conducted at the Hepatitis Center by Campbell and Pruitt (4). One hundred patients given 30 micrograms daily of vitamin B12 for the first 5 hospital days were compared with two comparable control groups selected from the records according to their maximum serum bilirubin levels. One control group received a high-calorie, high-protein diet plus vitamins and brewer's yeast; the other received the diet alone. The data revealed that anorexia and hepatomegaly disappeared more rapidly and the total duration of illness was less in the vitamin B12 treated group. No statistical analyses were applied to the results. A subsequent liver biopsy study revealed no morphological differences between the patients treated with vitamin B12 and the controls.


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During 1951 and 1952 the effects of diet, strict bed rest and exercise early in convalescence were investigated at the Hepatitis Center by a group from Harvard Medical School working under the sponsorship of the Commission on Liver Disease of the Armed Forces Epidemiological Board, in collaboration with the Army Medical Service Graduate School (5). Since distinct changes in the routine treatment of hepatitis, based on the conclusions of this study, have been recommended by the Armed Forces Epidemiological Board to The Surgeon General, the study will be reported in some detail here.

Four hundred and forty-two patients were studied. They had had symptoms for an average of 10 days and had been hospitalized elsewhere an average of 3 days before admission to each of the studies. The severity of their illness was similar to that encountered in previous epidemics among American military personnel. Although the overall mortality of the epidemic was about 0.2 percent, none of the study patients died. No relapses with jaundice were encountered. One hundred and eighty-eight of the four hundred and forty-two patients were selected for follow-up examinations from 6 to 18 months following their acute illness. Complete information, including liver function tests, was obtained on 179.

Criteria for admission to the studies included the presence of definite jaundice, duration of symptoms of less than 21 days, absence of recent plasma or blood transfusions, and absence of significant complicating disease. The treatment assignments were determined at random before the start of each study. Since the medical officer determining eligibility for admission did not know what treatment the patient would receive, there was no chance for unconscious bias to enter into the assignment to treatment groups. Numerous statistical checks at the completion of the studies revealed the groups to be similar in all details except for the treatments under investigation.

In a first study, involving 253 patients, the effects of strict bed rest were compared with ad lib rest and a forced, high-protein diet, supplemented with choline and vitamins, with the regular hospital diet eaten ad lib. Patients on the two ad lib rest wards were allowed out of bed all they wished, regardless of the degree of their jaundice, but were required to rest for 1 hour after each meal and to stay on their hospital wards. Those on the strict bed rest wards were required to stay in bed except for one trip to the latrine daily. Numerous bed checks were made each day to be sure that the patients adhered to their assigned treatment regimens. By the end of the first week in the hospital more than 50 percent of the ad lib rest patients, regardless of the depth of jaundice, were out of bed more than half of each day, and never more than 10 percent of the patients on the bed rest


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wards were caught out of bed more than once a day throughout their hospitalization.

As shown in figure 2, the ad lib rest groups had slightly shorter durations of acute illness than the strict bed rest groups. The difference was of borderline statistical significance and of no clinical significance. Relapses and residual abnormalities on follow-up examination were the same for each.

The patients on the forced diets, however, had significantly shorter durations of acute illness than those who ate the regular hospital diet ad lib (table 2).

Table 2. Design of the First Study and Results Expressed as Mean Durations of Illness in Days*

*For computational purposes these are geometric means and each is about 3 days less than the corresponding arithmetic mean. Duration of illness is defined as the time from admission (an average of 10 days after the onset of symptoms) to the time when the serum bilirubin drops below 1.5 mg. per 100 ml. and the bromsulphalein retention in 45 minutes below 6 percent.

Follow-up abnormalities were the same for each group. The forced-diet patients were forced to eat a minimum of 3,000 calories and 150 grams of protein. They averaged 4,000 calories and 220 grams of protein. The ad-lib-diet patients averaged 3,500 calories and 120 grams of protein.

A second study was designed to determine whether the dietary effect was related to the calorie, protein or supplement content of the forced diet. The results are presented in table 3. The only significant difference was a small one in favor of the high-protein diets. However, the patients on the 4,000-calorie, 190-gram protein diet had significantly more residual abnormalities on follow-up examination.


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Table 3.* Design of the Second Study and Results Expressed as Mean Durations of Illness in Days

*See footnote to table 2.

The conclusions from these studies regarding the dietary treatment of infectious hepatitis may be summarized as follows: Patients should be urged to eat a diet containing approximately 3,000 calories and 150 grams each of protein and fat. Intakes above this level should be ad lib. Although forced feeding may shorten the average duration of hospitalization by about 20 percent, the recommendation that all patients should be forced to a minimum level should be tempered by three items of interest: (1) The potential saving in time, although highly significant statistically, is small from the standpoint of the individual patient; (2) in a recent study by Leone, et al. (6) patients with homologous serum jaundice forced to eat a diet high in protein and low in fat did not do as well as those fed an ad lib diet; (3) recent studies in patients with severe cirrhosis have indicated that a high-protein diet may precipitate the syndrome of impending hepatic coma (7).

A third study was designed to determine whether the 2-week period usually necessary for patients to recuperate from the deleterious effects of prolonged rest in bed could with safety be eliminated from the hospitalization time of patients allowed ad lib rest throughout. All patients in the second study of 189 were allowed ad lib rest in the hospital and half were started on active physical reconditioning as soon as their total serum bilirubins were below 1.5 mg. per 100 ml. and


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their bromsulphalein retention in 45 minutes below 6 percent; the other half were kept in the hospital an extra 8 days as controls. There were no relapses precipitated by the early or late exercise. In some patients in the early exercise group the serum bilirubin rose above normal but it promptly dropped again while exercise was continued. In others there was a transient liver enlargement or return of minor symptoms, all of which disappeared while the patient continued to exercise. The two groups were similar at the time of their return to duty and on follow-up examination approximately one year later. Thus it was demonstrated that by eliminating strict bed rest and starting reconditioning earlier the average duration of hospitalization could with safety be decreased from 60 to around 40 days.

Summary

The incidence of infectious hepatitis reached epidemic proportions early in the Korean conflict.

Homologous serum jaundice occurred in 4 percent of wounded soldiers who received blood transfusions and in 22 percent of those who received blood and plasma.

Injections of vitamin B12 were thought to be effective in stimulating the appetite and shortening the acute illness.

The forcing of a high-protein diet significantly shortened the duration of jaundice but it is possible that the forcing of large amounts of dietary protein may be harmful to the most severely ill patients.

Finally, it was demonstrated in a carefully controlled study that enforced bed rest has no advantage over ad lib rest in the treatment of the acute disease. Early return to full activity of patients treated with ad lib rest was accompanied by no significant increase in residual abnormalities.

References

1. Korea. A Summary of Medical Experience, July 1950, to December 1952: Reprinted from Health of the Army, January, February, and March 1953, Office of The Surgeon General.

2. Sborov, V. M., Giges, B., and Mann, J. D.: Incidence of Hepatitis Following Use of Pooled Plasma. A Follow-up Study in 587 Korean Casualties. A. M. A. Arch. Int. Med. 92 : 678-683, 1953.

3. Deschamps, S. H., and Steer, Arthur.: Experience with Needle Liver Biopsies at the Hepatitis Center for Japan and Korea, 1950-1951. Am. J. Med. 13 : 674-687, 1952.

4. Campbell, R. E. and Pruitt, F. W.: Vitamin B12 in the Treatment of Viral Hepatitis. Am. J. Med. Sci. 224 : 252-262, 1952.

5. Chalmers, T. C., et al.: The Treatment of Acute Infectious Hepatitis. Controlled Studies of the Effects of Diet, Rest, and Physical Reconditioning on the Acute Course of the Disease and on the Incidence of Relapse and


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Residual Abnormalities. Report prepared for The Surgeon General, November 1953.

6. Leone, N. C., et al.: Clinical Evaluation of a High Protein, High Carbohydrate, Restricted Fat Diet in the Treatment of Viral Hepatitis. Annals of the N. Y. Acad. of Science. In press.

7. Phillips, G. B., et al.: The Syndrome of Impending Hepatic Coma in Patients with Cirrhosis of the Liver Given Certain Nitrogenous Substances. New England J. Med. 247 : 239, 1952.