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Chapter 3, Part 2

Medical Science Publication No. 4, Volume II

HEMORRHAGIC FEVER OF THE FAR EASTERN TYPE*

SIDNEY KATZ, M. D.

I. Introduction (1-3)

Hemorrhagic fever is an acute infectious disease that occurs in epidemic form in Northeast Asia. Patients characteristically manifest fever, prostration, anorexia, vomiting, and proteinuria. Cardiovascular instability, a hemorrhagic diathesis, and renal tubular damage become apparent and may in severe cases result in shock, hemorrhage, renal failure and death. The more recent American medical literature has referred to this disease, perhaps preferably, as epidemic hemorrhagic fever or Far Eastern hemorrhagic fever in order to differentiate it from a group of clinically related entities which occur in other parts of Asia and which have been named according to their geographic locations as, for example, Crimean hemorrhagic fever, Omsk hemorrhagic fever, Bukovinian hemorrhagic fever, and Uzbekistan hemorrhagic fever.

II. History and Epidemiology (1, 2, 4-14)

Early descriptions of a hemorrhagic disease, now presumed to have been the Far Eastern type of hemorrhagic fever, were reported by the Russians and Japanese about 15 to 20 years ago along the Siberian-Manchurian border. Investigators from these nations studied the disease concurrently and independently, the Russian in the Amur River basin region of Siberia and the Japanese in the Songo and Kokka districts of Manchuria. At first, the fact that this was a single disease was not recognized, as indicated by the variety of names assigned to scattered outbreaks, e. g., Songo fever, Kokka disease, Korin fever, Nidoko disease, hemorrhagic purpura, atypical scarlet fever, fever disease, war-nephritis, typhus, etc. During the early 1940's, however, the entity was defined and called hemorrhagic nephroso-nephritis (Nefrozo-Nefrit Gemorrhagicheskii) or endemic hemorrhagic nephroso-nephritis by the Russians and epidemic hemorrhagic fever (Ryukosei Shukketsu Netsu) by the Japanese.

Prior to 1951, the only reports of the existence of this disease in Korea had been descriptions by the Japanese of a few cases in the ex-


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


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treme northeastern corner of Korea along the borders of Siberia and Manchuria; thus, the 1951 outbreak among United Nations troops fighting north of the 38th parallel in Korea was unexpected. The pattern of occurrence among these troops has been generally similar to that previously described by the Russians and Japanese. Epidemics occur twice a year, in the late spring-early summer and fall seasons when rainfall is light, while sporadic cases occur during every month of the year. Epidemics consist principally of isolated cases within a large rural area, but approximately 10 percent of the cases may appear as small focal epidemics, each occurring as a single "wave" of cases with no apparent secondary instances of illness. This characteristic single "wave" pattern suggests that isolated foci of infection may exist. Distinctive environmental features have not been noted, and transmission of the disease is apparently neither by means of food and water nor directly from person to person. Limited evidence indicates that infection can involve persons of all nationalities, all ages and both sexes.

Although the etiology and mode of transmission are unknown, studies by the Americans, Japanese and Russians indicate that the disease is caused by a microorganism, possibly a virus, which may be transmitted by an athropod vector. The Russians were successful in producing a typical disease in human volunteers by inoculating them intravenously or intramuscularly with serum or urine from patients with illness of less than 5 days' duration. Such specimens remained infectious when filtered through a medium-grade Berkefeld filter. Japanese experimental work and American epidemiologic analyses have implied that blood-sucking mites or chiggers are insect vectors of the disease, and the existence of a rodent reservoir has been postulated. Proof of these implications, however, awaits more adequate evidence. The use of culture media and lower animals in attempts to isolate the etiologic agent has been unsuccessful.

III. Pathology (14-17)

Fatalities that occur early during the course of hemorrhagic fever are most often due to vascular collapse and irreversible shock associated with peripheral vascular damage and loss of fluid from the vascular space. Severe tissue edema, including pulmonary and/or cerebral edema, is occasionally responsible for death under such conditions, especially when excessive fluid is administered in an attempt to relieve the shock. Later, during the phase of diuresis that occurs subsequent to renal failure, patients may die following convulsions or in cardiovascular collapse associated with fluid and electrolyte imbalances. Severe hemorrhage or hemorrhage into vital organs may uncommonly cause death at almost any stage of the disease.


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Gross autopsy examination of early fatalities generally reveals evidence of edema, vascular congestion and hemorrhage. Effusions into body cavities, wet tissues, and swollen, heavy organs are signs of edema which often result in a remarkable degree of chemosis, retroperitoneal tissue edema, kidney swelling and pituitary edema. Vascular congestion is usually evident in the conjunctiva, mucous membranes, lining surfaces of hollow organs, and cut surfaces of certain parenchymatous organs as, for example, kidneys, anterior pituitary and liver. Hemorrhage is almost always from small vessels and is generally petechial or purpuric in nature, involving skin, mucous membranes, conjunctiva, serosa, lining surfaces of hollow organs, and less commonly parenchymatous organs. In rare instances, hemorrhage may involve any tissue or organ to severe degree. Necrosis may be apparent grossly in organs of patients who die later during the course of disease, especially in the kidney and pituitary. The characteristic microscopic findings include capillary dilatation, focal necrosis, and mononuclear cell infiltration. More advanced changes that are commonly noted are confluent necrosis, liquefaction necrosis, diapedesis of red blood cells, ruptured small vessels and hemorrhage.

Pathologic involvement of the kidneys is a consistent occurrence. Often the anterior pituitary and heart are affected, while abnormalities of the pancreas, liver, skin and adrenal are demonstrated less often. The cut surface of the heavy kidney is swollen and exhibits congested pyramids, a pale cortex and strikingly prominent corticomedullary junctions. Congestion of the pyramids is frequently so intense that the term "hemorrhagic kidney" has been used to describe this most typical finding in hemorrhagic fever. The kidneys also have casts in dilated tubules, peripelvic hemorrhage, partial focal or complete medullary necrosis and protein leakage through glomeruli. Focal myocarditis and right atrial subendocardial hemorrhage are commonly observed; and focal necrosis, mononuclear cell infiltration and congestion may be noted in pancreas, liver, skin and other organs. A marked degree of adrenal involvement is rare.

IV. Clinical Aspects (3, 14, 18, 19, 22)

Patients with hemorrhagic fever of the Far Eastern type generally become abruptly and acutely ill. Characteristically, an initial febrile episode lasts 3 to 6 days and is manifested by headache, fever, chills, weakness, thirst, restlessness, eye pain, photophobia, anorexia, vomiting, abdominal pain, backache, slight nasal congestion and slight cough. Snycope, weakness or dizziness upon changing body position or upon moving about, a flushed skin (especially face and neck), mucous membrane injection and conjunctival injection are early indications of cardiovascular involvement (principally peripheral


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vascular). This is subsequently evidenced by increased capillary permeability with hemoconcentration and edema, decreased peripheral vascular resistance, blood pressure lability, increased capillary fragility, occasional cardiac dilatation, cardiac arrhythmias, heart sounds of poor quality, and such postmortem findings as capillary dilatation, congestion, subendocardial hemorrhage and focal myocarditis. In about one-fifth of patients with severe peripheral vascular involvement, shock occurs for a short interval between the third and sixth days, usually as the febrile phase subsides. Shock may lead to a fulminant death in some instances. In others, it may be intermittent and prolonged for 24 to 72 hours, terminating in death between the fifth and tenth days. Edema during severe shock is due to loss of fluid from the "sieve-like" peripheral vascular system. This may not be readily apparent as indicated by the fact that such patients have been occasionally described as being dehydrated, only to be found to have marked tissue edema at autopsy. The presence of more severe tissue edema may be indicated by such findings as facial or periorbital puffiness, chemosis, basal lung rales, blurred vision, back pain, periumbilical pain, hepatomegaly, splenomegaly, hiccoughs, watery diarrhea and hemoconcentration.

Skin and mucous membrane petechiae appear about the third or fourth day of illness and are early manifestations of a hemorrhagic diathesis which is characterized by a decreased number of platelets, prolonged bleeding time and increased capillary fragility. Petechiae, purpura, ecchymoses and gross hemorrhage may be noted in any tissue, most often in association with trauma as, for example, coughing, retching, vomiting, rubbing or pressure; and episodes of hematuria, hemoptysis, epistaxis, hematemesis, melena or subconjunctival hemorrhage may be observed. Although the hemorrhagic diathesis usually lasts only a few days, it may be prolonged, especially in association with a prolonged febrile phase or in association with marked uremia.

Characteristically, kidney involvement becomes apparent about the fourth or fifth day of illness, at which time protein, erythrocytes, leukocytes and casts are found in the urine. Varying degrees of oliguria and azotemia occur, and renal concentrating and diluting functions decrease. Patients have tenderness in the regions of the costovertebral angles, bradycardia, hypertension and uremia. In rare instances, they have renal colic due to hemorrhage in the kidney, renal pelvis of ureter. Between the ninth and eleventh days, the onset of a spontaneous diuresis generally marks the beginning of convalescence. An occasional patient may, however, become more ill or may die after apparently entering this convalescent phase; and this phase has infrequently been associated with fluid and electrolyte im-


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balances such as hyponatremia, hypokalemia and "relative" hypervolemia. Examples of clinical findings that are associated with these imbalances are esthenia, anorexia, nausea, vomiting, diarrhea, pulmonary edema, tachycardia and cardiovascular collapse.

The average duration of illness from onset to complete recovery is about 5 or 6 weeks, an interval which includes complete recovery of weight, strength and renal function. In the vast majority of instances, there are apparently no sequelae; however, rare instances of permanent central nervous system damage have been associated with hemorrhage into the brain or spinal cord. Cases with permanent renal damage are similarly rare, although complete recovery of renal function occasionally may require several months or longer. In addition, concomitant disease such as malaria or pneumonia can complicate or prolong the course of disease.

V. Laboratory Findings (13, 14, 19-21)

Laboratory examinations of blood and urine reveal no abnormalities during the first 2 or 3 days of illness except for the appearance of leukopenia in about one-fifth of hospitalized patients, the occasional early appearance of increased numbers of red blood cells in the urine, or immature granulocytes in the peripheral blood. Characteristically, leukocytosis becomes evident during the last half of the first week of illness, and peak white blood cell counts are usually between 10,000 and 20,000 cells per cu. mm. Higher white cell counts are common and may occasionally exceed 100,000 cells per cu. mm. The leukocytosis has been described as a "leukemoid response" because of the numerous immature granulocytes that are usually present and that may sometimes make up 90 percent of the total white blood cell count. As this "leukemoid response" subsides at the end of the first week, atypical cells of the lymphoid series appear in increasing numbers, including many type I and type II cells (after Downey). Such cells often continue to be present during early convalescence. An increasing number of monocytes often appear at the same time as the increase in count of cells of the lymphoid series, and the presence of macroplatelets, toxic granulation of neutrophils, and nucleated red blood cells is often observed in peripheral blood smears during the acute phase of the disease.

Increases in red blood cell counts, hemoglobin contents and hematocrit values occur during the period of marked cardiovascular instability, while occasional decreases in these values are associated with instances of severe hemorrhage. Rarely, such decreases are insidiously obscured if hemorrhage occurs during the phase of hemoconcentration. The erythrocyte sedimentation rate is usually abnormally increased during the second week of illness and gradually returns to


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a normal rate during convalescence. Erythroid hyperplasia of bone marrow may be noted.

Thrombocytopenia is a characteristic occurrence, and about one-half of hospitalized patients have platelet counts of less than 100,000 cells per cu. mm. with occasional counts below 20,000 cells per cu. mm. Associated findings include increased capillary fragility, prolonged bleeding time and hemorrhagic manifestations. Although these findings are all related in duration and degree, the correlation is general and is neither absolute nor constant. Normal prothrombin values and coagulation times are the rule.

Proteinuria, one of the most characteristic findings in hemorrhagic fever, is usually noted about the fourth day of illness. Increased numbers of cells and casts appear in the urine and the daily volume of urine diminishes. Urine specific gravity approaches values near 1.010, and concentrating and diluting functions of the kidney become abnormally decreased. Azotemia is noted. CO2-combining power and serum calcium levels may decrease, while serum levels of potassium and inorganic phosphate may increase. Decreased chloride and sodium levels can be associated with severe episodes of vomiting. On approximately the tenth or eleventh day of illness, diuresis starts, and the above abnormalities usually adjust rapidly and spontaneously to normal. On occasion, diuresis may be associated with excessive losses of sodium, potassium or chloride.

Transient abnormalities in the results of cephalin-cholesterol flocculation and thymol turbidity tests are not uncommon, while prolonged abnormal results are rare. Serologic and bacteriologic studies have thus far demonstrated no relationship to diseases of known etiology. The cerebrospinal fluid is generally normal, but it may have an increased protein content, a few lymphocytes or evidence of hemorrhage. Chest x-rays are characteristically normal though instances of pulmonary congestion, pulmonary edema, cardiac dilatation, pneumonia or hemorrhage have been recorded. Electrocardiography demonstrates sinus bradycardia or sinus tachycardia and uncommon instances of heart block, bundle branch block, extrasystoles, auricular fibrillation, nodal rhythm, wandering pacemaker, electrical alternans, subepicardial or subendocardial injury, or evidence of electrolyte imbalance.

VI. Differential Diagnosis (14)

The chronologic description of the clinical and laboratory manifestations in hemorrhagic fever has been based on reported findings in large numbers of cases. It is here emphasized that such general decriptions may be misleading in individual cases due to the marked variation that occurs in the type, severity and duration of manifesta-


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tions. Findings during the first 2 or 3 days of illness simulate those of numerous other infectious diseases; thus, the presence of the hemorrhagic fever is suspected in a person who has an acute infectious disease and who has been in an endemic area. In the absence of specific diagnostic tests, subsequent confirmation depends upon observing the unique course and combination of systems involved, including the gastrointestinal, hematopoietic, cardiovascular and renal systems. Mild cases frequently offer the most difficult problems in diagnosis. A list of merely a few of the diseases that may have similar manifestations and are considered in the differential diagnosis of hemorrhagic fever is as follows: influenza, infectious mononucleosis, infectious hepatitis, atypical pneumonia, measles, hemorrhagic smallpox, dengue, yellow fever, scarlet fever, epidemic typhus, scrub typhus, malaria, relapsing fever, Weil's disease, typhoid fever, pyelonephritis, Waterhouse-Friderichsen syndrome, acute glomerulonephritis, erythema multiforme, allergic purpura, lower nephron nephrosis, idiopathic thrombocytopenic purpura, myeloid leukemia, appendicitis, and bleeding peptic ulcer.

VII. Treatment and Prognosis (14, 18, 22)

There is as yet no known specific therapy for hemorrhagic fever. Patients should be admitted into a hospital as soon as they are suspected of having the disease, and the responsible staff should be experienced and have special training in the problems of this illness. Trauma should be carefully avoided during moving or handling, and constant nursing care should include meticulous observation since successful, symptomatic medical management is based on an accurate evaluation of the patient's changing state of illness. The fluid balance of the patient is managed on the basis of detailed intake and output records with due consideration for the presence of edema, cardiovascular or renal abnormality. Actual fluid restriction may be indicated in such patients as those who have imbibed excessive fluid prior to admission, those who show evidence of marked edema with cardiovascular collapse following the administration of relatively small amounts of fluid during the early part of the disease, and those who have been given excessive parenteral fluids during the early phase of illness.

The conservative management of shock, hemorrhage and uremia is usually adequate, and recovery is complete. Use of the Trendelenberg position and elastic bandages around the extremities will alleviate shock in many patients, while the use of concentrated human albumin and vasoconstrictors (e. g., norepinephrine, phenylephrine, ephedrine) may be indicated in others. The most successful management of shock requires frequent evaluations of all abnormalities, including repeated


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blood pressure readings and hematocrit determinations. It is emphasized that overly enthusiastic early management of shock has no more overall effectiveness in general than cautious attempts, no matter what the type of therapy. Blood transfusions are needed infrequently since hemorrhage is almost always small in amount and from small vessels; however, exceptional instances do occur such as instances of large amounts of gastrointestinal hemorrhage or retroperitoneal hemorrhage. This bleeding may be "hidden" and may present additional problems in management. As stated before, the conservative management of renal failure and uremia is usually successful when primary attention is directed toward careful fluid and electrolyte management. In rare cases, cation exchange resins, peritoneal lavage, the artificial kidney, or combined injections of calcium gluconate, insulin and glucose have been used. The renal phase can be associated with such special problems as hyperkalemia or "relative" hypervolemia. During diuresis, excessive loss of sodium, potassium or chloride may require replacement.

Throughout the illness, rest in bed and adequate sedation are valuable adjuncts to therapy. During the acute phase, a low-salt, high-carbohydrate (protein-sparing) diet is usually recommended, and a liquid diet is often tolerated best in the presence of anorexia and vomiting. Intercurrent infections or infestations can occur, such as typhoid, malaria, pneumonia, bacillary dysentery and ascariasis. Constant awareness of the possible occurrence of such infections will lead to early specific therapy and will avoid unnecessary complicating factors-factors which may mean the difference between life and death.

During convalescence, abnormal signs and symptoms usually return rapidly to normal. In most cases, increased white blood cell counts, increased erthyrocytic sedimentation rates and decreased renal concentrating function are the last abnormalities to disappear; thus, they ordinarily serve as criteria for mobilization. In an occasional patient prolonged convalescence may be attributed to prolonged debilitating disease, hemorrhage into the central nervous system, severe renal disease, or persistent fluid and electrolyte imbalances. The average duration of illness from onset to complete recovery has been about 5 to 6 weeks, and the overall case fatality rate in the presence of good medical management has been about 4 or 5 percent.

References

1. Gajdusek, D. C.: Acute Infectious Hemorrhagic Fevers and Mycotoxicoses in the Union of Soviet Socialist Republics. Medical Science Publication No. 2. Army Medical Service Graduate School, Walter Reed Army Medical Center, Washington, D. C., May 1953.

2. Takami, R. M.: Epidemic Hemorrhagic Fever. Unpublished report of Medical Section, GHQ, FEC, Aug. 1951.


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3. Barbero, G. J., Katz, S., Kraus, H., and Leedham, C. L.: Clinical and Laboratory Study of Thirty-one Patients with Hemorrhagic Fever. Arch. Int. Med. 91 : 177-196, 1953.

4. TB MED 88: Medical and Sanitary Data on Khabarovsk Krai and Maritime Krai (Far Eastern Territory) U. S. S. R., (Excluding Kamchatka Oblast) Aug. 1944.

5. TB MED 208: Medical and Sanitary Data on Korea, Dec. 1945.

6. TB MED 216: Medical and Sanitary Data on Manchuria, Feb. 1946.

7. Smorodintsev, A. A., Al'tshuler, I. S., Dunaevskii, M. I., Kokhreidze, K. A., Neustroev, V. D., and Churilov, A. V.: Etiology and Clinics of Hemorrhagic Nephroso-nephritis. Moscow Medgiz: 26-27, 1944.

8. Bilibin, A. F.: Endemic Hemorrhagic Nephroso-nephritis. Moscow Medgiz: 197-200, 1950.

9. Mayer, C. F.: Epidemic Hemorrhagic Fever of the Far East (EHF) or Endemic Hemorrhagic Nephroso-nephritis. Lab. Invest. 1 : 291-311, 1952.

10. 406th Medical General Laboratory. Annual Historical Report: 18-28, 1951.

11. Murovannyi, I. L.: Epidemiological Peculiarities of the Hemorrhagic Nephroso-nephritis. Zhurnal Mikrobiologii, Epidemiologii i Immunobilogii, Nu. 6 : 62-66, 1945.

12. Smadel, J. E., Gauld, R. L., Geiman, Q. M., Smithburn, K. C. Hertig, M., and Traub, R.: Unpublished Report of Activities of Epidemic Hemorrhagic Fever Field Unit, July 1952.

13. Gauld, R. L., and Craig, J. P.: Epidemiologic Pattern of Localized Outbreaks of Epidemic Hemorrhagic Fever. Am. J. Hyg. 59 : 32-38, 1954.

14. TB MED 240: Epidemic Hemorrhagic Fever, May 1953.

15. Honzin, R., Kurata, Y., and Ikeda, K.: Study of the Inflammatory Process of a New Disease, Infectious Hemorrhagic Fever. Tr. Soc. pathologicae jap. 34 : 10-11, 1944.

16. Hullinghorst, R. L., and Steer, A.: Pathology of Epidemic Hemorrhagic Fever. Ann. Int. Med. 38 : 77-101 (Jan.), 1953.

17. Steer, A., and Hullinghorst, R. L.: Epidemic Hemorrhagic Fever, a Special Article. Yearbook of Pathology and Clinical Pathology. The Yearbook Publishers, Chicago, July 1951.

18. Katz, S., Leedham, C. L., and Kessler, W. H.: Medical Management of Hemorrhagic Fever. J. A. M. A. 150 : 1363-1366 (Dec.), 1952.

19. Powell, G. M.: Hemorrhagic Fever; Clinical and Laboratory Findings in 300 Cases. Thesis submitted to the Faculty of the Graduate School of Medicine of the University of Pennsylvania, May 1952.

20. Potter, G. V.: The Electrocardiographic Changes in Epidemic Hemorrhagic Fever (Preliminary Report.) Unpublished paper presented at the Symposium of Epidemic Hemorrhagic Fever, Medical Section, GHQ, FEC, Feb. 1952.

21. Speers, R. W., Katz, S., et al.: A Laboratory Study of Hemorrhagic Fever with Discussion of Diagnostic and Prognostic Findings. Publication pending.

22. Smadel, J. E.: Personal communication.