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 epidemicform in Northeast Asia. Patients characteristically manifest fever, prostration,anorexia, vomiting, and proteinuria. Cardiovascular instability, a hemorrhagicdiathesis, and renal tubular damage become apparent and may in severe casesresult in shock, hemorrhage, renal failure and death. The more recent Americanmedical literature has referred to this disease, perhaps preferably, asepidemic hemorrhagic fever or Far Eastern hemorrhagic fever in order todifferentiate it from a group of clinically related entities which occurin other parts of Asia and which have been named according to their geographiclocations as, for example, Crimean hemorrhagic fever, Omsk hemorrhagicfever, 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 beenthe Far Eastern type of hemorrhagic fever, were reported by the Russiansand 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 Japanesein the Songo and Kokka districts of Manchuria. At first, the fact thatthis was a single disease was not recognized, as indicated by the varietyof 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-NefritGemorrhagicheskii) or endemic hemorrhagic nephroso-nephritis by the Russiansand epidemic hemorrhagic fever (Ryukosei Shukketsu Netsu) by the Japanese.
Prior to 1951, the only reports of the existence of this disease inKorea 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 andManchuria; thus, the 1951 outbreak among United Nations troops fightingnorth of the 38th parallel in Korea was unexpected. The pattern of occurrenceamong these troops has been generally similar to that previously describedby the Russians and Japanese. Epidemics occur twice a year, in the latespring-early summer and fall seasons when rainfall is light, while sporadiccases occur during every month of the year. Epidemics consist principallyof isolated cases within a large rural area, but approximately 10 percentof 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 isolatedfoci of infection may exist. Distinctive environmental features have notbeen noted, and transmission of the disease is apparently neither by meansof food and water nor directly from person to person. Limited evidenceindicates that infection can involve persons of all nationalities, allages and both sexes.
Although the etiology and mode of transmission are unknown, studiesby the Americans, Japanese and Russians indicate that the disease is causedby a microorganism, possibly a virus, which may be transmitted by an athropodvector. The Russians were successful in producing a typical disease inhuman volunteers by inoculating them intravenously or intramuscularly withserum or urine from patients with illness of less than 5 days' duration.Such specimens remained infectious when filtered through a medium-gradeBerkefeld filter. Japanese experimental work and American epidemiologicanalyses have implied that blood-sucking mites or chiggers are insect vectorsof the disease, and the existence of a rodent reservoir has been postulated.Proof of these implications, however, awaits more adequate evidence. Theuse of culture media and lower animals in attempts to isolate the etiologicagent has been unsuccessful.
III. Pathology (14-17)
Fatalities that occur early during the course of hemorrhagic fever aremost often due to vascular collapse and irreversible shock associated withperipheral vascular damage and loss of fluid from the vascular space. Severetissue edema, including pulmonary and/or cerebral edema, is occasionallyresponsible for death under such conditions, especially when excessivefluid is administered in an attempt to relieve the shock. Later, duringthe phase of diuresis that occurs subsequent to renal failure, patientsmay die following convulsions or in cardiovascular collapse associatedwith fluid and electrolyte imbalances. Severe hemorrhage or hemorrhageinto vital organs may uncommonly cause death at almost any stage of thedisease.
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Gross autopsy examination of early fatalities generally reveals evidenceof edema, vascular congestion and hemorrhage. Effusions into body cavities,wet tissues, and swollen, heavy organs are signs of edema which often resultin a remarkable degree of chemosis, retroperitoneal tissue edema, kidneyswelling and pituitary edema. Vascular congestion is usually evident inthe conjunctiva, mucous membranes, lining surfaces of hollow organs, andcut surfaces of certain parenchymatous organs as, for example, kidneys,anterior pituitary and liver. Hemorrhage is almost always from small vesselsand is generally petechial or purpuric in nature, involving skin, mucousmembranes, conjunctiva, serosa, lining surfaces of hollow organs, and lesscommonly parenchymatous organs. In rare instances, hemorrhage may involveany tissue or organ to severe degree. Necrosis may be apparent grosslyin organs of patients who die later during the course of disease, especiallyin the kidney and pituitary. The characteristic microscopic findings includecapillary dilatation, focal necrosis, and mononuclear cell infiltration.More advanced changes that are commonly noted are confluent necrosis, liquefactionnecrosis, diapedesis of red blood cells, ruptured small vessels and hemorrhage.
Pathologic involvement of the kidneys is a consistent occurrence. Oftenthe anterior pituitary and heart are affected, while abnormalities of thepancreas, liver, skin and adrenal are demonstrated less often. The cutsurface of the heavy kidney is swollen and exhibits congested pyramids,a pale cortex and strikingly prominent corticomedullary junctions. Congestionof the pyramids is frequently so intense that the term "hemorrhagickidney" has been used to describe this most typical finding in hemorrhagicfever. The kidneys also have casts in dilated tubules, peripelvic hemorrhage,partial focal or complete medullary necrosis and protein leakage throughglomeruli. Focal myocarditis and right atrial subendocardial hemorrhageare commonly observed; and focal necrosis, mononuclear cell infiltrationand 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 becomeabruptly and acutely ill. Characteristically, an initial febrile episodelasts 3 to 6 days and is manifested by headache, fever, chills, weakness,thirst, restlessness, eye pain, photophobia, anorexia, vomiting, abdominalpain, backache, slight nasal congestion and slight cough. Snycope, weaknessor dizziness upon changing body position or upon moving about, a flushedskin (especially face and neck), mucous membrane injection and conjunctivalinjection are early indications of cardiovascular involvement (principallyperipheral
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vascular). This is subsequently evidenced by increased capillary permeabilitywith hemoconcentration and edema, decreased peripheral vascular resistance,blood pressure lability, increased capillary fragility, occasional cardiacdilatation, cardiac arrhythmias, heart sounds of poor quality, and suchpostmortem findings as capillary dilatation, congestion, subendocardialhemorrhage and focal myocarditis. In about one-fifth of patients with severeperipheral vascular involvement, shock occurs for a short interval betweenthe third and sixth days, usually as the febrile phase subsides. Shockmay lead to a fulminant death in some instances. In others, it may be intermittentand prolonged for 24 to 72 hours, terminating in death between the fifthand tenth days. Edema during severe shock is due to loss of fluid fromthe "sieve-like" peripheral vascular system. This may not bereadily apparent as indicated by the fact that such patients have beenoccasionally described as being dehydrated, only to be found to have markedtissue edema at autopsy. The presence of more severe tissue edema may beindicated 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 fourthday of illness and are early manifestations of a hemorrhagic diathesiswhich is characterized by a decreased number of platelets, prolonged bleedingtime and increased capillary fragility. Petechiae, purpura, ecchymosesand gross hemorrhage may be noted in any tissue, most often in associationwith trauma as, for example, coughing, retching, vomiting, rubbing or pressure;and episodes of hematuria, hemoptysis, epistaxis, hematemesis, melena orsubconjunctival hemorrhage may be observed. Although the hemorrhagic diathesisusually lasts only a few days, it may be prolonged, especially in associationwith a prolonged febrile phase or in association with marked uremia.
Characteristically, kidney involvement becomes apparent about the fourthor fifth day of illness, at which time protein, erythrocytes, leukocytesand casts are found in the urine. Varying degrees of oliguria and azotemiaoccur, and renal concentrating and diluting functions decrease. Patientshave tenderness in the regions of the costovertebral angles, bradycardia,hypertension and uremia. In rare instances, they have renal colic due tohemorrhage in the kidney, renal pelvis of ureter. Between the ninth andeleventh days, the onset of a spontaneous diuresis generally marks thebeginning of convalescence. An occasional patient may, however, becomemore ill or may die after apparently entering this convalescent phase;and this phase has infrequently been associated with fluid and electrolyteim-
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balances such as hyponatremia, hypokalemia and "relative"hypervolemia. Examples of clinical findings that are associated with theseimbalances are esthenia, anorexia, nausea, vomiting, diarrhea, pulmonaryedema, tachycardia and cardiovascular collapse.
The average duration of illness from onset to complete recovery is about5 or 6 weeks, an interval which includes complete recovery of weight, strengthand renal function. In the vast majority of instances, there are apparentlyno sequelae; however, rare instances of permanent central nervous systemdamage have been associated with hemorrhage into the brain or spinal cord.Cases with permanent renal damage are similarly rare, although completerecovery of renal function occasionally may require several months or longer.In addition, concomitant disease such as malaria or pneumonia can complicateor prolong the course of disease.
V. Laboratory Findings (13, 14, 19-21)
Laboratory examinations of blood and urine reveal no abnormalities duringthe first 2 or 3 days of illness except for the appearance of leukopeniain about one-fifth of hospitalized patients, the occasional early appearanceof increased numbers of red blood cells in the urine, or immature granulocytesin the peripheral blood. Characteristically, leukocytosis becomes evidentduring the last half of the first week of illness, and peak white bloodcell counts are usually between 10,000 and 20,000 cells per cu. mm. Higherwhite cell counts are common and may occasionally exceed 100,000 cellsper cu. mm. The leukocytosis has been described as a "leukemoid response"because of the numerous immature granulocytes that are usually presentand that may sometimes make up 90 percent of the total white blood cellcount. As this "leukemoid response" subsides at the end of thefirst week, atypical cells of the lymphoid series appear in increasingnumbers, including many type I and type II cells (after Downey). Such cellsoften continue to be present during early convalescence. An increasingnumber of monocytes often appear at the same time as the increase in countof cells of the lymphoid series, and the presence of macroplatelets, toxicgranulation of neutrophils, and nucleated red blood cells is often observedin peripheral blood smears during the acute phase of the disease.
Increases in red blood cell counts, hemoglobin contents and hematocritvalues occur during the period of marked cardiovascular instability, whileoccasional decreases in these values are associated with instances of severehemorrhage. Rarely, such decreases are insidiously obscured if hemorrhageoccurs during the phase of hemoconcentration. The erythrocyte sedimentationrate is usually abnormally increased during the second week of illnessand gradually returns to
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a normal rate during convalescence. Erythroid hyperplasia of bone marrowmay be noted.
Thrombocytopenia is a characteristic occurrence, and about one-halfof hospitalized patients have platelet counts of less than 100,000 cellsper cu. mm. with occasional counts below 20,000 cells per cu. mm. Associatedfindings include increased capillary fragility, prolonged bleeding timeand hemorrhagic manifestations. Although these findings are all relatedin duration and degree, the correlation is general and is neither absolutenor constant. Normal prothrombin values and coagulation times are the rule.
Proteinuria, one of the most characteristic findings in hemorrhagicfever, is usually noted about the fourth day of illness. Increased numbersof cells and casts appear in the urine and the daily volume of urine diminishes.Urine specific gravity approaches values near 1.010, and concentratingand diluting functions of the kidney become abnormally decreased. Azotemiais noted. CO2-combining power and serum calcium levels may decrease,while serum levels of potassium and inorganic phosphate may increase. Decreasedchloride 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 tonormal. On occasion, diuresis may be associated with excessive losses ofsodium, potassium or chloride.
Transient abnormalities in the results of cephalin-cholesterol flocculationand thymol turbidity tests are not uncommon, while prolonged abnormal resultsare rare. Serologic and bacteriologic studies have thus far demonstratedno relationship to diseases of known etiology. The cerebrospinal fluidis generally normal, but it may have an increased protein content, a fewlymphocytes or evidence of hemorrhage. Chest x-rays are characteristicallynormal though instances of pulmonary congestion, pulmonary edema, cardiacdilatation, pneumonia or hemorrhage have been recorded. Electrocardiographydemonstrates sinus bradycardia or sinus tachycardia and uncommon instancesof heart block, bundle branch block, extrasystoles, auricular fibrillation,nodal rhythm, wandering pacemaker, electrical alternans, subepicardialor subendocardial injury, or evidence of electrolyte imbalance.
VI. Differential Diagnosis (14)
The chronologic description of the clinical and laboratory manifestationsin hemorrhagic fever has been based on reported findings in large numbersof cases. It is here emphasized that such general decriptions may be misleadingin 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 thoseof numerous other infectious diseases; thus, the presence of the hemorrhagicfever is suspected in a person who has an acute infectious disease andwho has been in an endemic area. In the absence of specific diagnostictests, subsequent confirmation depends upon observing the unique courseand combination of systems involved, including the gastrointestinal, hematopoietic,cardiovascular and renal systems. Mild cases frequently offer the mostdifficult problems in diagnosis. A list of merely a few of the diseasesthat may have similar manifestations and are considered in the differentialdiagnosis 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-Friderichsensyndrome, 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. Patientsshould be admitted into a hospital as soon as they are suspected of havingthe disease, and the responsible staff should be experienced and have specialtraining in the problems of this illness. Trauma should be carefully avoidedduring moving or handling, and constant nursing care should include meticulousobservation since successful, symptomatic medical management is based onan accurate evaluation of the patient's changing state of illness. Thefluid balance of the patient is managed on the basis of detailed intakeand output records with due consideration for the presence of edema, cardiovascularor renal abnormality. Actual fluid restriction may be indicated in suchpatients as those who have imbibed excessive fluid prior to admission,those who show evidence of marked edema with cardiovascular collapse followingthe administration of relatively small amounts of fluid during the earlypart of the disease, and those who have been given excessive parenteralfluids during the early phase of illness.
The conservative management of shock, hemorrhage and uremia is usuallyadequate, and recovery is complete. Use of the Trendelenberg position andelastic 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. Themost successful management of shock requires frequent evaluations of allabnormalities, including repeated
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blood pressure readings and hematocrit determinations. It is emphasizedthat overly enthusiastic early management of shock has no more overalleffectiveness in general than cautious attempts, no matter what the typeof therapy. Blood transfusions are needed infrequently since hemorrhageis almost always small in amount and from small vessels; however, exceptionalinstances do occur such as instances of large amounts of gastrointestinalhemorrhage or retroperitoneal hemorrhage. This bleeding may be "hidden"and may present additional problems in management. As stated before, theconservative management of renal failure and uremia is usually successfulwhen primary attention is directed toward careful fluid and electrolytemanagement. In rare cases, cation exchange resins, peritoneal lavage, theartificial kidney, or combined injections of calcium gluconate, insulinand glucose have been used. The renal phase can be associated with suchspecial problems as hyperkalemia or "relative" hypervolemia.During diuresis, excessive loss of sodium, potassium or chloride may requirereplacement.
Throughout the illness, rest in bed and adequate sedation are valuableadjuncts to therapy. During the acute phase, a low-salt, high-carbohydrate(protein-sparing) diet is usually recommended, and a liquid diet is oftentolerated best in the presence of anorexia and vomiting. Intercurrent infectionsor infestations can occur, such as typhoid, malaria, pneumonia, bacillarydysentery and ascariasis. Constant awareness of the possible occurrenceof such infections will lead to early specific therapy and will avoid unnecessarycomplicating factors-factors which may mean the difference between lifeand death.
During convalescence, abnormal signs and symptoms usually return rapidlyto normal. In most cases, increased white blood cell counts, increasederthyrocytic sedimentation rates and decreased renal concentrating functionare the last abnormalities to disappear; thus, they ordinarily serve ascriteria for mobilization. In an occasional patient prolonged convalescencemay be attributed to prolonged debilitating disease, hemorrhage into thecentral nervous system, severe renal disease, or persistent fluid and electrolyteimbalances. The average duration of illness from onset to complete recoveryhas been about 5 to 6 weeks, and the overall case fatality rate in thepresence of good medical management has been about 4 or 5 percent.
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