 In the early 1930s, the Russians observed a new infectious disease in their troops stationed along the Russo-Manchurian border. They called this disease hemorrhagic nephrosonephritis. At the same time, the Japanese were observing this disease in their own troops in Manchuria, where it was called epidemic hemorrhagic fever. The known endemic areas in the far east are shown in the shaded portion of this map. During human volunteers, the Russians and Japanese showed the disease to be infectious and to be caused by a filterable agent. They believed that rodent served as reservoirs and that probably some arthropod transmitted the disease to man. This same disease exists in Korea, where it first appeared in United Nations troops during the summer of 1951. Hemorrhagic fever has become an important military problem in Korea. As shown on this map, the known endemic area extends as a belt across the peninsula, bounded on the north by the battle line, or main line of resistance. Hemorrhagic fever is chiefly a disease of rural areas. It occurs in troops who come into intimate contact with brush and vegetation. Although most cases are seen during the two seasonal peaks of the disease in spring and fall, cases also occur in winter, a fact which rules out flying insects as vectors. The distribution of cases is spotty, usually occurring as isolated incidents, but there are sometimes small, very localized outbreaks. There are no primary lesions or itching insect bites which might indicate the sight or the mode of transmission. All these points indicate that the vectors are probably ectoparasites of animals. The trombiculate mites commonly called chiggers fit the epidemiology particularly well. It should be borne in mind that until a susceptible laboratory animal is found, the real reservoir and vector cannot be determined experimentally. Here we see one of the rodents which are so common in the endemic area. The systematic investigation of hemorrhagic fever has included a thorough study of these rodents and their ectoparasites. This close-up of the ear of a mouse shows the chiggers in their usual sight. Many rodent chiggers readily attach to men. Since these chiggers are so very small and do not cause any itching, they are easily overlooked. The current preventive measures were worked out against chigger-borne disease, but are actually effective against all rodent ectoparasites. These measures include the use of rodenticides, residual insecticides in and around camps, and the routine dipping of uniforms in mite repellents. Hemorrhagic fever occurs sporadically throughout the year, but has two seasonal peaks. The curve of chigger abundance on wild rodents is quite similar to this one. The changes in chigger population precede the changes in clinical cases by a period of two to three weeks. This is about equal to the incubation period. Cases begin to increase in April, reach a peak in June, and fall off sharply in late July. In the fall, the increase in case incidents begins in September, reaches a maximum in October or November, and declines rapidly in December. Particularly during these months, should the diagnosis of hemorrhagic fever be suspected in federal patients coming from the endemic area. The abrupt onset of the disease is usually of such severity as to prompt men in the endemic area to seek medical attention early. The disease itself is characterized by fever, diffuse capillary damage, and renal insufficiency. The course is divided into different phases named for the predominant clinical findings at that time. In order of occurrence, these are designated as the incubation period, febrile phase, hypotensive or shock phase, oliguric phase, diuretic phase, and convalescent phase. In the early febrile phase, symptoms are nonspecific. They are headache, nausea, vomiting, backache, dizziness, and blurred vision. These commonly occur with other febrile illnesses such as malaria, meningococcemia, scrub typhus, and infectious mononucleosis. The headache is usually frontal or retroorbital. Brain on eye movement and photophobia are common. Flush of the face and neck appear early as does congestion of the mucus membrane of the eye and the soft palate. The marked congestion of the conjunctiva is clearly evident here. Periorbital edema may also be present. Dryness of the throat occurs, but real soreness is uncommon despite the presence of diffuse injection. More of the examination at this time includes the search for patiki, but they are ordinarily not seen this early. The fever lasts from five to seven days. During the first two to three days, when only the nonspecific symptoms are present, the diagnosis is difficult. Patiki do not appear until the third or fourth day. Mucus membrane injection of the soft palate and conjunctivy may be the only signs during the first few days. Therefore, the disease is suspected in any febrile patient with possible exposure, particularly during epidemic periods. A compatible history and the absence of localizing signs of infection give further support to the diagnosis of hemorrhagic fever and evacuation of the patient to a hospital in the rear is indicated. This is done by helicopter even from the forward areas. Their evacuation is utilized in order to eliminate the trauma of surface transportation over rough terrain. Here we see an example of terrain over which ambulances must travel. The effect of a bumpy ambulance ride on a patient with an unstable vascular system and a bleeding tendency can well be imagined. Note the changes in the terrain and degree of cultivation of the land as this helicopter proceeds south to the hemorrhagic fever center. These factors may have significance in the geographic localization of this disease. The patient is now approaching his final destination, the hemorrhagic fever center located just outside of Seoul. All patients are admitted as hemorrhagic fever suspects. Of these, about 50% are subsequently diagnosed as hemorrhagic fever confirmed. Many of the remaining patients are finally diagnosed as having fever of unknown origin. While a specific serological test is available, it cannot be determined how many of these have had subclinical or abortive hemorrhagic fever. On all admissions, particular note is made for epidemiological purposes of the patient's army unit and its location with respect to the endemic area. From the admitting office, the patient is taken directly to X-ray for a chest film. Besides the possibility of demonstrating lung involvement on admission, this film also provides a record of heart size and broncovascular markings. This record is of value in the late oliguric phase when pulmonary complications are prone to occur. All patients are weighed on admission and at frequent intervals thereafter. A 10 to 15 pound weight loss during the acute phase is common. A 30 to 40 pound weight loss is rather frequent. This patient has been admitted on the fourth day of disease, a time when many characteristic physical findings are present. One of the most prominent is the flush of the face and neck. This is clearly evident. Note also that slight periorbital edema is present. In most cases, the flush is limited to the head and neck. Other patients show marked flush over the entire trunk. The conjunctiva now reveal both injection and small patechee. Patechee also appear on the soft palate. A careful search is made for skin patechee. They are usually present by the fourth day of the disease and are most consistently found along the posterior axillary fold. Their distribution and number varies greatly from patient to patient. They may be few or numerous. When patechee are prevalent, their distribution is heaviest in areas subjected to pressure. This patient has many patechee over the area covered by bootlaces. Patechee persists for three to four days. One of the fundi reveals the complete absence of patechee over the retina. The lungs are usually normal on physical examination at this stage. Tenderness over the costo vertebro angle and lumbar musculature may be quite marked. Note again the prominent flush of the face and neck. Though the heart is normal, it should be noted that a relative bradycardia is usually present. A pulse rate of 120 or more on admission is poor prognostic sign. Abdominal tenderness is frequently present. On rare occasions, its severity has prompted surgical intervention on patients with uncomplicated hemorrhagic fever. In the early febbro phase, laboratory findings are usually normal. During the first few days, the white blood cell count may show a slight leukopenia. On the third or fourth day of disease, the white count begins to rise and reaches its peak after the temperature has returned to normal. It is highest in those patients who are severely ill. The platelet count drops in the febbro phase of the disease, remains low for several days, and gradually returns to normal. Albium and urea appears on about the fourth day of disease. This is the first evidence of renal involvement and it is one of the important characteristics of hemorrhagic fever. Protein urea is first detected as a slight trace demonstrated by the sulfosalicylic acid test. It becomes marked with four plus reaction within eight to 24 hours. At present, the final diagnosis of hemorrhagic fever is not made without evidence of renal damage. The protein urea seen here is one manifestation of capillary damage. This lesion is diffuse and results in plasma leakage. Much of this leakage is into the retroperitoneal space and probably contributes to the severity of the backache. Shock often occurs in the patient when capillary leakage is extensive. Other important contributory factors to the shock phase include pulling of blood in capillaries and reduced peripheral vasoconstriction. This chart represents the course of a patient who develops shock. With deprovescence, lability of blood pressure is frequently noted. Shock requiring special therapy occurs in one patient of every six. Note that the blood pressure starts to fall as the temperature returns toward normal. At the same time, plasma volume is reduced by leakage through the damaged capillaries. This is reflected by a rising hematocrit. Accordingly, the blood pressure is checked frequently late in the febrile phase and serial hematocrites are obtained. Because of its simplicity, as seen here, the copper sulfate method is used for these determinations. This involves the determination of the specific gravities of whole blood and plasma. As might be expected, the presence of damaged leaking capillaries makes management of fluid balance difficult. Large volumes of fluids given intravenously actually can be harmful. Symptoms become more severe, suggesting the rapid loss of this injected fluid from the vascular system. Consequently, intravenous infusions are restricted at this time. As a prophylactic measure, during the late febrile period, fluids are given as though the patient were a febrile. His daily fluid intake is maintained at a volume equal to recorded output, plus insensible loss. The fact that he may have a temperature of 103 or over is ignored. The shock phase lasts from a few hours to three or four days, averaging about 36 hours. At the time of onset of the severe hypotension, most patients do not present the usual picture of surgical shock. A relative bradycardia is present, and the skin is usually warm and dry. This suggests minimal peripheral vasoconstriction in response to the fall in blood pressure. Hemodynamic data support this view. This patient is having his blood pressure checked frequently by the corpsman. This corpsman notifies the ward nurse and ward doctor whenever a significant change in the patient's blood pressure occurs. When needed, the doctor orders appropriate measures to counteract the fall in blood pressure. The initial therapy is shock blocks. This alone may be adequate treatment for very mild shock. Frequent blood pressure determinations are continued. In more severe cases, additional therapy is indicated. The two agents most commonly used are noradrenaline and human serum albumin. One ampule or four cc's of noradrenaline is diluted in 400 cc's of 5% glucose made up in distilled water. This gives a final concentration of 10 gamma of noradrenaline per cc. The initial dosage employed is from 10 to 15 gamma per minute. The dosage is varied according to the needs of the patient. More concentrated solutions may be used to prevent overhydration of the patient. Noradrenaline as initial therapy is indicated in those patients where lack of peripheral vasoconstriction as evidenced by warm, dry extremities is the predominant cause of the shock. Hemoconcentration is mild to moderate in these patients. During the shock phase, patients are frequently restless. Because of the danger of infiltration of noradrenaline, this potent vasoconstrictor is usually given through an indwelling polyethylene tubing. The simplest way to insert the polyethylene tubing is through a thin walled 18 gauge needle. As you see here, this is being done in an anti-cubital vein. Ordinarily, the saponous vein is used in order to leave both arms free. In spite of the precautionary use of this polyethylene tubing, one or two cases of mild superficial tissue necrosis have followed the use of noradrenaline. Rarely when a vein cannot be found for needle insertion, a cut down is required. This patient was already receiving noradrenaline, but because of increasing hemoconcentration, albumin therapy was also necessary. Human serum albumin is available as a 25% solution. As a plasma expander, one unit of albumin is equivalent to 500 cc's of plasma. As initial therapy, albumin is indicated in those patients with marked hemoconcentration, hematocrites near 60% or even over. These patients may have cool or possibly cold extremities and present the more classical picture of shock. The immediate clinical response to albumin is correlated with the fall in the hematocrit, which usually lasts two to four hours. Frequent hematocrit determinations are done throughout the shock phase as a guide to the further need of albumin. The gradual fall of the hematocrit towards normal levels heralds the end of the shock phase. We will briefly summarize the treatment of the shock phase of this disease. Shock blocks are used initially and may suffice. Noradrenaline is given when there is insufficient peripheral vasoconstriction and significant plasma loss has not occurred. The indication for albumin is marked plasma loss with significant alteration of hematocrit. Here, we see a patient with severe hemorrhagic fever. He was admitted to the hospital on the third day of his illness and went into shock the following morning. Initially, he was given noradrenaline, to which he responded well. But later, albumin therapy was required. This patient remained febrile throughout his hospital course, expiring on the seventh day of his disease in irreversible shock, which was unresponsive to noradrenaline, albumin, or plasma. He was anuric throughout the shock phase and in the presence of the high fever developed uremia quite rapidly. There was, therefore, no demarcation between the febrile, shock, and uremic phase of hemorrhagic fever in this patient. When patients who die of hemorrhagic fever are autopsied, unusual lesions in two organs are always found, which indicate the true diagnosis by inspection alone, even in the absence of clinical history. Regardless of the duration or course of the disease, one always finds marked congestion and hemorrhage in the wall of the right atrium and in the medulla of the kidneys. The other pathologic changes, which are frequently found, are usually related to the stage of disease at the time of death. Thus, patients dying in the shock stage often have unusual retroperitoneal edema, while patients dying during the later stages frequently have severe pulmonary complications. Although there is considerable variation in different epidemics, the total American experience indicates that approximately one-third of the fatalities occurred in the shock stage and two-thirds in the oliguric and diuretic stages of the disease. Because the findings may be varied, the following demonstration is a composite of several autopsies. This patient died during the shock stage and the autopsy was performed less than one hour after death. The pleural surfaces are smooth and contain many fatigue. Marked edema, congestion, and beginning consolidation can be seen. These changes are evident when the lung is sectioned. This patient died during the first few days of the oliguric stage. In addition to frothy material indicating pulmonary edema, there is beginning accumulation of tenacious, thick bronchial secretions which interfere with pulmonary dynamics. When the disease is of longer duration, these secretions become inspisated and frequently lead to the severe pulmonary complications which often are the immediate cause of death. When the pericardial sac is opened, fatigial hemorrhages are often seen on all surfaces as in this case of short duration. The pericardial fluid is sometimes increased in amount and the heart may be soft and flabby. Fatigue are also seen in the epicardium. There is no evidence of an inflammatory reaction and exudate and adhesions are not found. The heart does show in all cases regardless of the duration of disease, diffuse hemorrhage into the wall of the right atrium. This hemorrhage may vary in severity and tends to be less striking in cases of long duration. Small focal hemorrhages may be found in the walls of the other chambers, but these are never as consistent or as prominent as the hemorrhage in the right atrium. There are no recognizable endocardial or valvular changes on inspection. Microscopic sections of the right atrium show diffuse hemorrhage without cellular reaction or changes in the muscle fibers. Study of cases of long duration shows no evidence of destruction or phagocytosis of the red blood cells or accumulation of blood pigments. Microscopic study of the other chambers, however, shows an unexpected cellular reaction consisting of a distinctive mild, but diffuse infiltration of mononuclear cells beneath the intact unaltered endocardial surface. Often, there is edema immediately beneath the endocardium. Similar inflammatory cells may be found beneath the endothelium of small vessels and may produce a mild, diffuse myocarditis. This section is from a patient who died during the shock stage. These changes are less prominent when the disease is of longer duration. When the peritoneal cavity is examined, the mesentery may contain numerous fatigue as in this case in which the disease was of short duration. In some cases, usually of less than two weeks duration, there is widespread retroperitoneal hemorrhage which may extend from above the kidneys to the pelvis. Rarely is this hemorrhage of itself severe enough to cause shock. Patients who died during the hypotensive stage when the disease is of short duration frequently show unusual and dramatic retroperitoneal edema. This may be so extensive as to obliterate the paravirtebral gutters. Sometimes the fluid is trapped in locules and appears semi-gelatinous. When the retroperitoneal tissues are incised or when pressure is applied to the loose tissue about the kidneys, the fluid may spill out as from a squeezed sponge. Such retroperitoneal edema is not seen when the disease is of longer duration, although it is suspected that most patients who have had an episode of hemoconcentration had at the same time some degree of this retroperitoneal edema. The kidneys are always enlarged and may weigh 600 grams or more. The capsule strips with ease, revealing a smooth, sometimes congested surface. When sectioned, the kidneys always show this characteristic appearance of marked severe congestion and hemorrhage beginning abruptly at the corticomedulary junction and extending into the medulla. The cortex is sharply demarcated and by contrast appears pale. These illustrations from autopsies of patients with disease of both short and long duration show how consistent are these changes. Perhaps it is for this reason that the Russians have coined the name hemorrhagic nephrosonephritis for this disease. On microscopic examination, the cortex shows few changes. In the subcortical area, severe hemorrhage separates and apparently replaces tubules. The remaining tubules lie in a sea of blood cells. As in the right atrium, cellular reaction to this hemorrhage is not seen regardless of the duration of the disease. The tubules may contain castes of all types, including pigmented castes. There is degeneration and desquamation of the tubular epithelium. Sometimes the tubules in focal areas are entirely necrotic. Such foci may merge so that most of the medulla appears imparted. Although no consistent vascular abnormalities have been found in the kidneys, it is suspected that all of these changes are on an anoxic bases. The gastrointestinal tract is frequently severely congested. This is particularly true of the stomach which often presents the picture of an acute severe hemorrhagic gastritis. However, there is no inflammatory reaction on microscopic examination. The pituitary stalk and the anterior lobe of the pituitary gland are usually soft and hemorrhagic. On section, necrosis of the anterior lobe is frequently found. This, however, varies considerably and may involve only a few cells in small focal areas or may involve almost the entire anterior lobe. Except for congestion, the posterior lobe shows no changes. In approximately one third of the fatal cases, areas of hemorrhage and necrosis are found in the adrenals. In no case is more than one half of an adrenal involved in this process. The majority of patients have no shock and with deferrescence proceed directly into the oliguric phase which lasts three to five days. As shown here, the urine output decreases late in the febrile phase and during the subsequent period of renal insufficiency, this oliguria is associated with marked proteinuria and azotemia. There is wide variation in the duration and severity of this phase, but the majority of patients show only transient nitrogen retention and have few uremic symptoms. These rapidly clear as the patient enters the diuretic phase. A few patients, such as the one shown here, have a more difficult time during oliguria. They have marked abdominal pain. Pickups are often distressing. Adequate caloric intake is difficult to maintain and marked weight loss can appear rapidly. Severe protracted retching and vomiting are common. As you have seen, the gastric mucosa is extremely hemorrhagic. It is not surprising then that these patients have hematemesis. Fluid balance continues to be a problem, but in general, fluid intake is restricted to an amount equal to total output plus insensible loss. In some cases, saline or lactate solutions are needed. Subconjunctival hemorrhages are frequently noted in patients with severe vomiting. These hemorrhages probably result from the combination of capillary fragility and increased venous pressure, which accompanies retching. Frequent injections of analgesics and sedatives may be required. These injections are followed by a small amount of subcutaneous hemorrhage so that by the time diuresis begins, the arms and buttocks may be covered with echemosis. Since electrolyte imbalance most frequently occurs during oliguria, serum electrolyte determinations and electrocardiograms are made periodically during this phase. Hyperkalemia is the most common electrolyte imbalance seen during acute renal insufficiency. And along with this, hyponatremia is usually apparent. An electrocardiogram provides evidence of the disturbance of potassium balance. This patient's record demonstrates the typical high-peak T-waves characteristic of hyperkalemia. The electrolyte imbalance is rarely severe enough to require treatment on the artificial kidney. The more conservative measures, such as administrations of insulin, glucose with intravenous sodium and calcium, usually suffice. Low serum calcium is common during the period of renal insufficiency, but EKG changes as shown here and symptoms referable to hypocalcemia are uncommon. During the oliguric phase, hypertension develops in 25% of the patients. This hypertension is labile and is mainly systolic. It is usually present for about five days, but may last a month. It occurs more commonly in those patients who have been through a shock phase earlier in their disease. During this hypertensive oliguric period, the patient frequently exhibits confusion, irritability, convulsive episodes, and epistaxis. In a small percentage of patients, a syndrome suggestive of hypervolemia develops. This is particularly prominent in those patients who have been treated for severe shock. The outstanding findings include warm skin with markedly elevated peripheral blood flow. The hand visible on your right is that of a hemorrhagic fever patient. The hand on the left is that of a normal person. Note the greater distention of veins of the patient and the rapidity with which these veins refill after being emptied. The venous pressure is normal or slightly elevated in the hemorrhagic fever patient. It is at this time that pulmonary edema is most apt to occur. Therefore, parenteral fluids should be given cautiously if they are needed. The syndrome can develop quite rapidly following the shock phase and may be related to the rapid return of previously extravasated fluids into the vascular system. The oliguric phase is ended by the appearance of diuresis on the 10th to 12th day of illness. The urine output can be quite high during the first few days of this diuresis, but then it gradually returns toward normal levels as the patient enters convalescence. Electrolyte imbalance can also occur during the marked diuresis. Large quantities of potassium can be lost in the urine and the EKG pattern of hypokalemia may appear. Though the onset of diuresis is accompanied by some symptomatic improvement, the patient remains lethargic and weak. The marked weight loss in this patient is apparent. Here we see another patient who shows fairly marked evidence of weight loss. This patient also shows extensive areas of echemosis over shoulders and arms. He was at the height of the diuretic phase when these pictures were taken and he was excreting eight liters of urine per day. With such marked fluid loss, dehydration may occur as it has in this patient. Note the marked loss of tissue turgor. Here is a patient you have seen before. He eats, but without relish. From simple bland meals and fruits, the patient continues on to regular meal habits. The patient is kept in bed until his urine is albumin-free. Thereafter, his urine-specific gravity is checked frequently and periodic urine concentration tests are done. Here is the same patient three days later. Now he enjoys his meal. Following ambulation, the patient is moved to the convalescent wards where his level of activity is progressively increased depending on his return of strength and improvement in renal function. Over 90% of the patients with hemorrhagic fever make a complete recovery and are sent back to full duty after an average of about 40 days total hospitalization. Approximately 2% of the patients do not recover completely from hemorrhagic fever during the four months they may be kept at the hemorrhagic fever center. The residual is in the form of persistent renal damage for which the patients are evacuated to the United States. The usual symptoms are persistent polyuria and nocturia, and the laboratory findings reveal evidence of poor concentrating power and phenol-red excretion. Here we see convalescent patients observing and participating in outdoor sports. They begin as observers. Later as their strength returns and renal function improves, they take a more active part. The patient whom you saw in the severe uremic phase is the one you see on the right. His recovery is almost complete. He is well and strong and has gained an appreciable amount of the weight he had lost. When recovery is completed by evidence of their return to strength and return of all the abnormal laboratory findings to normal, then the patients go back to their original unit.