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Chapter 4, Part II

Table of Contents

Chapter 4, Part II


Fever of Undetermined Origin

Colonel John J. Deller, Jr., MC, USA (Ret)


In 50 years, the United States has engaged in four major wars. Despite the trend of history, people tend to forget the knowledge gained from wars past-perhaps that is why wars continue to happen. Likewise, we tend to forget from one war to the next the knowledge gained in military medicine, for each war has called upon a new generation of physicians to solve the medical problems of American soldiers. Tropical disease was not a popular subject in American medicine at the time of the Vietnam conflict; its scholars were few and, for the most part, belonged to an earlier generation. Within the military services, however, a few scholars of this field remained. Their foresight and well laid plans for a "Vietnam contingency" allowed the new generation of physicians a quick start when it was needed.

The problem of FUO (fever of undetermined origin) was perhaps one of the greatest diagnostic dilemmas for military physicians in Vietnam. Historically, it was not very different from the FUO problem in World War II. At one time during the Pacific campaign there had been so many FUO diagnoses that Col. Henry M. Thomas, Jr., MC, Senior Consultant in Medicine, Southwest Pacific Area, 1943, was instructed to investigate the matter (MD-IM1, pp. 534-36). In every case he observed, he agreed that the etiology was indeed uncertain; in response, he compiled a list of the differential diagnoses of acute fevers (USASOS-TM). Despite the magnitude of the problem, however, no comprehensive FUO studies are recorded in the medical history of World War II. Several studies attempting to clarify the FUO problem were conducted when it emerged in Vietnam. This review is based primarily upon these studies and related published reports.


The first available statistics on the magnitude of the FUO problem in Vietnam stem from the USARV (U.S. Army, Vietnam) medical consultants' monthly reports beginning in October 1965 (USARV-MC). During the last 3 months of that year, disposition diagnoses from three major hospitals in Vietnam-the 3d


This chapter is a revised version of an article by the author entitled "History of fevers of undetermined origin in American soldiers in Vietnam," originally published in Present Concepts Int. Med 5 (supp. 1): 1-17, 1972.


Field Hospital, the 8th Field Hospital, and the 85th Evacuation Hospital-revealed 479 FUO cases. The average duration of hospitalization for this group was 7 days (AMEDS-AR65, p.18). The monthly reports continued to show FUO as a major cause of hospitalization among American troops in the Republic of Vietnam through 1970. Between 1966 and 1969, monthly morbidity reports reflected an average incidence rate of 58 cases per 1,000 average strength per year (ranging from 35 to 100 per 1,000) (AMEDS/AMEDD-AR). These figures include nonhospitalized patients receiving division-level medical care and patients treated in field and evacuation hospitals.

In comparison with other common diseases, the diagnosis of FUO ranked second only to venereal disease; common respiratory disease, diarrheal diseases, skin diseases, and malaria all ranked lower. The average duty time lost because of FUO between 1965 and 1970 was 4.5 days (USARV-MC). Monthly incidence rates, as reflected in morbidity reports, are markedly inflated because a number of ill-defined conditions were reported as FUO from admission reports but were not reclassified after a more definitive diagnosis was established (Bartley 1968). Nevertheless, FUO probably constituted a major cause of man-days lost.

Combat troops had significantly more cases of FUO than did support troops and rear support troops (Bartley 1968). This distribution correlates with expected exposure to arthropod vectors and other environmental conditions conducive to development of tropical febrile diseases. In the first analysis of FUO in American soldiers in Vietnam, Deller and Russell (1967) found that a history of the soldier's activity -whether he had been in combat and exposed to the jungle or in a support unit at a large encampment-provided key information in separating the various causes of FUO. For example, the arbovirus diseases and murine typhus occurred most frequently in areas of heavy population density because such areas were the natural habitat of the vectors, whereas malaria and scrub typhus were contracted in heavily forested or jungle areas, the natural habitats of their vectors.


A major hindrance to defining the spectrum of tropical febrile diseases in the early years of the war was the lag in obtaining adequate laboratory support. Although most hospitals arrived in South Vietnam with a full complement of personnel, the pathologists, bacteriologists, and laboratory technicians were as unfamiliar with tropical diseases as were the clinical personnel. More importantly, they did not have the equipment to accomplish the sophisticated laboratory procedures necessary to support tropical disease hospitals. It was only through USAMRTV (U.S. Army Medical Research Team, Vietnam) in Saigon and their close working relationship with the SEATO (Southeast Asia Treaty Organization) Laboratory in Bangkok that early studies were at all possible. Not until 1968 was full laboratory capability to investigate infectious disease established in Vietnam. The 9th Medical Laboratory established a separate department of infectious disease and made available multiple screening procedures for the serodiagnosis of FUO.


Although world health surveys of major disease prevalences had been conducted in Vietnam in the early 1950's (HD-5; HD-25), the data were incomplete for the needs of the U.S. Army physician. Nevertheless, they provided a beginning. By analyzing the surveys and reports from the French Indochina experience and from the archives of l'Institut Pasteur in Saigon, one could predict potential tropical disease problems. Table 8 lists some of the acute febrile diseases which one might have expected to encounter in Southeast Asia; such a probability table can serve as a useful guide.

The FUO story was written by physicians of various disciplines, few of whom had been in the field of tropical medicine. Thrown together on a common ground of frustration by the exigencies of war, they were faced with a new chapter in their medical careers. At first all febrile diseases seemed to be "FUO"; the triad of fever, chills, and headache was so common that everyone appeared to suffer from the same malady. It became obvious, however, that there was a spectrum of diseases within this massive group which could and should be separated.

The first step was to design a study which would survey the possible etiologies, prove in the laboratory what each patient actually had, and then attempt to correlate differentiating clinical features with specific disease entities. It would thus be possible to separate the various diseases on clinical grounds and reduce the number of FUO diagnoses to the minimum.

This approach was conceived at the 93d Evacuation Hospital in the spring of 1966. The hospital had just been converted from tents in a recently cut forest to crossed Quonset huts in an area which subsequently developed into the massive Long Binh military complex. It had a basic laboratory, but the study required

TABLE 8.- Probability of acute febrile disease acquisition by American soldiers in Vietnam


more sophisticated laboratory support. The idea of an FUO study was presented to Lt. Col. (later Col.) Robert J. T. Joy, MC, commander of USAMRTV. He was encouraging and arranged for Maj. (later Col.) Philip K. Russell, MC, at the SEATO Laboratory in Bangkok, to perform the appropriate diagnostic work on the specimens. Despite generator-run freezers, makeshift portable dry ice chests, 110o F weather, unsure jeep transportation to Saigon and courier airlifts to Bangkok, specimens were collected, stored, and delivered to their destination. Results were returned in record time. Not long after the first results were returned, it was possible to separate many of the FUO's into a limited number of specific diagnoses.

This initial study (Deller and Russell 1967) was conducted from April through August 1966. Two subsequent studies (Reiley and Russell 1969; Colwell et al. 1969) were done with the support of USAMRTV and the SEATO Laboratory. In addition, a study was conducted by the Navy in 1967 (Berman, Irving, and Kundin 1968), and another by the Air Force in 1967-68 (Deaton 1969). The combined results of these studies, which were done over a period of 2 years during various seasons and in different geographical zones, provide a good sample of the total spectrum of FUO among American servicemen in Vietnam.


An FUO in the context of this chapter is defined as a febrile illness which required admission of the patient to a field or evacuation hospital and which could not be more specifically diagnosed during the initial 3 days of hospitalization. Among the five major FUO studies, the definition varied from "cases not diagnosed within the first 24 hours" to "cases remaining febrile during their hospital stay," but in general an undiagnosed fever for 3 days is applicable to all the data.

The Army studies of Deller and Russell (1967), Reiley and Russell (1969), and Colwell and associates (1969) were prospective and comparable in design. The study by Berman and associates (1968) specifically excluded all cases of malaria, whereas Deaton's retrospective study (1969) included all hospitalized malaria cases. Thus, there are some numerical differences between the nonArmy studies and the Army studies. However, the data are similar enough to permit an appraisal of those illnesses which can initially masquerade as FUO as well as those which remain truly undiagnosable fevers.

The results of the studies are presented in table 9. The data indicate that it is possible to distinguish the specific diagnostic category for nearly three-fourths of all patients initially considered to have an FUO. The five major groups are: group A and B arboviruses-chikungunya, dengue, Japanese B encephalitis; rickettsial diseases-scrub and murine typhus; leptospirosis; malaria; and miscellaneous.

Table 10 divides the miscellaneous group into categories. Only two major categories represent significant contribution to the total FUO problem: enteric diseases, constituting 28 cases of the combined series, and respiratory tract


TABLE 9.-Results of five FUO studies' in Vietnam, 1966-68

diseases, of which there were 13 cases, including acute respiratory disease, bacterial pneumonia, and viral pneumonia.

The remaining truly undiagnosable fevers made up from one-fourth to one-half of the cases depending on the completeness of laboratory screening. These cases can be separated into two major groups on the basis of the clinical picture: approximately half of the cases had clinical features (fever patterns, rash, leukopenia) suggesting an arbovirus or typhus fever;* the remaining cases were a heterogeneous group usually with fevers of less than 72 hours' duration and often with upper respiratory or gastrointestinal symptoms. Perhaps more significant in an analysis of the total group is that all truly undiagnosable fevers were self-limited. Thus, even if a specific viral or rickettsial etiology was responsible, the outcome was favorable and no major life-threatening illnesses were unrecognized.


*In the Army studies of Deller and Russell (1967), Reiley and Russell (1969), and Colwell and associates (1969), the Weil-Felix test was not used to screen for rickettsial disease nor was the specific complement fixation test for murine typhus. Thus, a number of the "truly undiagnosable fev ers" included in these reports may actually have been murine typhus.


TABLE 10.- Miscellaneous diagnoses recorded in FUO studies' in Vietnam, 1966-68


Studies of FUO in South Vietnam served two major purposes: they established the spectrum of tropical febrile disease affecting American soldiers in different seasons and locations in the country; and they clarified important differential diagnostic features of specific illnesses which masquerade as fevers of undetermined origin.

The diagnostic features of the major diseases uncovered in these studies will be reviewed in subsequent pages. Relative incidences are shown in table 9. It is of both historical and practical significance that throughout the period of our highest troop concentration in Vietnam (1965 through 1970) the same diseases were encountered and only the relative frequencies varied.


Malaria was the tropical disease of greatest concern in South Vietnam because it produced the most medical casualties (as well as the most cases of acute febrile disease imported into the United States from South Vietnam). Thus, in any patient with an FUO malaria received prime consideration. Four types of malaria were acquired by Americans in Southeast Asia, but 99 percent of the cases were caused by Plasmodium falciparum and Plasmodium vivax (Sheehy 1967).


Malaria is generally easy to diagnose if a peripheral blood smear can be examined and interpreted. Smears, however, do not always reveal parasites at the initial presentation, and thus a diagnosis of FUO may be recorded for conditions which are subsequently proven to be malaria. Since the Anopheles mosquito (the primary vector of malaria) is a jungle breeder, this disease was most often suspected in a soldier who had been in combat.

The majority of patients with malaria have a fever within the first 72 hours of illness. Frequently, the temperature rises to 105 0 or 106 0 F; when temperatures of this elevation are found, the diagnosis is usually malaria. The fever becomes even more distinctive when, following a spike, the temperature returns to 99 0 F or lower before the next paroxysmal elevation. Such a pattern is distinctly unusual in other tropical infections. The shaking chill, the hallmark of malaria, is generally present and is accompanied by headache, moderately severe myalgias, and a variety of gastrointestinal complaints in the majority of patients. The most remarkable feature about the physical examination is the absence of specific findings; except for percussion tenderness over the liver or spleen, or both, the examination is frequently negative unless the patient has one of the major complications of falciparum malaria. Splenomegaly is variable and probably depends on the duration of the subclinical illness before the onset of recognizable disease. When malaria is suspected, a series of blood smears, both thick and thin, must be done to confirm the diagnosis. A Wright-stained thin smear, carefully examined, may be the best diagnostic method for the physician. Thick smears, although reliable, are better left for the specialist or parasitologist to interpret.

Malaria is perhaps the most important tropical disease to rapidly distinguish from other FUO's because its treatment must be timely and specific. The treatment of malaria underwent several changes following the recognition of chloroquine-resistant strains of P. falciparum, by 1965, in South Vietnam. Despite increasing numbers of multidrug-resistant strains of P. falciparum after that time, the available drugs effected a primary cure in over 90 percent of the cases. Since over 90 percent of P. falciparum infections acquired in Vietnam were resistant to chloroquine, quinine was substituted for that drug. When used alone quinine was effective in only about 50 percent of P. falciparum cases, but it was curative in 90 to 98 percent when combined with an antifolic acid compound, such as pyrimethamine, and a sulfonamide (Modell 1968). Thus, a triple therapy program for falciparum malaria eventually evolved. The treatment schedule which emerged as standard is presented in Part III of this volume. The treatment of vivax malaria did not change as P. vivax did not demonstrate any significant resistance to the standard drugs.

Mixed infections may occur; in these cases treatment for falciparum malaria plus additional therapy, such as chloroquine, for the erythrocytic phase of vivax malaria should be administered. Patients with malaria of either type may also have another tropical disease simultaneously. In several FUO studies, scrub typhus was the disease most commonly associated with malaria, probably because both are acquired in the same jungle environment.



Dengue was the most common of the three significant arthropodborne viruses presenting initially as FUO. It is usually acquired by a soldier residing in a large base encampment or urban area rather than in the jungle because the vector, the Aedes mosquito, is basically an urban dweller. The symptoms of dengue are not distinctive; three-fourths of the patients have a flu-like illness with malaise, backache, anorexia, fever, chills, and frequently severe frontal headache. They may present with lymphadenopathy, an important physical finding because patients with malaria do not have adenopathy and patients with scrub typhus generally develop adenopathy several days after the onset of the illness. A fleeting macular rash is present in at least one-third of the patients, and spontaneous petechiae occurring within this setting, especially on the lower extremities, provide good clinical evidence of an arbovirus disease. On occasion, the tourniquet test may be positive and unassociated with a reduction in platelet count. The course of dengue is usually short. Fever is rarely over 104 0 F, symptoms subside within 5 to 7 days, and few patients have a prolonged convalescence. Occasionally a patient will show a slight fever on the fifth day before a return to normal temperature by the seventh day. No specific therapy is indicated.


Chikungunya was first recognized in Tanganyika in 1952 when an epidemic characterized by high fever and severe polyarthritis occurred among the natives. Specimens collected from patients and pools of Aedes mosquitoes during this epidemic were subsequently analyzed, and a new virus was reported in 1956. It was given the name "chikungunya," the natives' term for the disease, which means "that which bends up the joints."

Since the original epidemic, chikungunya has been identified throughout Southeast Asia and the southern parts of Africa and India. The clinical disease was not recognized in Americans in South Vietnam before the study of Deller and Russell (1968). Chikungunya has covered a wide clinical spectrum from severe polyarthritis to a dengue-like illness with mild arthritis to frank hemorrhagic fever. The same virus has been cultured from all these varieties.

One feature that distinguishes this disease from dengue is polyarthritis. Even though dengue has been referred to as "break-bone fever," it is not associated with true arthritis but rather with severe myalgias and arthralgias. Chikungunya is a known viral disease that can mimic rheumatoid arthritis or acute rheumatic fever and from which an organism can also be readily cultured. The arthritis of chikungunya may linger for several weeks following the return of the temperature to normal and the disappearance of all other clinical manifestations. Except for the arthritis, chikungunya among American troops was a mild dengue-like illness; it did not produce the severe crippling arthritis of the type reported in the initial epidemic, nor did it cause hemorrhagic fever. Like dengue, it requires no specific therapy.


Japanese B Encephalitis

Japanese B encephalitis is a more recently recognized arbovirus disease, first appearing in epidemic form in the summer of 1969 in South Vietnam (Ketel and Ognibene 1971). The virus is transmitted primarily by the Culex mosquito. Although an epidemic of encephalitis was recognized as a clinical entity in Japan as early as 1871, virus isolation and characterization did not occur until 1935. Japanese B encephalitis first became a military problem among American troops in Guam and Okinawa in World War II. It appeared in Korea during the summer of 1947, and in 1948 and 1950. The classical presentation of Japanese B encephalitis among American troops has been a persistent headache followed by chills, fever, anorexia, general weakness, and nuchal stiffness. Within a few days following the onset of these symptoms, somnolence occurs. In most instances, the disease is self-limited, with fever lasting 7 to 8 days and rapid recovery thereafter. However, in the Korean epidemic in the summer of 1950, of approximately 200 patients with Japanese B encephalitis, 8.5 percent died (Lincoln and Sivertson 1952).

In the more recent Vietnam experience, several fatalities were attributable to Japanese B encephalitis. An occasional case had subacute onset, while a few cases had hyperacute onset with dramatic presentation of psychosis, seizures, and early death. In contrast to the other arbovirus diseases seen in Vietnam, leukocytosis was present in most of these cases (average peripheral white blood cell count of 13,000/mm3). Spinal fluid in all cases showed a pleocytosis with a cell count of 10 to 2,000/mm3 and an average spinal fluid white cell count of 200/mm' of which greater than 70 percent were lymphocytes (Ketel and Ognibene 1971). The disease can be positively diagnosed by isolation of the virus from the blood or from tissues in autopsy cases. Specific serologic tests using neutralizing antibodies, complement fixation, and hemagglutination techniques can confirm the diagnosis.

Rickettsial Diseases

Scrub typhus is caused by a miteborne rickettsia (Rickettsia tsutsugamushi and is classically manifested by the triad of rash, eschar, and positive therapeutic response to tetracycline. With these features present, it is usually easy to diagnose. Unfortunately, not all cases present so clearly. Sometimes the eschars are hidden and may be overlooked on physical examination, or they may not be present at all, especially in dark-skinned races. Like malaria, scrub typhus was usually acquired by the combat soldier since the mites that carry the rickettsial organism breed in the scrub jungle areas of Vietnam. Hence, the history of exposure to the jungle environment is important for diagnosis.

The fever, chills, headache, malaise, adenopathy, and backache common to the other tropical diseases are also characteristic of scrub typhus. Severe retroorbital headache is generally the most prominent complaint. Patients frequently have marked conjunctival suffusion, which increases the difficulty of differentiating this disease from leptospirosis. Cough and dyspnea are also common


symptoms. The most important feature on physical examination is the eschar, which typically resembles a cigarette burn. It is usually painless and has a black, necrotic center with a narrow rim of erythema. A macular rash, which is not so fleeting as the rashes of the arbovirus diseases and does not become confluent, is also a diagnostic sign. Lymphadenopathy and splenomegaly are occasionally found. Early recognition of this disease is important because, when treated promptly, it responds dramatically to tetracycline therapy (1 g every hour for four doses followed by 1 g every 6 hours for 5 to 7 days). Within 48 hours, and often within 12 hours, there is a dramatic lysis in fever. Patients not treated early may have a typical "saddleback" fever curve, and if the disease goes untreated for more than 10 days to 2 weeks, there is some morbidity and occasional mortality. Definitive diagnosis requires specific serological testing. A trial of therapy with tetracycline is warranted when there is a strong clinical suspicion of scrub typhus.

In Southeast Asia, human cases of murine typhus have been reported from Malaysia, the Philippines, and Thailand (Sankasuwan et al. 1969). Murine typhus, caused by Rickettsia typhi (mooseri, is probably the rickettsial disease most apt to be confused clinically with scrub typhus. Epidemiologically, however, these two conditions are quite different in that murine typhus is generally "urban acquired," from the infected rat flea, while scrub typhus is generally "jungle acquired." The diagnostic hallmark of scrub typhus, the eschar, is absent in murine typhus. Since this is not an invariable feature, its absence alone cannot be relied upon to make a differential diagnosis, and clinically there is little else to distinguish the two illnesses; thus, the final diagnosis must rest with the laboratory. Agglutinins against the OX-K strain of Proteus vulgaris occur in the serum of patients with scrub typhus while agglutinins against the OX-19 strain occur in murine typhus. The most definitive finding, however, is either a fourfold rise in titer against specific complement-fixing antibodies during convalescence, or the isolation of the specific rickettsial agents. However, the results of these laboratory tests may not be immediately available to help diagnose the condition in the patient. Although in most cases murine typhus disease is uncomplicated and self-limited, tetracycline therapy will speed recovery when initiated early.

It is difficult to state with certainty whether or not murine typhus was present to any degree early in the conflict in South Vietnam. It may have been present and missed because the Weil-Felix reaction was not part of the screening procedures, and specific complement fixation tests for murine typhus were not performed (Elisberg 1972). The disease did appear later and was uncovered in the FUO study of Deaton (1969) seen in table 9. Probably a number of cases which were recorded as self-limited, truly undiagnosable fevers in the earlier studies were caused by R. typhi.


Leptospirosis was most commonly acquired in Vietnam by combat troops who came in contact with the organism in mudbanks and rice paddies. Lep-


tospirosis closely mimics dengue and scrub typhus and has few distinguishing characteristics of its own; profound myalgias constitute the most distinctive symptom. Patients generally have a spiking temperature and often a "saddleback" fever curve similar to that which occurs in scrub typhus. Conjunctival suffusion is an important sign and is frequently associated with blurred vision. Gastrointestinal complaints and hepatic tenderness are common and make differentiation from malaria difficult. A laboratory finding of leukocytosis is occasionally helpful since most of the other tropical diseases (except Japanese B encephalitis) are characterized by normal leukocyte counts or by leukopenia. Although a normal count may be present in approximately half the cases, a neutrophilia is usually evident. Leptospirosis actually encompasses a spectrum of disease from a benign, self-limited form, such as our troops experienced in Vietnam, to a more severe hemorrhagic disease with deep jaundice and renal failure. Since U.S. troops generally manifested a benign form, there were few serious complications (Allen and Weber 1967). Because the benign form of leptospirosis is self-limited, it requires no specific therapy.


Some of the major differential features of the five most important illnesses which present as tropical FUO's are given in table 11. Data for 1969, the year of

TABLE 11.- Differential features of patients having dengue, chikungunya, scrub typhus, leptospirosis, and malaria in five FUO studies' in Vietnam


the greatest troop concentration, extracted from the files of the 9th Medical Laboratory, allow an overview of the distribution of confirmed serological cases of infectious disease in Vietnam (chart 2 and tables 12, 13, and 14).

Chart 2.- Number of cases of group B arbovirus, leptospirosis, meliodosis, scrub typhus, and murine typhus in Vietnam, January-December 1969.


TABLE 12.- Serological diagnoses (probable and confirmed) of FUO cases in Vietnam, by month, 1969

TABLE 13. - History and symptoms of serologically confirmed FUO cases in Vietnam, 1969.


TABLE 13.- History and symptoms of serologically confirmed FUO cases in Vietnam, 1969 - Continued

The distribution (probable and confirmed) of FUO cases serologically diagnosed in 1969 was as follows:*

Scrub typhus - 228

Amebiasis - 212

Murine Typhus - 195

Group B arbovirus - 179

Leptospirosis - 179

Infectious mononucleosis - 96

Lymphogranuloma venereum - 59

Meliodosis - 45

Primary atypical pneumonia - 22

Parathyroid - 18

Tick typhus - 16

Typhoid - 5

Group A arbovirus - 2

* Records of Lt. Col. Andre J. Ognibene, USARV Medical Consultant, 1969, from data collected at the 9th Medical Laboratory, Long Binh, Vietnam.


TABLE 14.- FUO cases, by medical facility and diagnosis, Vietnam, 1969


Several lessons are to be learned from the FUO experience in Vietnam. First, a nucleus of tropical disease experts should be maintained from one generation to the next, as should an awareness of the major tropical diseases that might be encountered on future ventures into tropical countries. Second, worldwide tropical disease problems should be monitored so that one can accurately predict which diseases might be encountered in various areas of the world. Third, ongoing medical research studies in the less developed countries should be supported. These can contribute to eradication of such diseases in those countries. Finally, properly equipped laboratories for the study of tropical disease should accompany initial military units into all tropical environments so that unfamiliar medical problems can be recognized early and preventive measures instituted.


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