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Like so many biologic functions, human body temperature normally displays circadian rhythmicity, often rising from values of 36. 1° C (97.0° F) or lower in the predawn hours to 37.4° C (99.3° F) or higher in the afternoon. This diurnal flux has two important practical consequences. First, fever associated with disease states is superimposed on the normal cycle and tends to peak in the evening; hence, a patient cannot be considered afebrile until his or her temperature has been monitored for at least 24 hours. Second, temperatures exceeding what is generally regarded as the normal value of 37.0° C (98.6° F) are often recorded in perfectly healthy individuals. Unfortunately, many patients with temperature elevations that are entirely physiologic have been subjected to potentially hazardous tests and treatments because their elevated temperatures were incorrectly regarded as pathological.

Within the limits of the circadian rhythm, however, body temperature is closely regulated by homeostatic mechanisms that strike a balance between heat production and heat dissipation. Heat is a by-product of all metabolic processes; at rest, metabolic activity in the liver and heart produce much of the body's heat, whereas metabolic activity in skeletal muscle accounts for the greatly enhanced thermal load of exercise. Heat is dissipated at the body's surfaces; the skin accounts for about 90 percent of heat loss, with the lungs contributing most of the remaining 10 percent. In the basal state, about 70 percent of the body's thermal load is dissipated by radiational cooling, and 30 percent is removed by the evaporation of insensible perspiration; convection and conduction are less important mechanisms of heat removal. When the ambient temperature rises or when metabolic heat production increases, evaporation accounts for the major share of heat dissipation.

The preoptic nucleus of the anterior hypothalamus functions as the thermal control center and acts to maintain the body temperature at a set value, the so-called hypothalamic thermal set point. In response to elevations in core body temperature (i.e., the temperature of the blood perfusing the internal organs), the hypothalamus stimulates the autonomic nervous system to produce cutaneous vasodilatation and sweating, both of which dissipate heat. In response to either a falling core temperature or a falling skin temperature, the hypothalamus conserves heat by causing cutaneous vasoconstriction. When cold stress is severe, the hypothalamus acts to increase heat production by stimulating muscular activity in the form of shivering; shivering is mediated by the action of somatic nerves, but it is an automatic and involuntary process.

Abnormal elevation of body temperature, or pyrexia, can occur in one of two ways: hyperthermia or fever . In hyperthermia, thermal control mechanisms fail, so that heat production exceeds heat dissipation. In contrast, in fever, the hypothalamic thermal set point rises, and intact thermal control mechanisms are brought into play to bring body te mperature up to the new set point. The distinction between fever and hyperthermia is more than academic: hyperthermia is best treated with physical cooling methods that promote heat dissipation, whereas fever is best treated with aspirin, acetaminophen, or other drugs that lower the thermal set point.

Numerous clinical disorders can disrupt thermoregulatory homeostasis by causing increased heat production, decreased heat dissipation, or hypothalamic insult, thereby inducing hyperthermia . Mild forms of hyperthermia are common. In dehydration, for example, cutaneous vasoconstriction and cessation of sweating occur in response to the decrease in intravascular volume, as a means of conserving further loss of fluid and of minimizing the consequences of fluid loss. As a result, heat dissipation is impaired and body temperature may rise. In contrast, during exercise, heat production can increase up to 20-fold, often overwhelming heat dissipation mechanisms. Exertional hyperthermia may be an incidental finding , but exertional heatstroke is a life-threatening emergency .

In some cases, thermoregulatory disorders cause extreme pyrexia, in which body temperatures rise to 41.1° C (106.0° F) or higher; examples of these thermoregulatory disorders are thyroid storm, malignant hyperthermia of anesthesia, heatstroke, and hypothalamic insult caused by infection, tumor, or drugs. Because infectious and inflammatory diseases can also cause extreme fever, the magnitude of elevation of a patient's temperature cannot be used to distinguish between hyperthermia and fever.

In most cases, hyperthermia is an acute rather than a recurrent problem, and the underlying disorder can be readily diagnosed by careful clinical examination. Exceptions occasionally occur in patients with endocrinologic or hypothalamic disorders who pre sent as diagnostic puzzles in the category of fever of undetermined origin [see Fever of Undetermined Origin, below].

Once thermoregulatory failure is recognized as the cause of hyperthermia, therapy should be directed at the underlying disorder. In some cases, specific therapy, such as dantrolene for malignant hyperthermia of anesthesia or antithyroid drugs for thyroid storm, provides effective control of hyperthermia. If rapid control of hyperthermia is required, the elevated temperature itself should be managed with physical cooling methods; metabolic and circulatory support are also important therapeutic measures.

Since antiquity, fever has been recognized as a cardinal feature of disease, but understanding of the pathophysiology of fever is much more recent. For more than 100 years, it has been known that pus is pyrogenic, but only with the work of Dr. Paul Beeson in 1948 did it become clear that the ultimate cause of fever is not a bacterial product (a so-called exogenous pyrogen) but a product of host inflammatory cells (i.e., an endogenous pyrogen). For years, the endogenous pyrogen was thought to be a product of polymorphonuclear leukocytes and was referred to as leukocytic pyrogen. Exciting studies, however, have demonstrated that mononuclear phagocytes are the principal source of endogenous pyrogen and that a variety of mononuclear cell products can mediate the febrile response. Moreover, these cell products, which are collectively categorized as monokines or cytokines, are also important as mediators of the acute-phase response to infection and inflammation. Many additional biologic activities have been attributed to the pyrogenic cytokines; the most important of these cytokines are interleukin-1 (IL-1), IL-6, interferon gamma, and tumor necrosis factor (TNF).

Interleukin-1 A great variety of stimuli can initiate IL-1 production by mononuclear phagocytes , such as microorganisms, exposure to endotoxin and other bacterial toxins or microbial products, phagocytosis, antigen-antibody immune complexes, and various forms of tissue injury. Although the most important sources of IL-1 are monocytes and macrophages, IL-1 can also be produced by polymorphonuclear leukocytes, T and B cells, endothelial cells, and virtually all other nucleated cells. IL-1 production is an active process that requires messenger RNA (mRNA) and protein synthesis. There are at least two distinct species of IL-1, termed IL-1a and IL-1b. Separate genes produce precursor proteins with a molecular weight of 31 kd. These proteins are then processed to active IL-1a and IL-1b, each of which has a molecular weight of 17.4 kd. Although only 26 percent of the amino acids of IL-1a and IL-1b are similar, the lymphokines appear to bind to the same receptors and have the same biologic activities. IL-1 a has been localized to the surface of mononuclear phagocytes, whereas IL-1b is found in the cytoplasm and is secreted on stimulation. Other molecular species of IL-1 may also exist. In addition, a synthetic nonapeptide derived from fragments 163-171 of IL-1b possesses the immunostimu latory properties of the parent protein without its pyrogenic and inflammatory properties. Studies with this peptide suggest that it may be possible to separate the immunostimulatory effects from the inflammatory effects of IL-1.

IL-1 production is closely regulated. IL-1 itself induces additional IL-1 production as well as additional IL-1 receptor expression on certain target cells. Interferon gamma, another pyrogenic cytokine, enhances the production of IL-1. In contrast, the cytokine IL-4 suppresses production of IL-1 and the other pyrogens, TNF and IL-6. IL-1 production is also down-regulated by glucocorticoids, which inhibit the inflammatory action of IL-1 as well. In addition, prostaglandin E inhibits production of IL-1 at the level of the ribosome by blocking the translation of IL-1 mRNA. Although a -melanocyte-stimulating hormone (a-MSH) does not affect the production of interleukin-1, it does inhibit the immunostimulatory and inflammatory actions of IL-1. Distinct inhibitors of IL-1 are present in polymorphonuclear leukocytes and in the urine of febrile patients. An antagonist of the IL-1 receptor has also been identified.

IL-1 and the pathogenesis of fever In the pathogenesis of fever, IL-1 acts as a hormone in that it is carried by the circulation from the local inflammatory site of production to the central nervous system, where it acts directly on the hypothalamic thermal control center. IL-1 binds wi th high affinity to a plasma membrane receptor, which has a molecular weight of 80 kd. Its mechanism of action appears to involve induction of phospholipases, which in turn cause the release of arachidonic acids from membrane phospholipids. As a result, prostaglandin levels rise, particularly levels of prostaglandin E. Elevated levels of prostaglandins appear to be important in raising the hypothalamic thermal set point; this mechanism explains why prostaglandin inhibitors such as aspirin are effective antipyretic agents.

Once the hypothalamic thermal set point has been elevated, thermoregulatory mechanisms are brought into play to raise the body temperature to the level of the new set point. Autonomic efferents lead to heat conservation through cutaneous vasoconstriction and cessation of sweating. Somatic nerves are responsible for increasing heat production via increased skeletal muscle tone or shivering. The myalgias that accompany many febrile states may in part be caused by this increased muscle tone; rigor, which is a dramatic precursor of some fever spikes, is nothing more than an exaggerated form of shivering that rapidly elevates body temperature in response to an increased hypothalamic thermal set point.

IL-1, immunostimulation, and the acute-phase host response In addition to pyrogenicity, IL-1 exhibits a number of biologic properties that help explain the immunologic and acute-phase host response to infectious and inflammatory states. Some of these properties may actually enhance host defense mechanisms. For example, IL-1 stimulates both T and B cells, probably by acting on helper T cells. T cell activation results in increased levels of lymphokines, most notably IL-2, which induces expansion of clones of helper, suppressor, and cytolytic T cells. T cell proliferation may activate macrophages and augment host immunity to intracellular parasites. IL-1 is also chemotactic for T cells. B cell activation results in increased antibody synthesis. Stimulation of both T and B cells by IL-1 is markedly augmented in vitro by increasing the temperature from 37° to 39° C. Hence, the pyrogenic properties of IL-1 actually enhance its effectiveness as an immunostimulator.

IL-1 stimulates mononuclear cells, endothelial cells, and fibroblasts to produce granulocyte-macrophage colony-stimulating factor (GM-CSF), and it also acts on the bone marrow to stimulate neutrophil release. IL-1 activates neutrophils, which possess about 1,700 IL-1 receptors per cell, and promotes chemotaxis. Thus, the blood leukocytosis and the infiltration of tissue by inflammatory cells that characterize many infections may in part be caused by IL-1. In addition, IL-1 stimulates lactoferrin release by neutrophils. Serum iron levels fall during many bacterial infections, and hypoferremia itself may retard bacterial growth.

IL-1 mediates various other responses to infection, including some that may be deleterious to the host. IL-1 has important effects on vascular endothelial cells: it increases vascular permeability and inhibits contraction of vascular smooth muscle, which may contribute to the vasodilatation and vascular leak characteristic of acute inflammation. Circulating IL-1 levels, however, do not correlate with severity of illness or morbidity in patients with the septicshock syndrome. Interleukin-1 causes endothelial proliferation, prostaglandin production, leukocyte and platelet adherence, and procoagulant activity, which may contribute to vasculitis and even atherogenesis. Interleukin-1 stimulates liver cells to produce acute-phase proteins; this response may account for the elevated erythrocyte sedimentation rates seen in most inflammatory diseases. Interleukin-1 increases muscle cell prostaglandin production and protein catabolism, resulting in amino acid release; negative nitrogen balance is common in febrile patients, and the myalgias such patients experience may reflect direct muscle injury mediated by IL-1. IL-1 acts on the central nervous system to induce sleep and may contribute to the lack of concentration noted by many febrile patients. Alveolar macrophages release large amounts of IL-1 during the adult respiratory distress syndrome, suggesting that IL-1 may contribute to tissue damage in patients with pneumonitis. Finally, IL-1 stimulates fibroblast proliferation and the production of collagen and hyaluronic acid; such activity may have a role in the local repair of tissue injury caused by infection but could also contribute to tissue damage, such as that which occurs in inflammatory arthritis.

Tumor necrosis factor TNF, like IL-1, is a cytokine that functions as a pyrogen by acting directly on the hypothalamus to elevate the thermal set point. In addition to its direct pyrogenic activity, TNF causes fever by stimulating IL-1 production. TNF displays many of the same inflammatory properties as IL-1, but TNF also appears to have a role in the pathogenesis of the cachexia of chronic infections and neoplastic diseases.

Endotoxin is the most potent stimulus of TNF production. Certain parasites, viruses, and enterotoxins, including toxic-shock syndrome toxin-1 (TSST-1), also stimulate TNF production, as does IL-1. Macrophages are the principal source of TNF; monocytes and natural killer (NK) cells also produce TNF, but TNF production has not yet been documented in the many other cells that are known to produce IL-1. TNF is first produced as a prohormone, which is then cleaved to release the active molecule. TNF is produced rapidly after endotoxin stimulation; peak serum levels occur in 90 minutes, but the half-life is short, and TNF is cleared from the circulation within three hours. Although TNF and IL-1 are very similar in molecular weight, they are structurally distinct and bind to different receptors. TNF receptors are present in the central nervous system, on vascular endothelium, on adipose tissue, and on liver, kidney, and lung tissues. Glucocorticoids inhibit TNF production; other inhibitors have been identified in human urine.

In addition to pyrogenicity, TNF has many biologic effects similar to those of IL-1. For example, TNF induces synthesis of GM-CSF and activates neutrophils and macrophages. TNF also induces endothelial cell activation, prostaglandin synthesis, osteoclast -mediated bone resorption, collagen synthesis and fibroblast proliferation, muscle proteolysis, and hepatic synthesis of acute-phase reactants (i.e., fibrinogen, C-reactive protein, haptoglobulin, and ceruloplasmin). TNF enhances T cell-dependent antibody synthesis. Some of the immunologic effects of TNF are enhanced by elevated temperatures. TNF has increased resistance to infection in some experimental models, but it has not yet been shown to have the broad immunostimulatory properties of IL-1. Central nervous system effects of TNF include sleep induction and inhibition of adrenocorticotropic hormone (ACTH) release. TNF also has properties distinct from those of IL-1, including the ability to produce necrosis of certain tumors.

Evidence suggesting that TNF is an important mediator of septic shock is rapidly accumulating. TNF acts on vascular endothelium to increase permeability and on vascular smooth muscle, where it stimulates both IL-1 and TNF production. Infusion of TNF into experimental animals produces the metabolic, hematologic, and hemodynamic equivalents of gram-negative bacteremic shock. Endotoxin-resistant mice do not produce TNF; transfusion of marrow cells from a related strain of mice restores TNF production and endotoxin sensitivity. Anti-TNF antiserum protects experimental animals from the lethal effects of endotoxin and gram-negative bacteremia. In human volunteers, administration of small doses of endotoxin causes TNF to be released into the circulation and also produces fever, leukocytosis, and endocrinologic changes. Finally, TNF has been detected in the blood of children with meningococcemia, with the highest levels in patients who are in shock.

TNF may also be responsible for certain aspects of the response to chronic infection. TNF inhibits lipoprotein lipase and mediates severe weight loss in animals with certain tumors. Human recombinant TNF administered repeatedly in sublethal doses to mice produces cachexia, anemia, and pathological evidence of inflammation in multiple organ systems. Serum TNF levels are elevated in patients with the acquired immunodeficiency syndrome (AIDS).

IL-6 and interferon gamma Like IL-1 and TNF, IL-6 and interferon gamma are pyrogenic cytokines that act directly on the hypothalamus to raise the thermal set point. IL-6, also known as interferon beta-2, is a glycoprotein produced by human mononuclear cells, T cells, and many other cells. Synthesis of IL-6 is enhanced by many of the stimuli that promote IL-1 and TNF produc tion, including endotoxin, IL-1, and TNF. On a molar basis, stimulated mononuclear cells produce two to three times less IL-6 than IL-1 or TNF. In addition to its pyrogenic effects, IL-6 modulates many of the same immuno logic and inflammatory responses as the other pyrogenic cytokines ; however, unlike TNF and IL-1, which stimulate further cytokine production, IL-6 suppresses IL-1 and TNF production. IL-6 has been detected in the circulation of febrile, neutropenic children. Interferon gamma is produced by antigen-stimulated T cells and IL-2-stimulated NK cells and displays a broad range of im munomodulatory functions.

Of all endogenous pyrogens, IL-1 is the most potent, but the relative importance of these other cytokines in the production of fever has not yet been determined.

Although fever is a common response to infection in many species, there is no direct evidence that it is beneficial to host defense mechanisms in humans. However, new insights into the immunostimulatory properties of IL-1 and TNF have led to speculation that fever itself may promote recovery from infection. IL-1 and TNF appear to act across species, order, and class barriers and probably evolved 300 million years ago; this evolutionary stability further suggests that fever plays a role in host defense mechanisms.

Fever does appear to be of benefit in certain species. Poikilothermic (cold-blooded) lizards and fish seek warmer environments when they are infected; both the local inflammatory response to infection and host survival are enhanced by elevated body temperature in these species. Fever retards the rate of bacterial replication in rabbits with experimentally induced pneumococcal meningitis. Recombinant IL-1 promotes clearance of Listeria monocytogenes from mice, as does interferon gamma. IL-1 and TNF display antiviral properties in tissue culture, and both cytokines can enhance nonspecific resistance to infection as well as resistance to radiation in mice. Five controlled trials have explored the effects of antipyretics in nonhuman mammals with severe experimental infections; in four of the trials, antipyretic therapy was associated with increased mortality. Antipyretic therapy has also increased viral shedding in some animal studies.

In humans, fever appears to decrease serum iron levels. Many microbes need iron for growth, and it has been suggested that fever-induced hypoferremia is a helpful host defense mechanism. Fever is also marked by a metabolic shift away from glucose, an exc ellent substrate for bacteria, to fat and protein as energy sources. In addition, some microbes, including gonococci and Treponema pallidum, are quite heat sensitive and can be killed in experimental animals by artificially induced fevers. However, natural infection never produces body temperatures that are high enough to have this effect. Although systemic fever therapy has not been shown to be helpful in human infection, local nasal hyperthermia may provide symptomatic benefit for patients with nasopharyngitis.

Therapeutic hyperthermia is also being used for noninfectious diseases. Regional hyperthermia is a traditional therapy for many musculoskeletal disorders. Such techniques as heating pads, whirlpools, and ultrasonography have all been used to increase the temperature of injured tissues. Despite widespread endorsements by patients and practitioners, however, heat treatments for musculoskeletal injuries have not been subjected to controlled clinical trials.

Hyperthermia is also being investigated for a possible role in treating malignancies. Adjunctive regional hyperthermia often improves the rate of response when compared with radiotherapy or chemotherapy; superficial tumors respond most favorably, but better responses may be obtained with internal malignancies as techniques for deep heating are improved. Whole body hyperthermia has been studied less extensively, but early clinical trials provide some hope that it may improve responses to chemotherapy or radiotherapy.

Pyrexia can have deleterious consequences, but complications depend more on the underlying cause of the temperature elevation and the patient's overall condition than on the level of the temperature. Elevated body temperatures are most harmful to the very young and very old. Febrile seizures are a risk in children between six months and six years of age. Although febrile convulsions are generally benign, they are alarming, and it is always necessary to exclude underlying neurologic illnesses, including meningitis. About one third of children who have had febrile seizures have subsequent unprovoked seizures; this susceptibility probably reflects the presence of an underlying seizure diathesis rather than neurologic damage that has resulted from the febrile seizures. In the absence of unprovoked seizures, long-term anticonvulsant therapy is not usually necessary in children with febrile seizures and may even be deleterious in such patients. Diazepam, administered orally only when fever occurs, is a safe and effective way to reduce the risk of recurrent febrile seizures.

Febrile seizures do not occur in adults, but fever often produces decreased concentration and sleepiness; high temperatures commonly produce an altered sensorium, including stupor and delirium.

Metabolic rate and oxygen consumption rise as body temperature increases. Tachycardia is such a universal response to fever that its absence may be a clue to factitious fever [see Fever of Undetermined Origin, below] or to certain infections (e.g., salmonellosis or Legionnaires' disease). In healthy young persons, the heart rate has been noted to rise by 8.5 beats/min/1° C in natural infections and by 25 beats/min/1° C in experimental hyperthermia. Although healthy hearts can tolerate the tachycardia associated with fever, pyrexia that occurs in elderly patients or those with cardiovascular or pulmonary disease can precipitate arrhythmias, hypotension, ischemia, or congestive heart failure. With each 1° F rise in body temperature, oxygen consumption increases by seven percent, and a diseased cardiovascular system may not be able to accommodate the increase in cardiac output that is required to meet the increased tissue demand for oxygen.

Extreme pyrexia may be surprisingly well tolerated. In a series of 100 children who had temperatures exceeding 41.1° C (106.0° F), only 39 patients required hospital admission. One death occurred and was caused by gram-negative bacteremia; the only residual abnormalities were in two children with bacterial meningitis. In a series of 28 adults with extreme pyrexia, the mortality was 28 percent. However, only two deaths were temporally related to the hyperthermia: one in a patient with heatstroke and the other in a patient with septic shock; the remaining deaths occurred subsequently as a result of underlying disease.

It seems likely that the widespread tissue damage, multiple laboratory abnormalities, and high mortality observed in disorders such as heatstroke, malignant hyperthermia of anesthesia, thyroid storm, and the neuroleptic malignant syndrome are caused by the underlying disorder rather than the elevated temperature itself. Indeed, in the preantibiotic era, fever therapy was well tolerated, with little evidence of tissue damage, despite the fact that temperatures as high as 41.7° C (107.1° F) were induced.

Whole body hyperthermia has been studied as an experimental adjunct to cancer chemotherapy. In a study of 14 patients with advanced malignant disease, body temperatures as high as 41.7° C (107.1° F) were maintained for up to four hours. Tachycardia and elevated cardiac outputs were universal, but hypotension and myocardial ischemia did not occur. Other common but transient complications were leukocytosis, respiratory alkalosis, decreased serum magnesium and phosphate levels, and elevated serum levels of liver and muscle enzymes. Although most of these seriously debilitated patients reported that they were uncomfortable, the only significant toxic side effect of fever therapy was peripheral neuropathy (noted in 30 percent of the patients).

The approach to the febrile patient involves three elements: diagnosis and management of the underlying disorder; cardiac, respiratory, and metabolic support; and cooling. Infection is the leading cause of elevated body temperature; all febrile patients should be systematically evaluated for infection, and antibiotics should be administered whenever appropriate.

In patients with extreme pyrexia, additional laboratory studies are important both to screen for hyperthermia caused by thermoregulatory defects and to assess tissue damage. Electrolytes, renal and liver function tests, coagulation parameters, muscle enzymes, and arterial blood gases should all be measured. Studies of thyroid and adrenal function may be indicated. Cardiac function, blood pressure, urine output, and neurologic status should be monitored closely. Adequate hydration is mandatory; circulatory or respiratory support may be necessary.

Proper management of the elevated temperature itself depends on the clinical circumstances. Because many patients tolerate high body temperatures very well, antipyretic therapy may actually produce more discomfort than the pyrexia itself. In other individuals, myalgias, flushing, fatigue, loss of concentration, shivering, or chills can be very uncomfortable, and antipyretic therapy should be used for symptomatic relief. Significant pyrexia should always be treated in young children, in elderly or debilitated patients, and in persons with cardiopulmonary disease because these patient groups are most likely to suffer adverse consequences. Hyperthermia should be treated in all patients with malignant hyperthermia of anesthesia, heatstroke, the neuroleptic malignant syndrome, or thyroid storm. Finally, it seems prudent to treat any patient with a temperature in excess of 40.0° C (104.0° F), even a healthy young adult.

The choice of cooling technique depends on the pathogenesis of the temperature elevation . In patients with fever caused by infection or other inflammatory states, an elevated hypothalamic thermal set point is responsible for the pyrexia. Aspirin or acetaminophen should be used to lower the set point; the drugs seem equally effective as antipyretics, but acetaminophen is preferred in pediatric patients because aspirin may precipitate Reye's syndrome in children with influenza or varicella. If physical cooling methods are used without antipyretic drugs, homeostatic mechanisms will continue to operate in an attempt to raise body temperature, resulting in intense vasoconstriction and shivering.

In contrast, patients who are hyperthermic because of thermoregulatory failure do not have an elevated hypothalamic thermal set point. Hence, these patients require physical cooling rather than antipyretic medications. If a reduction in body temperature is required, sponging with tepid water or alcohol, hypothermic mattresses, or, in urgent circumstances, ice packs or ice-water immersion may be employed. These treatments are all very uncomfortable and should be used only when the hyperthermia itself is truly deleterious. More elaborate methods of cooling, such as the infusion of cooled intravenous fluids, gastric lavage or enemas using ice water, or peritoneal dialysis with cooled fluids, appear to offer few advantages and may pose additional hazards.

In practice, most patients with marked pyrexia will receive both antipyretics and physical cooling. Indeed, combined therapy is appropriate because many of the disorders that produce pyrexia are etiologically multifaceted. In all patients, careful attent ion is required to prevent hypothermic overshoot on the one hand and recurrent fever on the other. Although pyrexia may be the most spectacular symptom, meticulous attention to the underlying disorder is of primary importance in all cases.

Fever occurs in about one third of all hospitalized patients; in most cases, diagnostic studies reveal the cause of fever, but in 12 to 18 percent of patients, the cause of fever cannot be determined. Infection causes 67 percent of nosocomial fevers, which have adverse prognostic implications. Even when the cause of fever in hospitalized patients goes undiagnosed, however, the fever usually resolves spontaneously within a brief period. In contrast, prolonged fever of undetermined origin (FUO) presents one of the most challenging and perplexing problems in clinical medicine. Such fevers may persist for weeks or months in the absence of characteristic clinical findings or clues. Ultimately, most such obscure fevers prove to be caused by common diseases presenting in an atypical fashion rather than by rare and exotic illnesses.

Petersdorf and Beeson in their classic monograph specified three criteria to define FUO:

1. Duration: at least three weeks. This requirement eliminates from consideration febrile illnesses of obvious cause, most short-lived fevers of indeterminate or viral origin, and pyrexias of postoperative patients, in whom fevers of one or two weeks' duration may stem from sequential processes.

2. Magnitude: a temperature that is greater than 38.3° C (101.0° F) on at least several occasions. This criterion eliminates from consideration individuals (usually young females) with habitual hyperthermia, in whom the body temperature normally ranges from 37.3° to 38.0° C (99.1° to 100.4° F). If such individuals are not clinically ill, their elevated temperature should not cause too much concern.

3. Obscure nature: perplexing enough to defy diagnosis after one week of study. In the early series, inpatient study was required to evaluate FUO, but with changing admission practices, "intelligent and invasive" outpatient study is now considered sufficient.

It is helpful to approach the problem of obscure fever in a particular patient by reviewing the established causes and their relative frequencies. These diagnostic considerations can then be viewed in the light of evidence from the patient's history, clinical findings, and initial laboratory data. Further specific studies are then obtained, with the aim of confirming or eliminating the more likely diagnoses. Although geographic factors are relevant, the leading causes of FUO are reasonably uniform throughout the United States. The relative frequencies of the etiologic categories responsible for FUO seemed quite stable from the 1950s to the 1970s; however, a subtle change was noted in a 1982 study, with neoplasms replacing infections as the leading cause of FUO . In a 1992 study of 86 patients evaluated at community hospitals, however, infection was the leading cause of FUO. Noninvasive studies provided the diagnosis in 42 percent of patients, with serologies and lysis centrifugation blood cultures being the most useful noninvasive techniques. CT-guided percutaneous biopsies were the most useful invasive procedures. Only nine percent of patients remained undiagnosed. In a 1992 European study of FUO in 199 patients, further changes in the etiology of FUO were noted. Neoplasms accounted for a much smaller percentage of cases, but 23 percent of patients were not diagnosed, probably reflecting the especially difficult cases, which were referred to tertiary care centers. With dramatic changes in host factors, further changes in the final diagnosis will undoubtedly occur. As a result, it may be prudent to consider so-called classic FUO separately from FUO in patients with human immunodeficiency virus (HIV) infection, ne utropenia, or nosocomial fevers.

Despite changes in host factors and diagnostic techniques, the basic categorization of the causes of FUO remains valid.

Infections always merit initial consideration because of their frequency and specific therapeutic implications.

Systemic infections The two major systemic infections to consider in the evaluation of FUO are tuberculosis (usually disseminated but sometimes confined predominantly to the liver and spleen) and infective endocarditis . Most FUO cases caused by miliary tuberculosis arise in elderly patients in whom dissemination has followed breakdown of quiescent foci. Often, in cases caused by miliary tuberculosis, the intermediate-strength (five tuberculin units) purified protein derivative skin test is negative, and miliary pulmonary lesions are not present on the chest x-ray. Anemia and leukopenia caused by bone marrow involvement or, less often, by hypersplenism may be evident. A leukemoid reaction (usually myelocytic and, rarely, lymphocytic) may indicate bone marrow involvement and provide a valuable clue to diagnosis; bone marrow biopsy is a very helpful diagnostic test in patients in whom miliary tuberculosis is suspected. An isolated elevation of the serum alkaline phosphatase level may indicate miliary involvement of the liver by tuberculosis, other infection, or neoplasm. The histologic findings on liver biopsy often suggest the diagnosis, and a portion of the specimen should always be cultured for the presence of tubercle bacilli.

Infective endocarditis, usually subacute, is also an important diagnostic consideration. Most patients with subacute bacterial endocarditis have a heart murmur. In about five percent of cases, however, particularly in the elderly, the murmur may be absent or may be considered functional. If the murmur is disregarded, the febrile illness without localizing features is often attributed to influenza, a urinary tract infection, or some other plausible cause. Blood cultures would be expected to provide the diagnosis in a patient with subacute bacterial endocarditis, particularly because only five percent of patients with endocarditis have negative blood cultures. The leading cause of negative blood cultures in patients with endocarditis is the administration of antibiotics such drugs may also inhibit bacterial growth sufficiently to cause cultures taken some days after cessation of the antibiotics to remain negative. It is therefore very important that multiple blood cultures be obtained, including some as long as five to 10 days after antibiotics have been withdrawn. Other causes of culture-negative endocarditis that should be considered in patients with FUO include infection with fastidious bacteria, chlamydial infection, and Q fever.

Careful scrutiny for the peripheral stigmas of endocarditis, such as petechiae, subungual splinter hemorrhages, Osler nodes, Janeway lesions, Roth's spots in the fundi, splenomegaly, peripheral emboli, and microscopic hematuria, is essential in the evalu ation of any patient with FUO. Rheumatoid factor is present in the serum of 50 percent of patients with subacute bacterial endocarditis and may provide a valuable diagnostic clue. Circulating immune complexes also may be present. Echocardiography may reveal valvular vegetations in patients with endocarditis. Left atrial myxomas mimic culture-negative endocarditis but may be detected with echocardiography.

Other systemic infections, including bacteremias that occur in the absence of any obvious primary site of involvement, only rarely cause FUO . Viral infections are usually self-limited and do not produce fevers that last longer than three weeks. An important exception to this generalization is cytomegalovirus (CMV) infection.

CMV infection may occasionally present as FUO (often with some mononucleosis-like features) in otherwise well individuals. More frequently, CMV infection develops in patients who have received multiple blood transfusions or who have undergone organ trans plantation. CMV disease, either alone or accompanied by other systemic infections or by allograft rejection, is the cause of 50 percent of all febrile episodes in renal transplant recipients; it underlies 70 percent of those episodes that last longer than three weeks. CMV infection is a major diagnostic consideration in a renal transplant patient with prolonged obscure fever unaccompanied by localized findings, particularly when the fever occurs between two and 20 weeks after transplantation.

Localized infections The more common types of localized infection that present as FUO include hepatic abscess, subphrenic abscess, and subhepatic and pericholecystic abscess . Sites of previous surgery may harbor an abscess in a patient with FUO the surgery may have been performed as long ago as 12 months before the onset of fever. An unvarying gastric air bubble may suggest a subdiaphragmatic abscess.

Liver abscesses are often occult the physician should look for a history that includes biliary tract disease symptomatology, recent blunt abdominal trauma, or travel, which might suggest the diagnosis of amebiasis. Hepatomegaly may be absent initially. The serum alkaline phosphatase level is usually elevated even when the abscess is solitary. Serologic tests for amebiasis are positive in patients with amebic liver abscess. Elevation of the diaphragm, particularly when accompanied by overlying pulmonary atelectasis or a pleural effusion, should raise suspicion of a subphrenic abscess. Ultrasonography and computed tomography are valuable in identifying such collections; gallium scans are less useful for this purpose.

Localized infection in the urinary tract is an important consideration in a patient with FUO. Perinephric abscess and renal carbuncle are difficult to diagnose, even with intravenous pyelography. Ultrasonography, CT, or renal angiography may be necessary to establish the diagnosis.

Many other localized infections occasionally present as FUO; occult dental infections are one such example and illustrate the need for thoroughness in the evaluation of patients with obscure fevers.

Lymphoma, particularly Hodgkin's disease, is the most common neoplastic cause of obscure fever. Lymphoma may be difficult to diagnose when the principal site of involvement is the retroperitoneal nodes, but abdominal CT scans greatly facilitate this diagnosis. Because the rapid DNA turnover in lymphoma could produce an increase in the serum uric acid level, an isolated, unexplained elevation of this level may also suggest the diagnosis. Although so-called Pel-Ebstein recurrent fevers suggest Hodgkin's disease, they are observed in only a minority of patients with this disorder.

The development of fever in a patient who has myeloma or chronic lymphocytic leukemia is usually caused by superimposed infection and not by the neoplastic process. In some patients, however, the febrile course appears to be caused by the leukemia itself. Occasionally, a patient with the preleukemia syndrome will present with fever and atypical blood and bone marrow changes, suggesting myeloid metaplasia or a leukemoid response. Only after some months can the hematologic picture be established as leukemia.

Fever associated with hypernephroma may be mild or marked. Occasionally, such tumors are extremely vascular and produce changes characteristic of a high-output state (e.g., cardiomegaly and flow murmurs). A renal vascular bruit in the upper quadrants may provide a diagnostic clue. Recrudescence of fever months or years after removal of a hypernephroma may indicate local recurrence or distant metastases. Up to 10 percent of patients with colorectal carcinoma present with fever either extension of the tumor through the bowel wall, producing a paracolonic abscess, or necrosis and abscess formation in a polypoid intraluminal lesion may be the underlying mechanism.

Widespread metastatic cancer may be responsible for continuing fever; hepatic involvement is not necessary for fever to occur. Occasionally, a neuroblastoma involving bone or soft tissues or a pheochromocytoma may have a febrile course.

Fevers caused by malignant disease often respond to therapy with nonsteroidal anti-inflammatory drugs; fevers caused by infections are less likely to respond completely to these agents.

A variety of connective tissue disorders and vasculitides may produce prolonged fevers before the development of articular or other characteristic manifestations. In the elderly, polymyalgia rheumatica and the closely related disorder giant cell arteritis (temporal arteritis) are the most common connective tissue disorders presenting as FUO. Malaise, weight loss, muscle weakness, mild arthralgias without overt arthritis, and a markedly elevated sedimentation rate (usually > 100 mm/hr) are usual features. Jaw claudication, visual symptoms, and a tender or thickened temporal artery suggest the diagnosis of giant cell arteritis. Up to 15 percent of cases of giant cell arteritis present as FUO, and in some patients, the vasculitis itself remains occult. Similarly, virtually all patients with adult-onset Still's disease are febrile, and systemic symptoms such as fever and weakness may antedate by weeks or months the evolution of the more characteristic clinical manifestations of rheumatoid arthritis in patients with the adult type of juvenile rheumatoid arthritis the occurrence of an evanescent salmon-colored maculopapular rash, particularly on the trunk, may point toward the diagnosis. In other patients, involvement of the paranasal sinuses and mastoid or the rapid excavation of a pulmonary lesion suggests W egener's granulomatosis. Many other connective tissue diseases, ranging from classic vasculitides such as systemic lupus erythematosus to uncommon disorders such as relapsing polychondritis, can also present as FUO.

Granulomatous diseases Other than those granulomatous diseases caused by known infectious agents, granulomatous diseases that may be responsible for FUO include sarcoidosis, granulomatous hepatitis of unknown etiology, and starch peritonitis. The presence of noncaseating granulomas in lymph nodes or the liver is characteristic but not pathognomonic of sarcoidosis. There are about 40 diseases that may be associated with hepatic granulomas. Treatable infectious granulomatous diseases (e.g., tuberculosis, brucellosis, histo plasmosis, and cat-scratch disease) must be ruled out by cultures, skin tests, serologic tests, and special stains of biopsied tissues. In rare instances, despite extensive investigation and therapeutic trials with antituberculous drugs, an etiologic diagnosis cannot be made in patients with noncaseating hepatic granulomas who have a febrile illness of many months' duration. Whether such cases of granulomatous hepatitis of unknown origin represent a single entity or merely the hepatic response to a variety of agents is not clear. Beneficial results have been achieved in such cases by giving corticosteroids after excluding the other specific granulomatous diseases methotrexate also appears to be bene ficial. Corticosteroids have been beneficial for other patients with idiopathic granulomatosis and FUO.

Prolonged fever is uncommon in sarcoidosis, but when it does occur, prominent hilar adenopathy, ocular involvement, erythema nodosum, and hepatic granulomas are usually also present. Biopsy of involved lymph nodes, mus cle, or liver usually shows noncaseating granulomas. Such lesions are not specific for sarcoidosis, but the histologic diagnosis is reinforced if a zone of dense collagenized connective tissue is found to surround the granulomas.

Starch peritonitis represents a febrile granulomatous response to starch introduced on surgical gloves. The nature of the process may not be appreciated for weeks; the initial supposition is that a doughy abdominal mass and fever are caused by a postoperative abscess.

Inflammatory bowel disease Bowel symptoms are prominent in almost all patients with idiopathic ulcerative colitis, granulomatous colitis, or regional enteritis, and the diagnosis is obvious in such febrile patients. In an occasional patient, however, bowel symptoms may not be marked or may be of such long duration that they have become accepted as the norm. In this setting, FUO may be the presenting complaint in a patient with inflammatory bowel disease. The evaluation of any patient with an obscure fever must include detailed questioning regarding bowel function as well as an examination of the stool for mucus and occult blood.

Alcoholic hepatitis and cirrhosis Fever is observed occasionally in chronic liver disease. Attention should first be directed to possible complicating infections, such as enterogenous bacteremias, salmonellosis, or tuberculosis, or to an unrelated process. Active hepatocellular necrosis may occur in the course of alcoholic hepatitis and may account for low-grade fever. Occasionally, a patient shows a higher temperature than one might expect on the basis of the aspartate aminotransferase (AST) level. In such a situation, other causes of fever should be pursued, but often, alcoholic hepatitis ultimately proves to be the cause.

Pulmonary emboli Rarely, a patient may have multiple small pulmonary emboli but not exhibit any significant changes in arterial blood gases or on the chest film and will present primarily with a problem of unexplained fever. The fever may exceed 39. 0° C (102.2° F), but high-grade fevers caused by pulmonary emboli rarely persist longer than one week. The thrombi may be in symptomless calf veins or, more often, in pelvic veins in patients who have recently undergone pelvic surgery or in postpartum patients. Pelvic thrombophlebitis itself may be a source of protracted fever, even in the absence of pulmonary emboli.

Drug fever Drug fever frequently occurs in the absence of other manifestations of hypersensitivity, such as rash and eosinophilia. Antimicrobial agents (e.g., b-lactams, sulfonamides, nitrofurantoin, or isoniazid), antihypertensives (e.g., hydralazine or methyldopa), anticonvulsants (e.g., phenytoin), and allopurinol are among the most common offenders, but many other drugs have been implicated in isolated cases. In most instances, the diagnosis of drug fever is considered within the first several weeks of onset of FUO, and any recently administered drugs are discontinued. Several drugs, however, such as phenytoin, methyldopa, and isoniazid, may not produce drug fever until weeks or months after their initial use. Drugs such as these may be overlooked just because they have been administered for some time without producing side effects.

Intramuscular injections of analgesics can produce FUO, which may or may not be accompanied by the presence of a sterile abscess or other gross evidence of tissue injury.

Factitious fever Rarely, a patient may simulate illness by deliberately producing false elevations in temperature. Factitious fever is one of the most challenging etiologic categories of FUO. The patients are usually female and are often paramedical personnel. The underlying problem may be malingering or a more complicated emotional disorder. Discordance between the marked temperature elevations and the pulse rate, distortion of the usual diurnal temperature curve, and absence of diaphoresis when the fever abates suggest the diagnosis. Some patients generate a factitious fever by applying friction to the tip of the thermometer within the mouth or anal canal; others enter the hospital with their own thermometers, which are then preheated and given to the attendant at the appropriate time. Comparison of the serial number of the thermometer that is given with that of the one reclaimed from the patient may substantiate suspicion. Measurement of simultaneous rectal and urinary temperatures may distinguish between true and factitious fevers.

Miscellaneous causes The diagnosis of familial Mediterranean fever is suggested by ethnic background, episodic occurrence of fever in association with abdom inal pain or other signs of polyserositis, and well-being between attacks . The diagnosis of familial Mediterranean fever can be difficult when fever is its only symptom or when it occurs in individuals who are not of Mediterranean ancestry. New insights into the genetics and pathogenesis of this disorder may eventually aid in making the diagnosis. Until such data are available, the diagnosis is based on clinical findings and is facilitated by the observation that maintenance therapy with colchicine frequently succeeds in preventing attacks.

Whipple's disease is a multisystem infection caused by a gram-positive actinomycete that has been tentatively named Tropheryma whippelii. It may present as a prolonged febrile illness with weight loss, arthralgias, and weakness. Malabsorption is usually present but may not be a prominent feature in some patients. Anergy during the active phase of the disease and the finding of noncaseating granulomas in lymph nodes may erroneously suggest a diagnosis of sarcoidosis. Periodic acid-Schiff (PAS) stains of biopsy material may reveal characteristic PAS-positive macrophages; electron microscopy may reveal bacilliform bodies even when PAS stains are negative. A polymerase chain reaction test for the causative organism has been developed.

Rarely, inflammatory pseudotumor of intra-abdominal lymph nodes may present as FUO. The clinical features of this disorder may resemble those of Whipple's disease, but the pathological findings are distinctive and surgical excision of the involved nodes may induce prolonged remissions.

Rarely, endocrinologic abnormalities, such as subacute thyroiditis, or metabolic disorders, such as hypertriglyceridemia, hypercholesterolemia, or glycosphingolipid storage disease (Fabry's disease), present as FUO.

Unusual infections such as visceral leishmaniasis (kala-azar) or trypanosomiasis, acquired in endemic areas abroad, are responsible for a few cases of persisting FUO seen in the United States.

Central nervous system lesions are decidedly uncommon causes of FUO, except in very obtunded patients with extensive brain damage. However, a small number of conscious patients with primary disorders of thermoregulation and recurring episodes of unexplained fever have been reported. These patients cannot maintain body temperature in the cold; thus, they respond to a reduction in environmental temperature as if they were poikilotherms.

Fever is extremely common in patients infected with HIV typically, the diagnostic challenge is not in determining the source of fever but in deciding which of several potentially pyrogenic processes is most important. However, patients infected with HIV can also present with prolonged, diagnostically obscure fevers. Most often, such patients have advanced AIDS. Infections account for 82 percent of FUO cases in such patients, with mycobacterial infections responsible for more than half of all cases of FUO. Blood cultures are often diagnostic; although more invasive, bone marrow or liver biopsy may provide more rapid diagnosis by allowing direct visualization of organisms.

Although different types of fever have been described, usually neither the degree of elevation of the temperature nor the pattern of fever permits discrimination among the causes of FUO. Many patterns are altered by the use of antipyretics. A sustained fever is one in which the temperature is consistently elevated and the usual diurnal variation is absent; this pattern is seen in untreated typhoid fever and in some cases of miliary tuberculosis. The use of salicylates, however, can convert such fevers to a remittent pattern with two or more daily peaks. An intermittent fever is one in which the daily fluctuations are wide but the morning temperatures are usually normal. Such a pattern is commonly observed with abscesses and other pyogenic infections. Pel-Ebstein fever, occasionally observed in patients with Hodgkin's disease, may be sufficiently distinctive in its periodicity (five to 10 days of fever alternating with similar periods without fever) to suggest the diagnosis. The characteristic periodicities of relapsing fever, malaria, and familial Mediterranean fever will suggest the diagnosis of these entities.

Detailed review of the history is essential, particularly regarding travel, animal exposure, occupational risks, and other epidemiological factors; previous trauma or surgery; or features relevant to each of the diagnoses outlined. When physical findings are being evaluated, particular attention should be paid to structures that may be inapparent sources of obscure fever, such as the cardiovascular system, abdominal viscera, and genitourinary tract. Lymph nodes should be examined not only in the usual distribution but also in the epitrochlear areas and along the medial aspect of the upper arm. Search of the skin, nail beds, and mucous membranes for petechiae and vasculitic lesions may provide important clues to the diagnosis of endocarditis or of collagen vascular diseases. Funduscopic examination may reveal choroidal tubercles or signs of vasculitis or endocarditis. Rectal examination is particularly important in the elderly or obtunded patient, in whom a perirectal or prostatic abscess may be overlooked. The testes should be carefully palpated for tumor or for evidence of epididymitis, which may indicate tuberculosis, brucellosis, or collagen vascular disease.

Blood cultures Blood cultures should include aerobic (five to 10 percent CO₂ tension) and anaerobic cultures that have been incubated for at least two weeks. Newer blood culture techniques, including the use of lysis centrifugation and the BACTEC radiometric mycobacterial culture system, may be helpful in some patients.

Serologic tests Serologic tests employed in cases of FUO include Brucella agglutination, Salmonella agglutination (usually not very helpful), antistreptolysin-O (ASO) titer if acute rheumatic fever is suspected, Venereal Disease Research Laboratories (VDRL) test for syphilis, sero logic tests for less common infections (e.g., psittacosis, toxoplasmosis, and cytomegalovirus), the test for rheumatoid factor, antinuclear antibody test, and the test for the lupus erythematosus cell. A serum specimen obtained during an acute-phase host response can be frozen for subsequent comparison with a late or conva lescent-phase specimen to look for rising titers to specific pathogens. HIV testing should be performed to evaluate host factors that may predispose to FUO.

Sedimentation rate A sedimentation rate greater than 100 mm/hr suggests vasculitis but does not differentiate between this disorder and neoplasms, tuberculosis, or pyogenic infections.

Serum enzymes and chemistries The results of liver function tests may indicate primary involvement (e.g., caused by hepatitis or a liver abscess) or secondary infiltration (e.g., miliary tuberculosis) of the liver. Measurement of the serum alkaline phosphatase level is particularly helpful in the diagnosis of secondary hepatic infiltration.

Skin tests Skin testing may aid in diagnosis if positive results are obtained (e.g., a positive tuberculin test would suggest tuberculosis) or if anergy, a characteristic finding in sarcoidosis, Whipple's disease, and Hodgkin's disease, is demonstrated.

Spinal fluid examination Examination of the spinal fluid is usually unrewarding unless the patient has CNS signs or symptoms, such as headache or stiff neck.

Various radiologic studies in addition to chest films may assist in making the diagnosis:

1. Ultrasonography and CT scans have become very valuable for detecting intra-abdominal and pelvic abscesses and retroperitoneal adenopathy. The use of CT scans has decreased the number of biopsies of normal tissues in patients studied for FUO. The use of magnetic resonance imaging in patients with FUO is under investigation.

2. Radionuclide bone scans are considerably more sensitive than bone x-rays in the detection of osseous metastases or foci of osteomyelitis. Liver-spleen scans can help define hepatic metastases. Gallium scans are occasionally useful in detecting occult abscesses, but this technique has had mixed results in patients with fever of undetermined origin scans utilizing indium-111-labeled leukocytes are being investigated, as are scans employing indium-111-labeled human immunoglobulin G and technetium-99m-labeled ciprofloxacin.

3. Intravenous pyelograms may indicate intrarenal or perirenal abscesses or renal tumors. Some parenchymal lesions can be demonstrated only with the use of a renal angiogram.

4. Upper and lower gastrointestinal tract x-rays may indicate regional enteritis, ulcerative colitis, or large-bowel neoplasms.

5. Lymphangiograms may be helpful in suggesting retroperitoneal lymphoma; however, significant morbidity is associated with this procedure in some patients. Definitive histologic diagnosis of lymphoma will still require laparotomy.

7. Other radiographic examinations, such as cholangiograms, aortograms, and celiac angiograms, may also be useful but should only be performed on the basis of clinical clues that suggest specific diagnoses.

All biopsied material should be cultured for bacteria, mycobacteria, and fungi and examined histologically. Biopsies that may help determine the diagnosis in pa tients with FUO include the following:

1. Percutaneous liver biopsy. Neoplastic or granulomatous diseases can generally be detected more easily by percutaneous liver biopsy than by bone marrow biopsy, particularly if hepatomegaly, abnormalities of hepatic function, or both are present.

2. Bone marrow biopsy. This technique may also be used to detect granulomatous diseases or metastatic tumor; it may be rewarding in patients in whom hematologic abnormalities are evident.

3. Lymph node biopsy. Enlarged, matted, or unusually situated nodes are the most favorable for biopsy. Because of the frequent occurrence of chronic inflammation in inguinal lymph nodes, biopsy of these nodes is unsatisfactory.

4. Skin and muscle biopsy. Biopsy of skin and muscle may prove useful in diagnosing collagen vascular disease (e.g., polyarteritis or dermatomyositis); biopsy may also be useful in sarcoidosis.

5. Temporal artery biopsy. Biopsy of the temporal artery may be the only way to establish the diagnosis of giant cell arteritis in an elderly patient who has FUO, an elevated sedimentation rate, and some thickening of the temporal artery.

Therapeutic trials have generally proved more misleading than helpful when applied to the patient with prolonged FUO. Coincidental temporary defervescence can suggest a specific therapeutic response, thus delaying measures that may provide the correct diagnosis. Occasionally, a therapeutic trial may be reasonable when directed at a specific diagnosis. Thus, a one- to two-week trial of a penicillin or vancomycin and an aminoglycoside may be employed when endocarditis is a realistic possibility; aspirin may be tried in patients who may have adult-type juvenile rheumatoid arthritis; and isoniazid and rifampin may be tried in cases in which miliary tuberculosis is definitely a possibility. Patients with disseminated tuberculosis presenting as FUO often show a clinical response within two weeks after appropriate chemotherapy.

On occasion, laparotomy has been advocated and employed successfully to provide the diagnosis of FUO. Newer, noninvasive radiologic techniques, especially when combined with percutaneous needle biopsies (see above), have generally supplanted laparotomy for the diagnosis of FUO. Early abdominal exploration in the absence of clinical or laboratory clues pointing to the abdomen is usually unrewarding. Laparotomy should be reserved for those patients in whom the clinical and laboratory findings point to an intra-abdominal or retro peritoneal source for the fever, particularly when the fever has followed a prolonged and debilitating course.

In a few patients with FUO, no helpful clues are found during the workup and the disease process is not very prolonged, is not progressive, and is not associated with marked weight loss. In these patients, the wisest course may be to pause temporarily. Reevaluation of the patient some weeks, or even months, later may provide the diagnosis.

Five to 10 percent of patients with FUO seem to recover in the absence of a diagnosis of the specific fever source; therefore, fevers that abate after several months do not necessarily recur and do not always indicate a serious underlying process such as neoplasm or collagen vascular disease.