ACP medicine, 3rd Edition

Infectious Disease

Hyperthermia, Fever, and Fever of Undetermined Origin

Harvey B. Simon MD, FACP1

Associate Professor of Medicine

1Harvard Medical School, Health Sciences and Technology Faculty, Massachusetts Institute of Technology; Physician, Massachusetts General Hospital

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

March 2006

Thermoregulation and Abnormal Elevation of Body Temperature

REGULATION OF BODY TEMPERATURE

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 mistakenly regarded as the normal value of 37.0° C (98.6° F) are often recorded in perfectly healthy individuals.1 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 pathologic.

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.2 Heat is a by-product of all metabolic processes. At rest, metabolic activity in the liver and heart produces much of the body's heat; 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% of heat loss, with the lungs contributing most of the remaining 10%. In the basal state, about 70% of the body's thermal load is dissipated by conduction; 30% is removed by the evaporation of insensible perspiration. Radiation and convection are less important mechanisms of heat removal. When the ambient temperature rises or 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.3 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.

MEASUREMENT OF BODY TEMPERATURE

Body temperature can be measured in several ways. In most clinical circumstances, rectal temperature is an accurate reflection of central (core) temperature. Sublingual (oral) temperature measurements are also useful; they are typically 0.4° C (0.7° F) lower than rectal temperatures4 and are subject to more technical variation, especially when patients are unable to fully cooperate. Tympanic membrane temperatures are typically 0.4° C (0.7° F) below sublingual readings and have even greater variability.4,5 Axillary temperature measurements are unreliable6 but are often used in acutely ill patients.

HYPERTHERMIA AND FEVER

Abnormal elevation of body temperature, or pyrexia, can occur in one of two ways: hyperthermia7 or fever [see Figure 1]. 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 temperature 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 drugs that lower the thermal set point, such as aspirin, other cyclooxygenase inhibitors,8 or acetaminophen.

 

Figure 1. Mechanisms of hyperthermia vs. fever

Body temperature can rise to abnormal levels in one of two ways: hyperthermia or fever. In hyperthermia, thermal control mechanisms fail. In fever, by contrast, the hypothalamic thermal set point rises.

Hyperthermia

Hyperthermia is caused by the failure of thermoregulation; the pyrexia associated with it can be mild or severe. The most important causes of severe hyperthermia are heatstroke, neuroleptic syndrome, and malignant hyperthermia of anesthesia.

ETIOLOGY

Numerous clinical disorders can disrupt thermoregulatory homeostasis by causing increased heat production, decreased heat dissipation, or hypothalamic insult, thereby inducing hyperthermia [see Table 1]. 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. The hyperthermia of dehydration is usually mild and is readily corrected by fluid replacement. In some cases, however, thermoregulatory disorders cause extreme pyrexia, in which body temperatures rise to 41.1° C (106.0° F) or higher9; examples of these thermoregulatory disorders are heatstroke, malignant hyperthermia of anesthesia, thyroid storm, and hypothalamic insult caused by infection, tumor, or drugs [see 8:I Management of Poisoning and Drug Overdose].

Table 1 Causes of Hyperthermia

Cause

Example

Excessive heat production

Delirium tremens

Drug abuse (cocaine or amphetamines)

Exertional hyperthermia

Generalized tetanus

Heatstroke (exertional)*

Lethal catatonia

Malignant hyperthermia of anesthesia

Neuroleptic malignant syndrome*

Pheochromocytoma

Salicylate intoxication

Serotonin syndrome

Status epilepticus

Thyrotoxicosis

Diminished heat dissipation

Anticholinergic drugs

Autonomic dysfunction

Dehydration

Heatstroke (classic)*

Neuroleptic malignant syndrome*

Occlusive dressings

Drug abuse (cocaine)

Hypothalamic dysfunction

Cerebrovascular accidents

Encephalitis

Idiopathic hypothalamic dysfunction

Neuroleptic malignant syndrome*

Sarcoidosis and granulomatous infections

Trauma

Tumors

*Pathogenesis of these disorders is mixed.

Numerous exogenous agents, including cocaine10 and amphetamine, may cause severe hyperthermia. Because salicylates uncouple oxidative phosphorylation in skeletal muscle, excessive heat production is probably responsible for the hyperthermia seen in some children with severe aspirin toxicity.

The hyperthermia that may accompany thyroid storm and pheochromocytoma crisis also results from increased heat production, triggered in these cases by the calorigenic properties of thyroid hormones11 and catecholamines.12 Anticholinergic drugs may impair heat dissipation by reducing sweat production.

Hypothalamic disorders are uncommon causes of hyperthermia. Cerebrovascular accidents, however, may be responsible for sustained hyperthermia; this so-called central fever is easily confused with true fever caused by infection or drug hypersensitivity in patients who are hospitalized for major cerebrovascular accidents.

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.9

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 occur in patients with endocrinologic12 or hypothalamic disorders who present as diagnostic puzzles in the category of fever of undetermined origin (FUO) [see Fever of Undetermined Origin, below].

HEATSTROKE

Heatstroke is a life-threatening emergency characterized by a body temperature of 40° C (104° F) or higher and neurologic dysfunction that may include delirium, seizures, or coma.13 Heatstroke occurs in warm, humid conditions: the high ambient temperature impairs heat loss by conduction, and the high ambient humidity limits heat dissipation by the evaporation of sweat. Sustained daily elevations in ambient temperature increase risk.14 In one form of the syndrome, exertional heatstroke, exercise imposes the additional thermal burden of increased heat production.15 In classic heatstroke, which is more common than the exertional form, increased heat production does not occur, but heat dissipation is often impaired as a result of a failure of sweating (anhidrosis), as well as of more subtle thermoregulatory problems imposed by underlying diseases and the medications used to treat them.

Epidemiology

Heatstroke is far from rare. Between 1979 and 2002, more than 4,780 deaths in the United States were attributed to excessive heat exposure16; it seems likely that many cases of heatstroke go unrecognized or unreported and that hyperthermia also contributes to the morbidity and mortality attributed to underlying diseases.17

Classic heatstroke is the most common hyperthermic emergency.7 Occurring principally during summer heat waves, classic heatstroke is most likely to affect the elderly and patients with serious underlying diseases. The urban poor are particularly vulnerable to classic heatstroke. Women are affected more often than men, and infants are also at risk.

Whereas classic heatstroke occurs in outbreaks, exertional heatstroke occurs sporadically and typically affects young, healthy individuals who engage in strenuous exercise. Exertional heatstroke is much more common in men than in women. In the United States, military recruits, industrial workers, and athletes such as runners and football players are at greatest risk; in Saudi Arabia, both forms of heatstroke are particularly common during the annual hajj, the pilgrimage to Mecca.

Prevention

Hot, humid conditions are predisposing factors for both classic and exertional heatstroke. In addition to ambient weather conditions and muscular exertion, predisposing factors for exertional heatstroke include inappropriately heavy clothing, exposure to direct sunlight, dehydration,18 lack of cardiovascular conditioning, lack of acclimatization to heat, and the use of performance-enhancing supplements such as Ma-huang (ephedrine) and creatine.19 Because all of these factors can be anticipated and corrected, exertional heatstroke is preventable.

Classic heatstroke can be prevented16 by publicizing community heat-wave alerts; providing cool environments for people at risk; encouraging the use of fans if air conditioners are not available; instructing those at risk to limit physical activity and sun exposure indoors and outdoors, to avoid cooking, to wear lightweight clothing, and to maintain adequate hydration; and promoting judicious use of diuretics, tranquilizers, antidepressants, and anticholinergic medications.

Pathophysiology

The crucial pathophysiologic events causing classic heatstroke are excessive ambient heat and humidity and impaired heat dissipation caused by anhidrosis. The typical victim of classic heatstroke is an elderly or debilitated person who is confined to a poorly ventilated room without benefit of an air conditioner or fan during a summer heat wave. Dehydration, which limits heat dissipation, is an important predisposing condition. Other factors that increase risk include neurologic and cardiovascular diseases, obesity, the use of diuretics, and the use of neuroleptics and other medications with anticholinergic properties; alcohol consumption also contributes to some cases.

The second form of heatstroke is triggered by exercising in a warm, humid environment. The major pathophysiologic mechanism responsible for exertional heatstroke is increased heat production from exercising skeletal muscles. Working at maximal intensity, muscle can increase its energy consumption to levels 20 times its basal rate; because the body's efficiency is only about 25%, much of this energy is converted into heat, which is transferred from muscle to blood, raising the core temperature. Patients who suffer exertional heatstroke do not appear to have intrinsic abnormalities of their thermoregulatory mechanisms, but they may have a high proportion of type II skeletal muscle fibers and lower work efficiency.20

Diagnosis

Early diagnosis is critical to prevent life-threatening complications. People who experience weakness or undue fatigue, lack of concentration or confusion, light-headedness or dizziness, headaches, nausea, or muscle cramps in the heat should cease exercise, get to a cool environment, and drink cool fluids to avert more serious heat injury. They should also be sure that medical help is available if symptoms progress.

Clinical features

Despite differences in pathophysiology and epidemiology, the major manifestations of the classic and exertional heatstroke syndromes are similar. An abrupt rise in body temperature is universal; most patients with heatstroke have core temperatures in excess of 40.5° C (105° F). Disordered mentation is no less common and may span a spectrum ranging from confusion and lethargy to delirium, stupor, coma, and seizures. Virtually all patients with heatstroke also exhibit cardiovascular abnormalities. Tachycardia is present in most patients, and hypotension is present in many; shock, arrhythmias, myocardial ischemia, and pulmonary edema are most likely to occur early in elderly or debilitated patients with classic heatstroke but are also frequent preterminal events in patients with exertional heatstroke. Most heatstroke victims present with hyperventilation and respiratory alkalosis; pulmonary abnormalities may also include pulmonary edema, acute respiratory distress syndrome, and aspiration pneumonia. Other common clinical manifestations of heatstroke include oliguria, vomiting, and diarrhea; hematuria and gastrointestinal bleeding may reflect disseminated intravascular coagulation (DIC). Cutaneous manifestations of heatstroke may include hemorrhagic lesions; the skin is hot and dry in many patients with classic heatstroke but is often moist and clammy in patients with exertional heatstroke.

Laboratory findings

Laboratory abnormalities in patients with heatstroke reflect widespread damage to a number of organ systems. Leukocytosis is common, and hemoconcentration may raise the hematocrit in patients who are volume depleted. Thrombocytopenia is frequently present and may be severe; prolonged prothrombin times, depressed fibrinogen levels, and elevated levels of fibrin split products indicate DIC, which is more common in exertional heatstroke than in classic heatstroke. DIC in heatstroke has been attributed to direct thermal injury to vascular endothelium; clinically significant bleeding may result from the coagulopathy, which can persist for 36 hours after the onset of heatstroke.

Renal abnormalities are common in heatstroke. The urine may sometimes be dilute despite hypotension and oliguria; hematuria, myoglobinuria, proteinuria, and casts are frequently observed. The blood urea nitrogen (BUN) and creatinine levels are usually elevated; acute renal failure occurs in about one third of patients with exertional heatstroke but is less common in patients with classic heatstroke.

Elevated bilirubin levels in patients with heatstroke may reflect hepatic injury, hemolysis, or both. Elevated transaminase levels are the rule, reflecting damage to both liver and muscle cells. Elevated creatine phosphokinase (CPK) and aldolase levels indicate muscle injury; severe rhabdomyolysis with myoglobinuria and renal failure is much more common in exertional than in classic heatstroke.

Heatstroke causes numerous metabolic abnormalities. Respiratory alkalosis is common early in the syndrome, particularly in classic heatstroke; lactic acidosis may supervene, particularly in exertional heatstroke. Potassium levels are variable, sometimes being low early and high later in the course of heatstroke. Hypophosphatemia is the rule; hypokalemia may occur, particularly in exertional heatstroke. Hypoglycemia, perhaps reflecting depletion of glycogen stores, has been reported in many patients with exertional heatstroke. Electrocardiographic abnormalities include conduction disturbances and ST-T segment changes. Elevated levels of pyrogenic cytokines have been reported in heatstroke patients,21 but it is unclear whether the cytokines participate in the pathogenesis of heatstroke or simply reflect a subsequent host response to tissue injury.13

Differential Diagnosis

The differential diagnosis of elevated body temperature with numerous clinical and laboratory abnormalities is broad and includes sepsis, the systemic inflammatory response syndrome, and the other causes of hyperthermia. In practical terms, the major challenge is to distinguish classic heatstroke from sepsis and to distinguish exertional heatstroke from less severe exercise-induced abnormalities, such as exertional hyperthermia and heat exhaustion.15

Treatment

Heatstroke necessitates prompt and aggressive therapy. Lowering body temperature is the crucial element in management; because the pathogenesis of heatstroke involves thermoregulatory failure rather than an elevated hypothalamic set point, physical cooling is essential, but antipyretic medications are ineffective.

Field management includes removing the patient's clothing, fanning the patient, and bathing the patient's skin with cool water; ice packs should be applied if they are available. First-aid measures to maintain the patient's airway and prevent injury are important. The patient should be protected from sunlight and should be moved to a cool environment and evacuated to an emergency ward as soon as possible. Hypothermic mattresses or, in urgent circumstances, ice-water immersion may be employed. These treatments are very uncomfortable and should be used only when the hyperthermia is truly deleterious. Cool intravenous fluids should be administered as soon as parenteral therapy becomes available, but oral hydration is inadvisable because of the risk of aspiration.

Physical cooling must continue after the patient arrives in the emergency ward; many techniques are available, but choosing among them is difficult. Immersion in ice water has been a standard approach. Another traditional technique is the application of ice packs to the body surface. Both techniques have the disadvantage of producing cutaneous vasoconstriction, which could impede the transfer of heat from the body's surface; ice-water baths may also pose logistic difficulties in heatstroke patients who are combative and in those with seizures, vomiting, or diarrhea. Despite these drawbacks, ice-water baths are effective; there were no fatalities in a series of 252 marine recruits whose therapy for exertional heatstroke included ice-water immersion.22 A newer technique for cooling relies on evaporation rather than conduction to dissipate heat: the patient is sprayed with water at a temperature of 15° C; then warm air at a temperature of 30° to 35° C is blown on the patient. A special body-cooling unit that facilitates evaporative cooling has been used with good results in Saudi Arabia.23Although alcohol is more volatile than water, it should not be used for evaporative cooling because of the risk of alcohol intoxication, especially in children. Many other cooling techniques, ranging from ice-water enemas and gastric lavage to the use of the downdraft from helicopter blades, have been used to treat heatstroke but are of secondary importance. In general, hospitals in the United States should choose a cooling technique on the basis of their experience and facilities.

Body temperature should be monitored continuously during cooling; in most cases, body temperature will decline significantly in 10 to 40 minutes, at which time cooling should be reduced to avoid hypothermic overshoot with associated shivering and rigors.

The administration of room-temperature intravenous fluids is an important aspect of therapy, helping to lower core temperature and to correct dehydration; meticulous cardiovascular monitoring is essential to prevent fluid overload while ensuring adequate volume replacement. In addition to needing cardiovascular support, patients with heatstroke require careful respiratory monitoring and support, along with fluid and electrolyte monitoring and therapy. Complications such as rhabdomyolysis, renal failure, aspiration pneumonia, DIC, and seizures necessitate additional therapeutic interventions. Despite its efficacy in malignant hyperthermia of anesthesia (see below), dantrolene sodium is ineffective in heatstroke.21

Even with aggressive therapy, heatstroke has an appreciable mortality. Most patients who recover have normal thermoregulatory mechanisms and heat tolerance, but all should be instructed on ways to reduce the risk of recurrences.

NEUROLEPTIC MALIGNANT SYNDROME

Etiology

First described in 1960, the neuroleptic malignant syndrome (NMS) is uncommon, occurring in fewer than 1% of patients receiving neuroleptic agents [see 8:I Management of Poisoning and Drug Overdose and 13:VIII Anxiety Disorders]. NMS usually occurs within the first 30 days of therapy; haloperidol is most often implicated, but other butyrophenones (e.g., droperidol), various phenothiazines, thioxanthenes, atypical antipsychotics (e.g., resperidone and clozapine), tricyclic antidepressants, and mon o a mine oxidase (MAO) inhibitors may also be responsible.24,25,26 Non psychiatric drugs such as metoclopramide have occasionally been linked to NMS.25 NMS may also be precipitated by the withdrawal of amantadine, levodopa, or other dopaminergic drugs used to treat Parkinson disease.27 In some cases, dehydration and agitation are contributing factors.

Pathophysiology

NMS is primarily a disorder of excessive heat production. It is probably precipitated by the blockade of dopaminergic receptors in the nigrostriatal tracts, leading to uncontrolled contractions of skeletal muscle, which, in turn, produce excessive body heat. There is no genetic predisposition for NMS, nor does it occur as a result of a drug overdose. Physical exhaustion, dehydration, and underlying organic brain syndromes have been cited as predisposing factors. Some patients who have recovered from NMS have subsequently received neuroleptic agents without suffering recurrences of NMS, but recurrent NMS does develop in 30% of patients who are rechallenged with neuroleptics.

Diagnosis

The clinical features of NMS evolve progressively, usually over a period of 1 to 3 days. Hyperthermia is universal. Other symptoms include bradykinesia, severe muscular rigidity (some times described as lead-pipe rigidity); altered sensorium; autonomic dysfunction that produces tachycardia, labile blood pressure, and diaphoresis; and extrapyramidal abnormalities. Laboratory abnormalities include hypernatremia and other electrolyte abnormalities, acidosis, hemoconcentration and leukocytosis, rhabdomyolysis, and abnormal findings on renal and hepatic function tests.

Differential Diagnosis

The differential diagnosis of NMS includes infections, lethal catatonia,28 an uncommon psychiatric disorder in which agitation progresses to muscular rigidity and hyperthermia, and the serotonin syndrome (see below).

Treatment

The offending neuroleptic agent must be withdrawn in all cases of NMS. Physical cooling as treatment of NMS has not been evaluated in clinical trials but should prove useful in the acute phase of the disorder. Meticulous fluid and electrolyte therapy and careful cardiovascular support are mandatory. Dan trolene sodium, a muscle relaxant, and bromocriptine, a dopa mine agonist, have each been reported to reduce the duration of hyperthermia, but these agents have not been evaluated in controlled trials.29 Aggressive therapy has allowed the mortality associated with NMS to decline to about 10%; patients who recover face a 30% risk of recurrence.25

SEROTONIN SYNDROME

The serotonin syndrome30 has become more prevalent with the increasing use of selective serotonin reuptake inhibitors (SSRIs) and other serotoninergic agents. Because of its broad range of clinical manifestations and the large number of prescription, over-the-counter, and herbal products that have been implicated, the serotonin syndrome is often unrecognized. The actual prevalence is not known, but it occurs in 14% to 16% of patients who take overdoses of SSRIs. The syndrome results from excessive agonism of serotoninergic receptors in the central and peripheral nervous systems.

Diagnosis

The syndrome begins abruptly within 5 weeks of using serotoninergic agents, either singly or in combination. In mild cases, patients exhibit hyperkinesia, intermittent tremors, hyperreflexia and clonus, hyperactive bowel sounds, diarrhea, mydriasis, and tachycardia. Patients with mild cases of the syndrome may exhibit shivering and diaphoresis, but body temperature is normal. In moderate to severe cases, however, hyperthermia is the rule and may be severe. Muscular rigidity, agitation, and ocular clonus or inducible clonus are characteristic features of the severe serotonin syndrome.

Differential Diagnosis

The differential diagnosis includes infection, anticholinergic poisoning, which can be distinguished on the basis of its normal reflexes and absent bowel sounds, and malignant hyperthermia of anesthesia (see below). NMS is the major mimic of the serotonin syndrome, but the symptoms of NMS evolve more slowly, and patients typically display bradykinesia or akinesia and so-called lead-pipe muscular rigidity rather than hyperkinesia, tremors, hyperreflexia, and clonus.

Treatment

Management of the serotonin syndrome requires removal of the responsible drug or drugs and metabolic and hemodynamic support. In mild cases, agitation and tremors can often be controlled with benzodiazepines; however, severely ill patients require sedation, neuromuscular paralysis, and ventilator support. Antipyretics, beta blockers, bromocriptine, and dantrolene are not effective. Cyproheptadine, olanzapine, and chlorpromazine have been useful in isolated cases but have not been studied fully.30

MALIGNANT HYPERTHERMIA OF ANESTHESIA

Like NMS, malignant hyperthermia of anesthesia (MHA) is a high-mortality disorder of involuntary skeletal muscle hyperactivity and excessive heat production triggered by a pharmacologic agent. Unlike NMS and the serotonin syndrome, however, MHA is a genetically determined disorder precipitated by anesthetic agents such as halogenated inhalation agents and depolarizing muscle relaxants. Mutations in the gene encoding the skeletal muscle ryanodine receptor type I (RYRI) are often responsible for the disorder.30 Persons who are susceptible to MHA may be identified by a family history of the disorder and by performance of a muscle biopsy and a caffeine-halothane contracture test; mutation analysis and other noninvasive tests to identify susceptible individuals are being developed.31

Diagnosis

MHA usually begins shortly after the anesthetic is administered, but it may be delayed for hours. Muscular rigidity and severe hyperthermia are typical; other findings include tachycardia, hypotension, arrhythmias, hyperpnea, hypoxia, hypercapnia, hyperkalemia, lactic acidosis, rhabdomyolysis, and DIC.

Treatment

MHA is an anesthetic emergency. Early detection of hypercapnia during general anesthesia and prompt treatment using intravenously administered dantrolene sodium have markedly improved the prognosis of patients with MHA. Discontinuance of anesthesia is mandatory; physical cooling is therapeutically important, as are cardiopulmonary support and correction of the metabolic abnormalities.

Fever

Fever has been recognized as a cardinal feature of disease since antiquity, but only recently has the pathophysiology of fever come to be understood. Beginning with the work of Dr. Paul Beeson in 1948, it became 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—cytokines—can mediate the febrile response.32,33 Cytokines are also important as mediators of the acute-phase response to infection and inflammation.

PATHOPHYSIOLOGY

The cytokines interleukin-1 (IL-1), IL-6, interferon gamma, and tumor necrosis factor (TNF) function as pyrogens by acting directly on the hypothalamus to elevate the thermal set point. A variety of stimuli, such as microorganisms, exposure to endotoxin and other bacterial toxins or microbial products, phagocytosis, antigen-antibody immune complexes, and various forms of tissue injury, can initiate IL-1 production by mononuclear phagocytes and many other cells. 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 CNS, where it acts directly on the hypothalamic thermal control center. 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 accounts for why prostaglandin inhibitors such as aspirin are effective antipyretic agents.8

Although this classic model of pathogenesis has been validated by numerous studies of fever, further research suggests that several additional pathways may be involved. For example, pyrogenic cytokines may be produced locally in the CNS as well as systemically,34 and cytokines may signal the thermal control center by neural as well as hormonal mechanisms.35

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 conversion 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.

CONSEQUENCES OF ELEVATED BODY TEMPERATURE

Possible Benefits of Fever

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, insights into the immunostimulatory properties of IL-1 and TNF have led to speculation that fever itself may promote recovery from infection.36 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.

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 excellent 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.

Extreme pyrexia may be surprisingly well tolerated. It seems likely that the widespread tissue damage, multiple laboratory abnormalities, and high mortality observed in disorders such as heatstroke, MHA, thyroid storm, the serotonin syndrome, and NMS 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.

Therapeutic hyperthermia is being used to treat noninfectious diseases. Regional hyperthermia is a traditional therapy for many musculoskeletal disorders. 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 alone; superficial tumors respond most favorably, but better responses may be obtained with internal malignancies as techniques for deep heating are improved.

Complications of Fever

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 the very old. Because pyrexia increases oxygen consumption, it imposes circulatory demands that may precipitate ischemia, arrhythmias, or congestive heart failure in patients with cardiovascular disease. Fever during pregnancy does not appear to cause fetal death,37 but during the first trimester, fever may increase the risk of congenital heart disease.38 Febrile seizures are a risk in children between 6 months and 6 years of age. The patient's age and the degree of fever are the major risk factors; genetics may also influence vulnerability.39 Although febrile convulsions are generally benign, they are alarming, and it is always necessary to exclude underlying neurologic illnesses, including meningitis.40 Both intravenous diazepam and intranasal midazolam are effective in controlling febrile convulsions.41 In the absence of unprovoked seizures, long-term anticonvulsant therapy is usually unnecessary in children with febrile seizures and may even be deleterious; diazepam, administered orally only when fever occurs, safely and effectively reduces the risk of recurrent febrile seizures.42 The long-term prognosis is excellent.43

Febrile seizures do not occur in adults, but fever often results in decreased concentration and sleepiness; high temperatures commonly produce an altered sensorium, including stupor and delirium. Patients with strokes are at risk for additional brain injury from fever; the result is a marked increase in morbidity and mortality,44 especially when the pyrexia occurs soon after the stroke.45 Because of this, even modest elevations in temperature should be suppressed in patients with acute strokes.46 In addition, moderate induced hypothermia may improve the outcome of strokes, even in patients who are afebrile on presentation.47 Hypothermia may also improve outcome after traumatic brain injury48 in neonates with hypoxic-ischemic encephalopathy,49 and in patients receiving cardiopulmonary resuscitation.50

DIAGNOSIS

The diagnostic process involves determining whether the patient is febrile, which requires (1) accurate measurements of body temperature and comparisons of body temperature with the diurnal range of normal body temperature and (2) a determination of whether the elevation in temperature is the result of inflammation or infection (fever) rather than thermoregulative failure (hyperthermia).

TREATMENT

The approach to the febrile patient involves three elements: diagnosis and management of the underlying disorder; cardiac, respiratory, and metabolic support; and, when indicated, lowering of body temperature. 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, coagulation parameters, muscle enzymes, and arterial blood gases should all be measured, and renal and liver function should be assessed. 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, and circulatory or respiratory support may be necessary.

Proper management of the elevated temperature itself depends on the clinical circumstances. Although clinicians usually choose to suppress fever, it is unclear whether elevated body temperatures promote or impede recovery from infection; similarly, the risks and benefits of antipyretic therapy have not yet been defined.8,51,52 Because many patients tolerate high body temperatures very well, antipyretic therapy may actually produce more discomfort than the pyrexia itself. In other patients, 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 patients with strokes, 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 MHA, heatstroke, NMS, the serotonin syndrome, or thyroid storm. Finally, it may be prudent to treat any patient whose temperature exceeds 40° C (104° F), even a healthy young adult.

The choice of cooling technique depends on the pathogenesis of the temperature elevation [see Figure 1]. 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 syndrome in children with influenza or varicella. A broad range of nonsteroidal anti-inflammatory drugs (NSAIDs) and other cyclooxygenase-2 (COX-2) inhibitors can also lower the set point.8,53 Acetaminophen may act by inhibiting COX-3, a COX-1 variant.54 If physical cooling methods are used before antipyretic drugs are fully effective, homeostatic mechanisms will continue to operate in an attempt to raise body temperature, resulting in intense vasoconstriction and shivering,55 which produce adverse cardiovascular and metabolic effects, as well as intense patient discomfort. To avoid these problems, febrile patients who require physical cooling to rapidly lower body temperature should be heavily sedated and ventilated to prevent shivering in conjunction with physical cooling.56 In contrast, physical cooling is the treatment of choice for patients with hyperthermia. In all patients, careful attention is required to prevent hypothermic overshoot on the one hand and recurrent fever on the other.57 Although pyrexia may be the most spectacular symptom, meticulous attention to the underlying disorder is of primary importance in all cases.

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,58 specified three criteria to define FUO:

  1. Duration: at least 3 weeks. This requirement eliminates from consideration most short-lived fevers of indeterminate or viral origin and most postoperative fevers.
  2. Magnitude: a temperature higher than 38.3° C (100.9° F) on at least several occasions. This criterion eliminates from consideration persons with unusually prominent circadian fluctuations in body temperature with daily readings on the order of 38.0° C (100.4° F). If such persons are not clinically ill, their elevated temperature should not cause too much concern.
  3. Obscure nature: perplexing enough to defy diagnosis after 1 week of study. In the past, inpatient study was required to evaluate FUO, but with changing admission practices, intelligent and thorough study encompassing at least three outpatient visits or 3 days in the hospital is now considered sufficient.59

ETIOLOGIC CLASSIFICATION

Although geographic factors are relevant, the leading causes of FUO are reasonably uniform throughout the United States. The relative frequency of the etiologic categories responsible for FUO have been relatively stable over the past 5 decades [see Table 2]. In a community hospital study,60 noninvasive testing provided the diagnosis in 42% of patients, with serologies and lysis centrifugation blood cultures being the most useful noninvasive techniques. Computed tomography-guided percutaneous biopsies were the most useful invasive procedures. Only 9% of patients remained undiagnosed. With an increasing population of immunosuppressed and chronically ill patients, the relative importance of the disorders that cause FUO may change. As a result, it may be prudent to consider so-called classic FUO separately from FUO in patients with HIV infection, neutropenia, or nosocomial fevers.59,61,62,63 Despite changes in host factors and diagnostic techniques, the basic categorization of the causes of FUO remains valid.

Table 2 Causes of Fever of Undetermined Origin Over 5 Decades

Cause

Study

New Haven, 196158 (% of 100 Patients)

Boston, 1973104 (% of 128 Patients)

Seattle, 1982105 (% of 105 Patients)

Rhode Island, 199260 (% of 89 Patients)

Leuven, Belgium, 2003106 (% of 290 Patients*)

Infections

36

35

30

33

20

Neoplasms

19

23

31

24

20

Collagen vascular diseases

13

16

9

16

19

Other specific causes

25

18

18

18

18

Undiagnosed

7

8

12

9

34

*Percentages have been modified to conform to the diagnostic criteria used in the American series.

Infections

In the initial evaluation of FUO, the possibility of infection should be carefully considered.

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 [see Table 3]. Most FUO cases caused by miliary tuberculosis arise in elderly patients in whom dissemination has followed activation of quiescent foci. Often, in cases caused by miliary tuberculosis, the intermediate-strength (5 tuberculin units) purified protein derivative skin test is negative, and miliary pulmonary lesions are not present on the chest x-ray. Anemia, leukopenia, or, rarely, a leukemoid reaction caused by bone marrow involvement may be evident; 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.

Table 3 Causes of Fever of Undetermined Origin

Systemic Infections    Tuberculosis (miliary)
   Infective endocarditis (primarily bacterial endocarditis but also endocarditis with a fungal, Q fever, or chlamydial etiology)
   Bacteremia from an inapparent primary focus
   Chronic meningococcemia
   Brucellosis
   Listeriosis, vibriosis, leptospirosis, relapsing fever (caused by Borrelia recurrentis), rat-bite fever (caused by either Streptobacillus moniliformis or Spirillum minus)
   Miscellaneous
   Psittacosis, toxoplasmosis (disseminated acquired form), Q fever, disseminated deep mycotic infections (e.g., histoplasmosis, blastomycosis, cryptococcosis), cytomegalovirus infection, Whipple disease
Localized Infections and Abscesses
   Hepatic infections
   Liver abscess
   Cholangitis
   Intraperitoneal infections
   Upper abdomen: empyema of gallbladder, pericholecystic and subhepatic abscesses, right or left subphrenic abscesses, lesser sac abscess
   Lower abdomen: periappendiceal and peridiverticular abscesses
   Other intra-abdominal abscesses
   Tubo-ovarian abscess, pelvic inflammatory disease, pelvic abscess
   Retroperitoneal abscess, pancreatic abscess
   Urinary tract infections
   Perinephric abscess
   Renal carbuncle
   Pyelonephritis with ureteral obstruction and pyonephrosis
   Prostatic abscess
Neoplasms
   Hematopoietic malignancies: Hodgkin disease and other lymphomas, leukemias, myeloid metaplasia, malignant histiocytosis
   Other malignancies: renal cell cancer, colon cancer, hepatoma
   Benign neoplasms: left atrial myxoma, pheochromocytoma
Collagen Vascular Diseases
   Temporal arteritis, adult-onset juvenile rheumatoid arthritis, Wegener granulomatosis, polyarteritis, systemic lupus erythematosus, relapsing polychondritis
Granulomatous Diseases
   Sarcoidosis, idiopathic granulomatous hepatitis
Metabolic and Hereditary Disorders
   Familial Mediterranean fever, Fabry disease
Endocrine Disorders
   Adrenal insufficiency, thyrotoxicosis, hyperparathyroidism
Thermoregulatory Disorders
   Hypothalamic dysfunction (e.g., caused by strokes or tumors), encephalitis
Drug Fever
   Antimicrobial agents (β-lactam antibiotics, sulfonamides, nitrofurantoin, isoniazid), antihypertensives (hydralazine), anticonvulsants (phenytoin), allopurinol, and many others
Miscellaneous Conditions
   Pulmonary emboli, alcoholic hepatitis and cirrhosis, inflammatory bowel disease, thrombophlebitis, factitious fever

Infective endocarditis, usually subacute, is also an important diagnostic consideration. Most patients with subacute bacterial endocarditis have a heart murmur. In about 5% of cases, however, particularly in the elderly, the murmur may be absent or may be considered functional. Blood cultures would be expected to provide the diagnosis in a patient with subacute bacterial endocarditis, particularly because only 5% of patients with endocarditis have negative blood cultures. The leading cause of negative blood cultures in patients with endocarditis is the prior administration of antibiotics. It is therefore very important that a number of blood cultures be obtained, including some as long as 5 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 is essential in the evaluation of any patient with FUO. Echocardiography may reveal valvular vegetations in patients with endocarditis; transesophageal studies are more sensitive but more invasive than transthoracic echocardiography. 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 [see Table 3]. Viral infections are usually self-limited and do not produce fevers that last longer than 3 weeks. Important exceptions to this generalization are Epstein-Barr virus (EBV)64 and cytomegalovirus (CMV) infections, which may occasionally present as FUO (often with some mononucleosis-like features) in otherwise healthy individuals. More frequently, CMV infection develops in patients who have received multiple blood transfusions or who have undergone organ transplantation; CMV is the cause of 50% of all febrile episodes in renal transplant recipients.

Localized infections

The more common types of localized infection that present as FUO include hepatic abscess, subphrenic abscess, and subhepatic and pericholecystic abscess [see Table 3]. Liver abscesses are often occult; the physician should look for a history that includes symptoms of biliary tract disease, 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 CT 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 best diagnosed by ultrasonography or CT. 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.

Neoplasms

Lymphoma, particularly Hodgkin 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; a skin biopsy may help identify intravascular lymphoma as the cause of an FUO.65 Although so-called Pel-Ebstein recurrent fevers suggest Hodgkin 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 malignancy itself.66 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.

Solid tumors can also be associated with fever; hypernephroma is the leading example. As many as 10% of patients with co-lorectal 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. 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 NSAIDs; fevers caused by infections may be less likely to respond completely to these agents,67 but this distinction is not sufficient as a diagnostic test.68Hospitalization for FUO often reflects a poor prognosis in patients with malignancies.69

Collagen Vascular Disease

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 erythrocyte sedimentation rate (often > 100 mm/hr) are usual features. Jaw claudication, visual symptoms, and a tender or thickened temporal artery suggest the diagnosis of giant cell arteritis. As many as 15% 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 disease are febrile,70 and systemic symptoms such as fever and weakness may antedate by weeks or months the evolution of the more characteristic clinical manifestations of adult juvenile rheumatoid arthritis. In other patients, involvement of the paranasal sinuses and mastoid or the rapid excavation of a pulmonary lesion suggests Wegener 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.

Less Common Etiologic Categories

Granulomatous disease

Granulomatous diseases of noninfectious origin may be responsible for 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, muscle, or liver usually shows noncaseating granulomas. In addition to sarcoidosis, there are about 40 diseases that may be associated with hepatic granulomas. Treatable infectious granulomatous diseases (e.g., tuberculosis, brucellosis, histoplasmosis, and cat-scratch disease) must be ruled out by cultures, skin tests, serologic tests, and special stains of tissue biopsy specimens. 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.71 Beneficial results have been achieved in such cases by giving corticosteroids after excluding the other specific granulomatous diseases; methotrexate also appears to be helpful.72Corticosteroids have been beneficial for other patients with idiopathic granulomatosis and FUO.73 Starch peritonitis represents a febrile granulomatous response to starch introduced on surgical gloves. The nature of the process may not be appreciated for weeks; initially, findings of a doughy abdominal mass and fever are thought to be the result of 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. Occasionally, however, bowel symptoms may not be marked or may be of such long duration that they become accepted as the norm. In this setting, FUO may be the presenting complaint in a patient with inflammatory bowel disease.

Alcoholic hepatitis and cirrhosis

Fever is occasionally observed in cases of cirrhosis.74 Attention should first be directed to possible complicating infections—such as spontaneous bacterial peritonitis, enterogenous bacteremias, 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.

Pulmonary emboli

In rare instances, a patient may have multiple small pulmonary emboli, but no significant changes in arterial blood gases or on the chest film will be apparent; the patient 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 seldom persist longer than 1 week. 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., β-lactams, sulfonamides, nitrofurantoin, and isoniazid), antihypertensives (e.g., hydral a zine and methyldopa), anticonvulsants (e.g., phenytoin), and allopurinol are among the most common offenders, but many other drugs have been implicated. 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 pro duce FUO, which may or may not be accompanied by the presence of a sterile abscess or other gross evidence of tissue injury.

Factitious fever

In rare instances, a patient may simulate illness by deliberately producing false elevations in temperature.75 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.

Miscellaneous causes

The hereditary periodic fevers can present as FUOs.76 The diagnosis of familial Mediterranean fever is suggested by ethnic background, episodic occurrence of fever in association with abdominal pain or other signs of polyserositis, and well-being between attacks [see 15:VIII Systemic Vasculitis Syndromes]. The diagnosis can be difficult when recurrent fever is the only symptom77; molecular techniques can facilitate the diagnosis of various hereditary periodic fever syndromes.78

Whipple disease is a multisystem infection caused by the gram-positive actinomycete Tropheryma whippelii.79 Patients may present with a prolonged febrile illness in association with weight loss, arthralgias, and weakness.80 The use of special tissue culture and immunodiagnostic tests in diagnosis are being studied80; a poly merase chain reaction test for the causative organism is highly sensitive and specific,81 but false positive reactions have been reported.82 Inflammatory pseudotumor of intra-abdominal lymph nodes may present as FUO83; the clinical features of this disorder may resemble those of Whipple disease, but the pathologic findings are distinctive, and surgical excision of the involved nodes may induce prolonged remissions. Kikuchi-Fujimoto disease is another rare cause of fever and lymphadenopathy.84

CNS lesions are decidedly uncommon causes of FUO, except in very obtunded patients with extensive brain damage. Endocrinologic abnormalities, such as subacute thyroiditis, or metabolic disorders, such as hypertriglyceridemia, hypercholester olemia, or glycosphingolipid storage disease (Fabry disease), may occasionally present as FUO. Many other disorders as diverse as pernicious anemia85and xanthogranulomatous pyelo nephritis86 have been identified as rare causes of FUO.

FUO in the Elderly

Advanced age appears to blunt the febrile response to many illnesses (“the older, the colder”).87 Because of this, an elderly patient with a persistent rectal temperature as low as 37.5° C (99.5° F) may qualify for an FUO evaluation.88 The causes of FUO in the elderly are similar to those in younger patients; however, in elderly patients, tuberculosis is a more common infectious cause and temporal arteritis the most common vasculitic cause.88,89 The presence of multiple comorbidities may complicate the diagnosis of FUO in the elderly and may temper the use of invasive diagnostic studies.

FUO in Patients with AIDS

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, with CD4+ T cell counts of less than 100/mm3.90Infections account for more than 75% of FUO cases in such patients91; in one series, the more common diagnoses were disseminatedMycobacterium avium complex (31%), Pneumocystis carinii pneumonia (13%), CMV infection (11%), disseminated histoplasmosis (7%), and lymphoma (7%).92 Other infectious etiologies are toxoplasmosis, cryptococcosis, salmonellosis, and varicella-zoster virus infections. In Europe, leishmaniasis is also an important cause of FUO in patients with AIDS.93 Among noninfectious etiologies, lymphoma and drug fever are most prominent. HIV itself is an uncommon cause of FUO.

Blood cultures are the most useful diagnostic tests. Although more invasive than blood cultures, biopsies of bone marrow,93 liver,94 or lymph nodes may provide more rapid diagnosis by allowing direct visualization of organisms. Other useful tests include CT of the chest and abdomen and a serum cryptococcal antigen determination.

DIAGNOSIS

History and Physical Examination

With rare exceptions, neither the temperature nor the pattern of fever permits discrimination between the causes of FUO. Detailed review of the history is essential, particularly regarding travel,95 animal exposure, occupational risks, and other epidemiologic 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, the abdominal viscera, and the 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. A 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 elderly or obtunded patients, in whom a perirectal or prostatic abscess may be overlooked.

Common Laboratory Studies

Blood cultures

Blood cultures should include aerobic (5% to 10% CO2 tension) and anaerobic cultures that have been incubated for at least 2 weeks. Newer blood culture techniques, including the use of lysis centrifugation and the BACTEC radiometric mycobacterial culture system, may be helpful, particularly in HIV-positive patients.

Serologic tests

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

Sedimentation rate

In cases of FUO, 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., hepatitis or a liver abscess) or secondary infiltration (e.g., miliary tuberculosis) of the liver.

Skin tests

Skin testing may aid in diagnosis if other positive results are obtained or if anergy, a characteristic finding in sarcoidosis, Whipple disease, and Hodgkin disease, is demonstrated.

Spinal fluid examination

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

Radiologic Studies

In patients with FUO, various radiologic studies in addition to chest films may assist in making the diagnosis:

  1. Ultrasonography and CT scans are valuable for detecting intra-abdominal and pelvic abscesses and retroperitoneal adenopathy. The use of CT scans has led to a decrease in the number of biopsies of normal tissues performed in patients with FUO.96
  2. Radionuclide scans may also be helpful.97Bone scans are considerably more sensitive than bone x-rays in the detection of osseous metastases or foci of osteomyelitis. Gallium scans are occasionally useful in detecting occult abscesses, but gallium scanning has had mixed results in patients with FUO.98A limited number of studies have examined the usefulness of scans utilizing indium-111-labeled leukocytes in the diagnosis of FUO; the specificity of this test, although not high, appears adequate as a second-line investigative tool.99 Scans employing indium-111-labeled human immunoglobulin G100 and technetium-99m-labeled cipro flox a cin are also being investigated.101 Positron emission tomography may also prove helpful in selected cases.63,102
  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 GI tract x-rays may indicate regional enteritis, ulcerative colitis, or large-bowel neoplasms.
  5. Bone x-rays generally are not helpful in the absence of skeletal symptoms.
  6. Other radiographic examinations, such as cholangiograms, angiograms, and lymphangiograms, may occasionally be useful but should be performed only when clinical clues suggest specific diagnoses.

Biopsies

All biopsy specimens should be cultured for bacteria, mycobacteria, and fungi and examined histologically. Biopsies that may help determine the diagnosis in patients 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 less satisfactory.
  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 diagnosing 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 erythrocyte sedimentation rate, and some thickening of the temporal artery.

Exploratory Laparotomy

In the past, laparotomy was advocated and employed successfully in the diagnosis of FUO. However, noninvasive radiologic techniques, especially when combined with percutaneous needle biopsies (see above), have supplanted laparotomy for the diagnosis of FUO. Laparotomy should be reserved for patients in whom the clinical and laboratory findings point to an intra-abdominal or retroperitoneal source for the fever, particularly when the fever has followed a prolonged and debilitating course.

TREATMENT

Fever is a symptom, not an illness, and treatment of patients with FUO is directed at the underlying illness. Chemotherapeutic 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 1- to 2-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. Patients with disseminated tuberculosis presenting as FUO often show a clinical response within 2 weeks after appropriate chemotherapy.

UNDIAGNOSED FUO

In 10% to 15% of patients with FUO, a detailed workup fails to reveal the diagnosis.103 In about half these cases, the fever resolves spontaneously. Reevaluation of the patient some weeks or even months later may provide the diagnosis. The prognosis of patients with undiagnosed FUO is surprisingly good103; few require empirical corticosteroid therapy, and many can be managed symptomatically with NSAIDs.

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Editors: Dale, David C.; Federman, Daniel D.