Evaluation of Fever
Since antiquity, fever has been recognized as a cardinal manifestation of disease. Indeed, people identify fever as a sign of illness more readily than they recognize the importance of most other symptoms. In addition to causing concern, the presence of fever usually raises high therapeutic expectations. In the popular mind today, fever is equated with infection, and infections are expected to respond to the administration of antibiotics. As a result, the physician is faced with the challenge of defining the cause of the fever, instituting appropriate therapy, and explaining the reasons for limiting antibiotic use to bacterial infections. Persistent or relapsing fevers are among the most difficult of diagnostic challenges, necessitating an appreciation for the spectrum of causes and a thoughtful strategic approach to workup.
“Normal” Body Temperature and the Definition of Fever
Popular lore notwithstanding, 98.6°F (37°C) is not normal body temperature. In fact, there is no single normal value; like so many other biologic phenomena, body temperature displays a circadian rhythm. In healthy individuals, mean rectal temperatures vary from a low of about 97°F (36.1°C) in early morning to a high of about 99.3°F (37.4°C) in late afternoon. In children, the normal range may be even greater. Moreover, physiologic factors such as exercise and the menstrual cycle can further alter body temperature. In practical terms, understanding the diurnal rhythm of body temperature is important for two reasons. First, many patients have been unnecessarily subjected to extensive workups and even psychologically incapacitated in the erroneous quest for a cause of deviation from the mythical “normal” temperature of 98.6°F. Second, the fever of disease states is superimposed on the normal cycle so that fevers are generally highest in the evening and lowest in the morning. As a result, frequent temperature recordings throughout the
day are required to monitor fever in sick patients. The absence of fever in a single office visit does not exclude a febrile illness. A temperature in excess of 38.3°C is the standard definition of fever.
day are required to monitor fever in sick patients. The absence of fever in a single office visit does not exclude a febrile illness. A temperature in excess of 38.3°C is the standard definition of fever.
Mechanism of Fever
Fever ensues as a consequence of infection or tissue injury. The cytokines (e.g., interleukins, tumor necrosis factor [TNF]) constitute the endogenous pyrogens; microbial surface components account for most of the exogenous ones. The latter evoke fever either directly or through stimulation of the endogenous pyrogens. The final common pathway is triggering of increased prostaglandin E2 levels in thermoregulatory parts of the hypothalamus. Fever stimulates some components of the immune response and inhibits further release of pyrogenic mediators. Antipyretic drugs owe much of their efficacy to suppression of prostaglandin formation.
Clinical Manifestations of Fever
The presenting complaints of the febrile patient may be explained by the underlying disease process or by the fever itself. The signs and symptoms of fever vary tremendously. Some patients are asymptomatic; more often, they have a sensation of warmth or flushing. Malaise and fatigue are common. The hypothalamus, acting through somatic efferent nerves, increases muscle tone to generate heat and raise body temperature; many febrile patients experience myalgias as a result.
These same factors account for one of the most dramatic manifestations of fever: the shaking chill or rigor. It is taught that rigor is a manifestation of bacteremia, but in fact, any stimulus that raises the hypothalamic setpoint rapidly may produce a rigor. Patients experiencing a rigor exhibit uncontrolled violent shaking and trembling, and they characteristically heap themselves with blankets even as their temperatures are shooting up. This phenomenon also has a physiologic basis. Despite their high central or core temperature, these patients subjectively feel cold because their surface temperature is reduced. To generate fever in response to hypothalamic stimuli, cutaneous vasoconstriction occurs, skin temperature falls, and cold receptors in the skin sense this as cold. Quite the reverse occurs during defervescence; body temperature falls in response to cutaneous vasodilation, and drenching sweats typically terminate an episode of fever.
Other manifestations of temperature elevation include central nervous system symptoms that range from a mild inability to concentrate to confusion, delirium, or even stupor, especially in the elderly or debilitated patient. High fevers (104°F to 106°F) may produce convulsions in infants and young children without any primary neurologic disorder. Increased cardiac output is an invariable consequence of fever, and tachycardia typically accompanies fever. Tachycardia is so usual that its absence should lead one to suspect uncommon problems such as typhoid fever, in which relative bradycardia is typical (for unknown reasons), drug fever, and factitious fever. Patients with underlying heart disease may respond to the high-output stress of fever with angina or heart failure.
Another sign of fever is the so-called fever blister—labial herpes simplex. The problem is probably not precipitated by fever per se, for it is much more common in some infections, such as pneumococcal pneumonia and meningococcal meningitis, than in other febrile states. Because fever accompanies infection so frequently, numerous investigators have tried to determine whether fever has any protective or beneficial role. There are a few circumstances, such as central nervous system syphilis, in which elevations of body temperature may exceed the thermal tolerance of the infectious agent. In fact, induced fever was once a form of therapy for syphilis. In several animal models, fever enhances recovery from experimental infections; however, there is no such proven clinical benefit from fever in humans.
Consequences of Fever
Is fever detrimental? Most otherwise healthy individuals can tolerate temperatures up to 105°F (40.5°C) without ill effects, although even in these individuals, symptoms often warrant therapy. In children, high fevers should be suppressed because convulsions may occur. Patients with heart disease should also receive antipyretic therapy. Each increase of 1°F in temperature increases the basal metabolic rate by 7%, which results in increased demands on the heart, so that myocardial ischemia, failure, or even shock can ensue. In addition, extreme hyperthermia beyond 108°F (42.1°C) may cause direct cellular damage. Vascular endothelium seems particularly susceptible to such damage, and disseminated intravascular coagulation frequently accompanies extreme hyperthermia. Other structures that may be directly damaged are the brain, muscle, and heart. Finally, metabolic derangements such as hypoxia, acidosis, and sometimes hyperkalemia can result from extreme pyrexia and, in turn, further contribute to coma, seizures, arrhythmias, or hypotension, which can be lethal. Nevertheless, patients have survived temperatures of up to 108°F without demonstrable organ damage, although mortality in this temperature range is appreciable. Body temperatures as high as 113°F have been demonstrated in humans, but these have been uniformly lethal.
Many inflammatory, infectious, neoplastic, and hypersensitivity processes can produce fever. Most acute fevers encountered in the office setting are of obvious causes such as upper respiratory or urinary tract infection. Viral illnesses, drug allergy (especially to antibiotics), and connective tissue disease are other important precipitants.
Recurrent or intermittent fever is most characteristic of infectious conditions with cyclic features, such as malaria, hepatitis B, leptospirosis, brucellosis, and disseminated fungal infection. Migration of intraluminal parasites (as in schistosomiasis, amebiasis, and trypanosomiasis) can lead to intermittent fever, as can cell lysis by intracellular parasites (e.g., Bartonella and Ehrlichia). A cyclic pattern of high fevers for 1 to 2 weeks alternating with afebrile periods suggests the pathognomonic Pel-Ebstein fever of Hodgkin disease. Included in the list of causes for periodic fevers are the hereditary periodic fevers, which include familial Mediterranean fever (FMF), hyperimmunoglobulin D (IgD) syndrome, and TNF-receptor-associated periodic syndrome. All produce recurrent episodes of fever and are associated with a positive family history.
Travel-related fever in a Northern Hemisphere resident returning from a stay in the tropics is an increasingly common clinical problem. Whereas respiratory infections and bacterial enteritis are common causes in returning travelers (11% and 6%, respectively), tropical diseases are also a major concern, with the differential diagnosis being destination-dependent (Table 11-1). In those returning from Africa, malaria is the predominant cause (35%), followed by rickettsial infection (5%), dengue fever (4%), and schistosomiasis (3%). In those having visited tropical Asia, dengue fever accounts for 12%, malaria 9%, and enteric fever 4%. The Caribbean, Mexico, South Florida, and southern Texas have also been designated by the World Health Organization as having high suitability for dengue
transmission. Persons presenting with onset of fever within 2 weeks of returning from any one of these tropical or subtropical areas should be considered for dengue fever, especially if manifesting viral-illness symptoms (e.g., high temperature, headache, nausea/vomiting, myalgias, joint pain), especially if accompanied by petechiae or ecchymoses. Persons presenting months after travel often have malaria as the cause. Nearly 24% of cases are of unknown etiology but are invariably associated with a favorable outcome.
transmission. Persons presenting with onset of fever within 2 weeks of returning from any one of these tropical or subtropical areas should be considered for dengue fever, especially if manifesting viral-illness symptoms (e.g., high temperature, headache, nausea/vomiting, myalgias, joint pain), especially if accompanied by petechiae or ecchymoses. Persons presenting months after travel often have malaria as the cause. Nearly 24% of cases are of unknown etiology but are invariably associated with a favorable outcome.
TABLE 11-1 Fever in Persons Returning from Travel to the Tropics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Unexplained persistent fever can be a major diagnostic challenge. “Fevers of unknown origin” (FUOs) are defined as those persisting for 3 weeks, exceeding temperatures of 101°F, and eluding 1 week of intensive diagnostic study. The spectrum of illness depends on the setting. In reported series of immunocompetent FUO patients encountered in the outpatient community setting, noninfectious inflammatory conditions accounted for about one third of cases, followed by infection and malignancy (Table 11-2). Up to one third of cases remain undiagnosed after comprehensive workup, but only a small percentage of these eventually prove life threatening (usually from hematologic malignancy). Most cases of FUO represent unusual presentations of common diseases rather than rare conditions.
The spectrum of FUO disease has expanded markedly since first publication over five decades ago of the classic papers defining the syndrome. Immunocompromise due to HIV infection and immunosuppressive therapy raise a whole new set of infectious and neoplastic diagnostic possibilities (see Table 11-3 and Chapter 13). The rise in prevalence of IV drug abuse and implantation of prosthetic devices further expands the list of surreptitious but potentially serious infections such as atypical forms of endocarditis and osteomyelitis presenting as persistent unexplained fever with few localizing or specific symptoms. The increased appreciation for treatable tick-borne illnesses (e.g., Lyme disease, babesiosis, ehrlichiosis, anaplasmosis—see Table 11-4) has expended the differential diagnosis of unexplained febrile illnesses presenting nonspecifically with malaise, headache, myalgias, chills, and arthralgias. Onset is typically a week or two after a tick bite, which often is not recalled; untreated, the consequences can be serious.
TABLE 11-2 Causes of Fever of Undetermined Origin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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The acutely febrile patient presents a common but demanding problem in differential diagnosis. In most cases, a careful history and physical examination will reveal the diagnostic clues so that laboratory studies can be used selectively. The evaluation of persistent fever can be more demanding. The initial office evaluation should help to determine the proper pace of diagnostic testing and the need for therapeutic intervention. If the illness is insidious in onset and only slowly progressive or if the patient is nontoxic and clinically stable, one may proceed with the workup in a deliberate manner on an ambulatory basis, using serial clinical observations and time as key diagnostic tools. On the other hand, if the patient is a compromised host or is acutely ill and toxic, several immediate diagnostic studies are mandatory, and treatment may be required even before all the results are available; hospitalization is usually necessary in such cases. Table 11-5 lists some factors that should prompt an aggressive approach to diagnosis and therapy.
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