Fever of Undetermined Origin

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[edit] Fever of Undetermined Origin

Howard Libman

Sharon B. Brodie

Fever is a common presenting problem in primary care practice. Often its cause is determined by the presence of associated localized symptoms, and its course is self-limited. Examples include upper respiratory tract infection manifesting as fever and nasal congestion and acute gastroenteritis presenting with fever and diarrhea. Less frequently, fever occurs without localization of symptoms and is persistent. The concern with these patients is the possibility of occult disease, and diagnostic evaluation is warranted.

Febrile illnesses of less than 2 weeks' duration are often infectious in etiology, most frequently viral, or secondary to drug toxicity, and a specific diagnosis is sometimes not established. For an immunocompetent patient who does not appear particularly ill and has a normal physical examination, the diagnostic evaluation should be limited. Many systemic disorders begin with a prodrome characterized by fever, and observation ultimately leads to identification of the illness.

Fevers lasting longer than 2 weeks are generally associated with localized symptoms or signs that suggest an appropriate diagnostic evaluation. For patients without localized complaints, occult bacterial infection is more likely if they are age 50 or older or have diabetes mellitus, a complete blood count (CBC) characterized by leukocytosis or a leftward shift in the white cell count, or an erythrocyte sedimentation rate (ESR) of 30 or above. The physician should consider a hospital setting for evaluating such patients, as well as ill-appearing individuals, immunocompromised hosts, and patients with a history of valvular heart disease or injection drug use.^[1]

In 1961, Petersdorf and Beeson^[2] defined fever of undetermined origin (FUO) as a febrile illness of more than 3 weeks' duration in which temperatures exceed 38.3° C (101° F) on several determinations and no diagnosis is reached after 1 week of intensive evaluation.^[2] The purpose of these restrictive criteria is to eliminate most self-limited conditions. The differential diagnosis of FUO includes infections (approximately 30% of cases), neoplastic diseases (30%), inflammatory disorders (15%), and miscellaneous conditions (15% to 20%)^[3](Box 26-1). FUO is less often related to central nervous system (CNS) diseases that affect the thermoregulatory center of the hypothalamus directly. Because the medical literature predominantly describes hospitalized patients, however, the prevalence of specific diagnoses in an outpatient population with undifferentiated febrile illness may be different.^[4]

In a comparison of the two major studies of patients with FUO in 1961 and 1980,^[5][2] tuberculosis, subacute bacterial endocarditis (SBE), rheumatic fever, systemic lupus erythematosus (SLE), and familial Mediterranean fever were much less common in the latter series. Conditions that increased in frequency included cytomegalovirus (CMV) infection, osteomyelitis, sinusitis, malignant histiocytosis, juvenile rheumatoid arthritis of the adult (Still's disease), regional enteritis, and occult hematomas.

Technologic advances have permitted detection of many diseases without hospitalization, including infections by more sensitive culturing methods and serologic tests, neoplasms by radiologic techniques, and rheumatologic conditions by serologic testing. Durack and Street^[6] updated the definition of FUO to include etiologies detected in outpatient settings and classified FUOs in four categories: (1) classic, (2) nosocomial, (3) neutropenic, and (4) human immunodeficiency virus (HIV)–associated FUO.

Classic FUO is based on the original definition by Petersdorf and Beeson but only requires an evaluation of 3 days in the hospital, three outpatient visits, or 1 week of intensive outpatient testing without determination of the cause of fever. This is in contrast to the previous requirement of 1 week of intensive inpatient evaluation. Nosocomial FUO is limited to hospitalized patients who develop new fever after admission. The minimum evaluation required for diagnosis is 3 days, including 2 days for incubation of cultures. Neutropenic FUO encompasses febrile patients with a neutrophil count less than 500/μl with no specific cause identified after 3 days, including 2 days of culture incubation. HIV-associated FUO describes patients with documented HIV infection whose fevers persist for 4 weeks in the outpatient setting or 3 days in a tertiary care center with no source found after 3 days, including 2 days of incubation of cultures.

This classification scheme also suggests a tailored approach to diagnosis. For example, in patients with nosocomial FUO, potential etiologies of fever to be explored would include occult sites of hospital-acquired infections (e.g., sinusitis) and complications of medical treatment (e.g., Clostridium difficile diarrhea). This chapter focuses on the category of classic FUO, unless otherwise specified.

Etiologies of FUO to be considered differ according to patient country of origin and travel history. Even within the United States the prevalence of certain diseases varies dramatically among some subpopulations, such as elderly persons,^[7] injection drug users, and HIV-infected patients^[8] (see Chapter 32 ).

[edit] PATHOPHYSIOLOGY OF FEVER

Normal body temperatures taken orally in the basal state range between 36° and 37.8° C, with rectal temperatures generally 0.6° higher. Accurate oral temperatures may be difficult to obtain in patients with CNS impairment or hyperventilation, and rectal, axillary, or tympanic membrane temperatures are preferred. Diurnal variation in body temperature is usual in healthy individuals, with the lowest reading in the early morning and the highest in the late afternoon and early evening.

Fever, defined as a sustained abnormally high body temperature, occurs when heat production exceeds heat loss for an extended period. Chills, which may be experienced by the patient at the onset of fever, are characterized physiologically by muscular contraction, cutaneous vasoconstriction, and piloerection. Other associated symptoms include fatigue, sweats, arthralgias, and myalgias. Altered mental status may occur in chronically ill and elderly patients, especially with underlying cardiopulmonary or CNS disease. Although fevers above 41° C are uncommon, sustained higher temperatures are frequently associated with neurologic dysfunction and death.

Heat production occurs from energy-producing biologic reactions, and under normal circumstances, heat dissipation is accomplished through loss of water vapor during respiration and by insensible cutaneous evaporation. When a transient increase occurs in heat production (e.g., with vigorous exercise), sweating, hyperventilation, and cutaneous vasodilation provide additional heat loss.

The hypothalamus, or specifically, its thermoregulatory center located anteriorly near the base of the third ventricle, is important in the control of body temperature. This region serves to regulate the temperature set point and is susceptible to stimulation by cytokines known as endogenous pyrogens. These polypeptides are released by monocytes and tissue macrophages in response to a variety of stimuli, including exogenous pyrogens (e.g., viruses, bacterial products such as endotoxin, yeast, protozoa), phagocytosis, immune complexes, and tissue injury. The major endogenous pyrogens include interleukin-1 and tumor necrosis factor (cachectin). Interferons are also thought to be pyrogenic, although their pathophysiologic mechanism is as yet undefined. Endogenous pyrogens act on the hypothalamus by inducing phospholipases, which make arachidonic acid available for prostaglandin synthesis. Prostaglandin E₂, through the generation of cyclic adenosine monophosphate (cAMP), serves to increase the thermal set point of the hypothalamus. Aspirin and nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen lower body temperature by inhibiting cyclooxygenase activity, thereby blocking prostaglandin synthesis.^[9]

[edit] PATIENT EVALUATION

The general diagnostic approach to FUO begins with a careful history and physical examination, followed by a selective laboratory evaluation. Initial diagnostic efforts are directed at the early identification of potentially serious illnesses that are amenable to specific treatment. Common causes of FUO in young adults include CMV infection, lymphoma, SLE, and regional enteritis. In elderly patients, SBE, tuberculosis, lymphoma, and temporal arteritis should be considered. An atypical presentation of a common disease is more frequent than uncommon conditions. In immunocompromised patients the differential diagnosis is expanded to include opportunistic as well as common diseases (Table 26-1).

Table 26-1 Differential Diagnosis of Fever in Immunocompromised Patients

[edit] History

A careful history of the present illness is essential in focusing the differential diagnosis and determining an appropriate laboratory evaluation of the patient with FUO. An inaccurate or incomplete history may lead to inappropriate diagnostic tests and increased morbidity. The physician should consider the onset of symptoms and any localization over time. The history should include chronic or immunocompromising disorders, recent hospitalizations or surgeries, and medications. Travel history, exposure to tuberculosis, wild and domestic animal exposure, drug use, work environment, avocations, geographic origins, and HIV risk factors should be reviewed in detail. The patient should be questioned about similar symptoms in close contacts or other associates.

[edit] Physical Examination

A careful physical examination should be performed and repeated at periodic intervals. The physician should assess whether the patient appears acutely or chronically ill and describe any fever pattern. The skin may reveal peripheral stigmata of SBE, malar rash of SLE, maculopapular rash of drug eruption, generalized rash of secondary syphilis, or evidence of vasculitis. Lymphadenopathy may indicate CMV, Epstein-Barr virus (EBV), HIV infection, syphilis, or lymphoma. Funduscopic examination may reveal evidence of retinitis secondary to CMV infection or toxoplasmosis or Roth's spots suggestive of SBE. Percussion and transillumination of the sinuses may indicate sinusitis. Examination of the mouth and pharynx may show occult dental infection, pharyngitis or tonsillitis, or manifestations of HIV disease (e.g., thrush, oral hairy leukoplakia).

The presence of new or changing cardiac murmurs may indicate endocarditis or atrial myxoma. Cardiopulmonary auscultation may also establish the diagnosis of pneumonia, pericarditis, or pleuritis. Abdominal palpation may reveal hepatomegaly, splenomegaly, abscess, or a mass. Digital rectal examination may suggest prostatitis or show evidence of occult blood. Bimanual pelvic examination may indicate pelvic inflammatory disease. Musculoskeletal examination may show arthritis, bursitis, or localized bony tenderness suggesting osteomyelitis. Neurologic examination may reveal evidence of meningismus or occult focal deficits indicative of pyogenic CNS disease.

[edit] Fever Patterns.

Although fever patterns are generally nonspecific, the following patterns are sometimes useful in the differential diagnosis^[10]:

• Intermittent: characterized by an exaggeration of normal diurnal variation of temperature. This pattern is most often associated with irregular use of antipyretic drugs and with pyogenic abscesses, tuberculosis, and lymphoma.
  
• Sustained: characterized by little variation in temperature and is often related to significant systemic infections (e.g., SBE, pneumococcal pneumonia).
  
• Relapsing: characterized by alternating extended periods of fever and normal temperature and frequently occurs with malaria, lymphoma, and some unusual infections.
  
• Temperature-pulse disparity: characterized by high temperature with a disproportionately slow pulse. This pattern is typically described with salmonellosis, chlamydial and rickettsial infections, legionnaires' disease, drug fever, and factitious fever.
  

Febrile response to disease may be attenuated or absent in elderly patients, uremic and diabetic individuals, and persons receiving corticosteroid or antipyretic therapy.

[edit] DIAGNOSIS

[edit] Laboratory Evaluation

The initial laboratory evaluation of all patients with an occult febrile illness should consist of a CBC with differential count, kidney and liver function tests, blood cultures, syphilis serology, serum protein electrophoresis, skin test for tuberculosis (PPD), chest radiograph, and urinalysis (Box 26-2). An acute-phase serum sample should also be obtained. Additional diagnostic testing should be individualized based on findings from the history and physical examination.^[11]

The CBC may show (1) lymphocytosis, suggestive of viral infection; (2) leukocytosis or leftward shift of white cells, indicative of bacterial infection; or (3) evidence of leukemia. Monocytosis is described with tuberculosis, CMV infection, lymphoma, and metastatic carcinoma. Eosinophilia is often associated with lymphoma, drug fever, and vasculitis. Anemia and thrombocytosis are described with many acute and chronic infections and neoplastic and inflammatory diseases. Thrombocytopenia may indicate an acute infection or immune-mediated disorder. Liver function test abnormalities may suggest hepatitis or infiltrative disease of the liver or biliary tract disease, both of which are generally associated with a disproportionate increase in serum alkaline phosphatase. The ESR and C-reactive protein, nonspecific markers of acute and chronic diseases, are not sufficiently sensitive or specific to be clinically useful in most patients.

Three sets of blood cultures obtained through separate venipunctures are generally sufficient to diagnose conditions associated with continuous bacteremia (e.g., SBE). Infections with intermittent bacteremia (e.g., pneumonia, visceral abscess) may require repeated blood cultures over time. The microbiology laboratory should be notified if an atypical or slow-growing organism is suspected. The serum protein electrophoresis may show nonspecific hypergammaglobulinemia or a monoclonal spike characteristic of a plasma cell dyscrasia. Chest radiograph may reveal hilar adenopathy, diffuse or localized infiltrates, or pleural effusion suggestive of infectious, neoplastic, or connective tissue diseases. Urinalysis may show proteinuria, microscopic hematuria, or evidence of infection.

A positive screening test for syphilis should always be confirmed by specific serology. Hepatitis A, B, and C viral serologies are indicated with unexplained liver function test abnormalities. Serologies for EBV, CMV, HIV infection, Lyme disease, toxoplasmosis, and other infectious diseases should be considered in the appropriate clinical settings. The antinuclear antibody (ANA) test and rheumatoid factor are reserved for patients with suspected SLE and rheumatoid arthritis. An antistreptolysin O titer to establish antecedent streptococcal infection is indicated if rheumatic fever is a diagnostic consideration.

[edit] Radiologic Imaging Studies

Radiologic imaging studies are useful in establishing specific diagnoses suggested by history, physical examination, and initial laboratory evaluation. Sinus films may indicate the presence of sinusitis, and computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head may show occult brain abscesses. Echocardiography may reveal valvular vegetations indicative of endocarditis or atrial myxoma. Doppler studies of the lower extremities or ventilation/perfusion lung scan may suggest multiple pulmonary emboli.

The diagnosis of inflammatory bowel disease may be supported by findings on upper gastrointestinal series or barium enema. Abdominal/pelvic ultrasound or CT or MRI scan may show biliary tract disease, pelvic inflammatory disease, or occult abscess. Renal ultrasound or intravenous pyelogram with nephrotomogram may be useful in diagnosing renal cell carcinoma or abscess. Plain radiographs or radionuclide scans of the bone may suggest osteomyelitis. Gallium and indium scan findings are generally nonspecific but sometimes helpful in localizing an occult disease process.^[12][13]

[edit] Invasive Studies

Invasive studies and biopsy procedures should only be used (1) when the initial clinical assessment suggests systemic or localized disease but is insufficient to establish a definitive diagnosis and (2) when findings from the procedure may significantly alter clinical management.

Skin biopsy may be useful in establishing the diagnosis of vasculitis or drug toxicity. Lymph node biopsy is indicated if lymphoma or adenitis secondary to disseminated infection such as tuberculosis is suspected. In general an excisional biopsy is preferred; the inguinal region should be avoided, if possible, because of an increased rate of nonspecific findings. Liver biopsy should be considered with evidence of chronic hepatitis or infiltrative disease. In the context of pancytopenia, bone marrow biopsy may be useful in establishing the diagnosis of hematologic malignancy or disseminated infection. Abnormal fluid collections involving the pericardial, pleural, abdominal, or joint spaces should be aspirated and sent for cell count, chemistries, culture, and cytology. A lumbar puncture is indicated with meningismus or CNS dysfunction. Exploratory laparotomy is reserved for patients with compelling evidence of significant, undiagnosed intraabdominal disease.

[edit] DIFFERENTIAL DIAGNOSIS

[edit] Infections

Tuberculosis, SBE from slowly growing or difficult-to-grow organisms, biliary tract infection, intraabdominal abscess, septic pelvic vein thrombophlebitis, and viral infections (e.g., CMV, EBV, HIV) are frequent causes of FUO. Abscesses, the most common type of bacterial infection presenting as an FUO, are often localized in the abdomen or pelvis. Renal abscess with obstruction, perinephric abscess, or prostatic abscess in males may not be associated with any abnormalities on urinalysis. Diagnosis of these conditions is generally established with a radiologic imaging study (e.g., ultrasound, CT or MRI scan).

With the widespread use of blood cultures in recent years, intravascular infection is now a relatively infrequent cause of FUO, although atypical causes of endocarditis (e.g., Haemophilus species, fungi) and infections that cause intermittent bacteremia (e.g., salmonellosis, disseminated gonococcal infection, brucellosis) are still described. Culture-negative endocarditis is suggested by the presence of vegetations on echocardiogram. Diagnosis of other bacteremic infections may require multiple or special blood cultures, aspiration of fluid from affected body sites (e.g., bone marrow, joints), or specific serologic tests. Other occult bacterial infections that may cause FUO include sinusitis, mastoiditis, and chronic osteomyelitis. Iatrogenic infections should be considered in patients with prosthetic joints, vascular devices, or other implanted synthetic materials.

Tuberculosis, particularly extrapulmonary disease, and atypical mycobacterial infection, especially Mycobacterium avium complex in patients with advanced HIV disease, are important causes of FUO. After decades of decreasing prevalence, tuberculosis has increased in frequency in the United States, with urban areas affected disproportionately. Symptoms of extrapulmonary tuberculosis are variable and depend on the site(s) of involvement. Diagnosis is made by isolator blood culture or tissue biopsy. Symptoms of M. avium complex infection are generally nonspecific, but diagnostic evaluation may reveal evidence of bone marrow or liver involvement. Diagnosis is most often established by isolator blood culture.

EBV and CMV infections may be prolonged and have few, if any, localizing signs. Generalized lymphadenopathy, splenomegaly, and rash may be present. Diagnosis is made by serology or culture. Primary HIV infection may present in a similar manner, and patients with advanced HIV disease sometimes have persistent fever and constitutional symptoms not attributable to a specific opportunistic infection or neoplasm. Diagnosis of primary HIV infection is established serologically, and fever related to advanced HIV disease is determined by the exclusion of other conditions.

The chlamydial and rickettsial infections, psittacosis and Q fever, sometimes present with fever and constitutional symptoms. Their diagnosis is often suggested by history of contact with birds or farm animals and can be confirmed serologically. Parasitic infections that may cause FUO include malaria, amebic liver abscess, and toxoplasmosis in patients with advanced HIV disease. Diagnosis is made by appropriate serologic, imaging, and cytologic or histologic studies. Spirochete diseases, including secondary syphilis, Lyme disease, and leptospirosis, may also present with fever, but localized symptoms often suggest the etiology. Diagnosis of each condition is made serologically.

[edit] Neoplasms

Lymphoma, leukemia, renal cell carcinoma, hepatoma, and metastatic carcinoma to the bone, liver, or CNS are the most frequent neoplastic causes of FUO.^[14] Hodgkin's disease, especially early in its course, may present with fever alone, and lymphadenopathy may be limited to the abdomen or retroperitoneal space. Non-Hodgkin's lymphoma is generally associated with palpable lymphadenopathy, hepatosplenomegaly, or both. Diagnosis of lymphoma is made by excisional biopsy of affected lymph nodes or less often by bone marrow biopsy. Acute leukemia may present with high-grade fever in conjunction with anemia and leukopenia or leukocytosis. Bone marrow aspiration and biopsy are usually diagnostic. In patients with chronic lymphocytic or granulocytic leukemia, fever often indicates accompanying infection.

Most solid tumors are not associated with fever in the absence of obstruction or tissue necrosis. Notable exceptions include renal cell carcinoma, which may present with flank pain and hematuria, and hepatoma, which generally occurs in the context of chronic hepatitis B infection. Presumptive diagnosis is most often made by radiologic imaging study. Metastatic gastrointestinal and ovarian tumors to the bone, liver, or CNS may also be associated with fever. Atrial myxoma, an infrequent cause of FUO, may be clinically confused with bacterial endocarditis, presenting with fever, changing heart murmurs, and peripheral embolic phenomena. Diagnosis is suggested by echocardiography.

[edit] Inflammatory Diseases

Rheumatic fever, SLE, juvenile rheumatoid arthritis, mixed connective tissue disease, and vasculitis are the most common inflammatory disorders responsible for FUO. Rheumatic fever generally occurs during childhood or in a young adult, with the diagnosis established by specific clinical and laboratory criteria in the context of serologic evidence of recent streptococcal infection. The diagnosis of SLE is also established by specific clinical, laboratory, and serologic findings. Fever associated with SLE may represent a manifestation of the disease or of a complicating infection in patients receiving immunosuppressive therapy. The diagnosis of rheumatoid arthritis is generally established by the presence of polyarthritis and a positive rheumatoid factor. However, Still's disease, which manifests with fever, polyarthritis, generalized lymphadenopathy, organomegaly, and rash, is a diagnosis of exclusion.

Vasculitic conditions, including periarteritis nodosa, Wegener's granulomatosis, and temporal arteritis, may also present with fever. Diagnosis is made by angiography and biopsy. Polymyalgia rheumatica is a disease of elderly persons manifested by fever, headache, myalgias, and arthralgias. It may occur with or without temporal arteritis and is often associated with a very high ESR.

[edit] Miscellaneous Conditions

Drug fever, sarcoidosis and other granulomatous diseases, multiple pulmonary emboli, regional enteritis, Whipple's disease, alcoholic hepatitis, hemolytic episodes, occult hematomas, metabolic diseases, familial Mediterranean fever, factitious fever, and thermoregulatory disorders constitute the miscellaneous causes of FUO.

[edit] Drug Fever.

Drugs are a relatively common cause of fever, and drug fever should be considered in the differential diagnosis of all febrile illnesses. Although fever has been attributed to many different medications, it is usually associated with a relatively small number of agents (Box 26-3). Fever related to drug treatment may also be the result of endotoxin release in response to antibiotic therapy (e.g., Jarisch-Herxheimer reaction) or the lysis of tumor cells after chemotherapy. Self-limited fever is also common after administration of many vaccines.

Drug fever may be low or high grade and sustained or intermittent and sometimes is disproportionate to the degree of systemic toxicity. Its onset often immediately follows initial use of a medication but may be delayed weeks, months, or even years. Clinical improvement is generally noted within 24 to 48 hours of discontinuation of the causative agent. Drug fever may present with rash, hemolysis, bone marrow suppression, or eosinophilia. Certain drugs, especially barbiturates, methyldopa, penicillin, phenytoin, and sulfonamides, have been associated with a serum sickness–like syndrome, manifested by rash, lymphadenopathy, arthritis, nephritis, and edema. An SLE-like syndrome, characterized by fever, arthralgias, and positive ANA test, has been described with hydralazine, phenytoin, procainamide, and other agents.^[15]

[edit] Granulomatous Diseases.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Fever has been described in association with hilar lymphadenopathy, arthritis, or hepatic involvement. Diagnosis is made through biopsy of an affected organ, with the characteristic finding of noncaseating granuloma. Infectious causes of granulomatous disease must be ruled out. Granulomatous hepatitis manifests as fever, hepatomegaly, and increased serum alkaline phosphatase. Diagnosis is made by liver biopsy, with the differential diagnosis including tuberculosis, syphilis, histoplasmosis, lymphoma, sarcoidosis, drug reactions, and other conditions.

[edit] Other Disorders.

Multiple pulmonary emboli, generally the result of asymptomatic deep venous thrombosis of the lower extremities, typically present with recurrent respiratory symptoms associated with low-grade fever. Diagnostic evaluation includes Doppler studies of the legs, ventilation/perfusion lung scan, or pulmonary angiography. Myocardial infarction is also sometimes associated with a low-grade fever secondary to tissue necrosis.

Gastrointestinal disorders presenting with fever include regional enteritis and Whipple's disease (recently attributed to Tropheryma whippelii), which are usually characterized by weight loss, abdominal pain, and malabsorption syndrome. Alcoholic hepatitis may manifest as fever with unexplained abnormalities in liver function tests. Hemolysis from a hematologic disorder, systemic disease, or drug toxicity may present as fever without localizing symptoms, as may occult hematomas secondary to trauma or bleeding dyscrasia. Rarely, FUO is the result of metabolic diseases such as gout, hyperthyroidism, thyroiditis, hyperparathyroidism, or pheochromocytoma.

Familial Mediterranean fever, also known as periodic disease, is an uncommon autosomal recessive disease characterized by periodic fevers associated with atypical chest and abdominal pain in persons of Mediterranean background. Arthritis and skin lesions have also been described. Diagnosis is established clinically.

Thermoregulatory disorders caused by hypothalamic dysfunction secondary to encephalitis, stroke, or hemorrhage occur infrequently. Diagnosis may be suggested by CT or MRI scan of the brain. Fever secondary to hypothalamic disease may respond to chlorpromazine therapy.

[edit] Factitious Fever.

Factitious fever, most often described in young women and persons with medical training or experience, is a fever that has been artificially produced by the patient. Clinical clues to the diagnosis include lack of constitutional symptoms and systemic toxicity and presence of a temperature-pulse disparity. Diagnosis is established by supervised temperature measurements. Rarely, fraudulent fever may result from self-inoculation of pyogenic substances or ingestion of foreign material.

[edit] MANAGEMENT

Except for extreme hyperpyrexia, defined as temperature greater than 41° C, which can cause CNS dysfunction, no information suggests that fever is deleterious in humans. In addition, indirect evidence implies that fever may be beneficial to patients through the activation of specific host defense mechanisms. Indiscriminate treatment of fever could theoretically interfere with immune responsiveness. It could also obscure the natural history of an undiagnosed condition and the response to specific therapy of an identified disease. Despite these concerns, many physicians choose to initiate antipyretic therapy in febrile patients in an effort to alleviate their physical discomfort.

Definite indications for treatment of fever include avoidance of tachycardia in persons with a history of or at increased risk for congestive heart failure, hyperventilation in those with pulmonary decompensation or dehydration, encephalopathy in those with underlying CNS disease, and febrile convulsions in predisposed younger children. Antipyretic agents include acetaminophen, aspirin, and NSAIDs such as ibuprofen (Table 26-2). Each appears to be effective when given in adequate dosage. Aspirin is contraindicated for the management of fever related to viral illness in children because of its association with Reye's syndrome. Because intermittent antipyretic therapy usually results in alternating fever, chills, and sweats, continuous treatment is generally preferable. Alternative methods for fever control include sponging the body with tepid water and using cooling blankets, although the latter sometimes induces cutaneous vasoconstriction and shivering. Alcohol baths have no particular advantage. Extreme hyperpyrexia should be managed by immersing the patient in an ice water bath until fever is reduced to 39.5° C, followed by traditional measures.

Table 26-2 Management of Fever

✢Other nonsteroidal antiinflammatory agents can be used in equipotent dosages.

More than 90% of adults with FUO are diagnosed with a specific disorder over time, and with few exceptions, blind therapeutic trials should be avoided. Empiric antimicrobial therapy increases the risk of superinfection and drug toxicity. Antituberculous therapy is indicated for high-risk patients diagnosed with granulomatous disease pending culture results. The combination of penicillin G and an aminoglycoside is recommended if the working diagnosis is culture- negative SBE. Empiric corticosteroid therapy should be reserved for suspected connective tissue disease; it may mask the clinical symptoms of other disorders without affecting their natural history. A trial of NSAIDs has been suggested as a means of distinguishing infectious from neoplastic causes of fever in patients with preexisting cancer.

[edit] EVIDENCE-BASED MEDICINE

The primary source for this chapter was a MEDLINE electronic search dating back to 1990 conducted in January, 1999. It focused on identifying systematic reviews, meta-analyses, and large prospective studies with clinical endpoints.

[edit] REFERENCES