Paul G. Auwaerter
Clinicians may often encounter febrile patients whose initial history and physical examination offer few clues toward achieving a diagnosis. For patients who present with elevated temperatures, the fever may be a secondary concern; for example, when severe headache and meningismus focus attention on meningitis. In other circumstances, a fever with shaking chill may herald an illness soon recognized as pneumonia with the onset of a productive cough and dyspnea, or it may evolve into an apparently self-limiting viral illness. However, for isolated or persisting fevers, achieving a diagnosis often depends on medical sleuthing using a meticulous history, careful physical examination, and judicious application of diagnostic tests.
Measurement and Definitions
Patient temperatures are reported in the United States as either centigrade (C) or Fahrenheit (F). Values may be converted according to the following:
°C = 5/9(°F-32)
°F = (9/5)°C+32
Defining normal body temperature is an imprecise science, because values obtained from modern studies depend upon the study method used. An individual's normal oral temperature can range between 96°F and 100.7°F (35.6°C to 38.2°C). Normal circadian patterns cause body temperature to vary by 1.8°F (1°C), with the nadir reached typically at 6 a.m. and the peak between 4 and 6 p.m. Individual patient temperatures may differ depending on the recording instrument, because thermometers are often poorly calibrated and differ in design (mercury vs. electronic) and anatomic location of measurement (oral, axillary, rectal, tympanic).
Accurate oral readings depend on whether the probe is properly located in the sublingual pocket. Smokers may have higher than normal readings, whereas recent ingestion of a cold beverage may transiently lower oral readings. In very hot weather or after intense exercise, body temperature may rise 0.9°F to 1.8°F (0.5°C to 1.0°C).
The most commonly recognized “normal” body temperature of 98.6°F (37°C) is based on somewhat antiquated medical lore. Mackowiak et al. (1) described the
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likely 19th century origin of this criterion; it was derived from the work of a German physician, Carl Wunderlich, who obtained mostly axillary measurements in over 25,000 subjects. In his critical comparative study, Mackowiak et al. found that with modern readings in healthy men and women, the mean oral temperature was 98.2°F ± 0.7°F (36.8°C ± 0.4°C). Rectal thermometry provides measurements with less variation, but patients and health care providers dislike this more accurate form of temperature assessment. To compare temperatures by different methods, consider rectal temperatures as 0.7°F (0.4°C) higher than oral measurements and 1.4°F (0.8°C) higher than those obtained with the convenient and popular aural (tympanic membrane) device (2).
Because defining normal temperature is inexact, it is not surprising that fever terminology is also variable. Surveys of medical textbooks reveal varying proposals for defining fever that range from any temperatures greater than 98.6°F (37.0°C) to only those greater than 100.4°F (38.0°C) (3). Many clinicians define a significant fever as a temperature greater than 101.0°F (38.3°C), which is likely grounded in the classic study on fever of unknown origin (FUO) by Petersdorf and Beeson (4).
Fever of Abrupt Onset and Limited Duration
The clinician should first determine whether a fever needs any diagnostic investigation. Many illnesses without localizing signs in otherwise healthy individuals may be due to common viruses, such as rhinovirus infection causing the common cold. These fevers tend to be low grade, with temperatures less than 102.2°F (39°C), and do not last beyond 5 to 7 days. However, some infections that start only with fever and other nonspecific symptoms should be considered in certain situations. Table 31.1 lists selected infections that may first present in the office with fever and require additional attention.
For example, high fevers to 104°F (40°C) associated with chills, myalgia, and cough during wintertime may be due to influenza (see Chapter 33). In contrast, summertime fever with malaise and headache in an active outdoorsman or gardener may be the first sign of a tick-borne infection such as Lyme disease, ehrlichiosis, or Rocky Mountain spotted fever (see Chapter 38). Patients who use intravenous drugs or practice high-risk sex may have acute human immunodeficiency virus (HIV) infection (Chapter 39), viral hepatitis (hepatitis B or C, seeChapter 47), or venereal diseases such as syphilis or gonorrhea (see Chapter 37) as the cause of febrile illness. Teenagers or young adults may have an isolated fever before the development of pharyngitis or lymphadenopathy associated with infectious mononucleosis (seeChapters 33 and 58). Viral exanthems may present first with fever in adolescents or adults who are not naturally immune or who were not adequately vaccinated (see Chapter 18). Nowadays, consideration of bioterrorism agents, such as anthrax and smallpox in the evaluation of fever, may be necessary in certain circumstances.
In the elderly, fever generally indicates the presence of serious infection, most often caused by bacteria from urinary or respiratory sources, even when localizing symptoms are absent (5). Because significant temperature elevation may be absent in 20% to 30% of elderly patients with a serious infection, elderly patients should be considered febrile when they have an elevated body temperature of approximately 2°F (1°C) above baseline values.
Drug Fever
Elevation of temperature in response to a drug without the presence of rash is known as a drug fever, though it should be more properly termed “drug hypersensitivity.” Although the exact incidence of drug fever is unknown, it may occur in up to 10% of hospitalized patients (6). In ambulatory patients, who are typically on fewer medications, drug fever occurs less frequently.
Contrary to popular conceptions, drug fever usually does not cause a sustained pattern of temperature elevation. There is a variable lag time between initiation of the offending drug and onset of fever, most commonly occurring within 1 or 2 weeks (7). Relative bradycardia is an important clue that may assist the physician in considering drug fever as the cause of an otherwise unexplained temperature elevation, along with a general impression that the patient is not acutely ill. Such a pulse–temperature dissociation can only be determined if a patient has a fever greater than 102°F (38.8°C) and does not have a cardiac conduction disturbance such as sick sinus syndrome or medication effect (e.g., β-blockers). The appropriate pulse for a given temperature is estimated by taking the last digit of the Fahrenheit reading and subtracting 1 and then multiplying by 10 and adding 100 (6). For example, a patient with a temperature of 104°F (40°C) should have a pulse of 130 beats per minutes ([4 – 1] × 10 + 100).
Patients with drug fever will often be unaware of a significant fever, and chills are uncommon. A generalized maculopapular rash may eventually arise in some patients affected by drug fever. There are no diagnostic laboratory features, although the erythrocyte sedimentation rate (ESR) may be elevated to levels exceeding 100 millimeter per hour, and eosinophilia may be found in a small percentage of patients. Fever induced by drugs such as barbiturates, methyldopa, phenytoin, and sulfonamides may herald the development of a serum sickness syndrome with rash, lymphadenopathy, arthritis, and nephritis. Other
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drugs such as procainamide, quinine, and hydralazine may cause a lupus-like syndrome with arthritis, serositis, and production of antinuclear and antihistone antibodies.
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TABLE 31.1 Infections That May Present Initially with Fever Alone |
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Table 31.2 lists commonly prescribed medications that are most likely to cause drug fever. Drugs that are not known to cause hypersensitivity reactions include aminoglycosides, digitalis preparations, and insulins.
The diagnosis of drug fever requires a high index of suspicion, because the often insidious onset may obscure the cause. Withdrawal of the suspected offending agent should result in defervescence within several days but may take weeks in drugs requiring prolonged periods of elimination (e.g., amiodarone, iodides, isoniazid). Conclusive evidence that a drug has caused a febrile reaction can only be proved
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by rechallenge, but this should not be entertained unless that medication is expected to be important for future therapy and no end-organ damage was associated with initial administration.
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TABLE 31.2 Drugs Commonly Implicated in the Development of Fever due to Hypersensitivity |
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The most serious febrile reaction to drugs, malignant hyperthermia, occurs as an idiosyncratic response to neuroleptic medications such as haloperidol, thiothixene or phenothiazines (the neuroleptic malignant syndrome), or to certain anesthetic agents (8,9). Abrupt fever up to 105.8°F (41°C) is accompanied by altered mentation, muscular rigidity, and labile blood pressure. Few infectious processes cause temperatures elevations beyond 105.8°F (41°C), perhaps with the exception of malaria. The human body usually cannot survive fever greater than 107.6°F (42°C) (10). The differential diagnosis of extreme pyrexia otherwise includes only HIV infection, heat stroke, and central fevers because of hypothalamic injury by stroke, tumor, or infection.
Fever of Unknown Origin
Fevers of 101°F (38.3°C) or greater lasting for more than 3 weeks without a diagnosis, despite 1 week of intensive diagnostic investigation in hospital, or fever of unknown origin, has been the traditional definition of FUO (4,11). As a practical matter, this definition has become too restrictive because patients with FUO are less commonly hospitalized and even complex evaluations are now frequently performed on an outpatient basis. Therefore, a patient may be considered to have an FUO if temperature elevations to 101°F (38.3°C) or more persist beyond 3 weeks with negative blood culture studies and no other apparent explanation (12). It has also been proposed that FUO may be diagnosed when fevers remained undiagnosed despite at least three outpatient visits or at least 3 days in the hos-pital (13).
Diagnostic tests such as computed tomography (CT), magnetic resonance imaging (MRI), and serologic analyses have advanced considerably since the early published literature on FUO. Rheumatologic and infectious etiologies now comprise a smaller proportion of FUOs, although infectious causes remain the leading category, accounting for 25% to 50% of achieved diagnoses in recent series (14, 15, 16). Common causes of FUO (Table 31.3) account for up to half of the explanations in published series. Exhaustive lists of potential causes of FUO can be found in several reference sources (12,17).
Some recent demographic trends may be important in the evaluation of FUO. For the category of infection, classic pulmonary tuberculosis rarely leads to FUO because radiographic findings of cavitary disease suggest the proper diagnosis. Extrapulmonary tuberculosis such as
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tubercular lymphadenitis, pleural effusion, and miliary disease are the leading cause of infectious FUO in many series. These diagnoses require a high index of suspicion and confirmation by culture or biopsy of infected tissue. Extrapulmonary tuberculosis in the United States is now most commonly diagnosed in foreign-born individuals who acquired the infection in their native countries (18). An individual with FUO who is a native of a country with high rates of tuberculosis (especially Mexico, the Philippines, Vietnam, India, China, Haiti, and South Korea) should be thoroughly evaluated for tuberculosis (see Chapters 34 and 41).
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TABLE 31.3 Categories and Leading Diseases Causing Fever of Unknown Origin |
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Because of an aging population, malignancies account for an increasing proportion of diagnoses in many FUO series, most significantly non-Hodgkin lymphomas (14,19). Peritoneal carcinomatosis is a particularly challenging diagnosis, because routine screening tests, including imaging studies and endoscopy, often fail to disclose the primary problem. Metastatic disease to the liver or central nervous system may cause persistent low-grade fevers. Myelodysplastic disease, historically termed preleukemia, may be responsible for fever with findings of anemia and sometimes leukopenia or thrombocytopenia.
The most common rheumatologic causes of FUO are diseases that lack characteristic serologic findings. Giant cell arteritis should be considered in any patient with FUO over the age of 50. Marked elevations in nonspecific inflammatory parameters such as the ESR or C-reactive protein (CRP) suggest this diagnosis. The temporal arteries should be biopsied even when significant headache or visual symptoms are lacking. Still's disease is another frequent cause of FUO; it is a clinical diagnosis suggested by high hectic fevers with rigors, arthralgias or arthritis, patchy and evanescent rose-colored rash, and very high serum ferritin (500 to more than 1,000 mg [mg/dL] (20). A recent large study in Europe found that noninfectious inflammatory conditions are the most common diagnostic category in patients with FUO (13).
Among miscellaneous causes, drug fever is a frequently overlooked consideration. Cirrhosis is an unlikely cause of FUO, although patients with cirrhosis are prone to biliary tract infections and candidemia, which may present as isolated fever. Recurrent deep vein thromboses or chronic pulmonary emboli may occasionally cause FUO, although fevers are rarely greater than 102.2°F (39°C). Factitious fever invariably makes up a small but significant percentage of FUO. Patients presenting with factitious fever may have a medical background and have normal body temperature when it is measured under direct observation (21,22).
A group of hereditary periodic fever disorders may occasionally be considered in the evaluation of FUO. Familial Mediterranean fever (FMF), an autosomal recessive disease, is the most common genetically-based FUO. It is found mainly in people with Mediterranean basin ancestors, such as Arabs, Sephardic Jews, Turks, and Armenians, but may occasionally occur in other populations (23). This disorder typically causes the first attack of characteristic fever with serositis (such as arthritis, abdominal pain or pleurisy) by young adulthood. The diagnosis is suggested by episodes of fever with interludes of wellness in the patient and sometimes also in family members. Genetic testing documenting a mutant MEFV gene can be seen in approximately 85% of cases (24). More rare hereditary causes of periodic fever, usually presenting early in life, are the hyperimmunoglobulinemia D syndrome (HDS) and periodic fever syndrome, described in Dutch and French patients, and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS), formerly called familial Hibernian fever following descriptions in Irish and Scotch families, but now recognized in many ethnic groups (25).
In some series, 20% to 50% of patients with FUO remain without a diagnosis despite a thorough evaluation. The likelihood of making a specific diagnosis is higher in patients with a more continuous fever pattern than with episodic fevers (13). Many undiagnosed patients appear to have self-limited illnesses as fevers abate within 6 months (26).
Two special categories of FUO apply uniquely to the ambulatory patient. The first is FUO that lasts for more than 1 year and is not associated with laboratory abnormalities such as anemia or elevated ESR (27). The prognosis in these patients is generally excellent, and the diagnosis of habitual hyperthermia may be considered, especially in women, who may have a slightly higher than average temperature (99°F to 100.5°F [37.2°C to 38°C]) but no other findings (these patients do not fit within the strict definition of FUO). The second is episodic or recurrent FUO, in which fevers occur only after weeks or months of normal temperatures. These are more often due to the miscellaneous causes of FUO (Table 31.3), but up to half of such patients remain undiagnosed (28). Patients with episodic fever who remain without a diagnosis also generally have a good prognosis.
Diagnostic Approach
When a patient presents with fever, the initial evaluation should be guided by consideration of possible serious diagnoses while avoiding inappropriate or unnecessary testing for unlikely causes. Certain patients may be more thoroughly evaluated at the first visit, especially if they have an underlying chronic disorder such as HIV, active cancer, cirrhosis, organ transplantation, or splenectomy. It is important to remember that many patients with FUO are not suffering from rare and unusual diseases but rather are experiencing atypical manifestations of common ill-nesses (4).
For a patient who is not significantly ill and who presents with fever of less than 1 week, the office visit
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should focus on symptoms and signs that may guide the examiner to the most likely explanation for the illness. If no localizing symptoms are found and the patient does not appear seriously ill, then a tentative diagnosis of a viral illness is appropriate. Such patients should be reassured and advised to report if new signs or symptoms arise or if the fever persists beyond the 7 to 10 days that is consistent with self-limited viral infections.
Occasionally, a fever without localizing signs heralds an illness that should be recognized early to avoid significant morbidity and mortality. A short list of infectious considerations should include typhoid fever, malaria, ehrlichiosis, early Rocky Mountain spotted fever, or early viral hepatitis. Primary Epstein-Barr virus (EBV), cytomegalovirus (CMV), or initial HIV infections in the adult will often lack the typical features of mononucleosis-like syndromes and only present with profound malaise, fever, and liver function test abnormalities (29). Careful questioning based on recent residence or behaviors can help to determine whether these infections can be possible considerations.
If fevers persist or significant constitutional features develop (e.g., rigors, profound malaise, anorexia, weight loss, or dizziness), then the patient should be re-evaluated with consideration of whether hospitalization is appropriate. A thorough assessment of the history, including items such as residence, hobbies, past travels, history of international residence, history of tuberculosis exposure, HIV risk factors, alcohol use, recently prescribed medications, and family history of febrile syndromes or autoimmune diseases, should be undertaken. The review of systems should be enumerated meticulously because even trivial symptoms may hold a clue to diagnosing the disorder.
Repeated physical examination may detect problems that are either new or slowly evolving. Areas of particular interest should include attention to all regional lymph node groups, thyroid inspection, notation of oropharyngeal ulcers or exudates, careful auscultation for cardiac murmurs, assessment of liver and spleen size, survey of all joints, examination of nail beds for splinter hemorrhages or clubbing, scrutiny of the skin for rash, and neurologic examination especially looking for cranial nerve abnormalities (suggesting chronic meningitis) or mononeuritis multiplex (pointing to a vasculitis). Other clues may emerge from the ocular examination, such as Roth spots on the fundus (oval retinal hemorrhages with pale centers suggesting endocarditis but only rarely seen with that illness), scleritis, episcleritis or uveitis (painful red eye syndromes associated with rheumatologic diseases, syphilis, tuberculosis, sarcoidosis, and inflammatory bowel disease, the diagnosis of which usually requires a slit lamp examination; see Chapter 109). Palpation of the temporal arteries may reveal cords or tenderness that suggest giant cell arteritis. In women, the pelvic examination may hold the first clue of subtle pelvic inflammatory disease or neoplasm, whereas in men the scrotal, rectal, and prostate examinations are essential to assess for an occult abscess or malignancy.
Fever Patterns
Although usually dismissed as antiquated observations, specific fever patterns can occasionally aid in suggesting the correct diagnosis and require that patients frequently obtain and log their temperatures so they can be studied (17). A stepwise daily fever elevation associated with a pulse–temperature dissociation (see Drug Fever, above) may suggest typhoid fever. Two daily fever spikes (double-quotidian fever) is a rarity but if present should suggest Still disease, mixed malaria infection caused by more than one Plasmodium species, or gonococcal endocarditis. The biphasic or camelback fever pattern occurs over a 4-day interval with a steady rise and fall of temperature and may represent an infection due to dengue fever, Colorado tick fever, yellow fever, viral hemorrhagic fever, brucellosis, or leptospirosis.
Diagnostic Tests
When a patient has a significant illness or the duration of fever extends beyond 3 weeks, the laboratory may provide important direction in the investigation of fever. Minimum testing should include a complete blood count, electrolyte and liver function panels, complete urinalysis and culture, and ESR, or CRP. A chest radiograph, preferentially with posteroanterior and lateral views, should also be obtained.
At least two aerobic and anaerobic blood culture sets should be inoculated. Up to five blood culture sets may be ordered in situations in which endocarditis is a likely possibility. For example, patients with a prosthetic heart valve or those who have new cardiac murmurs or peri-pheral emboli may have initial blood cultures that are negative. This should prompt consideration of a valvular infection with a fastidious organism, historically HACEK (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae) organisms, although these are now more easily cultured, and nowadays partially-treated bacterial endocarditis or Coxiella burnetti infections are more common causes of culture-negative endocarditis. If blood cultures are obtained from different sites and with at least several hours between each set, that will improve both sensitivity and specificity, the latter by helping to eliminate consideration of contaminating bacteria such as coagulase-negative staphylococci or Propionibacterium acne. A purified protein derivative of Mycobacterium tuberculosis should be placed, although the test may be negative in up to 25% of individuals with active tuberculosis. Lastly, antinuclear and antineutrophilic cytoplasmic antibodies and rheumatoid factor tests should be ordered.
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Many additional tests can be ordered in the evaluation of an FUO, but a “shotgun” approach rarely yields useful information and may frustrate physician and patient alike while increasing costs. The efficient evaluation of this challenging condition should be guided by a comprehensive knowledge of the disorders causing this syndrome (30). Although an evidence based approach has been proposed for diagnostic evaluations for FUO (31), such an approach may be premature because well-designed studies assessing currently available testing options are lacking (32).
A rational approach to FUO popularized by Petersdorf and Beeson (4) refers to “Sutton Law,” named after a notorious criminal of the 1930s who, when asked why he only robbed banks, replied “Why, that's where the money is.” Application of this “law” to patients with FUO directs attention to an obvious abnormality that then suggests the test most likely to yield a diagnostic result, rather than proceeding with rote testing (4). More recently, investigators have favored the term “potentially diagnostic clue” (33,34). In one series of patients with FUO evaluated in a community hospital setting, 90% of patients were diagnosed by abnormalities detected either by the physical examination or by routine laboratory tests (35).
Diagnostic Imaging
CT or MRI of pertinent body areas is often helpful. When these studies are not diagnostic, radionuclide scans may be useful in the evaluation of FUO, but also have drawbacks. Gallium scans or indium-labeled white blood cell scans can demonstrate an abnormal area not previously considered in a patient with FUO; however, the rate of false positive and false negative studies probably outweigh routine use. Ultrasonography, CT or MRI are more accurate (36, 37, 38) in detecting specific abnormalities, although a negative 111In-granulocyte scan may be useful in ruling out an infectious etiology (39). When the detection of an infected vascular graft or mycotic aneurysm, especially involving a large vessel such as the aorta, is under consideration, a gallium or white blood cell scan may be useful. Technetium bone scans have a role in the diagnosis of osteomyelitis but may be falsely positive, especially in areas of overlying soft tissue inflammation such as diabetic foot ulcers.
A newer technology, the 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) scan, developed to help diagnose malignant tumors, has been advocated for use in the diagnosis of FUO (34). Although one prospective study of FUO patients suggested that FDG-PET imaging contributed to the diagnosis in the majority of those with abnormal studies (40), the high false-positive rate of these scans warrants caution (41).
Standard transthoracic echocardiography is inadequate to rule out the presence of valvular vegetation in infectious endocarditis. Transesophageal echocardiography is superior but may fail to detect vegetations in 5% to 10% of patients with infectious endocarditis, and a repeat study should be done if clinical suspicion of the diagnosis remains high (42).
When repeated history and physical examinations and laboratory testing do not produce results, consultation may be helpful. Diagnostic consultations for FUO fall into many hands, but traditionally internists, rheumatologists, and infectious disease specialists evaluate most of these cases. If fever and a possibly associated abnormality persist, it may be advantageous, for example, to call upon a gastroenterologist or hepatologist for help with fever and transaminase evaluation or a hematologist for fever and pancytopenia. One of the most frequently overlooked strategies that may quickly lead to diagnosis is biopsy of any suspicious skin lesion or abnormal lymph node.
Bone marrow aspirate and biopsy is a generally safe procedure that may yield evidence of a disseminated granulomatous disorder and provide culture information helpful in the evaluation of fungal or mycobacterial disorders (43). Liver biopsy is an option when persistent liver function test abnormalities are not explained by noninvasive testing, although the yield of this procedure is only 5% to 17% (44). In areas of endemic fungal infection such as histoplasmosis or coccidioides, liver biopsy may still yield diagnostic information even in the absence of blood test abnormalities. Finally, direct observation through exploratory laparotomy or laparoscopy is rarely performed now because imaging technologies have greatly advanced; however, it may be occasionally required especially in disorders isolated to the peritoneum such as tuberculous peritonitis or abdominal carcinomatosis (45).
The so-called naproxen test has been used to discriminate between fevers due to infection or malignancy (46). Fevers due to neoplasia are purportedly more responsive to the nonsteroidal anti-inflammatory agents (NSAIDs) than those caused by infection. A recent study suggests that responsiveness to nonsteroidal anti-inflammatory drugs (NSAIDS) generally is poor in patients with FUO and that the naproxen test is of limited value (47). The naproxen test is probably most useful in patients with a known malignancy who develop fevers of uncertain cause rather than in those with FUO new to a diagnostic evaluation.
Treatment
In the noncritically ill patient, reaching a diagnosis is invariably more difficult if empirical therapies obfuscate the cause of fever. Empiric trials of antibiotics have no role in the treatment of fever, unless one is certain of a diagnosis (e.g., Lyme disease manifested by erythema migrans or culture-negative endocarditis supported by echocardiographic findings). Patients with progressive illness who are suspected to have tuberculosis should have empirical therapy initiated before they become critically ill, but this
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should not be done with an ambulatory patient who can wait until the diagnosis of tuberculosis is certain (48).
High-dose corticosteroids should be reserved for patients with proven vasculitis or other inflammatory disorders, although lower dose steroid therapy may be helpful both diagnostically and therapeutically with cases of temporal arteritis. Occasionally, some patients with FUO have no easily definable illness but remain significantly sick with all diagnostic options exhausted. Such patients could be considered for the very careful initiation of corticosteroids to treat a putative inflammatory disorder (49).
Antipyretic Therapy
Although there is considerable evidence suggesting that fever benefits host immune defenses, especially in infectious disorders (50), physicians routinely prescribe antipyretics. There appears to be little clear benefit from treating fever with acetaminophen, aspirin, or NSAIDs. Therefore, many sources suggest withholding antipyretic agents (51). Only in special situations should they be considered, such as fever in either the very young or very old at risk for febrile seizures, fever in patients unable to tolerate the increased metabolic demands because of ischemic heart disease, or in the uncommon patient who is unable to tolerate the discomfort associated with the temperature elevation (52).
Although antipyretics are perceived as benign medications, this is not always the case. Acetaminophen can be associated with hepatic or renal toxicity if higher than recommended doses (greater than 4 grams per day) are taken. Patients who use ethanol or are fasting are at higher risk of hepatotoxicity from acetaminophen overdose (53). In children, aspirin has been linked to fulminant hepatitis in influenza- or varicella-related Reye syndrome, and it can increase bleeding risk and cause hepatic and renal toxicity. Corticosteroids may effectively reduce fever, but their significant side-effect profile makes them unacceptable choices for antipyresis alone.
Because fever may produce benefit, and occasionally some diagnostic insight based on its pattern, it may be best to limit the prescription of antipyretics for FUO and instead direct efforts toward the most effective antipyretic—reaching a definite diagnosis and specific therapy.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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