Introduction
Fever is a common complaint encountered by primary caregivers, internists, and surgeons. We all experience fever throughout our lives, and although frequently the cause of fever is never explained, few of us experience a true “classic” fever of unknown origin (FUO). The term FUO should be reserved for patients who experience all of the following:
Fever >3 weeks
Oral temperature ≥101° F (38.3° C) on several occasions
No definitive diagnosis after an evaluation that includes a comprehensive history, physical examination, and laboratory testing.
Most FUO series have required at least three outpatient visits or a 3-day hospitalization for an individual to be diagnosed with an FUO. Experienced infectious disease physicians frequently cringe when the term FUO is used for fever that does not meet the noted criteria. The concern is that the literature relevant to patients with a true “classic” FUO is not relevant to patients who have had fever for a brief time, who have “fever” but never to 101° F (38.3° C), or who have not had a competent provider consider their symptoms and conduct a thoughtful evaluation. Most cases of fever are due to self-limited viral infections, and many people experience a sensation of fever or report mildly elevated temperatures above their baseline after a major infection or other stress. Diagnosing patients with lower temperatures as having an FUO results in the inclusion of many patients with stress-related hyperthermia and chronic fatigue syndrome. Resources are wasted, and patients with benign or self-limited illnesses can be harmed by the intensive evaluation that is often required to sort out a classic FUO. Individuals with fever that does not meet the criteria for a classic FUO but with laboratory evidence of inflammation often have a similar spectrum of illness as individuals with classic FUO. Immunosuppressed patients and patients that acquire their infection in the hospital have a different set of illnesses that account for prolonged fever and will often require empiric treatment, which should usually be avoided in immunocompetent patients with a FUO. This chapter will review the evaluation and differential diagnosis for an immunocompetent patient with a classic, non-nosocomial acquired FUO.
Understanding Fever
An understanding of the basic pathophysiology behind fever is helpful in understanding the causes of FUO. Normal body temperature varies during the course of a day and is regulated by the hypothalamus. Healthy adults have temperature readings higher in the late afternoon and early evening than in the early morning. A study by Mackowiak and colleagues in 1992 of 144 healthy adults found a mean oral temperature of 36.8° C, with temperature later in the day averaging 0.5° C higher than in the early morning. There was considerable variation in temperature oscillation between subjects, with some increasing by 1.3° C and others by only 0.05° C. The highest “normal” 6 am temperature recorded in this study was 37.2° C and highest 4 pm temperature was 37.7° C. Oral temperatures are about 0.6° C lower than rectal temperatures. Tympanic membrane temperatures are similar to oral temperatures but will be lower if the ear canal is obstructed or if the ambient air temperature is cold resulting in cooling of the tympanic membrane. Oral temperatures can be temporarily altered by eating, drinking, or smoking. Exercise and eating a large meal tend to increase core temperatures. Ideally, temperature measurements should be obtained in a relaxed state, with a comfortable amount of clothing and no sooner than 30 minutes after smoking or eating.
Chronic fever from infection or illnesses associated with inflammation is usually related to an alteration in the set point of heat-sensitive receptors in the hypothalamus. Pyrogenic cytokines include tumor necrosis factor (TNF), interleukins 1β (IL1β) and 6 (IL6), and interferon (INF)-α. When they enter the hypothalamic circulation, these cytokines stimulate the release of local prostaglandins, which activate thermoregulatory neurons of the anterior hypothalamus and reset the hypothalamic thermoregulatory set point. Some older persons may have a blunted febrile response to infections related to decreased production of or response to pyrogenic cytokines. It is not clear if this blunted response is actually due to aging, because this also occurs with other conditions, including malnutrition. Fever can also result from disruption of the autonomic system and changes in neurochemicals.
Causes of FUO
The differential for an FUO is vast and includes chronic infection, malignancy, inflammatory disorders, and miscellaneous conditions, including some genetic syndromes. Worldwide, infection is the leading cause of FUO, with tuberculosis (TB) causing the highest number of cases. Infections most commonly reported to cause FUO in developing countries also include typhoid and malaria. Depending on the patient’s residence and travel history, systemic fungal infection—particularly histoplasmosis or coccidioidomycosis—will be seen more commonly in the United States. Clinicians in developed countries need to remain suspicious of TB as a cause of FUO, particularly among immigrants from and travelers to developing countries where the disease is common. FUO due to TB often presents with extrapulmonary manifestations and remains quite treatable.
Recent series reveal that the frequency of infection as a cause for FUO in developed countries has continued to decrease over the past 50 years, with noninfectious, inflammatory illness now being the most common cause. FUO in community settings is more likely to be due to infection than FUO seen in academic settings. Only 12% of FUO diagnoses were caused by infection in a 2007 study from the Netherlands, whereas 36% were found to have infection in the original US study by Dr. Petersdorf and colleagues from the 1950s.
Endocarditis can be due to any bacteria or fungus and is the classic infectious cause of FUO. Abdominal abscess is the most common localized infection in many recent series. Any localized infections can cause FUO, but others frequently seen include pulmonary abscess, empyema, cholangitis, chronic cholecystitis, hepatic abscess, mycotic aneurysm, prosthetic joint infection, pelvic inflammatory disease, pelvic abscess, prostatic abscess, and chronic prostatitis. Coxiella burnetii , the cause of Q fever, can cause endocarditis but frequently causes FUO without endocarditis and should be considered early in individuals with FUO, particularly if they have exposure to animals. See Table 6.1 for other infections that have a propensity for causing FUO unrelated to endocarditis or localized infection.
| Bacterial: Bartonella infections including cat scratch disease, brucellosis, Coxiella burnetti (the cause of Q fever), Salmonella infections, Streptobacillus moniliformis, Streptobacillus notomytis or Spirillum minus ( causes of rat bite fever ), Tropheryma whippelii ( the cause of Whipple disease), Mycobacterium tuberculosis (the most commonly cultured organism from patients with classic FUO), and Yersinia infection |
| Spirochetes: Leptospirosis, Lyme (rare), Borrelia species (which cause relapsing fever), and syphilis |
| Fungal: Blastomycosis, coccidioidomycosis, cryptococcosis, and histoplasmosis in the Midwest |
| Parasitic Infections: Babesiosis, Entamoeba histolytica (cause of amebic liver abscess), Leishmania species (primarily L. donovani and L. infantum , which cause the majority of visceral leishmaniasis), malaria, toxoplasmosis, trichinosis, and trypanosomiasis |
| Viral Infections: Cytomegalovirus (CMV); Epstein–Barr virus (EBV); hepatitis B, C, and E; human immunodeficiency virus (HIV); parvovirus |
Noninfectious systemic inflammatory and autoimmune illnesses have overtaken infection as the most common cause of FUO among adults in developed countries, particularly at tertiary care centers. Temporal arteritis is a common cause of FUO among the elderly and in several series is the most common cause of FUO in patients older than 65 years. Still’s disease is an unusual illness but a common cause of FUO at tertiary care centers among those under 50 years. Because it is a clinical diagnosis and many clinicians have little experience with it, diagnosis is often delayed until patients are referred to larger centers. The constellation of daily spikes of high fever, arthritis, and transient rash, often brought on by pressure, is highly suggestive of Still’s disease. Inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], and ferritin) are very high with active disease. Vasculitis, including allergic granulomatous angiitis, polyarteritis nodosum (PAN), hypersensitivity vasculitis, Takayasu arteritis, and granulomatosis with polyangiitis frequently present as an FUO. Other noninfectious, inflammatory causes of FUO include antiphospholipid syndrome, Bechet syndrome, cryoglobulinemia, gout, inflammatory bowel disease, pseudogout, reactive arthritis, rheumatic fever, rheumatoid arthritis (RA), serum sickness, and sarcoid. Systemic lupus erythematosus (SLE), which was common in older series, is now an uncommon cause of FUO, most likely because its tendency to cause fever is now well recognized and antinuclear antibody (ANA) testing is done early in the evaluation of unexplained fever. It is important to remember that endocarditis can cause positive autoantibodies, including ANA, and misdiagnosis of endocarditis as lupus or another autoimmune illness can result in disastrous consequences.
Nearly every cancer has been reported to occasionally cause FUO, but hematologic cancers, particularly lymphoma, are seen most commonly. Renal cell cancer, hepatocellular cancer, and metastatic cancer to the liver commonly cause FUO. Colon cancer and breast cancer rarely cause fever, but because they are common cancers, they need to be considered when evaluating a challenging FUO.
Atrial myxomas are unusual benign cardiac tumors, but when they occur they frequently cause FUO.
Nearly every drug has been reported to cause fever. Frequently this occurs shortly after the drug is started, and when associated with rash and eosinophilia, the culprit is usually obvious and the drug is stopped. Fever can, however, start weeks, months, or even years after the initiation of a medication, and drug-associated fever is not always associated with rash or eosinophilia. The relationship of fever to the drug can be challenging in these situations, and a FUO may develop if the drug is continued. Antimicrobials, antiepileptic drugs, and antiinflammatory drugs are the classes of drugs that most frequently cause fever. Drugs that should be viewed with significant suspicion and considered a potential cause of fever in a patient with FUO are listed in Table 6.2 .
| Allopurinol | Iodides |
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| Heparin | Procainamide |
| Hydralazine | Quinidine |
| Hydrochlorothiazide | Sulfonamides |
| Vancomycin | |
| Many others reported |
The miscellaneous causes of FUO are vast and varied. Pancreatitis, alcoholic hepatitis, and alcohol withdrawal are common problems that occasionally cause intermittent FUO. Cirrhosis can also cause FUO. Clots, particularly retroperitoneal hematomas, and pulmonary emboli can cause fever and occasionally FUO. Kikuchi disease is an unusual illness, causing fever and necrotizing, histiocytic lymphadenitis and is thought to be triggered by an infection. Endocrine causes of FUO include both adrenal insufficiency and pheochromocytoma in addition to hyperthyroidism and thyroiditis. Genetic causes include familial Mediterranean fever, TNF-1 receptor antibody syndrome (TRAPS), porphyria, Fabry disease, and periodic fever syndromes, which are most commonly seen in children. Factitious fever is an unusual cause of FUO that is seen more often at tertiary referral centers than by primary care clinicians.
Depending on the population, between 10% and 50% cases of FUO are never diagnosed despite an exhaustive workup. Diagnosis is more likely for the elderly and when fever is high and persistent. Fifty percent of the patients in the 2007 Netherlands study did not receive a diagnosis, whereas only 7% of patients were undiagnosed in Dr. Petersdorf’s original 1950s series. Fortunately, patients with an undiagnosable FUO generally have a good prognosis, and fever usually spontaneously resolves.
Historical Clues
A detailed history is critical in determining how to proceed with evaluation of a classic FUO. This starts with understanding the intensity and duration of the fever. Fever that has been present for less than 6 weeks is highly likely to be due to an undiagnosed infection. The longer the duration of the illness, the less likely infection is to be the cause of FUO, especially in developed countries. Fever >39° C is suggestive of lymphoma, Still’s disease, infection, or vasculitis. The pattern of fever is occasionally helpful, particularly if it is episodic with spells of fever separated by weeks or months. See Table 6.3 for specific illnesses that frequently cause episodic fever. Intermittent high spiking fever suggests an abscess, miliary TB, malaria, Still’s disease, or lymphoma. A double quotidian fever (two fever spikes daily) is suggestive of infection, including typhoid, malaria, visceral leishmaniasis, miliary TB, legionellosis, or Still’s disease.
| Adult Still’s disease |
| Atrial myxoma |
| Castleman disease |
| Crohn disease |
| Chronic prostatitis |
| Cyclic neutropenia |
| Dental abscess |
| Drug-induced fever |
| Subacute bacterial endocarditis (when inadequate empiric antibiotics given) |
| Fabry disease |
| Factitious fever |
| Periodic fever, aphthous ulcers, pharyngitis, and adenitis syndrome (PFAPA) |
| Familial Mediterranean fever |
| Granulomatous hepatitis |
| Hyper-IgD syndrome |
| Hypersensitivity pneumonitis |
| Hypertriglyceridemia |
| Malignancy (particularly lymphoma, but also occurs with solid tumors, including colon and breast cancer) |
| Pulmonary embolism |
| Subacute cholangitis |
| Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) |
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