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Copyright The McGraw-Hill Companies. All rights reserved. Harrison's Internal Medicine > Chapter 19. Fever of Unknown Origin > Definition and Classification Fever of unknown origin (FUO) was defined by Petersdorf and Beeson in 1961 as (1 ) temperatures of >38.3C (>101F) on several occasions; (2) a duration of fever of >3 weeks; and (3) failure to reach a diagnosis despite 1 week of inpatient inves tigation. While this classification has stood for more than 30 years, Durack and Street have proposed a new system for classification of FUO: (1) classic FUO; ( 2) nosocomial FUO; (3) neutropenic FUO; and (4) FUO associated with HIV infectio n. Classic FUO corresponds closely to the earlier definition of FUO, differing only with regard to the prior requirement for 1 week's study in the hospital. The ne wer definition is broader, stipulating three outpatient visits or 3 days in the hospital without elucidation of a cause or 1 week of "intelligent and invasive" ambulatory investigation. In nosocomial FUO, a temperature of 38.3C (101F) develop s on several occasions in a hospitalized patient who is receiving acute care and in whom infection was not manifest or incubating on admission. Three days of in vestigation, including at least 2 days' incubation of cultures, is the minimum r equirement for this diagnosis. Neutropenic FUO is defined as a temperature of 38 .3C (101F) on several occasions in a patient whose neutrophil count is <500/L or i s expected to fall to that level in 1 2 days. The diagnosis of neutropenic FUO is invoked if a specific cause is not identified after 3 days of investigation, inc luding at least 2 days' incubation of cultures. HIV-associated FUO is defined by a temperature of 38.3C (101F) on several occasions over a period of >4 weeks for outpatients or >3 days for hospitalized patients with HIV infection. This diagno sis is invoked if appropriate investigation over 3 days, including 2 days' incub ation of cultures, reveals no source. Adoption of these categories of FUO in the literature has allowed a more rationa l compilation of data regarding these disparate groups. In the remainder of this chapter, the discussion will focus on classic FUO in the adult unless otherwise specified. Causes of Classic FUO Table 19-1 summarizes the findings of several large studies of FUO carried out s ince the advent of the antibiotic era, including a prospective study of 167 adul t patients with FUO encompassing all eight university hospitals in the Netherlan ds and using a standardized protocol in which the first author reviewed every pa tient. Coincident with the widespread use of antibiotics, increasingly useful di agnostic technologies both noninvasive and invasive have been developed. Newer studi es reflect not only changing patterns of disease but also the impact of diagnost ic techniques that make it possible to eliminate many patients with specific ill ness from the FUO category. The ubiquitous use of potent broad-spectrum antibiot ics may have decreased the number of infections causing FUO. The wide availabili ty of ultrasonography, CT, MRI, radionuclide scanning, and positron emission tom ography (PET) scanning has enhanced the detection of localized infections and of occult neoplasms and lymphomas in patients previously thought to have FUO. Like wise, the widespread availability of highly specific and sensitive immunologic t

esting has reduced the number of undetected cases of systemic lupus erythematosu s and other autoimmune diseases. Table 19-1 Classic FUO in Adults

Authors (Year of Publication) Years of Study No. of Cases Infections (%) Neoplas ms (%) Noninfectious Inflammatory Diseases (%) Miscellaneous Causes (%) Undiagno sed Causes (%) Petersdorf and Beeson (1961) 1952 1957 100 36 19 19a 19a 7 Larson and Featherstone (1982) 1970 1980 105 30 31 16a 11a 12 Knockaert and Vanneste (1992) 1980 1989 199 22.5 7 23a 21.5a 25.5 de Kleijn et al. (1997, Part I) 1992 1994 167 26 12.5 24 8 30

aAuthors' raw data retabulated to conform to altered diagnostic categories. Source: Modified from de Kleijn et al., 1997 (Part I). Infections, especially extrapulmonary tuberculosis, remain the leading diagnosab le cause of FUO. Prolonged mononucleosis syndromes caused by Epstein-Barr virus, cytomegalovirus (CMV), or HIV are conditions whose consideration as a cause of FUO is sometimes confounded by delayed antibody responses. Intraabdominal absces ses (sometimes poorly localized) and renal, retroperitoneal, and paraspinal absc esses continue to be difficult to diagnose. Renal malacoplakia, with submucosal plaques or nodules involving the urinary tract, may cause FUO and is often fatal if untreated. It is associated with intracellular bacterial infection, is seen most often in patients with defects of intracellular bacterial killing, and is t reated with fluoroquinolones or trimethoprim-sulfamethoxazole. Occasionally, oth er organs may be involved. Osteomyelitis, especially where prosthetic devices ha ve been implanted, and infective endocarditis must be considered. Although true culture-negative infective endocarditis is rare, one may be misled by slow-growi ng organisms of the HACEK group (Haemophilus aphrophilus, Actinobacillus actinom ycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kinga e; Chap. 140), Bartonella spp. (previously Rochalimaea), Legionella spp., Coxiel la burnetii, Chlamydophila psittaci, and fungi. Prostatitis, dental abscesses, s inusitis, and cholangitis continue to be sources of occult fever. Fungal disease, most notably histoplasmosis involving the reticuloendothelial sy stem, may cause FUO. FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans. Malaria (which may result from transfusion, the fa ilure to take a prescribed prophylactic agent, or infection with a drug-resistan t strain) continues to be a cause, particularly of asynchronous FUO. A related p rotozoan infection, babesiosis, may cause FUO and is increasing in geographic di stribution and in incidence, especially among the elderly and immunosuppressed. In most earlier series, neoplasms were the next most common cause of FUO after i nfections (Table 19-1). In more recent series, a decrease in the percentage of F UO cases due to malignancy was attributed to improvement in diagnostic technolog ies in particular, high-resolution tomography, MRI, PET scanning, and tumor antige n assays. This observation does not diminish the importance of considering neopl asia in the initial diagnostic evaluation of a patient with fever. A number of p

atients in these series had temporal arteritis, adult Still's disease, drug-rela ted fever, and factitious fever. In recent series, ~25 30% of cases of FUO have re mained undiagnosed. The general term noninfectious inflammatory diseases applies to systemic rheumatologic or vasculitic diseases such as polymyalgia rheumatica , lupus, and adult Still's disease as well as to granulomatous diseases such as sarcoidosis and Crohn's and granulomatous hepatitis. In the elderly, multisystem disease is the most frequent cause of FUO, giant-cel l arteritis being the leading etiologic entity in this category. In patients >50 years of age, this disease accounts for 15 20% of FUO cases. Tuberculosis is the most common infection causing FUO in the elderly, and colon cancer is an importa nt cause of FUO with malignancy in this age group. Many diseases have been grouped in the various studies as "miscellaneous." On th is list are drug fever, pulmonary embolism, factitious fever, the hereditary per iodic fever syndromes (familial Mediterranean fever, hyper-IgD syndrome, tumor n ecrosis factor receptor associated periodic syndrome, familial cold urticaria, and the Muckle-Wells syndrome), and Fabry disease. A drug-related etiology must be considered in any case of prolonged fever. Any f ebrile pattern may be elicited by a drug. Virtually all classes of drugs cause f ever, but antimicrobial agents (especially -lactam antibiotics), cardiovascular drugs (e.g., quinidine), antineoplastic drugs, and drugs acting on the central n ervous system (e.g., phenytoin) are particularly common causes. It is axiomatic that, as the duration of fever increases, the likelihood of an i nfectious cause decreases, even for the more indolent infectious etiologies (e.g ., brucellosis, paracoccidioidomycosis, malaria due to Plasmodium malariae). In a series of 347 patients referred to the National Institutes of Health from 1961 to 1977, only 6% had an infection (Table 19-2). A significant proportion (9%) h ad factitious fevers i.e., fevers due either to false elevations of temperature or to self-induced disease. A substantial number of these factitious cases were in young women in the health professions. It is worth noting that 8% of the patien ts with prolonged fevers (some of whom had completely normal liver function stud ies) had granulomatous hepatitis, and 6% had adult Still's disease. After prolon ged investigation, 19% of cases still had no specific diagnosis. A total of 27% of patients had no actual fever during inpatient observation or had an exaggerat ed circadian temperature rhythm without chills, elevated pulse, or other abnorma lities. Table 19-2 Causes of FUO Lasting >6 Months

Cause Cases, % None identified 19 Miscellaneous causes 13 Factitious causes 9 Granulomatous hepatitis 8 Neoplasm 7 Still's disease 6 Infection 6 Collagen vascular disease 4 Familial Mediterranean fever 3 No fevera 27

aNo actual fever observed during 2 3 weeks of inpatient observation. Includes pati

ents with exaggerated circadian rhythm. Source: From a study of 347 patients referred to the National Institutes of Heal th from 1961 to 1977 with a presumptive diagnosis of FUO of >6 months' duration (R Aduan et al. Prolonged fever of unknown origin. Clin Res 26:558A, 1978). More than 200 conditions may be considered in the differential diagnosis of clas sic FUO in adults; the most common of these are listed in Table 19-3. This list applies strictly to the United States. Geographic considerations are paramount. For example, in Japan, human T cell lymphotropic virus type I is a consideration ; in China, infection plays a greater role and tuberculosis is prominent; and in Spain, visceral leishmaniasis may be a more common cause of FUO. The frequency of global travel underscores the need for a detailed travel history, and the con tinuing emergence of new infectious diseases makes this listing potentially inco mplete. The possibility of international and domestic terrorist activity involvi ng the intentional release of infectious agents, many of which cause illnesses p resenting with prolonged fever, underscores the need for obtaining an insightful environmental, occupational, and professional history, with early notification of public health authorities in cases of suspicious etiology (Chap. 214). Table 19-3 Causes of FUO in Adults in the United States

Infections Localized pyogenic infections Appendicitis Cat-scratch disease Cholangitis Cholecystitis Dental abscess Diverticulitis/abscess Lesser sac abscess Liver abscess Mesenteric lymphadenitis Osteomyelitis Pancreatic abscess Pelvic inflammatory disease Perinephric/intrarenal abscess Prostatic abscess Renal malacoplakia Sinusitis

Subphrenic abscess Suppurative thrombophlebitis Tuboovarian abscess Intravascular infections Bacterial aortitis Bacterial endocarditis Vascular catheter infection Systemic bacterial infections Bartonellosis Brucellosis Campylobacter infection Cat-scratch disease/bacillary angiomatosis (B. henselae) Gonococcemia Legionnaires' disease Leptospirosis Listeriosis Lyme disease Melioidosis Meningococcemia Rat-bite fever Relapsing fever Salmonellosis Syphilis Tularemia Typhoid fever Vibriosis Yersinia infection Mycobacterial infections M. avium/M. intracellulare infections Other atypical mycobacterial infections

Tuberculosis Other bacterial infections Actinomycosis Bacillary angiomatosis Nocardiosis Whipple's disease Rickettsial infections Anaplasmosis Ehrlichiosis Murine typhus Q fever Rickettsialpox Rocky Mountain spotted fever Mycoplasmal infections Chlamydial infections Lymphogranuloma venereum Psittacosis TWAR (C. pneumoniae) infection Viral infections Colorado tick fever Coxsackievirus group B infection Cytomegalovirus infection Dengue Epstein-Barr virus infection Hepatitis A, B, C, D, and E Human herpesvirus 6 infection Human immunodeficiency virus infection Lymphocytic choriomeningitis Parvovirus B19 infection Fungal infections

Aspergillosis Blastomycosis Candidiasis Coccidioidomycosis Cryptococcosis Histoplasmosis Mucormycosis Paracoccidioidomycosis Pneumocystis infection Sporotrichosis Parasitic infections Amebiasis Babesiosis Chagas' disease Leishmaniasis Malaria Strongyloidiasis Toxocariasis Toxoplasmosis Trichinosis Presumed infections, agent undetermined Kawasaki's disease (mucocutaneous lymph node syndrome) Kikuchi's necrotizing lymphadenitis Neoplasms Malignant Colon cancer Gall bladder carcinoma Hepatoma Hodgkin's lymphoma Immunoblastic T-cell lymphoma

Leukemia Lymphomatoid granulomatosis Malignant histiocytosis Non-Hodgkin's lymphoma Pancreatic cancer Renal cell carcinoma Sarcoma Benign Atrial myxoma Castleman's disease Renal angiomyolipoma Habitual Hyperthermia (Exaggerated circadian rhythm) Collagen Vascular/Hypersensitivity Diseases Adult Still's disease Behet's disease Erythema multiforme Erythema nodosum Giant-cell arteritis/polymyalgia rheumatica Hypersensitivity pneumonitis Hypersensitivity vasculitis Mixed connective-tissue disease Polyarteritis nodosa Relapsing polychondritis Rheumatic fever Rheumatoid arthritis Schnitzler's syndrome Systemic lupus erythematosus Takayasu's aortitis Weber-Christian disease

Wegener's granulomatosis Granulomatous Diseases Crohn's disease Granulomatous hepatitis Midline granuloma Sarcoidosis Miscellaneous Conditions Aortic dissection Drug fever Gout Hematomas Hemoglobinopathies Laennec's cirrhosis PFPA syndrome: periodic fever, adenitis, pharyngitis, aphthae Postmyocardial infarction syndrome Recurrent pulmonary emboli Subacute thyroiditis (de Quervain's) Tissue infarction/necrosis Inherited and Metabolic Diseases Adrenal insufficiency Cyclic neutropenia Deafness, urticaria, and amyloidosis Fabry disease Familial cold urticaria Familial Mediterranean fever Hyperimmunoglobulinemia D and periodic fever Muckle-Wells syndrome Tumor necrosis factor receptor associated periodic syndrome Type V hypertriglyceridemia Thermoregulatory Disorders

Central Brain tumor Cerebrovascular accident Encephalitis Hypothalamic dysfunction Peripheral Hyperthyroidism Pheochromocytoma Factitious Fevers "Afebrile" FUO (<38.3C)

Source: Modified from RK Root, RG Petersdorf, in JD Wilson et al (eds): Harrison 's Principles of Internal Medicine, 12th ed. New York, McGraw-Hill, 1991. Specialized Diagnostic Studies Classic FUO A stepwise flow chart depicting the diagnostic workup and therapeutic management of FUO is provided in Fig. 19-1. In this flow chart, reference is made to "pote ntially diagnostic clues," as outlined by de Kleijn and colleagues; these clues may be key findings in the history (e.g., travel), localizing signs, or key symp toms. Certain specific diagnostic maneuvers become critical in dealing with prol onged fevers. If factitious fever is suspected, electronic thermometers should b e used, temperature-taking should be supervised, and simultaneous urine and body temperatures should be measured. Thick blood smears should be examined for Plas modium; thin blood smears, prepared with proper technique and quality stains and subjected to expert microscopy, should be used to speciate Plasmodium and to id entify Babesia, Trypanosoma, Leishmania, Rickettsia, and Borrelia. Any tissue re moved during prior relevant surgery should be reexamined; slides should be reque sted, and, if need be, paraffin blocks of fixed pathologic material should be re examined and additional special studies performed. Relevant x-rays should be ree xamined; reviewing of prior radiologic reports may be insufficient. Serum should be set aside in the laboratory as soon as possible and retained for future exam ination for rising antibody titers. Figure 19-1

Approach to the patient with classic FUO. a"Potentially diagnostic clues," as ou tlined by de Kleijn and colleagues (1997, Part II), may be key findings in the h istory, localizing signs, or key symptoms. ANA, antinuclear antibody; CBC, compl ete blood count; CMV, cytomegalovirus; CRP, C-reactive protein; CT, computed tom ography; Diff, differential; EBV, Epstein-Barr virus; ESR, erythrocyte sedimenta

tion rate; FDG, fluorodeoxyglucose F18; NSAIDs, nonsteroidal anti-inflammatory d rugs; PET, positron emission tomography; PMN, polymorphonuclear leukocyte; PPD, purified protein derivative; RF, rheumatoid factor; SPEP, serum protein electrop horesis; TB, tuberculosis; TIBC, total iron-binding capacity; VDRL, Venereal Dis ease Research Laboratory test. bNeedle biopsy of liver as well as any other tiss ue indicated by "potentially diagnostic clues." cInvasive testing could involve laparoscopy. dEmpirical therapy is a last resort, given the good prognosis of mo st patients with FUO persisting without a diagnosis.

Febrile agglutinins is a vague term that in most laboratories refers to serologi c studies for salmonellosis, brucellosis, and rickettsial diseases. These studie s are seldom useful, having low sensitivity and variable specificity. Multiple b lood samples (no fewer than three and rarely more than six, including samples fo r anaerobic culture) should be cultured in the laboratory for at least 2 weeks t o ensure that any HACEK group organisms that may be present have ample time to g row (Chap. 140). Lysis-centrifugation blood culture techniques should be employe d in cases where prior antimicrobial therapy or fungal or atypical mycobacterial infection is suspected. Blood culture media should be supplemented with L-cyste ine or pyridoxal to assist in the isolation of nutritionally variant streptococc i. It should be noted that sequential cultures positive for multiple organisms m ay reflect self-injection of contaminated substances. Urine cultures, including cultures for mycobacteria, fungi, and CMV, are indicated. In the setting of recu rrent fevers with lymphocytic meningitis (Mollaret's meningitis), cerebrospinal fluid can be tested for herpesvirus, with use of the polymerase chain reaction ( PCR) to amplify and detect viral nucleic acid (Chap. 172). A recent report descr ibed a highly multiplexed oligonucleotide microarray using PCR amplification and containing probes for all recognized vertebrate virus species and for 135 bacte rial, 73 fungal, and 63 parasitic genera and species. The eventual clinical vali dation of such microarrays will further diminish rates of undiagnosed FUO of inf ectious etiology. In any FUO workup, the erythrocyte sedimentation rate (ESR) should be determined . Striking elevation of the ESR and anemia of chronic disease are frequently see n in association with giant-cell arteritis or polymyalgia rheumatica common causes of FUO in patients >50 years of age. Still's disease is suggested by elevations of ESR, leukocytosis, and anemia and is often accompanied by arthralgias, polys erositis (pleuritis, pericarditis), lymphadenopathy, splenomegaly, and rash. The C-reactive protein level may be a useful cross-reference for the ESR and is a m ore sensitive and specific indicator of an "acute-phase" inflammatory metabolic response. Antinuclear antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and serum cryoglobulins should be measured to rule out other collagen va scular diseases and vasculitis. Elevated levels of angiotensin-converting enzyme in serum may point to sarcoidosis. With rare exceptions, the intermediate-stren gth purified protein derivative (PPD) skin test should be used to screen for tub erculosis in patients with classic FUO. Concurrent control tests, such as the mu mps skin test antigen (Aventis-Pasteur, Swiftwater, PA), should be employed. It should be kept in mind that both the PPD skin test and control tests may yield n egative results in miliary tuberculosis, sarcoidosis, Hodgkin's disease, malnutr ition, or AIDS. Noninvasive procedures should include an upper gastrointestinal contrast study w ith small-bowel follow-through and colonoscopy to examine the terminal ileum and cecum. Colonoscopy is especially strongly indicated in the elderly. Chest x-ray s should be repeated if new symptoms arise. Sputum should be induced with an ult rasonic nebulizer for cultures and cytology. If there are pulmonary signs or sym ptoms, bronchoscopy with bronchoalveolar lavage for cultures and cytology should be considered. High-resolution spiral CT of the chest and abdomen should be per formed with both IV and oral contrast. If a spinal or paraspinal lesion is suspe

cted, however, MRI is preferred. MRI may be superior to CT in demonstrating intr aabdominal abscesses and aortic dissection, but the relative utility of MRI and CT in the diagnosis of FUO is unknown. At present, abdominal CT with contrast sh ould be used unless MRI is specifically indicated. Arteriography may be useful f or patients in whom systemic necrotizing vasculitis is suspected. Saccular aneur ysms may be seen, most commonly in renal or hepatic vessels, and may permit diag nosis of arteritis when biopsy is difficult. Ultrasonography of the abdomen is u seful for investigation of the hepatobiliary tract, kidneys, spleen, and pelvis. Echocardiography may be helpful in an evaluation for bacterial endocarditis, pe ricarditis, nonbacterial thrombotic endocarditis, and atrial myxomas. Transesoph ageal echocardiography is especially sensitive for these lesions. Radionuclide scanning procedures using technetium (Tc) 99m sulfur colloid, galli um (Ga) 67 citrate, or indium (In) 111 labeled leukocytes may be useful in identif ying and/or localizing inflammatory processes. In one study, Ga scintigraphy yie lded useful diagnostic information in almost one-third of cases, and it was sugg ested that this procedure might actually be used before other imaging techniques if no specific organ is suspected of being abnormal. It is likely that PET scan ning, which provides quicker results (hours vs days), will prove even more sensi tive and specific than 67Ga scanning in FUO. 99mTc bone scan should be undertake n to look for osteomyelitis or bony metastases; 67Ga scan may be used to identif y sarcoidosis (Chap. 322) or Pneumocystis infection (Chap. 200) in the lungs or Crohn's disease (Chap. 289) in the abdomen. 111In-labeled white blood cell (WBC) scan may be used to locate abscesses. With these scans, false-positive and fals e-negative findings are common. Fluorodeoxyglucose F18 (FDG) PET scanning appear s to be superior to other forms of nuclear imaging. The FDG used in PET scans ac cumulates in tumors and at sites of inflammation and has even been shown to accu mulate reliably at sites of vasculitis. Where available, FDG PET scanning should therefore be chosen over 67Ga scanning in the diagnosis of FUO. Biopsy of the liver and bone marrow should be considered in the workup of FUO if the studies mentioned above are unrevealing and if fever is prolonged. Granulom atous hepatitis has been diagnosed by liver biopsy, even when liver enzymes are normal and no other diagnostic clues point to liver disease. All biopsy specimen s should be cultured for bacteria, mycobacteria, and fungi. Likewise, in the abs ence of clues pointing to the bone marrow, bone marrow biopsy (not simple aspira tion) for histology and culture has yielded diagnoses late in the workup. When p ossible, a section of the tissue block should be retained for further sections o r stains. PCR technology makes it possible in some cases to identify and speciat e mycobacterial DNA in paraffin-embedded, fixed tissues at some research centers . Thus, in some cases, a retrospective diagnosis can be made on the basis of stu dies of long-fixed pathologic tissues. In a patient over age 50 (or occasionally in a younger patient) with the appropriate symptoms and laboratory findings, "b lind biopsy" of one or both temporal arteries may yield a diagnosis of arteritis . Tenderness or decreased pulsation, if noted, should guide the selection of a s ite for biopsy. Lymph node biopsy may be helpful if nodes are enlarged, but ingu inal nodes are often palpable and are seldom diagnostically useful. Exploratory laparotomy has been performed when all other diagnostic procedures f ail but has largely been replaced by imaging and guided-biopsy techniques. Lapar oscopic biopsy may provide more adequate guided sampling of lymph nodes or liver , with less invasive morbidity. Nosocomial FUO (See also Chap. 125) The primary considerations in diagnosing nosocomial FUO are the underlying susceptibility of the patient coupled with the potential complic ations of hospitalization. The original surgical or procedural field is the plac e to begin a directed physical and laboratory examination for abscesses, hematom as, or infected foreign bodies. More than 50% of patients with nosocomial FUO ar

e infected. Intravascular lines, septic phlebitis, and prostheses are all suspec t. In this setting, the best approach is to focus on sites where occult infectio ns may be sequestered, such as the sinuses of intubated patients or a prostatic abscess in a man with a urinary catheter. Clostridium difficile colitis may be a ssociated with fever and leukocytosis before the onset of diarrhea. In ~25% of p atients with nosocomial FUO, the fever has a noninfectious cause. Among these ca uses are acalculous cholecystitis, deep-vein thrombophlebitis, and pulmonary emb olism. Drug fever, transfusion reactions, alcohol/drug withdrawal, adrenal insuf ficiency, thyroiditis, pancreatitis, gout, and pseudogout are among the many pos sible causes to consider. As in classic FUO, repeated meticulous physical examin ations, coupled with focused diagnostic techniques, are imperative. Multiple blo od, wound, and fluid cultures are mandatory. The pace of diagnostic tests is acc elerated, and the threshold for procedures CT scans, ultrasonography, 111In WBC sc ans, noninvasive venous studies is low. Even so, 20% of cases of nosocomial FUO ma y go undiagnosed. Like diagnostic measures, therapeutic maneuvers must be swift and decisive, as m any patients are already critically ill. IV lines must be changed (and cultured) , drugs stopped for 72 h, and empirical therapy started if bacteremia is a threa t. In many hospital settings, empirical antibiotic coverage for nosocomial FUO n ow includes vancomycin for coverage of methicillin-resistant Staphylococcus aure us as well as broad-spectrum gram-negative coverage with piperacillin/tazobactam , ticarcillin/clavulanate, imipenem, or meropenem. Practice guidelines covering many of these issues have been published jointly by the Infectious Diseases Soci ety of America (IDSA) and the Society for Critical Care Medicine and can be acce ssed on the IDSA website (www.journals.uchicago.edu/IDSA/guidelines). Neutropenic FUO (See also Chap. 82) Neutropenic patients are susceptible to focal bacterial and fungal infections, to bacteremic infections, to infections involving catheters ( including septic thrombophlebitis), and to perianal infections. Candida and Aspe rgillus infections are common. Infections due to herpes simplex virus or CMV are sometimes causes of FUO in this group. While the duration of illness may be sho rt in these patients, the consequences of untreated infection may be catastrophi c; 50 60% of febrile neutropenic patients are infected, and 20% are bacteremic. Th e IDSA has published extensive practice guidelines covering these critically ill neutropenic patients; these guidelines appear on the website cited in the previ ous section. In these patients, severe mucositis, quinolone prophylaxis, coloniz ation with methicillin-resistant S. aureus, obvious catheter-related infection, or hypotension dictates the use of vancomycin plus ceftazidime, cefepime, or a c arbapenem with or without an aminoglycoside to provide empirical coverage for ba cterial sepsis. HIV-Associated FUO HIV infection alone may be a cause of fever. Infection due to Mycobacterium aviu m or Mycobacterium intracellulare, tuberculosis, toxoplasmosis, CMV infection, P neumocystis infection, salmonellosis, cryptococcosis, histoplasmosis, non-Hodgki n's lymphoma, and (of particular importance) drug fever are all possible causes of FUO. Mycobacterial infection can be diagnosed by blood cultures and by liver, bone marrow, and lymph node biopsies. Chest CT should be performed to identify enlarged mediastinal nodes. Serologic studies may reveal cryptococcal antigen, a nd 67Ga scan may help identify Pneumocystis pulmonary infection. FUO has an infe ctious etiology in >80% of HIV-infected patients, but drug fever and lymphoma re main important considerations. Treatment of HIV-associated FUO depends on many f actors and is discussed in Chap. 182. Fever of Unknown Origin: Treatment

The focus here is on classic FUO. Other modifiers of FUO neutropenia, HIV infectio n, a nosocomial setting all vastly affect the risk equation and dictate therapy ba sed on the probability of various causes of fever and on the calculated risks an d benefits of a guided empirical approach. The age and physical state of the pat ient are factors as well: the frail elderly patient may merit a trial of empiric al therapy earlier than the robust young adult. The emphasis in patients with classic FUO is on continued observation and examin ation, with the avoidance of "shotgun" empirical therapy. Antibiotic therapy (ev en that for tuberculosis) may irrevocably alter the ability to culture fastidiou s bacteria or mycobacteria and delineate ultimate cause. However, vital-sign ins tability or neutropenia is an indication for empirical therapy with a fluoroquin olone plus piperacillin or the regimen mentioned above (see "Nosocomial FUO"), f or example. Cirrhosis, asplenia, intercurrent immunosuppressive drug use, or rec ent exotic travel may all tip the balance toward earlier empirical anti-infectiv e therapy. If the PPD skin test is positive or if granulomatous hepatitis or oth er granulomatous disease is present with anergy (and sarcoid seems unlikely), th en a therapeutic trial with isoniazid and rifampin (and possibly a third drug) s hould be undertaken, with treatment usually continued for up to 6 weeks. A failu re of the fever to respond over this period suggests an alternative diagnosis. The response of rheumatic fever and Still's disease to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may be dramatic. The effects of glucocorticoids on temporal arteritis, polymyalgia rheumatica, and granulomatous hepatitis are equally dramatic. Colchicine is highly effective in preventing attacks of famili al Mediterranean fever but is of little use once an attack is well under way. Th e ability of glucocorticoids and NSAIDs to mask fever while permitting the sprea d of infection dictates that their use be avoided unless infection has been larg ely ruled out and unless inflammatory disease is both probable and debilitating or threatening. When no underlying source of FUO is identified after prolonged observation (>6 m onths), the prognosis is generally good, however vexing the fever may be to the patient. Under such circumstances, debilitating symptoms are treated with NSAIDs , and glucocorticoids are the last resort. The initiation of empirical therapy d oes not mark the end of the diagnostic workup; rather, it commits the physician to continued thoughtful reexamination and evaluation. Patience, compassion, equa nimity, and intellectual flexibility are indispensable attributes for the clinic ian in dealing successfully with FUO. Acknowledgments Sheldon M. Wolff, MD, now deceased, was an author of a previous version of this chapter. It is to his memory that the chapter is dedicated. The substantial cont ributions of Charles A. Dinarello, MD, to this chapter in previous editions are gratefully acknowledged. Further Readings Bleeker-Rovers CP et al: A prospective multicenter study on fever of unknown ori gin: The yield of a structured diagnostic protocol. Medicine 86:26, 2007 [PMID: 17220753] de Kleijn EM et al: Fever of unknown origin (FUO): I. A prospective multicenter study of 167 patients with FUO, using fixed epidemiologic entry criteria. Medici ne 76:392, 1997 et al: Fever of unknown origin (FUO): II. Diagnostic procedures in a prospective m

ulticenter study of 167 patients. Medicine 76:401, 1997 Goto M et al: A retrospective review of 226 hospitalized patients with fever. In tern Med 46:17, 2007 [PMID: 17202728] Hirschmann JV: Fever of unknown origin in adults. Clin Infect Dis 24:291, 1997 [ PMID: 9114175] Hughes WT et al: 2002 guidelines for the use of antimicrobial agents in neutrope nic patients with cancer. Clin Infect Dis 34:730, 2002 [PMID: 11850858] Knockaert DC et al: Fever of unknown origin in adults: 40 years on. J Intern Med 253:263, 2003 [PMID: 12603493] Mourad O et al: A comprehensive evidence-based approach to fever of unknown orig in. Arch Intern Med 163:545, 2003 [PMID: 12622601] O'Grady NP et al: Practice guidelines for evaluating new fever in critically ill adult patients. Clin Infect Dis 26:1042, 1998 [PMID: 9597223] Zenone T: Fever of unknown origin in adults: Evaluation of 144 cases in a non-un iversity hospital. Scand J Infect Dis 38:632, 2006 [PMID: 16857607]

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