CHAPTER 13: FEVER OF UNKNOWN ORIGIN

Chantal P. Bleeker-Rovers; Jos W. M. van der Meer

DEFINITION

Clinicians commonly refer to any febrile illness without an initially obvious etiology as fever of unknown origin (FUO). Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. The term FUO should be reserved for prolonged febrile illnesses without an established etiology despite intensive evaluation and diagnostic testing. This chapter focuses on classic FUO in the adult patient.

FUO was originally defined by Petersdorf and Beeson in 1961 as an illness of >3 weeks’ duration with fever of ≥38.3°C (101°F) on two occasions and an uncertain diagnosis despite 1 week of inpatient evaluation. Nowadays, most patients with FUO are hospitalized if their clinical condition requires it, but not for diagnostic purposes only; thus the in-hospital evaluation requirement has been eliminated from the definition. The definition of FUO has been further modified by the exclusion of immunocompromised patients, whose workup requires an entirely different diagnostic and therapeutic approach. For the optimal comparison of patients with FUO in different geographic areas, it has been proposed that the quantitative criterion (diagnosis uncertain after 1 week of evaluation) be changed to a qualitative criterion that requires the performance of a specific list of investigations. Accordingly, FUO is now defined as:

Fever >38.3°C (101°F) on at least two occasions
Illness duration of ≥3 weeks
No known immunocompromised state
Diagnosis that remains uncertain after a thorough history-taking, physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electrophoresis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST).

ETIOLOGY AND EPIDEMIOLOGY

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The range of FUO etiologies has evolved over time as a result of changes in the spectrum of diseases causing FUO, the widespread use of antibiotics, and the availability of new diagnostic techniques. The proportion of cases caused by intraabdominal abscesses and tumors, for example, has decreased because of earlier detection by CT and ultrasound. In addition, infective endocarditis is a less frequent cause because blood culture and echocardiographic techniques have improved. Conversely, some diagnoses, such as acute HIV infection, were unknown four decades ago.

Table 13-1 summarizes the findings of several large studies on FUO conducted over the past 20 years. In general, infection accounts for about 20–25% of cases of FUO in Western countries; next in frequency are neoplasms and noninfectious inflammatory diseases (NIIDs), the latter including “collagen or rheumatic diseases,” vasculitis syndromes, and granulomatous disorders. In geographic areas outside the West, infections are a much more common cause of FUO (43% vs 22%), while the proportions of cases due to NIIDs and neoplasms are similar. Up to 50% of cases caused by infections in patients with FUO outside Western nations are due to tuberculosis, which is a less common cause in the United States and Western Europe. The number of FUO patients diagnosed with NIIDs probably will not decrease in the near future, as fever may precede more typical manifestations or serologic evidence by months in these diseases. Moreover, many NIIDs can be diagnosed only after prolonged observation and exclusion of other diseases.

TABLE 13-1ETIOLOGY OF FEVER OF UNKNOWN ORIGIN (FUO) OVER THE PAST 20 YEARS: FINDINGS FROM LARGE FUO STUDIES

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TABLE 13-1 ETIOLOGY OF FEVER OF UNKNOWN ORIGIN (FUO) OVER THE PAST 20 YEARS: FINDINGS FROM LARGE FUO STUDIES

FIRST AUTHOR (COUNTRY, YEAR OF PUBLICATION)

NO. OF PATIENTS (RECRUITMENT PERIOD)

PERCENTAGE OF CASES DUE TO INDICATED CAUSE

INFECTIONS

NONINFECTIOUS INFLAMMATORY DISEASES

NEOPLASMS

MISCELLANEOUS

UNKNOWN

Western Countries

De Kleijn et al.

167

(Netherlands, 1997)

(1992–1994)

Vanderschueren et al.

185

(Belgium, 2003)

(1990–1999)

Zenone et al.

144

(France, 2006)

(1999–2005)

Bleeker-Rovers

(Netherlands, 2007)

(2003–2005)

Mansueto et al.

(Italy, 2008)

(1991–2002)

Efstathiou et al.

112

(Greece, 2010)

(2001–2007)

Total

772

Other Geographic Locations

Tabak et al.

117

(Turkey, 2003)

(1984–2001)

Saltoglu et al.

(Turkey, 2004)

(1994–2002)

Ergonul et al.

(Turkey, 2005)

(1993–1999)

Chin et al.

(Taiwan, 2006)

(2001–2002)

Colpan et al.

(Turkey, 2007)

(2001–2004)

Hu et al.

142

(China, 2008)

(2002–2003)

Kucukardali et al.

154

(Turkey, 2008)

(2003–2004)

Ali-Eldin et al.

(Egypt, 2011)

(2009–2010)

Total

838

In the West, the percentage of undiagnosed cases of FUO has increased in more recent studies. An important factor contributing to the seemingly high diagnostic failure rate is that a diagnosis is more often being established before 3 weeks have elapsed, given that patients with fever tend to seek medical advice earlier and better diagnostic techniques, such as CT and MRI, are widely available; therefore, only the cases that are more difficult to diagnose continue to meet the criteria for FUO. Furthermore, most patients who have FUO without a diagnosis currently do well, and thus a less aggressive diagnostic approach may be used in clinically stable patients once diseases with immediate therapeutic or prognostic consequences have been ruled out to a reasonable extent. This factor may be especially relevant to patients with recurrent fever who are asymptomatic in between febrile episodes. In patients with recurrent fever (defined as repeated episodes of fever interspersed with fever-free intervals of at least 2 weeks and apparent remission of the underlying disease), the chance of attaining an etiologic diagnosis is <50%.

DIFFERENTIAL DIAGNOSIS

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The differential diagnosis for FUO is extensive, but it is important to remember that FUO is far more often caused by an atypical presentation of a rather common disease than by a very rare disease. Table 13-2 presents an overview of possible causes of FUO. An atypical presentation of endocarditis, diverticulitis, vertebral osteomyelitis, and extrapulmonary tuberculosis are the more common infectious disease diagnoses. Q fever and Whipple’s disease are quite rare but should always be kept in mind as a cause of FUO since the presenting symptoms can be nonspecific. Serologic testing for Q fever, which results from exposure to animals or animal products, should be performed when the patient lives in a rural area or has a history of heart valve disease, an aortic aneurysm, or a vascular prosthesis. In patients with unexplained symptoms localized to the central nervous system (CNS), gastrointestinal tract, or joints, polymerase chain reaction (PCR) testing for Tropheryma whipplei should be performed. Travel to or (former) residence in tropical countries or the American Southwest should lead to consideration of infectious diseases such as malaria, leishmaniasis, histoplasmosis, or coccidioidomycosis. Fever with signs of endocarditis and negative blood culture results poses a special problem. Culture-negative endocarditis may be due to difficult-to-culture bacteria such as nutritionally variant bacteria, HACEK organisms (Haemophilus parainfluenzae, H. paraphrophilus, Aggregatibacter species [actinomycetemcomitans, aphrophilus], Cardiobacterium species [hominis, valvarum], Eikenella corrodens, and Kingella kingae; discussed below), Coxiella burnetii (as indicated above), T. whipplei, and Bartonella species. Marantic endocarditis is a sterile thrombotic disease that occurs as a paraneoplastic phenomenon, especially with adenocarcinomas. Sterile endocarditis is also seen in the context of systemic lupus erythematosus and antiphospholipid syndrome.

TABLE 13-2ALL REPORTED CAUSES OF FUO^a

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TABLE 13-2 ALL REPORTED CAUSES OF FUO^a

Infections

Bacterial, nonspecific

Abdominal abscess, adnexitis, apical granuloma, appendicitis, cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis, epidural abscess, infected vascular catheter, infected joint prosthesis, infected vascular prosthesis, infectious arthritis, infective myonecrosis, intracranial abscess, liver abscess, lung abscess, malakoplakia, mastoiditis, mediastinitis, mycotic aneurysm, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, renal abscess, septic phlebitis, sinusitis, spondylodiscitis, xanthogranulomatous urinary tract infection

Bacterial, specific

Actinomycosis, atypical mycobacterial infection, bartonellosis, brucellosis, Campylobacter infection, Chlamydia pneumoniae infection, chronic meningococcemia, ehrlichiosis, gonococcemia, legionellosis, leptospirosis, listeriosis, louse-borne relapsing fever (Borrelia recurrentis), Lyme disease, melioidosis (Pseudomonas pseudomallei), Mycoplasma infection, nocardiosis, psittacosis, Q fever (Coxiella burnetii), rickettsiosis, Spirillum minor infection, Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii), tuberculosis, tularemia, typhoid fever and other salmonelloses, Whipple’s disease (Tropheryma whipplei), yersiniosis

Fungal

Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Malassezia furfur infection, paracoccidioidomycosis, Pneumocystis jirovecii pneumonia, sporotrichosis, zygomycosis

Parasitic

Amebiasis, babesiosis, echinococcosis, fascioliasis, malaria, schistosomiasis, strongyloidiasis, toxocariasis, toxoplasmosis, trichinellosis, trypanosomiasis, visceral leishmaniasis

Viral

Colorado tick fever, coxsackievirus infection, cytomegalovirus infection, dengue, Epstein-Barr virus infection, hantavirus infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection, human herpesvirus 6 infection, parvovirus infection, West Nile virus infection

Noninfectious Inflammatory Diseases

Systemic rheumatic and autoimmune diseases

Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease, cryoglobulinemia, dermatomyositis, Felty syndrome, gout, mixed connective-tissue disease, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, rheumatic fever, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome

Vasculitis

Allergic vasculitis, Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, hypersensitivity vasculitis, Kawasaki disease, polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis

Granulomatous diseases

Idiopathic granulomatous hepatitis, sarcoidosis

Autoinflammatory syndromes

Adult-onset Still’s disease, Blau syndrome, CAPS^b (cryopyrin-associated periodic syndromes), Crohn’s disease, DIRA (deficiency of the interleukin 1 receptor antagonist), familial Mediterranean fever, hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome)

Neoplasms

Hematologic malignancies

Amyloidosis, angioimmunoblastic lymphoma, Castleman’s disease, Hodgkin’s disease, hypereosinophilic syndrome, leukemia, lymphomatoid granulomatosis, malignant histiocytosis, multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-Hodgkin’s lymphoma, plasmacytoma, systemic mastocytosis, vaso-occlusive crisis in sickle cell disease

Solid tumors

Most solid tumors and metastases can cause fever. Those most commonly causing FUO are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas.

Benign tumors

Angiomyolipoma, cavernous hemangioma of the liver, craniopharyngioma, necrosis of dermoid tumor in Gardner’s syndrome

Miscellaneous

ADEM (acute disseminated encephalomyelitis), adrenal insufficiency, aneurysms, anomalous thoracic duct, aortic dissection, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, Caroli disease, cholesterol emboli, cirrhosis, complex partial status epilepticus, cyclic neutropenia, drug fever, Erdheim-Chester disease, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fire-eater’s lung, fraudulent fever, Gaucher’s disease, Hamman-Rich syndrome (acute interstitial pneumonia), Hashimoto’s encephalopathy, hematoma, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, idiopathic normal-pressure hydrocephalus, inflammatory pseudotumor, Kikuchi’s disease, linear IgA dermatosis, mesenteric fibromatosis, metal fume fever, milk protein allergy, myotonic dystrophy, nonbacterial osteitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), polymer fume fever, post–cardiac injury syndrome, primary biliary cirrhosis, primary hyperparathyroidism, pulmonary embolism, pyoderma gangrenosum, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing mesenteritis, silicone embolization, subacute thyroiditis (de Quervain’s), Sweet syndrome (acute febrile neutrophilic dermatosis), thrombosis, tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis

Thermoregulatory Disorders

Central

Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction

Peripheral

Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, hyperthyroidism, pheochromocytoma

^aThis table includes all causes of FUO that have been described in the literature.

^bCAPS includes chronic infantile neurologic cutaneous and articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.

Of the NIIDs, large-vessel vasculitis, polymyalgia rheumatica, sarcoidosis, familial Mediterranean fever, and adult-onset Still’s disease are rather common diagnoses in patients with FUO. The hereditary autoinflammatory syndromes are very rare and usually present in young patients. Schnitzler’s syndrome, which can present at any age, is uncommon but can often be diagnosed easily in a patient with FUO who presents with urticaria, bone pain, and monoclonal gammopathy.

Although most tumors can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms. Sometimes the fever even precedes lymphadenopathy detectable by physical examination.

Apart from drug-induced fever and exercise-induced hyperthermia, none of the miscellaneous causes of fever is found very frequently in patients with FUO. Virtually all drugs can cause fever, even that commencing after long-term use. Drug-induced fever, including DRESS (drug reaction with eosinophilia and systemic symptoms; Fig. 14-49), is often accompanied by eosinophilia and also by lymphadenopathy, which can be extensive. More common causes of drug-induced fever are allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide, antimicrobial drugs (especially sulfonamides, minocycline, vancomycin, β-lactam antibiotics, and isoniazid), some cardiovascular drugs (e.g., quinidine), and some antiretroviral drugs (e.g., nevirapine). Exercise-induced hyperthermia is characterized by an elevated body temperature that is associated with moderate to strenuous exercise lasting from half an hour up to several hours without an increase in CRP level or ESR; typically these patients sweat during the temperature elevation. Factitious fever (fever artificially induced by the patient—for example, by IV injection of contaminated water) should be considered in all patients but is more common among young women in health care professions. In fraudulent fever, the patient is normothermic but manipulates the thermometer. Simultaneous measurements at different body sites (rectum, ear, mouth) should rapidly identify this diagnosis. Another clue to fraudulent fever is a dissociation between pulse rate and temperature.

Previous studies of FUO have shown that a diagnosis is more likely in elderly patients than in younger age groups. In many cases, FUO in the elderly results from an atypical manifestation of a common disease, among which giant cell arteritis and polymyalgia rheumatica are most frequently involved. Tuberculosis is the most common infectious disease associated with FUO in elderly patients, occurring much more often than in younger patients. As many of these diseases are treatable, it is well worth pursuing the cause of fever in elderly patients.

APPROACH TO PATIENT

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APPROACH TO THE PATIENT: Fever of Unknown Origin FIRST-STAGE DIAGNOSTIC TESTS

Figure 13-1 shows a structured approach to patients presenting with FUO. The most important step in the diagnostic workup is the search for potentially diagnostic clues (PDCs) through complete and repeated history-taking and physical examination and the obligatory investigations listed above. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis. Although PDCs are often misleading, only with their help can a concise list of probable diagnoses be made. The history should include information about the fever pattern (continuous or recurrent) and duration, previous medical history, present and recent drug use, family history, sexual history, country of origin, recent and remote travel, unusual environmental exposures associated with travel or hobbies, and animal contacts. A complete physical examination should be performed, with special attention to the eyes, lymph nodes, temporal arteries, liver, spleen, sites of previous surgery, entire skin surface, and mucous membranes. Before further diagnostic tests are initiated, antibiotic and glucocorticoid treatment, which can mask many diseases, should be stopped. For example, blood and other cultures are not reliable when samples are obtained during antibiotic treatment, and the size of enlarged lymph nodes usually decreases during glucocorticoid treatment, regardless of the cause of the lymphadenopathy. Despite the high number of false-positive ultrasounds and the relatively low sensitivity of chest x-rays, the performance of these simple, low-cost diagnostic tests remains obligatory in all patients with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are not. Abdominal ultrasound is preferred to abdominal CT as an obligatory test because of relatively low cost, lack of radiation burden, and absence of side effects.

Only rarely do biochemical tests (beyond the obligatory tests needed to classify a patient’s fever as FUO) lead directly to a definitive diagnosis in the absence of PDCs. The diagnostic yield of immunologic serology other than that included in the obligatory tests is relatively low. These tests more often yield false-positive rather than true-positive results and are of little use without PDCs pointing to specific immunologic disorders. Given the absence of specific symptoms in many patients and the relatively low cost of the test, investigation of cryoglobulins appears to be a valuable screening test in patients with FUO.

Multiple blood samples should be cultured in the laboratory long enough to ensure ample growth time for any fastidious organisms, such as HACEK organisms. It is critical to inform the laboratory of the intent to test for unusual organisms. Specialized media should be used when the history suggests uncommon microorganisms, such as Histoplasma or Legionella. Performing more than three blood cultures or more than one urine culture is useless in patients with FUO in the absence of PDCs (e.g., a high level of clinical suspicion of endocarditis). Repeating blood or urine cultures is useful only when previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation. FUO with headache should prompt microbiologic examination of cerebrospinal fluid (CSF) for organisms including herpes simplex virus (HSV; especially HSV-2), Cryptococcus neoformans, and Mycobacterium tuberculosis. In CNS tuberculosis, the CSF typically has elevated protein and lowered glucose concentrations, with a mononuclear pleocytosis. CSF protein levels range from 100 to 500 mg/dL in most patients, the CSF glucose concentration is <45 mg/dL in 80% of cases, and the usual CSF cell count is between 100 and 500 cells/μL.

Microbiologic serology should not be included in the diagnostic workup in patients without PDCs for specific infections. A TST is included in the obligatory investigations, but it may yield false-negative results in patients with miliary tuberculosis, malnutrition, or immunosuppression. Although the interferon γ release assay is less influenced by prior vaccination with bacille Calmette-Guérin or by infection with nontuberculous mycobacteria, its sensitivity is similar to that of the TST; a negative TST or interferon γ release assay therefore does not exclude a diagnosis of tuberculosis. Miliary tuberculosis is especially difficult to diagnose. Granulomatous disease in liver or bone marrow biopsy samples, for example, should always lead to a (re)consideration of this diagnosis. If miliary tuberculosis is suspected, liver biopsy for acid-fast smear, culture, and PCR probably still has the highest diagnostic yield; however, biopsies of bone marrow, lymph nodes, or other involved organs also can be considered.

The diagnostic yield of echocardiography, sinus radiography, radiologic or endoscopic evaluation of the gastrointestinal tract, and bronchoscopy is very low in the absence of PDCs. Therefore, these tests should not be used as screening procedures.

After identification of all PDCs retrieved from the history, physical examination, and obligatory tests, a limited list of the most probable diagnoses should be made. Since most investigations are helpful only for patients who have PDCs for the diagnoses sought, further diagnostic procedures should be limited to specific investigations aimed at confirming or excluding diseases on this list. In FUO, the diagnostic pointers are numerous and diverse but may be missed on initial examination, often being detected only by a very careful examination performed subsequently. In the absence of PDCs, the history and physical examination should therefore be repeated regularly. One of the first steps should be to rule out factitious or fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, including nonprescription drugs and nutritional supplements, should be discontinued early in the evaluation to exclude drug fever. If fever persists beyond 72 h after discontinuation of the suspected drug, it is unlikely that this drug is the cause. In patients without PDCs or with only misleading PDCs, funduscopy by an ophthalmologist may be useful in the early stage of the diagnostic workup. When the first-stage diagnostic tests do not lead to a diagnosis, scintigraphy should be performed, especially when the ESR or CRP level is elevated.

Recurrent Fever

In patients with recurrent fever, the diagnostic workup should consist of thorough history-taking, physical examination, and obligatory tests. The search for PDCs should be directed to clues matching known recurrent syndromes (Table 13-3). Patients should be asked to return during a febrile episode so that the history, physical examination, and laboratory tests can be repeated during a symptomatic phase. Further diagnostic tests, such as scintigraphic imaging (see below), should be performed only during a febrile episode because abnormalities may be absent between episodes. In patients with recurrent fever lasting >2 years, it is very unlikely that the fever is caused by infection or malignancy. Further diagnostic tests in that direction should be considered only when PDCs for infections, vasculitis syndromes, or malignancy are present or when the patient’s clinical condition is deteriorating.

Scintigraphy

Scintigraphic imaging is a noninvasive method allowing delineation of foci in all parts of the body on the basis of functional changes in tissues. This procedure plays an important role in the diagnosis of patients with FUO in clinical practice. Conventional scintigraphic methods used in clinical practice are ⁶⁷Ga-citrate scintigraphy and ¹¹¹In- or ^99mTc-labeled leukocyte scintigraphy. Focal infectious and inflammatory processes can also be detected by several radiologic techniques, such as CT, MRI, and ultrasound. However, because of the lack of substantial pathologic changes in the early phase, infectious and inflammatory foci cannot be detected at this time. Furthermore, distinguishing active infectious or inflammatory lesions from residual changes due to cured processes or surgery remains critical. Finally, CT and MRI routinely provide information only on part of the body, while scintigraphy readily allows whole-body imaging.

Fluorodeoxyglucose Positron Emission Tomography

¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an established imaging procedure in FUO. FDG accumulates in tissues with a high rate of glycolysis, which occurs not only in malignant cells but also in activated leukocytes, and thus permits the imaging of acute and chronic inflammatory processes. Normal uptake may obscure pathologic foci in the brain, heart, bowel, kidneys, and bladder. In patients with fever, bone marrow uptake is frequently increased in a nonspecific way due to cytokine activation, which upregulates glucose transporters in bone marrow cells. Compared with conventional scintigraphy, FDG-PET offers the advantages of higher resolution, greater sensitivity in chronic low-grade infections, and a high degree of accuracy in the central skeleton. Furthermore, vascular uptake of FDG is increased in patients with vasculitis. The mechanisms responsible for FDG uptake do not allow differentiation among infection, sterile inflammation, and malignancy. However, in patients with FUO, since all of these disorders are causes of FUO, FDG-PET can be used to guide additional diagnostic tests (e.g., targeted biopsies) that may yield the final diagnosis. Improved anatomic resolution by direct integration with CT (FDG-PET/CT) has further improved the accuracy of this modality.

Overall rates of helpfulness in final diagnosis of FUO are 40% for FDG-PET and 54% for FDG-PET/CT. In one study, FDG-PET was never helpful in diagnosing FUO in patients with a normal CRP level and a normal ESR. In two prospective studies in patients with FUO, FDG-PET was superior to ⁶⁷Ga-citrate scintigraphy, with a similar or better diagnostic yield and results that were available within hours instead of days. In one study, the sensitivity of FDG-PET was greater than that of ¹¹¹In-granulocyte scintigraphy (86% vs 20%) in patients with FUO.

Although scintigraphic techniques do not directly provide a definitive diagnosis, they often identify the anatomic location of a particular ongoing metabolic process and, with the help of other techniques such as biopsy and culture, facilitate timely diagnosis and treatment. Pathologic FDG uptake is quickly eradicated by treatment with glucocorticoids in many diseases, including vasculitis and lymphoma; therefore, glucocorticoid use should be stopped or postponed until after FDG-PET is performed. Results reported in the literature and the advantages offered by FDG-PET indicate that conventional scintigraphic techniques should be replaced by FDG-PET/CT in the investigation of patients with FUO at institutions where this technique is available. FDG-PET/CT is a relatively expensive procedure whose availability is still limited compared with that of CT and conventional scintigraphy. Nevertheless, FDG-PET/CT can be cost-effective in the FUO diagnostic workup if used at an early stage, helping to establish an early diagnosis, reducing days of hospitalization for diagnostic purposes, and obviating unnecessary and unhelpful tests.

LATER-STAGE DIAGNOSTIC TESTS

In some cases, more invasive tests are appropriate. Abnormalities found with scintigraphic techniques often need to be confirmed by pathology and/or culture of biopsy specimens. If lymphadenopathy is found, lymph node biopsy is necessary, even when the affected lymph nodes are hard to reach. In the case of skin lesions, skin biopsy should be undertaken. In one study, pulmonary wedge excision, histologic examination of an excised tonsil, and biopsy of the peritoneum were performed in light of PDCs or abnormal FDG-PET results and yielded a diagnosis.

If no diagnosis is reached despite scintigraphic and PDC-driven histologic investigations or culture, second-stage screening diagnostic tests should be considered (Fig. 13-1). In three studies, the diagnostic yield of screening chest and abdominal CT in patients with FUO was ~20%. The specificity of chest CT was ~80%, but that of abdominal CT varied between 63% and 80%. Despite the relatively limited specificity of abdominal CT and the probably limited additional value of chest CT after normal FDG-PET, chest and abdominal CT may be used as screening procedures at a later stage of the diagnostic protocol because of their noninvasive nature and high sensitivity. Bone marrow aspiration is seldom useful in the absence of PDCs for bone marrow disorders. With addition of FDG-PET, which is very sensitive in detecting lymphoma, carcinoma, and osteomyelitis, the value of bone marrow biopsy as a screening procedure is probably further reduced. Several studies have shown a high prevalence of giant cell arteritis among patients with FUO, with rates up to 17% among elderly patients. Giant cell arteritis often involves large arteries and in most cases can be diagnosed by FDG-PET. However, temporal artery biopsy is still recommended for patients ≥55 years of age in a later stage of the diagnostic protocol: FDG-PET will not be useful in vasculitis limited to the temporal arteries because of the small diameter of these vessels and the high levels of FDG uptake in the brain that overlies them. In the past, liver biopsies have often been performed as a screening procedure in patients with FUO. In each of two recent studies, liver biopsy as part of the later stage of a screening diagnostic protocol was helpful in only one patient. Moreover, abnormal liver tests are not predictive of a diagnostic liver biopsy in FUO. Liver biopsy is an invasive procedure that carries the possibility of complications and even death. Therefore, it should not be used for screening purposes in patients with FUO except in those with PDCs for liver disease.

In patients with unexplained fever after all of the above procedures, the last step in the diagnostic workup—with only a marginal diagnostic yield—comes at an extraordinarily high cost in terms of both expense and discomfort for the patient. Repetition of a thorough history-taking and physical examination and review of laboratory results and imaging studies (including those from other hospitals) are recommended. Diagnostic delay often results from a failure to recognize PDCs in the available information. In these patients with persisting FUO, waiting for new PDCs to appear probably is better than ordering more screening investigations. Only when a patient’s condition deteriorates without providing new PDCs should a further diagnostic workup be performed.

TABLE 13-3ALL REPORTED CAUSES OF RECURRENT FEVER^a

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TABLE 13-3 ALL REPORTED CAUSES OF RECURRENT FEVER^a

INFECTIONS

Bacterial, nonspecific

Apical granuloma, diverticulitis, prostatitis, recurrent bacteremia caused by colonic neoplasia or persistent focal infection, recurrent cellulitis, recurrent cholangitis or cholecystitis, recurrent pneumonia, recurrent sinusitis, recurrent urinary tract infection

Bacterial, specific

Bartonellosis, brucellosis, chronic gonococcemia, chronic meningococcemia, louse-borne relapsing fever (Borrelia recurrentis), melioidosis (Pseudomonas pseudomallei), Q fever (Coxiella burnetii), salmonellosis, Spirillum minor infection, Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii), tularemia, Whipple’s disease (Tropheryma whipplei), yersiniosis

Fungal

Coccidioidomycosis, paracoccidioidomycosis

Parasitic

Babesiosis, malaria, toxoplasmosis, trypanosomiasis, visceral leishmaniasis

Viral

Cytomegalovirus infection, Epstein-Barr virus infection, herpes simplex

Noninfectious Inflammatory Diseases

Systemic rheumatic and autoimmune diseases

Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease, cryoglobulinemia, gout, polymyositis, pseudogout, reactive arthritis, relapsing polychondritis, systemic lupus erythematosus

Vasculitis

Churg-Strauss syndrome, giant cell vasculitis/polymyalgia rheumatica, hypersensitivity vasculitis, polyarteritis nodosa, urticarial vasculitis

Granulomatous diseases

Idiopathic granulomatous hepatitis, sarcoidosis

Autoinflammatory syndromes

Adult-onset Still’s disease, Blau syndrome, CAPS^b (cryopyrin-associated periodic syndrome), Crohn’s disease, DIRA (deficiency of the IL-1 receptor antagonist), familial Mediterranean fever, hemophagocytic syndrome, hyper-IgD syndrome (HIDS, also known as mevalonate kinase deficiency), juvenile idiopathic arthritis, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, TRAPS (tumor necrosis factor receptor–associated periodic syndrome)

Neoplasms

Angioimmunoblastic lymphoma, Castleman’s disease, colon carcinoma, craniopharyngioma, Hodgkin’s disease, non-Hodgkin lymphoma, malignant histiocytosis, mesothelioma

Miscellaneous

Adrenal insufficiency, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, cholesterol emboli, cyclic neutropenia, drug fever, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fraudulent fever, Gaucher’s disease, hypersensitivity pneumonitis, hypertriglyceridemia, hypothalamic hypopituitarism, inflammatory pseudotumor, metal fume fever, milk protein allergy, polymer fume fever, pulmonary embolism, sclerosing mesenteritis

Thermoregulatory Disorders

Central

Hypothalamic dysfunction

Peripheral

Anhidrotic ectodermal dysplasia, exercise-induced hyperthermia, pheochromocytoma

^aThis table includes all causes of recurrent fever that have been described in the literature.

FIGURE 13-1

Structured approach to patients with FUO. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FDG-PET/CT, ¹⁸F-fluorodeoxyglucose positron emission tomography combined with low-dose computed tomography; LDH, lactate dehydrogenase; PDCs, potentially diagnostic clues (all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis); NSAID, nonsteroidal anti-inflammatory drug.

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TREATMENT

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TREATMENT Fever of Unknown Origin

Empirical therapeutic trials with antibiotics, glucocorticoids, or antituberculous agents should be avoided in FUO except when a patient’s condition is rapidly deteriorating after the aforementioned diagnostic tests have failed to provide a definite diagnosis.

ANTIBIOTICS AND ANTITUBERCULOUS THERAPY

Antibiotic or antituberculous therapy may irrevocably diminish the ability to culture fastidious bacteria or mycobacteria. However, hemodynamic instability or neutropenia is a good indication for empirical antibiotic therapy. If the TST is positive or if granulomatous disease is present with anergy and sarcoidosis seems unlikely, a therapeutic trial for tuberculosis should be started. Especially in miliary tuberculosis, it may be very difficult to obtain a rapid diagnosis. If the fever does not respond after 6 weeks of empirical antituberculous treatment, another diagnosis should be considered.

COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, AND GLUCOCORTICOIDS

Colchicine is highly effective in preventing attacks of familial Mediterranean fever but is not always effective once an attack is well under way. When familial Mediterranean fever is suspected, the response to colchicine is not a completely reliable diagnostic tool in the acute phase, but with colchicine treatment most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes within weeks to months. If the fever persists and the source remains elusive after completion of the later-stage investigations, supportive treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of adult-onset Still’s disease to NSAIDs is dramatic in some cases. The effects of glucocorticoids on giant cell arteritis and polymyalgia rheumatica are equally impressive. Early empirical trials with glucocorticoids, however, decrease the chances of reaching a diagnosis for which more specific and sometimes life-saving treatment might be more appropriate, such as malignant lymphoma. The ability of NSAIDs and glucocorticoids to mask fever while permitting the spread of infection or lymphoma dictates that their use should be avoided unless infectious diseases and malignant lymphoma have been largely ruled out and inflammatory disease is probable and is likely to be debilitating or threatening.

ANAKINRA

Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response. The availability of specific IL-1-targeting agents has revealed a pathologic role of IL-1-mediated inflammation in a growing list of diseases. Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β. Anakinra is extremely effective in the treatment of many autoinflammatory syndromes, such as familial Mediterranean fever, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, hyper-IgD syndrome, and Schnitzler’s syndrome. There is a growing list of other chronic inflammatory disorders in which the reduction of IL-1 activity can be highly effective. A therapeutic trial with anakinra can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests. Although most chronic inflammatory conditions without a known basis can be controlled with glucocorticoids, monotherapy with IL-1 blockade can provide improved control without the metabolic, immunologic, and gastrointestinal side effects of glucocorticoid administration.

PROGNOSIS

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FUO-related mortality rates have continuously declined over recent decades. The majority of fevers are caused by treatable diseases, and the risk of death related to FUO is, of course, dependent on the underlying disease. In a study by our group (Table 13-1), none of 37 FUO patients without a diagnosis died during a follow-up period of at least 6 months; 4 of 36 patients with a diagnosis died during follow-up due to infection (n = 1) or malignancy (n = 3). Other studies have also shown that malignancy accounts for most FUO-related deaths. Non-Hodgkin’s lymphoma carries a disproportionately high death toll. In nonmalignant FUO, fatality rates are very low. The good outcome in patients without a diagnosis confirms that potentially lethal occult diseases are very unusual and that empirical therapy with antibiotics, antituberculous agents, or glucocorticoids is rarely required in stable patients. In less affluent regions, infectious diseases are still a major cause of FUO, and outcomes may be different.

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CHAPTER 13: FEVER OF UNKNOWN ORIGIN

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DEFINITION

ETIOLOGY AND EPIDEMIOLOGY

DIFFERENTIAL DIAGNOSIS

APPROACH TO PATIENT

FIGURE 13-1

TREATMENT

PROGNOSIS

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