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Fever of Unknown Origin: A Clinical Approach

  • Burke A. Cunha
    Correspondence
    Requests for reprints should be addressed to Burke A. Cunha, MD, Winthrop-University Hospital, Mineola, NY and State University of New York, School of Medicine, Stony Brook, NY.
    Affiliations
    Infectious Disease Division, Winthrop-University Hospital, Mineola, NY

    State University of New York, School of Medicine, Stony Brook
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  • Olivier Lortholary
    Affiliations
    Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, IHU Imagine, Paris, France

    Université Paris Descartes, Paris, France
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  • Cheston B. Cunha
    Affiliations
    Infectious Disease Division, Rhode Island Hospital and The Miriam Hospital, Providence, RI

    Brown University Alpert School of Medicine, Providence, RI
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      Abstract

      Fevers of unknown origin remain one of the most difficult diagnostic challenges in medicine. Because fever of unknown origin may be caused by over 200 malignant/neoplastic, infectious, rheumatic/inflammatory, and miscellaneous disorders, clinicians often order non-clue-based imaging and specific testing early in the fever of unknown origin work-up, which may be inefficient/misleading. Unlike most other fever-of-unknown-origin reviews, this article presents a clinical approach. Characteristic history and physical examination findings together with key nonspecific test abnormalities are the basis for a focused clue-directed fever of unknown origin work-up.

      Keywords

      Clinical Significance
      • Fevers of unknown origin remain a difficult diagnostic challenge because over 200 disorders are in the differential diagnosis.
      • The focused fever of unknown origin diagnostic approach is based on hallmark clinical features characteristic of each disorder. Diagnostic significance of nonspecific clinical findings is enhanced when considered together.
      • The fever of unknown origin diagnostic approach should be clue driven to narrow diagnostic possibilities to direct the work-up to avoid excessive non-clue-directed testing.

      Classic Fever of Unknown Origin

      Prolonged fevers have been diagnostically problematic since antiquity. Among the ancients, typhoid fever and malaria were common causes of prolonged fevers.
      • Cunha C.B.
      Prolonged and perplexing fevers in antiquity: malaria and typhoid fever.
      Few infections are associated with prolonged fevers.
      • Cunha B.A.
      Fever of unknown origin: clinical overview and perspective.
      Petersdorf and Beeson
      • Petersdorf R.G.
      • Beeson P.B.
      Fever of unexplained origin: report on 100 cases.
      developed criteria for prolonged fevers, that is, fever of unknown origin, defined as fever ≥38.3°C (101°F) for >3 weeks that remains undiagnosed after a hospital work-up. Fever of unknown origin work-ups may be done as an outpatient.
      • Larson E.B.
      • Featherstone H.J.
      • Petersdorf R.G.
      Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970-80.
      Petersdorf also classified fevers of unknown origin by category, that is, infectious, malignant/neoplastic, rheumatic/inflammatory, and miscellaneous disorders (Table 1).
      • Cunha B.A.
      Fever of unknown origin: clinical overview and perspective.
      • Cunha B.A.
      Fever of unknown origin.
      • Cunha C.B.
      • Cunha B.A.
      Fever of unknown origin (FUO).
      Fevers of unknown origin also may be considered in the context of host subsets, for example, organ transplants, human immunodeficiency virus, returning travelers.
      • Larson E.B.
      • Featherstone H.J.
      • Petersdorf R.G.
      Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970-80.
      Table 1Fever of Unknown Origin (FUO): Classic Causes
      Adapted from: Cunha BA. Fever of unknown origin (FUO). In: Gorbach SL, Bartlett JB, Blacklow NR, eds. Infectious Diseases in Medicine and Surgery. (3rd ed.) Philadelphia: WB Saunders, 2004:1568–1577.
      • Cunha B.A.
      Fever of unknown origin.
      Cunha BA. Overview. In: Cunha BA, ed. Fever of Unknown Origin. New York: Informa Healthcare; 2007:1-16;2 Cunha CB, Cunha BA, Fever of unknown origin (FUO). In: Schlossberg D, ed. Clinical Infectious Disease. (2nd ed.) Cambridge, UK: Cambridge University Press; 2015:1-6.
      • Cunha C.B.
      • Cunha B.A.
      Fever of unknown origin (FUO).
      Type of DisorderCommonUncommonRare
      Malignancy/neoplastic disordersLymphoma
      May present as recurrent FUOs.


      Hypernephroma/renal cell carcinoma (RCC)
      Preleukemia (AML)
      May present as recurrent FUOs.


      Myeloproliferative disorders (MPDs)
      May present as recurrent FUOs.
      Atrial myxoma

      Multiple myeloma

      Colon carcinoma

      Pancreatic carcinoma

      Hepatoma

      CNS metastases

      Liver metastases

      Systemic mastocytosis
      May present as recurrent FUOs.
      Infectious diseasesMiliary TB

      Brucellosis
      May present as recurrent FUOs.
      If bacteremia suspected, obtain blood cultures.


      Q fever
      May present as recurrent FUOs.
      Intraabdominal/pelvic abscess
      If bacteremia suspected, obtain blood cultures.


      Intra/perinephric abscess
      If bacteremia suspected, obtain blood cultures.


      Typhoid/enteric fevers
      May present as recurrent FUOs.
      If bacteremia suspected, obtain blood cultures.


      Toxoplasmosis
      May present as recurrent FUOs.


      Cat scratch disease (CSD)
      May present as recurrent FUOs.


      EBV

      CMV

      HIV

      Extrapulmonary TB (renal TB, CNS TB)
      SBE
      If bacteremia suspected, obtain blood cultures.


      Periapical dental abscess
      May present as recurrent FUOs.


      Chronic sinusitis/mastoiditis

      Subacute vertebral osteomyelitis

      Aortoenteric fistula

      Vascular graft infections
      If bacteremia suspected, obtain blood cultures.


      Relapsing fever
      May present as recurrent FUOs.
      (Borrelia recurrentis)

      Rat bite fever
      May present as recurrent FUOs.
      If bacteremia suspected, obtain blood cultures.
      (Streptobacillus moniliformis or Spirillum minus)

      Leptospirosis

      Histoplasmosis

      Coccidiomycosis

      Visceral leishmaniasis (kala-azar)

      LGV

      Whipple's disease
      May present as recurrent FUOs.


      Multicentric Castleman's disease (MCD)
      May present as recurrent FUOs.


      Malaria
      May present as recurrent FUOs.


      Babesiosis
      May present as recurrent FUOs.


      Ehrlichiosis/anaplasmosis
      May present as recurrent FUOs.


      Chronic prostatitis

      Recurrent cholangitis
      May present as recurrent FUOs.
      If bacteremia suspected, obtain blood cultures.
      (with Caroli's disease)
      Rheumatologic/inflammatory disordersAdult Still's disease

      (juvenile rheumatoid arthritis [JRA])
      May present as recurrent FUOs.


      Giant cell arteritis (GCA)/temporal arteritis (TA)
      May present as recurrent FUOs.
      Periarteritis nodosa/microscopic polyangiitis (PAN/MPA)
      May present as recurrent FUOs.


      Late-onset rheumatoid arthritis (LORA)

      SLE
      May present as recurrent FUOs.
      Takayasu's arteritis
      May present as recurrent FUOs.


      Kikuchi's disease
      May present as recurrent FUOs.


      Sarcoidosis (CNS)

      Felty's syndrome

      Gaucher's disease

      Polyarticular gout

      Pseudogout

      Antiphospholipid syndrome (APS)

      Behçet's disease
      May present as recurrent FUOs.


      FAPA syndrome
      May present as recurrent FUOs.
      (Marshall's syndrome)
      Miscellaneous disordersDrug fever
      May present as recurrent FUOs.


      Cirrhosis
      May present as recurrent FUOs.
      Subacute thyroiditis
      May present as recurrent FUOs.


      Regional enteritis
      May present as recurrent FUOs.
      (Crohn's disease)
      Pulmonary emboli (small/multiple)

      Pseudolymphomas
      May present as recurrent FUOs.


      Rosai-Dorfman disease
      May present as recurrent FUOs.


      Erdheim-Chester disease (ECD)
      May present as recurrent FUOs.


      Cyclic neutropenia
      May present as recurrent FUOs.


      Familial periodic fever syndromes: FMF
      May present as recurrent FUOs.
      Hyper-IgD syndrome
      May present as recurrent FUOs.
      TNF receptor-1-associated periodic syndrome (TRAPS)
      May present as recurrent FUOs.
      Schnitzler's syndrome
      May present as recurrent FUOs.
      Muckle-Wells syndrome
      May present as recurrent FUOs.


      Hypothalamic dysfunction

      Hypertriglyceridemia (type V)
      May present as recurrent FUOs.


      Factitious fever
      May present as recurrent FUOs.
      AML = acute myelogenous leukemia; APS = antiphospholipid syndrome; CMV = cytomegalovirus; CNS = central nervous system; CSD = cat scratch disease; EBV = Epstein-Barr virus; ECD = Erdheim-Chester disease; FAPA = fever, aphthous ulcers, pharyngitis, adenitis; FMF = familial Mediterranean fever; GCA = giant cell arteritis; HIV = human immunodeficiency virus; LGV = lymphogranuloma venereum; LORA = late-onset rheumatoid arthritis; MCD = multicentric Castleman's disease; MPA = microscopic polyangiitis; MPDs = myeloproliferative disorders; PAN = periarteritis nodosa; RCC = renal cell carcinoma; SBE = subacute bacterial endocarditis; SLE = systemic lupus erythematosus; TA = temporal arteritis; TB = tuberculosis; TNF = tumor necrosis factor.
      May present as recurrent FUOs.
      If bacteremia suspected, obtain blood cultures.
      There is no standard diagnostic approach to fever of unknown origin.
      • Molavi A.
      • Weinstein L.
      Persistent perplexing pyrexia. Some comments on etiology and diagnosis.
      • Louria D.B.
      Fever of unknown etiology.
      • Jacoby G.A.
      • Swartz M.N.
      Fever of undetermined origin.
      • Cunha B.A.
      Fever of unknown origin.
      Fever of unknown origin requires a focused fever of unknown origin-relevant history, physical examination, and selective nonspecific laboratory tests rather than excessive overtesting.
      • Cunha B.A.
      Fever of unknown origin.
      • Lortholary O.
      • Bletry L.G.
      • Godeau P.
      Fever of unknown origin: a retrospective multicentre study of 103 cases, 1980-88.
      • Brusch J.L.
      • Weinstein L.
      Fever of unknown origin.
      • Knockaert D.C.
      • Vanderschueren S.
      • Blockmans D.
      Fever of unknown origin in adults: 40 years on.
      • Bryan C.S.
      Fever of unknown origin.
      • Arnow P.M.
      • Flaherty J.P.
      Fever of unknown origin.

      Diagnostic Approach to Classic Fever of Unknown Origin

      First, verify the prolonged fever meets the fever-of-unknown-origin definition.
      • Petersdorf R.G.
      • Beeson P.B.
      Fever of unexplained origin: report on 100 cases.
      • Arnow P.M.
      • Flaherty J.P.
      Fever of unknown origin.
      • Nubile M.J.
      Acute fevers of unknown origin. A plea for restraint.
      • Vanderschueren S.
      • Knockaert D.
      • Adriaenssens T.
      • et al.
      From prolonged febrile illness to fever of unknown origin: The Challenge Continues.
      • Ergonul O.
      • Wilke A.
      • Azap A.
      • et al.
      Revised definition of fever of unknown origin: limitations and opportunities.
      • Efstathiou S.P.
      • Pefanis A.V.
      • Tsiakou A.G.
      • et al.
      Fever of unknown origin: discrimination between infectious and non-infectious causes.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      The fever-of-unknown-origin work-up should be symptom (history) and sign (physical examination) driven.
      • Lortholary O.
      • Bletry L.G.
      • Godeau P.
      Fever of unknown origin: a retrospective multicentre study of 103 cases, 1980-88.
      • Brusch J.L.
      • Weinstein L.
      Fever of unknown origin.
      Second, based on history and physical clues, try to determine the appropriate category for the fever.
      • Arnow P.M.
      • Flaherty J.P.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Kazanjian P.H.
      Fever of unknown origin. Review of 86 patients treated in community hospital.
      Each fever of unknown origin category has clinical hallmarks, for example, usually, malignant/neoplastic disorders are associated with early anorexia and significant weight loss. With infectious fevers of unknown origin, chills are common, but weight loss less pronounced and anorexia late. Excluding vasculitis, synovitis is the rheumatic/inflammatory hallmark. While hallmark features suggest particular fever of unknown origin categories, some findings essentially eliminate a fever-of-unknown-origin category, for example, rigors eliminate the rheumatic/inflammatory category of fever.
      • Cunha B.A.
      Fever of unknown origin.
      • Brusch J.L.
      • Weinstein L.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      Third, within the fever-of-unknown-origin category, try to determine the pattern of organ involvement. Each disorder has a characteristic pattern of organ involvement that suggests/limits diagnostic possibilities. For example, pattern of organ involvement of systemic lupus erythematosus involves multiple organs but importantly, spares the liver. Similarly, while splenomegaly is a cardinal subacute bacterial endocarditis finding, hepatomegaly essentially rules out subacute bacterial endocarditis on the basis of pattern of organ involvement alone.
      • Brusch J.L.
      • Weinstein L.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Kazanjian P.H.
      Fever of unknown origin. Review of 86 patients treated in community hospital.
      The most diagnostically difficult fevers of unknown origin have no localizing signs.
      Key clues may be overlooked with a thorough but not fever of unknown origin focused history and physical examination.
      • Molavi A.
      • Weinstein L.
      Persistent perplexing pyrexia. Some comments on etiology and diagnosis.
      • Louria D.B.
      Fever of unknown etiology.
      • Jacoby G.A.
      • Swartz M.N.
      Fever of undetermined origin.
      In the fever of unknown origin focused physical examination, special attention should be given to the eyes, skin, nodes, liver, and spleen.
      • Louria D.B.
      Fever of unknown etiology.
      • Jacoby G.A.
      • Swartz M.N.
      Fever of undetermined origin.
      Testing should be selective and based on diagnostic probabilities, not possibilities, for example, routine blood cultures.
      • Cunha B.A.
      Fever of unknown origin.
      Blood cultures are useful for bacteremic fevers of unknown origin, for example, brucellosis, typhoid/enteric fever, intravascular infections, and abscesses, but blood cultures are unnecessary and may be misleading for nonbacteremic infections, malignant/neoplastic, rheumatic/inflammatory, and miscellaneous fevers of unknown origin.
      • Cunha B.A.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      Subacute bacterial endocarditis is not an uncommon infection, but now is a relatively rare cause of fever of unknown origin.
      • Knockaert D.C.
      • Vanderschueren S.
      • Blockmans D.
      Fever of unknown origin in adults: 40 years on.
      • Vanderschueren S.
      • Knockaert D.
      • Adriaenssens T.
      • et al.
      From prolonged febrile illness to fever of unknown origin: The Challenge Continues.
      • Kazanjian P.H.
      Fever of unknown origin. Review of 86 patients treated in community hospital.

      History

      Malignant/Neoplastic Disorders

      Significant weight loss (>2 lbs/week), particularly if accompanied by early anorexia, is a hallmark of malignant/neoplastic fevers of unknown origin.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Cunha B.A.
      Fever of unknown origin in malignancies.
      • Zhang J.
      • Chen B.
      • Xu X.
      • et al.
      Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.
      Post-hot bath pruritus suggests a malignant/neoplastic disorder.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Cunha B.A.
      Fever of unknown origin in malignancies.
      • Zhang J.
      • Chen B.
      • Xu X.
      • et al.
      Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      A malignant/neoplastic fever of unknown origin should be considered in those with a history of adenopathy or malignancy.

      Infectious Diseases

      The history should include prior/invasive procedures or surgeries (abscesses), dentition (apical abscesses, subacute bacterial endocarditis), antecedent/concomitant infections, and tuberculosis.
      • Arnow P.M.
      • Flaherty J.P.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      Animal or pet contact suggests Q fever, brucellosis, toxoplasmosis, cat scratch disease, or trichinosis.
      • Bryan C.S.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Mosquito or tick exposure suggests ehrlichiosis/anaplasmosis, babesiosis, or malaria, while rodent exposure suggests rat bite fever, relapsing fever, or leptospirosis.
      • Brusch J.L.
      • Weinstein L.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Blood transfusions may be an important clue to ehrlichiosis/anaplasmosis, babesiosis, cytomegalovirus, or human immunodeficiency virus. In normal hosts, the only clue to cytomegalovirus may be secretion exposure.
      • Manfredi R.
      • Calza L.
      • Chiodo F.
      Primary cytomegalovirus infection in otherwise healthy adults with fever of unknown origin: a 3-year prospective survey.
      Immunosuppressive drugs predispose to particular pathogens, for example, cytomegalovirus, tuberculosis. Disparate multiple symptoms/signs suggest multisystem disease, for example, miliary tuberculosis or Whipple's disease, rather than several different disorders.
      • Cunha B.A.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.

      Rheumatic/Inflammatory Disorders

      With prominent arthralgias/myalgias, a rheumatic/inflammatory fever of unknown origin is likely, but chills argue against a rheumatic/inflammatory etiology.
      • Carsons S.E.
      Fever in rheumatic and autoimmune disease.
      • Zenone T.
      Fever of unknown origin in rheumatic diseases.
      • Cunha B.A.
      Fever of unknown origin in rheumatic diseases.
      Dry cough also may be a subtle clue of giant cell arteritis/temporal arteritis.
      • Cunha B.A.
      • Parchuri S.
      • Mohan S.
      Fever of unknown origin: temporal arteritis presenting with persistent cough and elevated serum ferritin levels.
      With a fever of unknown origin, oral ulcers suggest Behçet's syndrome or systemic lupus erythematosus.
      • Carsons S.E.
      Fever in rheumatic and autoimmune disease.
      • Zenone T.
      Fever of unknown origin in rheumatic diseases.
      The pattern of organ involvement in a fever of unknown origin with a history of joint symptoms and generalized lymphadenopathy points to adult Still's disease or systemic lupus erythematosus.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha B.A.
      Fever of unknown origin in rheumatic diseases.
      A history of acalculous cholecystitis in a fever of unknown origin is an easily overlooked clue of systemic lupus erythematosus or periarteritis nodosa.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha B.A.
      Fever of unknown origin in rheumatic diseases.
      A family history is important if Behçet's disease is being considered.

      Miscellaneous Disorders

      If the history does not suggest a particular category, miscellaneous causes of fever of unknown origin should be considered. Fever periodicity may be the only clue to cyclic neutropenia.
      • Cunha B.A.
      • Nausheen S.
      Fever of unknown origin due to cyclic neutropenia with relative bradycardia.
      A history of lymphadenopathy may suggest Rosai-Dorfman or Kikuchi's disease.
      • Cunha B.A.
      • Mickail N.
      • Durie N.
      • Pherez F.M.
      • Strollo S.
      Fever of unknown origin caused by Kikuchi's disease mimicking lymphoma.
      • Cunha B.A.
      • Durie N.
      • Selbs E.
      • Pherez F.
      Fever of unknown origin due to Rosai-Dorfman disease with mediastinal adenopathy mimicking lymphoma: diagnostic importance of elevated serum ferritin levels and polyclonal gammopathy.
      Neck/jaw pain, easily dismissed as dental pain, may be a clue to subacute thyroiditis.
      • Brendan M.W.
      • Matthew J.H.
      • Dennis P.M.
      Subacute thyroiditis manifesting as fever of unknown origin.
      • Cunha B.A.
      • Thermidor M.
      • Mohan S.
      • et al.
      Fever of unknown origin: subacute thyroiditis versus typhoid fever.
      • Cunha B.A.
      • Chak A.
      • Strollo S.
      Fever of unknown origin: de Quervain's subacute thyroiditis with highly elevated ferritin levels mimicking temporal arteritis (TA).
      • Cunha B.A.
      • Berbari N.
      Subacute thyroiditis (de Quervain's) due to influenza A: presenting as fever of unknown origin.
      Factitious fever should be considered in medical personnel.
      • Murray H.W.
      Factitious fever updated.
      Specifically, inquire about inflammatory bowel disease (regional enteritis), alcoholism (cirrhosis), and medications (pseudolymphoma, drug fever).
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Johnson D.H.
      • Cunha B.A.
      Drug fever.
      Some miscellaneous fevers of unknown origin are familial, for example, familial Mediterranean fever or hyper-IgD syndrome.
      • Drenth J.P.H.
      • Haagsma C.J.
      • van der Meer J.W.M.
      International Hyper-IgD Study Group. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients.
      • Wolf S.M.
      • Fauci A.S.
      • Dale D.C.
      Unusual etiologies of fever and their evaluation.

      Physical Examination

      Malignant/Neoplastic Disorders

      Hectic fevers of lymphoma may resemble infection.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Zhang J.
      • Chen B.
      • Xu X.
      • et al.
      Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.
      • Norman D.C.
      • Wong M.B.
      Fever of unknown origin in older persons.
      Relative bradycardia may accompany lymphoma or central nervous system malignancy.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha B.A.
      Diagnostic significance of relative bradycardia.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Eye examination may be helpful, for example, Roth spots (lymphoma, atrial myxoma), cytoid bodies (atrial myxoma), or retinal hemorrhages (preleukemia).
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha C.B.
      • Wilkinson M.J.
      • Quillen D.A.
      Ophthalmologic clues to infectious diseases.
      A murmur is a key finding in subacute bacterial endocarditis, noninfectious culture-negative endocarditis, for example, marantic endocarditis or atrial myxoma.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha B.A.
      The mimics of endocarditis.
      Sternal tenderness points to a bone marrow disorder (preleukemia, myeloproliferative disorders).
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Cunha B.A.
      Fever of unknown origin in malignancies.
      • Zhang J.
      • Chen B.
      • Xu X.
      • et al.
      Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Isolated hepatomegaly in a fever of unknown origin limits diagnostic possibilities to hepatoma, renal cell carcinoma, or liver metastases.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha C.B.
      Infectious disease differential diagnosis.

      Infectious Diseases

      The approach to infectious fevers of unknown origin begins with fever pattern analysis.
      • Esposito A.L.
      • Gleckman R.A.
      A diagnostic approach to the adult with fever of unknown origin.
      • Esposito A.L.
      Planning and proceeding with the diagnostic evaluation.
      • Cunha B.A.
      Fever of unknown origin: a focused diagnostic approach.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      Morning temperature spikes suggest miliary tuberculosis, typhoid/enteric fever, or Whipple's disease.
      • Cunha B.A.
      Fever of unknown origin: a focused diagnostic approach.
      • Cunha B.A.
      The diagnostic significance of fever curves.
      • Cunha B.A.
      • Krakakis J.
      • McDermott B.P.
      Fever of unknown origin caused by miliary tuberculosis: diagnostic significance of morning temperature spikes.
      Relative bradycardia is a cardinal finding in typhoid/enteric fever, malaria, babesiosis, ehrlichiosis/anaplasmosis, leptospirosis, and Q fever.
      • Cunha B.A.
      Diagnostic significance of relative bradycardia.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Twice daily fever spikes (double quotidian fevers) suggest malaria, miliary tuberculosis, or visceral leishmaniasis.
      • Cunha B.A.
      The diagnostic significance of fever curves.
      • Cunha B.A.
      Fever of unknown origin caused by adult juvenile rheumatoid arthritis: the diagnostic significance of double quotidian fevers and elevated serum ferritin levels.
      Two fever peaks per week (camel back fever curve) may be one of the few clues to ehrlichiosis/anaplasmosis, leptospirosis, brucellosis, or rat bite fever.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha B.A.
      The diagnostic significance of fever curves.
      Fundoscopic findings may be a clue to toxoplasmosis, tuberculosis, histoplasmosis, or cat scratch disease.
      • Nubile M.J.
      Acute fevers of unknown origin. A plea for restraint.
      Spinal tenderness points to subacute vertebral osteomyelitis, typhoid/enteric fever, spinal tuberculosis, or brucellosis.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha B.A.
      • Hage J.E.
      • Nouri Y.
      Recurrent fever of unknown origin: aseptic meningitis, hepatosplenomegaly, pericarditis and a double quotidian fever due to juvenile rheumatoid arthritis (JRA).
      Hepatomegaly alone suggests Q fever, typhoid/enteric fever, visceral leishmaniasis, brucellosis, rat bite fever, or relapsing fever.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Splenomegaly narrows diagnostic possibilities to miliary tuberculosis, Epstein-Barr virus, cytomegalovirus, typhoid/enteric fever, brucellosis, histoplasmosis, ehrlichiosis/anaplasmosis, malaria, Q fever, subacute bacterial endocarditis, cat scratch disease, and rat bite fever.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Epididymo-orchitis/epididymal nodule is an easily overlooked sign of Epstein-Barr virus, renal tuberculosis, or brucellosis.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.

      Rheumatic/Inflammatory Disorders

      Morning temperature spikes are an important clue to periarteritis nodosa while a double quotidian fever is a key finding in adult Still disease.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin caused by adult juvenile rheumatoid arthritis: the diagnostic significance of double quotidian fevers and elevated serum ferritin levels.
      • Cunha B.A.
      • Hage J.E.
      • Nouri Y.
      Recurrent fever of unknown origin: aseptic meningitis, hepatosplenomegaly, pericarditis and a double quotidian fever due to juvenile rheumatoid arthritis (JRA).
      In a fever of unknown origin, rash, if present, suggests sarcoidosis, systemic lupus erythematosus, or adult Still's disease.
      • Cunha B.A.
      Fever of unknown origin caused by adult juvenile rheumatoid arthritis: the diagnostic significance of double quotidian fevers and elevated serum ferritin levels.
      Unequal pulse suggests Takayasu's arteritis.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      Lacrimal gland enlargement is a clue to late-onset rheumatoid arthritis, sarcoidosis, or systemic lupus erythematosus.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      External eye/fundi may provide many diagnostic clues in rheumatic/inflammatory fevers of unknown origin, for example, cytoid bodies (systemic lupus erythematosus, giant cell arteritis/temporal arteritis, periarteritis nodosa, adult Still's disease), Roth spots (systemic lupus erythematosus, periarteritis nodosa), or retinal artery occlusion (Takayasu's arteritis, giant call arteritis/temporal arteritis, systemic lupus erythematosus).
      • Louria D.B.
      Fever of unknown etiology.
      • Jacoby G.A.
      • Swartz M.N.
      Fever of undetermined origin.
      • Cunha B.A.
      Diagnostic significance of relative bradycardia.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha C.B.
      • Wilkinson M.J.
      • Quillen D.A.
      Ophthalmologic clues to infectious diseases.
      In a fever of unknown origin, oral ulcers suggest Behçet's disease or systemic lupus erythematosus.
      • Cunha B.A.
      Fever of unknown origin.
      Lymphadenopathy suggests systemic lupus erythematosus, late-onset rheumatoid arthritis, or sarcoidosis.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      In a fever of unknown origin with systemic lupus erythematosus, a murmur with negative blood cultures suggests possible Libman-Sacks endocarditis.
      • Carsons S.E.
      Fever in rheumatic and autoimmune disease.
      Hepatomegaly without splenomegaly argues against a rheumatic/inflammatory fever of unknown origin etiology. Epididymitis/epididymal nodules are subtle clues to periarteritis nodosa, systemic lupus erythematosus, or sarcoidosis.
      • Zenone T.
      Fever of unknown origin in rheumatic diseases.
      • Cunha B.A.
      Fever of unknown origin in rheumatic diseases.
      • Cunha C.B.
      Infectious disease differential diagnosis.

      Miscellaneous Disorders

      Miscellaneous fevers of unknown origin are more likely to be diagnosed by historical clues rather than physical findings. Relative bradycardia is a clue to drug fever or factitious fever.
      • Murray H.W.
      Factitious fever updated.
      • Johnson D.H.
      • Cunha B.A.
      Drug fever.
      • Cunha B.A.
      Diagnostic significance of relative bradycardia.
      Lipemia retinalis may be the only sign of hypertriglyceridemia. Lymphadenopathy may be due to pseudolymphoma or hyper-IgD syndrome.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Cirrhosis is an often-overlooked cause of fever of unknown origin. Splenomegaly is an important clue to regional enteritis, cirrhosis, or hyper-IgD syndrome.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.

      Nonspecific Laboratory Tests

      In each fever of unknown origin category, nonspecific tests often provide useful diagnostic clues.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      • Purnendu S.
      • Louria D.B.
      Non-invasive and invasive diagnostic procedures and laboratory methods.
      • Cunha B.A.
      • Petelin A.
      Fever of unknown origin due to large B-cell lymphoma: the diagnostic significance of highly elevated alkaline phosphatase and serum ferritin levels.
      • Cunha B.A.
      Fever of unknown origin: diagnostic importance of serum ferritin levels.
      Elevated erythrocyte sedimentation rate, serum ferritin, alkaline phosphatase, and rheumatoid factor titers are particularly useful in fever of unknown origin diagnosis.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      • Kosmin A.
      • Lorber B.
      Specific tests in the diagnosis of fever of unknown origin.
      Diagnostic specificity of nonspecific laboratory abnormalities is increased when considered together. Degree of test abnormality itself limits diagnostic possibilities, for example, an elevated erythrocyte sedimentation rate is very sensitive/not specific, but a highly elevated erythrocyte sedimentation rate (>100 mm/h) narrows diagnostic possibilities to very few entities. Similarly, 6% atypical lymphocytes (drug fever, toxoplasmosis) have a different differential than 36% atypical lymphocytes (Epstein-Barr virus, cytomegalovirus). Nonspecific findings may be exclusionary clues, for example, eosinophilia argues strongly against typhoid/enteric fever.
      Complete blood count often contains easily overlooked clues, for example, leukopenia, monocytosis, lymphocytosis-relative lymphopenia, eosinophilia, basophilia, atypical/abnormal lymphocytes, thrombocytosis, and thrombocytopenia,.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      In a fever of unknown origin, an isolated alkaline phosphatase elevation suggests lymphoma.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Serum protein electrophoresis also may provide diagnostic clues, for example, elevated α12 globulin elevations (lymphoma, systemic lupus erythematosus); monoclonal gammopathy (multiple myeloma, hyper-IgD syndrome, multicentric Castleman's disease); and polyclonal gammopathy (human immunodeficiency virus, cytomegalovirus, cirrhosis, sarcoidosis, malaria).
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Microscopic hematuria may be the only clue to subacute bacterial endocarditis, renal tuberculosis, brucellosis, periarteritis nodosa, lymphoma, or renal cell carcinoma.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      A common error is to order numerous non-clue-directed specific tests early in the work-up without considering the value of hallmark clinical and characteristic nonspecific laboratory clues in narrowing the differential diagnosis. Specific diagnostic testing should be ordered later in the fever of unknown origin work-up and based on narrowed diagnostic possibilities (Table 2).
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Table 2FUOs: Laboratory Clues by FUO Category
      Adapted from Cunha CB. Infectious disease differential diagnosis. In: Cunha BA, Ed. Antibiotic Essentials, 14th ed. New Delhi, India: JP Medical Publishers; 2015:475-506.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      WBC abnormalities
       LeukocytosisInfectious: Most infections

      Rheumatic/inflammatory: Adult Still's disease (juvenile rheumatoid arthritis [JRA])

      Miscellaneous: Drug fever
       LeukopeniaMalignant/neoplastic: Leukemias

      Infectious: Miliary TB, typhoid/enteric fever, malaria, brucellosis, visceral leishmaniasis (kala-azar), EBV, CMV, histoplasmosis, relapsing fever, ehrlichiosis/anaplasmosis

      Rheumatic/inflammatory: RA (Felty's syndrome), Gaucher's disease, SLE, sarcoidosis

      Miscellaneous: Cyclic neutropenia
       Relative lymphocytosisMalignant/neoplastic: ALL, lymphomas, carcinomas, multiple myeloma

      Infectious: Whipple's disease, miliary TB, brucellosis, histoplasmosis, EBV, CMV, visceral leishmaniasis (kala-azar), toxoplasmosis, typhoid/enteric fever

      Rheumatic/inflammatory: LORA
       Relative lymphopeniaMalignant/neoplastic: Lymphoma, cirrhosis

      Infectious: CMV, HIV, Miliary TB, typhoid/enteric fever, Q fever, brucellosis, malaria, babesiosis, histoplasmosis, ehrlichiosis/anaplasmosis, Whipple's disease

      Rheumatic/inflammatory: Sarcoidosis, SLE, LORA

      Miscellaneous: Cirrhosis
       MonocytosisMalignant/neoplastic: MPDs, lymphomas

      Infectious: Miliary TB, SBE, histoplasmosis, brucellosis, visceral leishmaniasis (kala-azar), malaria, typhoid/enteric fever, babesiosis, EBV, CMV

      Rheumatic/inflammatory: Sarcoidosis, Gaucher's disease, LORA, SLE, PAN, GCA/TA

      Miscellaneous: Regional enteritis (Crohn's disease), ulcerative colitis
       Atypical lymphocytesInfectious: EBV, CMV, toxoplasmosis, brucellosis, malaria, babesiosis, ehrlichiosis/anaplasmosis

      Miscellaneous: Drug fever
       EosinophiliaMalignant/neoplastic: Lymphomas, MPDs

      Infectious: Trichinosis, histoplasmosis, coccidioidomycosis

      Rheumatic/inflammatory: PAN, sarcoidosis

      Miscellaneous: Hyper-IgE syndrome, drug fever, regional enteritis (Crohn's disease), ulcerative colitis
       BasophiliaMalignant/neoplastic: Preleukemia (AML), acute leukemias, lymphomas, MPDs
      RBC abnormalities
       ErythrophagocytosisMalignant/neoplastic: Lymphomas, acute leukemias, multiple myeloma, MPDs

      Infectious: HIV, EBV, CMV, malaria, babesiosis, toxoplasmosis, visceral leishmaniasis (kala-azar), histoplasmosis, typhoid/enteric fever, SBE, Q fever, Miliary TB, brucellosis

      Rheumatic/inflammatory: SLE, sarcoidosis, LORA
      Platelet abnormalities
       ThrombocytopeniaMalignant/neoplastic: Leukemias, lymphomas, carcinomas, MPDs, multiple myeloma

      Infectious: EBV, CMV, ehrlichiosis/anaplasmosis, malaria, babesiosis, histoplasmosis, visceral leishmaniasis (kala-azar), HIV, miliary TB, relapsing fever, brucellosis

      Rheumatic/inflammatory: Gaucher's disease

      Miscellaneous: Drugs, cirrhosis
       ThrombocytosisMalignant/neoplastic: Malignancies, MPDs, lymphomas

      Infectious: Miliary TB, chronic infections (eg, osteomyelitis, abscess), SBE, Q fever

      Rheumatic/inflammatory: GCA/TA, PAN

      Miscellaneous: Drugs
      Pancytopenia
       PancytopeniaInfectious: Miliary TB, brucellosis, histoplasmosis, ehrlichiosis/anaplasmosis, CMV, HIV

      Rheumatic/inflammatory: Gaucher's disease, sarcoidosis, SLE
      Serum test abnormalities
       ↑ Erythrocyte sedimentation rate (highly elevated)Malignant/neoplastic: Malignancies

      Infectious: SBE, osteomyelitis, abscess, Q fever

      Rheumatic/inflammatory: GCA/TA, adult Still's disease (JRA), SLE, LORA, PAN

      Miscellaneous: Cirrhosis, drug fever
       SPEP (polyclonal gammopathy)Malignant/neoplastic: Atrial myxoma

      Infectious: HIV, malaria, visceral leishmaniasis (kala-azar), LGV, rat bite fever, Q fever

      Rheumatic/inflammatory: SLE, PAN, Takayasu's arteritis

      Miscellaneous: Cirrhosis
       SPEP (monoclonal gammopathy)Malignant/neoplastic: Multiple myeloma, Waldenström's macroglobulinemia

      Infectious: CMV, visceral leishmaniasis (kala-azar), typhoid/enteric fever
       ↑ Ferritin levels (highly elevated)Malignant/neoplastic: Preleukemias (AML), leukemias, lymphomas, multiple myeloma, Waldenström's macroglobulinemia hepatomas, liver/CNS metastases

      Infectious: EBV, CMV, malaria, ehrlichiosis/anaplasmosis, HIV, miliary TB

      Rheumatic/inflammatory: LORA, adult Still's disease (JRA), SLE, GCA/TA, Kawasaki's disease

      Miscellaneous: Cirrhosis
       ↑ Cold agglutininsMalignant/neoplastic: Lymphomas, multiple myeloma, Waldenström's macroglobulinemia

      Infectious: EBV, CMV, malaria, Q fever, HIV

      Rheumatic/inflammatory: SLE
       ↑ Lactate dehydrogenase (LDH)Malignant/neoplastic: Malignancies

      Infectious: Malaria, babesiosis, ehrlichiosis/anaplasmosis, SBE, histoplasmosis, miliary TB, toxoplasmosis, trichinosis, CMV

      Rheumatic/inflammatory: Adult Still's disease (JRA)

      Miscellaneous: Pulmonary emboli
      Liver test abnormalities
       ↑ Alkaline phosphatase (AP) mildly elevatedMalignant/neoplastic: Multiple myeloma, pre/acute leukemias, liver metastasis, lymphomas, carcinomas

      Infectious: liver abscess, EBV, CMV, Q fever, ehrlichiosis/anaplasmosis, malaria, histoplasmosis, HIV, miliary TB, relapsing fever

      Rheumatic/inflammatory: Gaucher's disease

      Miscellaneous: Drug fever, cirrhosis, ulcerative colitis (UC)
       ↑ Serum transaminases (SGOT/SGPT) mildly elevatedInfectious: Q fever, relapsing fever, brucellosis, ehrlichiosis/anaplasmosis, liver abscess, EBV, CMV, malaria

      Rheumatic/inflammatory: Adult Still's disease (JRA)

      Miscellaneous: Drug fever, cirrhosis, ulcerative colitis (UC)
       ↑ GGT (GGTP)Malignant/neoplastic: Hepatoma, liver metastases, hypernephroma/renal cell carcinoma (RCC)

      Infectious: EBV

      Miscellaneous: Cirrhosis
      Rheumatic test abnormalities
       ↑ Rheumatoid factors (RF)Malignant/neoplastic: Malignancy

      Infectious: SBE, miliary TB, visceral leishmaniasis (kala-azar), EBV, typhoid/enteric fever

      Rheumatic/inflammatory: Sarcoidosis, LORA, Behçet's disease, SLE

      Miscellaneous: Cirrhosis
       ↑ Antinuclear antibody titers (ANA)Infectious: HIV, EBV, CMV, TB, SBE, visceral leishmaniasis (kala-azar), malaria

      Rheumatic/inflammatory: SLE, LORA, sarcoidosis
       ↑ Angiotensin-converting enzyme levels (ACE)Malignant/neoplastic: Multiple myeloma, lymphoma

      Infectious: Miliary TB, coccidiomycosis

      Rheumatic/inflammatory: Gaucher's disease

      Miscellaneous: Cirrhosis
      AML = acute myelogenous leukemia; CMV = cytomegalovirus; EBV = Epstein-Barr virus; FUO = fever of unknown origin; GCA = giant cell arteritis; HIV = human immunodeficiency virus; LGV = lymphogranuloma venereum; LORA = late-onset rheumatoid arthritis; MPDs = myeloproliferative disorders; PAN = periarteritis nodosa; RA = rheumatoid arthritis; RBC = red blood cell; SBE = subacute bacterial endocarditis; SLE = systemic lupus erythematosus; SPEP = serum protein electrophoresis; TA = temporal arteritis; TB = tuberculosis; WBC = white blood cell.
      A common clinical problem is to differentiate infectious from malignant/neoplastic fevers of unknown origin. While the work-up is in progress, the Naprosyn test may be done early to differentiate infectious from malignant fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      During the 3-day Naprosyn test, if temperatures decrease markedly, then a malignant/neoplastic disorder is likely (positive Naprosyn test). However, if fevers remain elevated/only slightly decrease, an infectious etiology is likely (negative Naprosyn test).
      • Chang J.C.
      • Gross H.M.
      Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer.
      • Cunha B.A.
      • Bouyarden M.
      • Hamid N.
      Multiple myeloma presenting as a fever of unknown origin: the diagnostic importance of the naprosyn test.

      Imaging Studies

      Imaging studies should be clue directed and should be selected on the basis of fever of unknown origin category and likely pattern of organ involvement.
      • Trivedi Y.
      • Yung E.
      • Katz D.S.
      Imaging in fever of unknown origin.
      With hepatic/splenic enlargement, abdominal computed tomography scans are helpful in detecting other abnormalities, for example, retroperitoneal adenopathy or intra-abdominal/pelvic abscesses/masses.
      • Trivedi Y.
      • Yung E.
      • Katz D.S.
      Imaging in fever of unknown origin.
      Gallium/indium scans are useful, but indium scans are relatively insensitive (false negative) with bone infections, for example, chronic osteomyelitis and malignancies. Cardiac echocardiography is important in culture negative endocarditis, and atrial myxoma. Positron emission tomography-computed tomography scans are most useful in detecting obscure infectious/neoplastic fevers of unknown origin, for example, lymphomas, Erdheim-Chester disease, Q fever endocarditis, or aortic graft infection.
      • Pedersen T.I.
      • Roed C.
      • Knudsen L.S.
      • Loft A.
      • Skinhoj P.
      • Nielsen S.D.
      Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDG-PET/CT.

      Invasive Tests

      Lymph node biopsy is the most frequent invasive test.
      • Kosmin A.
      • Lorber B.
      Specific tests in the diagnosis of fever of unknown origin.
      If possible, anterior cervical, axillary, or inguinal node biopsies should be avoided because biopsies of these nodes are usually unhelpful/nondiagnostic and are often reported as “non-specific inflammatory changes, cannot rule out infection/malignancy.” More likely to be diagnostic are posterior cervical, supra/infraclavicular, or epitrochlear node biopsies.
      • Cunha B.A.
      Fever of unknown origin.
      • Cunha B.A.
      Fever of unknown origin: clinical overview of classic and current concepts.
      • Cunha B.A.
      Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
      Hilar, mediastinal, or retroperitoneal node biopsies have a high diagnostic yield.
      • Wang C.
      • Armstrong D.
      Neoplastic diseases.
      If bone involvement is likely, bone marrow biopsy may be diagnostic, for example, myeloproliferative disorders, preleukemias (due to acute myelogenous leukemia), Gaucher's disease, lymphoma, Erdheim-Chester disease, miliary tuberculosis, disseminated histoplasmosis, multicentric Castleman's disease, Whipple's disease, or typhoid/enteric fever (Table 3).
      • Ben-Baruch S.
      • Canaani J.
      • Braunstein R.
      • et al.
      Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin.
      When blood cultures are negative, bone marrow biopsy or culture may be positive in subacute bacterial endocarditis or typhoid/enteric fevers.
      • Jha A.
      • Sarda R.
      • Gupta A.
      • Talwar O.P.
      Bone marrow culture vs blood culture in Fever of Unknown Origin.
      Epididymal nodule biopsy may be diagnostic of brucellosis, tuberculosis, leptospirosis, rat bite fever, relapsing fever, lymphoma, systemic lupus erythematosus, periarteritis nodosa, sarcoidosis, or familial Mediterranean fever. Ileal biopsy can be done for suspected ileocecal tuberculosis or regional enteritis. With image directed percutaneous biopsies, exploratory laparotomy is now rarely needed for fever of unknown origin diagnosis.
      • DeKleijn E.M.
      • van Lier H.J.
      • van der Meer J.W.
      Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group.
      • Zenone T.
      Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital.
      Table 3FUO: Further Focused Testing (Nonimaging Tests)
      Adapted from Cunha CB. Infectious Disease Differential Diagnosis. In: Cunha BA (Ed.) Antibiotic Essentials. 14th ed. New Delhi, India: JP Medical Publishers; 2015:475-506.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Cunha BA. A focused diagnostic approach and non-specific tests in the diagnosis of FUO. In: Cunha BA, ed. Fever of Unknown Origin. New York: Informa Healthcare; 2007:9-16.
      • Cunha B.A.
      Fever of unknown origin: a focused diagnostic approach.
      Cunha BA. Nonspecific tests in the diagnosis of fever of unknown origin. In: Cunha BA, ed. Fever of Unknown Origin. New York: Informa Healthcare; 2007:151-158
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      and Cunha CB, Cunha BA. Fever of unknown origin (FUO). In: Schlossberg D. Clinical Infectious Diseases. 2nd ed. Cambridge, UK: Cambridge University Press; 2015:1-9.
      • Cunha C.B.
      • Cunha B.A.
      Fever of unknown origin (FUO).
      FUO Infectious Disease TestsFUO Neoplastic Disease TestsFUO Rheumatic/Inflammatory TestsMiscellaneous Other Tests
      Blood tests (if suspected by history and physical examination)
      • Q fever IgM/IgG titers• Brucella IgM/IgG titers• Bartonella IgM/IgG titers• Salmonella IgM/IgG titers• EBV IgM/IgG titers• CMV IgM/IgG titers• HHV-8 IgM/IgG titersCulture-positive endocarditis (SBE)Blood CulturesCulture-negative endocarditis (CNE)TTE shows a vegetationplusnegative blood culturesplusperipheral signs of SBE presentNoninfectious CNE (marantic endocarditis)If infectious CNE work-up negative → proceed with marantic endocarditis work-up (malignancy, lymphoma, etc.)Infectious CNEIf vegetation on TTE/TEE and blood cultures are negative, and peripheral signsof SBE present → proceed with infectious CNE workup (Q fever, Brucella, Bartonella, etc.)• Ferritin
      Repeat if already done.


      • LDH
      Repeat if already done.


      • B12 levels

      • ACE
      Repeat if already done.


      • β2 microglobulins
      • ANA
      Repeat if already done.


      • Ds DNA

      • ACE
      Repeat if already done.


      • Antiphospholipid antibodies

      • Anti-CCP titers

      • Ferritin
      Repeat if already done.
      • TFTs

      (Thyroid function tests)

      If subacute thyroiditis suspected

      ATAs

      (Antithyroid antibody tests)

      If subacute thyroiditis suspected

      • GGTP

      If alcoholic cirrhosis

      suspected

      • B12 levels

      If alcoholic cirrhosis suspected

      • MEFV gene studies

      If FMF suspected
      Radiologic tests (if suspected by history, physical examination, or nonspecific tests)
      • TTEIf blood cultures positive for endocarditis pathogen• TEEIf PVE, atrial myoma, or CNEmarantic endocarditis suspected• CT/MRI abdomen/pelvis
      Chest/head CT/MRI (if head/chest infectious etiology suspected).
      If intra-abdominal/pelvic infection suspected• Gallium/indium scanIf occult infection suspected• Panorex film of jawsIf apical root abscess suspected• PET-CT scanIf Q fever endocarditis, infected graft/ focal vascular infection suspected
      • CT/MRI abdomen/pelvis If intra-abdominal/ pelvic neoplasm suspected

      • Gallium/indium scan If neoplasm suspected

      • PET-CT scan If occult neoplasm suspected
      • CT/MRI abdomen If hepatomegaly/ splenomegaly or retroperitoneal adenopathy suspected• Abdominal CT scan If regional enteritis (Crohn's disease) suspected

      • Gallium/indium scan If regional enteritis (Crohn's disease) suspected

      • Chest CT (pulmonary embolus protocol) If pulmonary emboli suspected

      • CT-PET scan If Erdheim-Chester disease suspected (bone involvement, periaortic fibrosis or “coated aorta”)
      Other tests (if suspected by history, physical examination, or nonspecific tests)
      • Naprosyn testIf FUO DDx infection vs Malignancy suspected• Anergy panel/PPD or T-spotIf TB suspected• BM biopsy/cultureIf miliary TB, SBE, brucellosis, Q fever, typhoid/enteric fevers suspected• Naprosyn test If FUO DDx infection vs malignancy suspected

      • BM biopsy If myelophthisic anemia/abnormal WBCs

      • β-2 microglobulins If lymphoma suspected
      • Temporal artery biopsy If GCA/TA suspected

      • Low-dose steroids If PMR suspected (prednisone 10 mg/day diagnostic for PMR)

      • ASA therapy If adult Still's disease (JRA) suspected
      ACE = angiotensin-converting enzyme; AML = acute myelogenous leukemia; ASA = acetylsalicylic acid; BM = bone marrow; CCP = cyclic citrullinated peptide; CMV = cytomegalovirus; CT = computed tomography; DDx = differential diagnosis; EBV = Epstein-Barr virus; FMF = familial Mediterranean fever; FUO = fever of unknown origin; GCA = giant cell arteritis; GGTP = gamma glutamyl transpeptidase; HHV-6 = human herpes virus; HIV = human immunodeficiency virus; IgG = immunoglobulin G; IgM = immunoglobulin M; JRA = juvenile rheumatoid arthritis; LDH = lactate dehydrogenase; LGV = lymphogranuloma venereum; LORA = late-onset rheumatoid arthritis; MEFV = Mediterranean fever; MPDs = myeloproliferative disorders; MRI = magnetic resonance imaging; PAN = periarteritis nodosa; PET = positron emission tomography; PMR = polymyalgia rheumatica; PVE = prosthetic valve endocarditis; PPD = purified protein derivative; RA = rheumatoid arthritis; RBC = red blood cell; SBE = subacute bacterial endocarditis; TA = temporal arteritis; TB = tuberculosis; TEE = transesophageal echocardiogram; TFT = thyroid function test; TTE = transthoracic echocardiogram; WBC = white blood cell.
      Repeat if already done.
      Chest/head CT/MRI (if head/chest infectious etiology suspected).

      Fever of Unknown Origin Subsets

      Aside from the classical fevers of unknown origin, there are important subsets—for example, human immunodeficiency virus, organ transplants, and returning travelers that present especially difficult diagnostic challenges.

      Fever of Unknown Origin in Human Immunodeficiency Virus

      Acute human immunodeficiency virus may present as a fever of unknown origin with a mononucleosis-like syndrome with fever, rash, and lymphadenopathy. Human immunodeficiency virus patients often present with fever of unknown origin as their initial clinical manifestation of opportunistic infection or malignancy.
      • Mayo J.
      • Collazos J.
      • Martinez E.
      Fever of unknown origin in the HIV-infected patient: new scenario for an old problem.
      • Armstrong W.S.
      • Katz J.T.
      • Kazanjian P.H.
      Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      • Miralles P.
      • Moreno S.
      • Perez-Tascon M.
      • Cosin J.
      • Diaz M.D.
      • Bouza E.
      Fever of uncertain origin in patients infected with the human immunodeficiency virus.
      Highly active antiretroviral therapy has reduced human immunodeficiency virus associated fevers of unknown origin in the Western world, but has not altered its etiologic spectrum.
      • Lozano F.
      • Torre-Cisneros J.
      • Santos J.
      • et al.
      Impact of highly active antiretroviral therapy on fever of unknown origin in HIV-infected patients.
      The relative frequency of causes in human immunodeficiency virus fevers of unknown origin is influenced by highly active antiretroviral therapy, CD4 count, geographical area, and endemic infection prevalence, which may provide clues to the diagnosis. Most cases of human immunodeficiency virus fevers of unknown origin are due to infection, and common noninfectious causes are malignancies and drug fevers.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      • Miralles P.
      • Moreno S.
      • Perez-Tascon M.
      • Cosin J.
      • Diaz M.D.
      • Bouza E.
      Fever of uncertain origin in patients infected with the human immunodeficiency virus.
      Worldwide, tuberculosis is the most common adult immunodeficiency syndrome defining illness. With human immunodeficiency virus fevers of unknown origin, extrapulmonary or disseminated disease is common, which become more frequent as human immunodeficiency virus progresses.
      • Havlir D.V.
      • Barnes P.F.
      Tuberculosis in patients with human immunodeficiency virus infection.
      Disseminated Mycobacterium avium-intracellulare was a leading cause of human immunodeficiency virus fevers of unknown origin in the Western world. Other mycobacteria causing human immunodeficiency virus fevers of unknown origin include M. kansasii and M. genavense. In human immunodeficiency virus fevers of unknown origin, a single positive blood culture or mycobacteria recovered from a sterile body site is considered evidence of disseminated M. avium-intracellulare.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      • Havlir D.V.
      • Barnes P.F.
      Tuberculosis in patients with human immunodeficiency virus infection.
      While cryptococcosis may present as human immunodeficiency virus fever of unknown origin, concomitant meningoencephalitis is frequent and justifies cerebrospinal fluid analysis.
      • Park B.J.
      • Wannemuehler K.A.
      • Marston B.J.
      • Govender N.
      • Pappas P.G.
      • Chiller T.M.
      Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS.
      Pneumocystis jirovecii pneumonia accounts for 5%-13% of human immunodeficiency virus fevers of unknown origin, depending on regional prevalence/variations.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      P. jirovecii pneumonia often presents as a fever of unknown origin before respiratory symptoms with very low CD4 counts.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      Interestingly, in France (2004-2011) among 1259 patients diagnosed with P. jirovecii pneumonia, 666 (53%) were subsequently diagnosed with human immunodeficiency virus, while 593 (47%) were known human immunodeficiency virus infected.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      Cytomegalovirus accounts for 5% of human immunodeficiency virus fevers of unknown origin.
      • Micol R.
      • Buchy P.
      • Guerrier G.
      • et al.
      Prevalence, risk factors, and impact on outcome of cytomegalovirus replication in serum of Cambodian HIV-infected patients (2004-2007).
      Cytomegalovirus is the most common human immunodeficiency virus associated viral opportunistic infection, typically manifesting when latent cytomegalovirus reactivates with CD4 counts <100/mm3. Serum cytomegalovirus deoxynucleic acid is present in 55% with CD4+ count <100/mm3. Both cytomegalovirus deoxynucleic acid and viremia are strong predictors of death.
      • Nokta M.A.
      • Holland F.
      • De Gruttola V.
      • et al.
      Cytomegalovirus polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to cytomegalovirus disease.
      • Deayton J.R.
      • Prof Sabin C.A.
      • Johnson M.A.
      • Emery V.C.
      • Wilson P.
      • Griffiths P.D.
      Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy.
      Cytomegalovirus chorioretinitis remains the most common initial manifestation in 30% of adult immunodeficiency syndrome.
      Disseminated Histoplasma capsulatum var. capsulatum accounted for 7% of cases of human immunodeficiency virus fevers of unknown origin in the US, but there have been imported cases in Europe.
      • Peigne V.
      • Dromer F.
      • Elie C.
      • Lidove O.
      • Lortholary O.
      French Mycosis Study Group
      Imported acquired immunodeficiency syndrome-related histoplasmosis in metropolitan France: a comparison of pre-highly active anti-retroviral therapy and highly active anti-retroviral therapy eras.
      Histoplasmosis should be considered in human immunodeficiency virus fevers of unknown origin in endemic areas/previous history of travel to endemic areas, however remote.
      • Wheat L.J.
      • Connolly-Stringfield P.A.
      • Baker R.L.
      • et al.
      Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.
      Other endemic mycoses such as coccidioidomycosis and Penicillium marneffei may present as fevers of unknown origin in advanced human immunodeficiency virus patients who have traveled/lived in endemic arid areas of the Western US, Central/South America, Southeast Asia, South China, and India.
      • Woods C.W.
      • McRill C.
      • Plikaytis B.D.
      • et al.
      Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention.
      • Fish D.G.
      • Ampel N.M.
      • Galgiani J.N.
      • et al.
      Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.
      • Wong S.S.
      • Wong K.H.
      • Hui W.T.
      • et al.
      Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients.
      Skin lesions, most commonly papules with central necrotic umbilication, in 70% of human immunodeficiency virus fevers of unknown origin are due to disseminated P. marneffei.
      • Wong S.S.
      • Wong K.H.
      • Hui W.T.
      • et al.
      Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients.
      Visceral leishmaniasis accounts for <5% of human immunodeficiency virus fevers of unknown origin reported in 35 countries.
      • Jarvis J.N.
      • Lockwood D.N.
      Clinical aspects of visceral leishmaniasis in HIV infection.
      Central nervous system or pulmonary toxoplasmosis, Aspergillus sp. or Bartonella sp. infections may present as human immunodeficiency virus fevers of unknown origin.
      • Fish D.G.
      • Ampel N.M.
      • Galgiani J.N.
      • et al.
      Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.
      • Wong S.S.
      • Wong K.H.
      • Hui W.T.
      • et al.
      Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients.
      • Jarvis J.N.
      • Lockwood D.N.
      Clinical aspects of visceral leishmaniasis in HIV infection.
      • Zylberberg H.
      • Robert F.
      • Le Gal F.A.
      • Dupouy-Camet J.
      • Zylberberg L.
      • Viard J.P.
      Prolonged isolated fever due to attenuated extracerebral toxoplasmosis in patients infected with human immunodeficiency virus who are receiving trimethoprim-sulfamethoxazole as prophylaxis.
      • Koehler J.E.
      • Sanchez M.A.
      • Tye S.
      • et al.
      Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever.
      • Lortholary O.
      • Meyohas M.C.
      • Dupont B.
      • et al.
      Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS.
      Malignancies represent about 8% of human immunodeficiency virus fevers of unknown origin. Lymphomas, especially non-Hodgkin's lymphomas, occur in 4%-7%.
      • Goedert J.J.
      • Cote T.R.
      • Virgo P.
      • et al.
      Spectrum of AIDS-associated malignant disorders.
      A higher risk of Hodgkin's disease occurs even in highly active antiretroviral therapy-treated human immunodeficiency virus. Fevers of unknown origin due to primary brain lymphoma or Kaposi's sarcoma (associated or not with Castleman's disease) are less common. Other cancers, such as bronchogenic carcinoma and hepatoma, are increasingly common in human immunodeficiency virus and may present as fever of unknown origin, even in those receiving highly active antiretroviral therapy.
      • Goedert J.J.
      • Cote T.R.
      • Virgo P.
      • et al.
      Spectrum of AIDS-associated malignant disorders.
      In contrast to classic fevers of unknown origin, rheumatic/inflammatory disorders are rare.
      In human immunodeficiency virus fevers of unknown origin, drug fever is common (3%-20%). Drug-related rashes are estimated to be 100× more common in those infected with human immunodeficiency virus than in the general population. Isolated drug fever is responsible for 1.7%, and maculopapular/pruritic rash for 17% of all adverse drug reactions.
      • Cribb A.E.
      • Lee B.L.
      • Trepanier L.A.
      • Spielberg S.P.
      Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis.
      • Carr A.
      • Cooper D.A.
      Adverse effects of antiretroviral therapy.
      Multiple drugs, including highly active antiretroviral therapy, increase risk for adverse reactions. Drugs commonly involved include antimicrobials (trimethoprim-sulfamethoxazole, beta-lactam antibiotics, sulfonamides, Sulfa containing laxatives (Colace) and diuretics [Lasix]), but highly active antiretroviral therapy drugs have become increasingly important.
      • Cribb A.E.
      • Lee B.L.
      • Trepanier L.A.
      • Spielberg S.P.
      Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis.
      • Carr A.
      • Cooper D.A.
      Adverse effects of antiretroviral therapy.
      • Fellay J.
      • Boubaker K.
      • Ledergerber B.
      • et al.
      Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study.
      Early in highly active antiretroviral therapy, immune reconstitution inflammatory syndrome may occur. Immune reconstitution inflammatory syndrome occurs in 8%-45% of human immunodeficiency virus with tuberculosis, 35% with disseminated M. avium-intracellulare, 8%-31% with Cryptococcus neoformans, and 18%-62% with cytomegalovirus. Most immune reconstitution inflammatory syndrome cases occur <60 days after initiating highly active antiretroviral therapy.
      • Shelburne S.A.
      • Visnegarwala F.
      • Darcourt J.
      • et al.
      Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy.
      Immune reconstitution inflammatory syndrome is often associated with more specific, infection-associated signs such as respiratory symptoms or inflammatory adenopathies with tuberculosis or raised intracranial pressure with cryptococcosis, which are clues to the diagnosis of immune reconstitution inflammatory syndrome in human immunodeficiency virus fevers of unknown origin.
      • Fellay J.
      • Boubaker K.
      • Ledergerber B.
      • et al.
      Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study.
      Unaltered in the highly active antiretroviral therapy era, the cause of human immunodeficiency virus fevers of unknown origin remains unknown in 6%-14%.
      • Shelburne S.A.
      • Visnegarwala F.
      • Darcourt J.
      • et al.
      Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy.

      Fever of Unknown Origin in Solid Organ Transplants

      The diagnostic approach to solid organ transplant fevers of unknown origin is based on 4 major factors: degree/duration of immunosuppression time of posttransplant fever of unknown origin, recent/remote epidemiological exposure (health care-related or community-acquired infections), and clinical manifestations.
      • Bouza E.
      • Loeches B.
      • Munoz P.
      Fever of unknown origin in solid organ transplant recipients.
      Immunosuppression status is not based on a single specific biomarker, for example, CD4 counts as in human immunodeficiency virus, but is related to the additive immunosuppressive effect of underlying disease requiring transplantation, magnitude/type of immunosuppressive therapy, renal failure, diabetes, associated neutropenia, and co-infection with immunosuppressive viruses (cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus). Three different posttransplantation periods are recognized to approach the differential diagnosis of solid organ transplant fevers of unknown origin, from 1-6 months and >6 months.
      • Bouza E.
      • Loeches B.
      • Munoz P.
      Fever of unknown origin in solid organ transplant recipients.
      • Bonham C.A.
      • Dominguez E.A.
      • Fukui M.B.
      • et al.
      Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management.
      • Ionescu D.N.
      • Dacic S.
      Persistent fever in a lung transplant patient.
      • Wulf M.W.
      • van Crevel R.
      • Portier R.
      • et al.
      Toxoplasmosis after renal transplantation: implications of a missed diagnosis.
      Clinical symptoms should direct the diagnostic approach. Subacute/chronic meningitis suggests tuberculosis, cryptococcosis, or endemic fungi while focal brain lesions suggest nocardiosis, toxoplasmosis, aspergillosis, or lymphoma. Meningoencephalitis suggests a viral cause (cytomegalovirus, varicella-zoster virus, West Nile virus). Skin lesions (umbilicated papules) may suggest disseminated fungal infections (Fusarium sp.). Noninfectious causes of solid organ transplant fevers of unknown origin include drug fever/rash. Post-transplant lymphoproliferative disorders and transplant rejection may present as solid organ transplant fevers of unknown origin.
      • Hot A.
      • Schmulewitz L.
      • Viard J.P.
      • Lortholary O.
      Fever of unknown origin in HIV/AIDS patients.
      • Ionescu D.N.
      • Dacic S.
      Persistent fever in a lung transplant patient.
      • Wulf M.W.
      • van Crevel R.
      • Portier R.
      • et al.
      Toxoplasmosis after renal transplantation: implications of a missed diagnosis.

      Fever of Unknown Origin in Returning Travelers

      Specific fever of unknown origin etiologies in returning travelers is determined by geographical areas visited/duration of stay, eating exposures (uncooked meat/fish, shellfish, unpasteurized milk products), insect exposure (mosquitos, tick bite), and time interval after return.
      • Maegraith B.
      Unde venis?.
      • Saxe S.E.
      • Gardner P.
      The returning traveler with fever.
      Ingestion of unpasteurized milk suggests possible brucellosis. In fevers of unknown origin, tick or louse-borne relapsing fevers should be considered with headache, conjunctival suffusion, and liver/spleen enlargement.
      • Speil C.
      • Mushtaq A.
      • Adamski A.
      • Khardori N.
      Fever of unknown origin in the returning traveler.
      • Cleri D.J.
      • Ricketti A.J.
      • Vernaleo J.R.
      Fever of unknown origin due to zoonoses.
      • Botelho-Nevers E.
      • Raoult D.
      Fever of unknown origin due to rickettsioses.
      In returning travelers from malarious areas, malaria should be suspected, but other causes should be considered, including viral hepatitis, typhoid/enteric fever, leptospirosis, endemic mycoses, and rickettsial diseases (Rickettsia africae or R. typhi, R. conorii, Orientia tsutsugamushi, depending on geographical area), amebic liver abscess, schistosomiasis, African trypanosomiasis, endemic arboviral infections (dengue fever, chikungunya fever, yellow fever, West Nile encephalitis, Japanese encephalitis), and acute human immunodeficiency virus.
      • O'Brien D.
      • Tobin S.
      • Brown G.V.
      • et al.
      Fever in returned travelers: review of hospital admissions for a 3-year period.
      • Lortholary O.
      • Charlier C.
      • Lebeaux D.
      • Lecuit M.
      • Consigny P.H.
      Fungal infections in immunocompromised travelers.

      Easily Missed Causes of Fever of Unknown Origin

      In each fever of unknown origin category, there are some diagnoses that are particularly important either because they are easily overlooked or because they are potentially life threatening.
      • Cunha C.B.
      • Cunha B.A.
      Fever of unknown origin (FUO).
      The four most common/important malignant/neoplastic fevers of unknown origin that should be carefully considered are lymphoma, hypernephroma, preleukemia, and atrial myxoma. Infections that merit careful diagnostic evaluation are cytomegalovirus, miliary tuberculosis, typhoid/enteric fever, and culture-negative endocarditis. In the rheumatic/inflammatory category, systemic lupus erythematosus, giant cell arteritis/temporal arteritis, adult Still's disease, and periarteritis nodosa may be particularly elusive diagnoses. Among miscellaneous fevers of unknown origin, drug fever, factious fever, cyclic neutropenia, and subacute thyroiditis are not to be missed diagnoses
      • Esposito A.L.
      • Gleckman R.A.
      A diagnostic approach to the adult with fever of unknown origin.
      • Esposito A.L.
      Planning and proceeding with the diagnostic evaluation.
      • Cunha B.A.
      Fever of unknown origin: a focused diagnostic approach.
      (Table 4).
      Table 4FUO: Clinical Clue Summaries of Common Easily Missed Diagnoses (Malignant/Neoplastic Disorders)
      Adapted from: Cunha CB. Infectious disease differential diagnosis. In: Cunha BA, ed. Antibiotic Essentials. 14th ed. New Delhi, India: JP Medical Publishers; 2015:475-506.
      • Cunha C.B.
      Infectious disease differential diagnosis.
      Cunha BA. A focused diagnostic approach and non-specific tests in the diagnosis of FUO. In: Cunha BA, ed. Fever of Unknown Origin. New York: Informa Healthcare; 2007:9-16.
      • Cunha B.A.
      Fever of unknown origin: a focused diagnostic approach.
      Cunha BA. Nonspecific tests in the diagnosis of fever of unknown origin. In: Cunha BA, ed. Fever of Unknown Origin. New York: Informa Healthcare; 2007:151-158.
      • Cunha B.A.
      Nonspecific tests in the diagnosis of fever of unknown origin.
      Cunha BA. Fever of unknown origin (FUO). In: Gorbach SL, Bartlett JB, Blacklow NR, eds. Infectious Diseases in Medicine and Surgery. 3rd ed. Philadelphia: WB Saunders; 2004:1568–1577
      • Cunha B.A.
      Fever of unknown origin.
      and Cunha CB, Cunha BA. Fever of unknown origin (FUO). In: Schlossberg D. Clinical Infectious Diseases, 2nd ed. Cambridge, UK: Cambridge University Press; 2015:1-9.
      • Cunha C.B.
      • Cunha B.A.
      Fever of unknown origin (FUO).
      Lymphomas (HL/NHL)History clues:





      Physical clues:

      Laboratory clues:
      Treatment for HL, primary immune deficiencies, post-transplant immunosuppressive, HIV, hectic/septic fevers (Pel-Ebstein in some), night sweats, weight loss, pruritus, malabsorption symptoms (NHL), bone pain (NHL)

      Regional adenopathy (Hodgkin's lymphoma), hepatomegaly, splenomegaly

      Relative lymphopenia; monocytosis; eosinophilia; basophilia; thrombocytosis; thrombocytopenia (if ITP); ↑ alkaline phosphatase, SPEP (↑ α12 globulins or hypogammaglobulinemia), ↑ ferritin, + cryoglobulins, ↑ cold agglutinins, ↑ LAP, ↑ haptoglobin, ↑B12 level, ↑β2 microglobulins, ↑ α1-antitrypsin, + Coombs test, ↓ folate, ↑ uric acid, ↑LDH
      Hypernephroma(renal cell carcinoma)History clues:



      Physical clues:

      Laboratory clues:
      Von Hippel-Lindau disease, adult polycystic kidney disease, excessive phenacetin use, flank pain, hematuria

      Flank mass, left hydrocele

      Gross/microscopic hematuria, ↑ alkaline phosphatase, ↑ GGT, ↑ calcium
      Preleukemia (AML)History clues:

      Physical clues:

      Laboratory clues:
      Night sweats, weight loss

      Sternal tenderness

      Metamyelocytes, nucleated or teardrop RBCs, ↑ ESR, ↑ LDH, ↑ ferritin, ↑ uric acid
      Atrial myxomaHistory clues:

      Physical clues:

      Laboratory clues:
      Heart murmur, weight loss

      Cytoid bodies (cotton wool spots), Roth's spots, heart murmur, splinter hemorrhages

      ↑ ESR, SPEP (polyclonal gammopathy), TTE/TEE (vegetations with negative blood cultures)
      Infectious culture-negative endocarditis(CNE)History clues:





      Physical clues:



      Laboratory clues:
      Night sweats, weight loss, arthralgias, heart murmur, recent dental or surgical (below waist) or urologic procedure, recent or unexplained LUQ pain, back pain, recent or unexplained CVA

      Roth's spots, conjunctival hemorrhages, heart murmur, splinter hemorrhages, Osler's nodes, Janeway lesions, splenomegaly, spinal tenderness, joint pain or effusion

      Leukocytosis, monocytosis, thrombocytosis, ↑ ESR, ↑ RF, + VDRL, microscopic hematuria
      Miliary TBHistory clues:



      Physical clues:



      Laboratory clues:
      Previous TB or exposure, immunosuppressive disorder or drugs, night sweats, weight loss (with intact appetite)

      Morning temperature spikes, choroid tubercles, hepatomegaly, splenomegaly, generalized adenopathy

      Leukopenia, lymphopenia, thrombocytopenia, ↑ LFTs, + CT/MRI or gallium/indium scans, - PPD (anergic), + AFB smear or culture of liver or bone marrow
      Typhoid/enteric feverHistory clues:



      Physical clues:

      Laboratory clues:
      Recent contaminated food or water exposure, recent foreign travel, headache or mental status changes, night sweats, weight loss

      Morning temperature spikes, relative bradycardia, splenomegaly, hepatomegaly

      Leukopenia, relative lymphopenia, eosinopenia, ↑ LFTs, + CT/MRI or gallium/indium scans, ↑IgM titers, Salmonella sp., + blood, urine, stool or BM cultures
      CMVHistory clues:

      Physical clues:

      Laboratory clues:
      Recent body secretion exposure, blood transfusions

      Palatal petechiae, adenopathy, splenomegaly

      Leukopenia, relative lymphopenia, atypical lymphocytes, ↑ LFTs, gallium/indium scans, ↑ IgM titers, + CMV PCR
      SLEHistory clues:





      Physical clues:





      Laboratory clues:
      Photosensitivity, alopecia, eye symptoms, seizures, headache or mental confusion, sore throat, arthralgias, chest or abdominal pain, tender fingertips, rash, testicular pain, acalculous cholecystitis

      Alopecia, oral ulcers, scleritis, iritis, uveitis, Roth's spots, cytoid bodies (cotton wool spots), heart murmur (if Libman-Sacks endocarditis), Osler's nodes, adenopathy, splenomegaly, epididymo-orchitis

      Leukopenia, relative lymphopenia, monocytosis, ↑ ferritin, ↑ ANA, cryoglobulins, ↓ complement, thrombocytopenia, SPEP (polyclonal gammopathy), ↑ DsDNA, ↑ anti-SM antibodies, ↑ antiphospholipid antibodies, proteinuria
      GCA/TAHistory clues:

      Physical clues:



      Laboratory clues:
      Depression, amaurosis fugax, headache, eye pain, myalgias, jaw pain

      Scalp nodules, temporal artery tenderness, episcleritis, optic disc pallor, cytoid bodies (cotton wool spots), cranial nerve palsies

      Monocytosis, ↑ ESR, ↑ alkaline phosphatase
      Adult Still's disease (JRA)History clues:

      Physical clues:



      Laboratory clues:
      Eye symptoms, sore throat, truncal rash (evanescent), arthralgias

      Conjunctival suffusion, double quotidian fever, uveitis, arthritis (late), if rash, dermatographia, (Köebner's phenomenon), adenopathy, splenomegaly

      Marked leukocytosis count, ↑ ESR, ↑ alkaline phosphatase, ↑ ferritin
      PANHistory clues:

      Physical clues:





      Laboratory clues:
      Hearing loss, watery eyes, acalculous cholecystitis, hypertension

      Morning temperature spikes, watery eyes, episcleritis, cytoid bodies (cotton wool spots), optic neuritis (with “macular star”), Roth's spots, cranial nerve palsies, mononeuritis multiplex

      ↑ ESR, ↑ alkaline phosphatase, SPEP (polyclonal gammopathy)
      Drug feverHistory clues:

      Physical clues:

      Laboratory clues:
      Often atopic, usually sensitivity during prolonged exposure (not a recent/new drug).

      Relative bradycardia, look “inappropriately well” for degree of fever, no rash

      Leukocytosis, atypical lymphocytes, eosinophils (eosinophilia less common), ↑ ESR, mildly ↑ LFTs, blood cultures negative (excluding contaminants)
      Subacute thyroiditisHistory clues:



      Physical clues:

      Laboratory clues:
      Often a history of antecedent viral infection, no history of thyroid disease, often history of multi-nodular goiter, headache, neck/jaw pain common, sore throat

      Thyroid (isthmus) tenderness

      Relative lymphocytosis, ↑ ESR
      Factitious feverHistory clues:



      Physical clues:

      Laboratory clues:
      Personality disorder common, usually medical personnel, multiple hospitalizations for obscure fevers

      Relative bradycardia, look “inappropriately well” for degree of fever

      Normal CBC, LFTs, ESR, normal urine temperature <body temperature
      Cyclic neutropeniaHistory clues:



      Physical clues:

      Laboratory clues:
      Recurrent fevers, systemic symptoms occur at varying intervals but fevers always occur At 7 day multiples (usually every 21 or 28 days).

      Unremarkable, completely well during fever free intervals

      Leukopenia during febrile intervals, but WBC normal between attacks
      AML = acute monocytic leukemia; ANA = antinuclear antibody; BM = bone marrow; CBC = complete blood count; CMV = cytomegalovirus; CT = computed tomography; CVA = cerebrovascular accident; Ds DNA = double stranded deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; GCA = giant cell arteritis; GGTP = gamma glutamyl transpeptidase; HIV = human immunodeficiency virus; HL = Hodgkin lymphoma; IgM = immunoglobulin M; ITP = idiopathic thrombocytopenic purpura; JRA = juvenile rheumatoid arthritis; LAP = leucine aminopeptidase; LDH = lactic acid dehydrogenase; LFT = liver function test; LUQ = left upper quadrant; MCD = multicentric Castleman disease; MPA = microscopic polyangiitis; MPDs = myeloproliferative disorders; MRI = magnetic resonance imaging; NHL = non-Hodgkin lymphoma; PAN = periarteritis nodosa; PCR = polymerase chain reaction; PPD = purified protein derivative; RBC = red blood cell; SLE = systemic lupus erythematosus; SPEP = serum protein electrophoresis; TA = temporal arteritis; TB = tuberculosis; TEE = transesophageal echocardiogram; TTE = transthoracic echocardiogram; VDRL = Venereal Disease Research Laboratory test.

      Recurrent and Undiagnosed Fevers of Unknown Origin

      Relatively few fever of unknown origin disorders may become recurrent. Recurrent fevers of unknown origin limit diagnostic possibilities and give further opportunities for a definite diagnosis. Recurrent fevers of unknown origin may be defined as at least 2 episodes of prolonged fever separated by at least 2 weeks of fever free intervals.
      • Knockaert D.C.
      • Durjardin K.S.
      • Bobbaers H.J.
      Long-term follow-up of patients with undiagnosed fever of unknown origin.
      Miscellaneous disorders are more likely the longer the duration of recurrent fevers of unknown origin.
      • Collazos J.
      • Guerra E.
      • Mayo J.
      • et al.
      Tuberculosis as a cause of recurrent fever of unknown origin.
      • Lekstrom-Himes J.A.
      • Dale J.K.
      • Kingma D.W.
      • et al.
      Periodic illness associated with Epstein-Barr virus infection.
      • Munoz-Gomez S.
      • Cunha B.A.
      Recurrent fever of unknown origin in an adult due to FAPA syndrome.
      • Weinstein L.
      Clinically benign fever of unknown origin: a personal retrospective.
      • Knockaert D.C.
      Recurrent fevers of unknown origin.
      The diagnostic approach to recurrent fevers of unknown origin is based on clues from serial observations/testing during/between febrile episodes, as new findings become apparent, the work-up should be redirected based on new clues.
      • Weinstein L.
      Clinically benign fever of unknown origin: a personal retrospective.
      If a recurrent fever of unknown origin remains undiagnosed for >1 year, a definitive diagnosis is unlikely.
      • Knockaert D.C.
      Recurrent fevers of unknown origin.
      Some fevers of unknown origin remain undiagnosed even after a focused diagnostic work-up. The longer that a fever of unknown origin remains undiagnosed, the less likely infectious or neoplastic etiology or a definitive diagnosis.
      • Knockaert D.C.
      • Durjardin K.S.
      • Bobbaers H.J.
      Long-term follow-up of patients with undiagnosed fever of unknown origin.

      Therapy of Fever of Unknown Origin

      Fevers of unknown origin are a diagnostic challenge and not a therapeutic problem. Until a definite fever-of-unknown-origin diagnosis, antipyretic or antimicrobial therapy may mask, delay, or obscure clinical manifestations and should be avoided.
      • Bryan C.S.
      • Ahuja D.
      Fever of unknown origin: is there a role for empiric therapy?.
      Empiric therapy is prudent in a few difficult-to-diagnose life-threatening fevers of unknown origin, for example, central nervous system or miliary tuberculosis, or giant cell arteritis/temporal arteritis.
      • Eiko L.M.
      • Bryan C.S.
      Empiric therapy in fever of unknown origin: a cautionary note.

      References

        • Cunha C.B.
        Prolonged and perplexing fevers in antiquity: malaria and typhoid fever.
        Infect Dis Clin North Am. 2007; 21: 857-866
        • Cunha B.A.
        Fever of unknown origin: clinical overview and perspective.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 1-8
        • Petersdorf R.G.
        • Beeson P.B.
        Fever of unexplained origin: report on 100 cases.
        Medicine (Baltimore). 1961; 40: 1-30
        • Larson E.B.
        • Featherstone H.J.
        • Petersdorf R.G.
        Fever of undetermined origin: diagnosis and follow-up of 105 cases, 1970-80.
        Medicine (Baltimore). 1982; 61: 269-292
        • Cunha B.A.
        Fever of unknown origin.
        in: Gorbach S.L. Bartlett J.G. Blacklow N.E. Infectious Diseases in Medicine and Surgery. 3rd ed. Lippincott Williams & Wilkins, Philadelphia2004: 1568-1577
        • Cunha C.B.
        • Cunha B.A.
        Fever of unknown origin (FUO).
        in: Schlossberg D. Clinical Infectious Disease. 2nd ed. Cambridge University Press, Cambridge, UK2015: 1-6
        • Molavi A.
        • Weinstein L.
        Persistent perplexing pyrexia. Some comments on etiology and diagnosis.
        Med Clin North Am. 1970; 54: 379-396
        • Louria D.B.
        Fever of unknown etiology.
        Del Med J. 1971; 43: 343-348
        • Jacoby G.A.
        • Swartz M.N.
        Fever of undetermined origin.
        N Engl J Med. 1973; 289: 1407-1410
      1. Tumulty P.A. The Patient with Fever of Unknown Origin: The Effective Clinician. WB Saunders, Philadelphia1973
        • Cunha B.A.
        Fever of unknown origin.
        Infect Dis Clin North Am. 1996; 10: 111-128
        • Lortholary O.
        • Bletry L.G.
        • Godeau P.
        Fever of unknown origin: a retrospective multicentre study of 103 cases, 1980-88.
        Eur J Med. 1992; 3: 109-120
        • Brusch J.L.
        • Weinstein L.
        Fever of unknown origin.
        Med Clin North Am. 1988; 72: 1247-1261
        • Knockaert D.C.
        • Vanderschueren S.
        • Blockmans D.
        Fever of unknown origin in adults: 40 years on.
        J Intern Med. 2003; 253: 263-275
        • Bryan C.S.
        Fever of unknown origin.
        Arch Intern Med. 2003; 163: 1003-1004
        • Arnow P.M.
        • Flaherty J.P.
        Fever of unknown origin.
        Lancet. 1997; 350: 575-580
        • Nubile M.J.
        Acute fevers of unknown origin. A plea for restraint.
        Arch Intern Med. 1993; 153: 2525-2526
        • Vanderschueren S.
        • Knockaert D.
        • Adriaenssens T.
        • et al.
        From prolonged febrile illness to fever of unknown origin: The Challenge Continues.
        Arch Intern Med. 2003; 163: 1033-1041
        • Ergonul O.
        • Wilke A.
        • Azap A.
        • et al.
        Revised definition of fever of unknown origin: limitations and opportunities.
        J Infect. 2005; 51: 1-5
        • Efstathiou S.P.
        • Pefanis A.V.
        • Tsiakou A.G.
        • et al.
        Fever of unknown origin: discrimination between infectious and non-infectious causes.
        Eur J Intern Med. 2010; 21: 137-143
        • Cunha B.A.
        Fever of unknown origin: clinical overview of classic and current concepts.
        Infect Dis Clin North Am. 2007; 21: 867-915
        • Kazanjian P.H.
        Fever of unknown origin. Review of 86 patients treated in community hospital.
        Clin Infect Dis. 1992; 15: 968-973
        • Wang C.
        • Armstrong D.
        Neoplastic diseases.
        in: Murray H.W. Fever of Undetermined Origin. Futura Publishing, Mount Kisco, NY1983: 39-48
        • Cunha B.A.
        Fever of unknown origin in malignancies.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 27-34
        • Zhang J.
        • Chen B.
        • Xu X.
        • et al.
        Clinical features of 66 lymphoma patients presenting with a fever of unknown origin.
        Intern Med. 2012; 51: 2529-2536
        • Cunha B.A.
        Fever of unknown origin: focused diagnostic approach based on clinical clues from the history, physical examination and laboratory tests.
        Infect Dis Clin North Am. 2007; 21: 1137-1188
        • Manfredi R.
        • Calza L.
        • Chiodo F.
        Primary cytomegalovirus infection in otherwise healthy adults with fever of unknown origin: a 3-year prospective survey.
        Infection. 2006; 34: 87-90
        • Carsons S.E.
        Fever in rheumatic and autoimmune disease.
        Infect Dis Clin North Am. 1996; 10: 67-84
        • Zenone T.
        Fever of unknown origin in rheumatic diseases.
        Infect Dis Clin North Am. 2007; 21: 1115-1136
        • Cunha B.A.
        Fever of unknown origin in rheumatic diseases.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 59-64
        • Cunha B.A.
        • Parchuri S.
        • Mohan S.
        Fever of unknown origin: temporal arteritis presenting with persistent cough and elevated serum ferritin levels.
        Heart Lung. 2006; 35: 112-116
        • Cunha B.A.
        • Nausheen S.
        Fever of unknown origin due to cyclic neutropenia with relative bradycardia.
        Heart Lung. 2009; 38: 350-353
        • Cunha B.A.
        • Mickail N.
        • Durie N.
        • Pherez F.M.
        • Strollo S.
        Fever of unknown origin caused by Kikuchi's disease mimicking lymphoma.
        Heart Lung. 2009; 38: 450-456
        • Cunha B.A.
        • Durie N.
        • Selbs E.
        • Pherez F.
        Fever of unknown origin due to Rosai-Dorfman disease with mediastinal adenopathy mimicking lymphoma: diagnostic importance of elevated serum ferritin levels and polyclonal gammopathy.
        Heart Lung. 2009; 38: 83-88
        • Brendan M.W.
        • Matthew J.H.
        • Dennis P.M.
        Subacute thyroiditis manifesting as fever of unknown origin.
        South Med J. 2000; 93: 926-929
        • Cunha B.A.
        • Thermidor M.
        • Mohan S.
        • et al.
        Fever of unknown origin: subacute thyroiditis versus typhoid fever.
        Heart Lung. 2005; 34: 147-151
        • Cunha B.A.
        • Chak A.
        • Strollo S.
        Fever of unknown origin: de Quervain's subacute thyroiditis with highly elevated ferritin levels mimicking temporal arteritis (TA).
        Heart Lung. 2010; 39: 73-77
        • Cunha B.A.
        • Berbari N.
        Subacute thyroiditis (de Quervain's) due to influenza A: presenting as fever of unknown origin.
        Heart Lung. 2013; 42: 77-78
        • Murray H.W.
        Factitious fever updated.
        Arch Intern Med. 1979; 139: 739-740
        • Johnson D.H.
        • Cunha B.A.
        Drug fever.
        Infect Dis Clin North Am. 1996; 10: 85-92
        • Drenth J.P.H.
        • Haagsma C.J.
        • van der Meer J.W.M.
        International Hyper-IgD Study Group. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients.
        Medicine (Baltimore). 1994; 73: 133-144
        • Wolf S.M.
        • Fauci A.S.
        • Dale D.C.
        Unusual etiologies of fever and their evaluation.
        Annu Rev Med. 1975; 26: 277-281
        • Norman D.C.
        • Wong M.B.
        Fever of unknown origin in older persons.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 109-114
        • Cunha B.A.
        Diagnostic significance of relative bradycardia.
        Clin Microbiol Infect. 2000; 6: 633-634
        • Cunha C.B.
        Infectious disease differential diagnosis.
        in: Cunha B.A. Antibiotic Essentials. 14th ed. JP Medical Publishers, New Delhi, India2015: 475-506
        • Cunha C.B.
        • Wilkinson M.J.
        • Quillen D.A.
        Ophthalmologic clues to infectious diseases.
        in: Cunha B.A. Infectious Diseases in Critical Care Medicine. 3rd ed. Informa, New York2010: 66-75
        • Cunha B.A.
        The mimics of endocarditis.
        in: Brusch J.L. Infective Endocarditis: Management in the Era of Intravascular Devices. Informa Healthcare, New York2006: 345-354
        • Esposito A.L.
        • Gleckman R.A.
        A diagnostic approach to the adult with fever of unknown origin.
        Arch Intern Med. 1979; 139: 575-578
        • Esposito A.L.
        Planning and proceeding with the diagnostic evaluation.
        in: Murray H.W. Fever of Undetermined Origin. Futura Publishing, Mount Kisco, NY1983: 141-145
        • Cunha B.A.
        Fever of unknown origin: a focused diagnostic approach.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 9-16
        • Cunha B.A.
        Nonspecific tests in the diagnosis of fever of unknown origin.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 151-158
        • Cunha B.A.
        The diagnostic significance of fever curves.
        Infect Dis Clin North Am. 1996; 10: 33-44
        • Cunha B.A.
        • Krakakis J.
        • McDermott B.P.
        Fever of unknown origin caused by miliary tuberculosis: diagnostic significance of morning temperature spikes.
        Heart Lung. 2009; 38: 77-82
        • Cunha B.A.
        Fever of unknown origin caused by adult juvenile rheumatoid arthritis: the diagnostic significance of double quotidian fevers and elevated serum ferritin levels.
        Heart Lung. 2004; 33: 417-421
        • Cunha B.A.
        • Hage J.E.
        • Nouri Y.
        Recurrent fever of unknown origin: aseptic meningitis, hepatosplenomegaly, pericarditis and a double quotidian fever due to juvenile rheumatoid arthritis (JRA).
        Heart Lung. 2012; 41: 177-180
        • Purnendu S.
        • Louria D.B.
        Non-invasive and invasive diagnostic procedures and laboratory methods.
        in: Murray H.W. Fever of Undetermined Origin. Futura Publishing, Mount Kisco, NY1983: 159-190
        • Cunha B.A.
        • Petelin A.
        Fever of unknown origin due to large B-cell lymphoma: the diagnostic significance of highly elevated alkaline phosphatase and serum ferritin levels.
        Heart Lung. 2013; 42: 67-71
        • Cunha B.A.
        Fever of unknown origin: diagnostic importance of serum ferritin levels.
        Scand J Infect Dis. 2007; 39: 651-652
        • Kosmin A.
        • Lorber B.
        Specific tests in the diagnosis of fever of unknown origin.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 159-208
        • Chang J.C.
        • Gross H.M.
        Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer.
        Am J Med. 1984; 76: 597-603
        • Cunha B.A.
        • Bouyarden M.
        • Hamid N.
        Multiple myeloma presenting as a fever of unknown origin: the diagnostic importance of the naprosyn test.
        Heart Lung. 2006; 35: 358-362
        • Trivedi Y.
        • Yung E.
        • Katz D.S.
        Imaging in fever of unknown origin.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 209-228
        • Pedersen T.I.
        • Roed C.
        • Knudsen L.S.
        • Loft A.
        • Skinhoj P.
        • Nielsen S.D.
        Fever of unknown origin: a retrospective study of 52 cases with evaluation of the diagnostic utility of FDG-PET/CT.
        Scand J Infect Dis. 2012; 44: 18-23
        • Ben-Baruch S.
        • Canaani J.
        • Braunstein R.
        • et al.
        Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin.
        Mayo Clin Proc. 2012; 87: 136-142
        • Jha A.
        • Sarda R.
        • Gupta A.
        • Talwar O.P.
        Bone marrow culture vs blood culture in Fever of Unknown Origin.
        J Nepal Med Assoc. 2009; 48: 135-138
        • DeKleijn E.M.
        • van Lier H.J.
        • van der Meer J.W.
        Fever of unknown origin (FUO). II. Diagnostic procedures in a prospective multicenter study of 167 patients. The Netherlands FUO Study Group.
        Medicine (Baltimore). 1997; 76: 401-414
        • Zenone T.
        Fever of unknown origin in adults: evaluation of 144 cases in a non-university hospital.
        Scand J Infect Dis. 2006; 38: 625-631
        • Mayo J.
        • Collazos J.
        • Martinez E.
        Fever of unknown origin in the HIV-infected patient: new scenario for an old problem.
        Scand J Infect Dis. 1997; 29: 327-336
        • Armstrong W.S.
        • Katz J.T.
        • Kazanjian P.H.
        Human immunodeficiency virus-associated fever of unknown origin: a study of 70 patients in the United States and review.
        Clin Infect Dis. 1999; 28: 341-345
        • Hot A.
        • Schmulewitz L.
        • Viard J.P.
        • Lortholary O.
        Fever of unknown origin in HIV/AIDS patients.
        Infect Dis Clin North Am. 2007; 21: 1013-1032
        • Miralles P.
        • Moreno S.
        • Perez-Tascon M.
        • Cosin J.
        • Diaz M.D.
        • Bouza E.
        Fever of uncertain origin in patients infected with the human immunodeficiency virus.
        Clin Infect Dis. 1995; 20: 872-875
        • Lozano F.
        • Torre-Cisneros J.
        • Santos J.
        • et al.
        Impact of highly active antiretroviral therapy on fever of unknown origin in HIV-infected patients.
        Eur J Clin Microbiol Infect Dis. 2002; 21: 137-139
        • Havlir D.V.
        • Barnes P.F.
        Tuberculosis in patients with human immunodeficiency virus infection.
        N Engl J Med. 1999; 340: 367-373
        • Park B.J.
        • Wannemuehler K.A.
        • Marston B.J.
        • Govender N.
        • Pappas P.G.
        • Chiller T.M.
        Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS.
        AIDS. 2009; 23: 525-530
        • Micol R.
        • Buchy P.
        • Guerrier G.
        • et al.
        Prevalence, risk factors, and impact on outcome of cytomegalovirus replication in serum of Cambodian HIV-infected patients (2004-2007).
        J Acquir Immune Defic Syndr. 2009; 51: 486-491
        • Nokta M.A.
        • Holland F.
        • De Gruttola V.
        • et al.
        Cytomegalovirus polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to cytomegalovirus disease.
        J Infect Dis. 2002; 185: 1717-1722
        • Deayton J.R.
        • Prof Sabin C.A.
        • Johnson M.A.
        • Emery V.C.
        • Wilson P.
        • Griffiths P.D.
        Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy.
        Lancet. 2004; 363: 2116-2121
        • Peigne V.
        • Dromer F.
        • Elie C.
        • Lidove O.
        • Lortholary O.
        • French Mycosis Study Group
        Imported acquired immunodeficiency syndrome-related histoplasmosis in metropolitan France: a comparison of pre-highly active anti-retroviral therapy and highly active anti-retroviral therapy eras.
        Am J Trop Med Hyg. 2011; 85: 934-941
        • Wheat L.J.
        • Connolly-Stringfield P.A.
        • Baker R.L.
        • et al.
        Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.
        Medicine (Baltimore). 1990; 69: 361-374
        • Woods C.W.
        • McRill C.
        • Plikaytis B.D.
        • et al.
        Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention.
        J Infect Dis. 2000; 181: 1428-1434
        • Fish D.G.
        • Ampel N.M.
        • Galgiani J.N.
        • et al.
        Coccidioidomycosis during human immunodeficiency virus infection. A review of 77 patients.
        Medicine (Baltimore). 1990; 69: 384-391
        • Wong S.S.
        • Wong K.H.
        • Hui W.T.
        • et al.
        Differences in clinical and laboratory diagnostic characteristics of penicilliosis marneffei in human immunodeficiency virus (HIV)- and non-HIV-infected patients.
        J Clin Microbiol. 2001; 39: 4535-4540
        • Jarvis J.N.
        • Lockwood D.N.
        Clinical aspects of visceral leishmaniasis in HIV infection.
        Curr Opin Infect Dis. 2013; 26: 1-9
        • Zylberberg H.
        • Robert F.
        • Le Gal F.A.
        • Dupouy-Camet J.
        • Zylberberg L.
        • Viard J.P.
        Prolonged isolated fever due to attenuated extracerebral toxoplasmosis in patients infected with human immunodeficiency virus who are receiving trimethoprim-sulfamethoxazole as prophylaxis.
        Clin Infect Dis. 1995; 21: 680-681
        • Koehler J.E.
        • Sanchez M.A.
        • Tye S.
        • et al.
        Prevalence of Bartonella infection among human immunodeficiency virus-infected patients with fever.
        Clin Infect Dis. 2003; 37: 559-566
        • Lortholary O.
        • Meyohas M.C.
        • Dupont B.
        • et al.
        Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. French Cooperative Study Group on Aspergillosis in AIDS.
        Am J Med. 1993; 95: 177-187
        • Goedert J.J.
        • Cote T.R.
        • Virgo P.
        • et al.
        Spectrum of AIDS-associated malignant disorders.
        Lancet. 1998; 351: 1833-1839
        • Cribb A.E.
        • Lee B.L.
        • Trepanier L.A.
        • Spielberg S.P.
        Adverse reactions to sulphonamide and sulphonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis.
        Adverse Drug React Toxicol Rev. 1996; 15: 9-50
        • Carr A.
        • Cooper D.A.
        Adverse effects of antiretroviral therapy.
        Lancet. 2000; 356: 1423-1430
        • Fellay J.
        • Boubaker K.
        • Ledergerber B.
        • et al.
        Prevalence of adverse events associated with potent antiretroviral treatment: Swiss HIV Cohort Study.
        Lancet. 2001; 358: 1322-1327
        • Shelburne S.A.
        • Visnegarwala F.
        • Darcourt J.
        • et al.
        Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy.
        AIDS. 2005; 19: 399-406
        • Bouza E.
        • Loeches B.
        • Munoz P.
        Fever of unknown origin in solid organ transplant recipients.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 79-100
        • Bonham C.A.
        • Dominguez E.A.
        • Fukui M.B.
        • et al.
        Central nervous system lesions in liver transplant recipients: prospective assessment of indications for biopsy and implications for management.
        Transplantation. 1998; 66: 1596-1604
        • Ionescu D.N.
        • Dacic S.
        Persistent fever in a lung transplant patient.
        Arch Pathol Lab Med. 2005; 129: e153-e154
        • Wulf M.W.
        • van Crevel R.
        • Portier R.
        • et al.
        Toxoplasmosis after renal transplantation: implications of a missed diagnosis.
        J Clin Microbiol. 2005; 43: 3522-3547
        • Maegraith B.
        Unde venis?.
        Lancet. 1963; 1: 401-403
        • Saxe S.E.
        • Gardner P.
        The returning traveler with fever.
        Infect Dis Clin North Am. 1992; 6: 427-439
        • Speil C.
        • Mushtaq A.
        • Adamski A.
        • Khardori N.
        Fever of unknown origin in the returning traveler.
        Infect Dis Clin North Am. 2007; 21: 1091-1114
        • Cleri D.J.
        • Ricketti A.J.
        • Vernaleo J.R.
        Fever of unknown origin due to zoonoses.
        Infect Dis Clin North Am. 2007; 21: 963-996
        • Botelho-Nevers E.
        • Raoult D.
        Fever of unknown origin due to rickettsioses.
        Infect Dis Clin North Am. 2007; 21: 997-1011
        • O'Brien D.
        • Tobin S.
        • Brown G.V.
        • et al.
        Fever in returned travelers: review of hospital admissions for a 3-year period.
        Clin Infect Dis. 2001; 5: 603-609
        • Lortholary O.
        • Charlier C.
        • Lebeaux D.
        • Lecuit M.
        • Consigny P.H.
        Fungal infections in immunocompromised travelers.
        Clin Infect Dis. 2013; 56: 861-869
        • Knockaert D.C.
        • Durjardin K.S.
        • Bobbaers H.J.
        Long-term follow-up of patients with undiagnosed fever of unknown origin.
        Arch Intern Med. 1996; 156: 618-620
        • Collazos J.
        • Guerra E.
        • Mayo J.
        • et al.
        Tuberculosis as a cause of recurrent fever of unknown origin.
        J Infect. 2000; 41: 269-272
        • Lekstrom-Himes J.A.
        • Dale J.K.
        • Kingma D.W.
        • et al.
        Periodic illness associated with Epstein-Barr virus infection.
        Clin Infect Dis. 1996; 22: 22-27
        • Munoz-Gomez S.
        • Cunha B.A.
        Recurrent fever of unknown origin in an adult due to FAPA syndrome.
        J Clin Med. 2013; 2: 45-48
        • Weinstein L.
        Clinically benign fever of unknown origin: a personal retrospective.
        Rev Infect Dis. 1985; 7: 692-699
        • Knockaert D.C.
        Recurrent fevers of unknown origin.
        Infect Dis Clin North Am. 2007; 21: 1189-1211
        • Bryan C.S.
        • Ahuja D.
        Fever of unknown origin: is there a role for empiric therapy?.
        Infect Dis Clin North Am. 2007; 21: 1213-1220
        • Eiko L.M.
        • Bryan C.S.
        Empiric therapy in fever of unknown origin: a cautionary note.
        in: Cunha B.A. Fever of Unknown Origin. Informa Healthcare, New York2007: 229-236