Some Causes of Fever of Unknown Origin (FUO)
Cause | Suggestive Findings | Diagnostic Approach* |
|---|---|---|
Infectious | ||
Abdominal or pelvic discomfort, usually tenderness Sometimes history of surgery, trauma, diverticulosis, peritonitis, or gynecologic procedure | CT or MRI | |
History of being scratched or licked by a cat Regional adenopathy, Parinaud oculoglandular syndrome, headache | Culture (sometimes of lymph node aspirate), antibody titers, polymerase chain reaction testing | |
History of blood transfusion from CMV-positive donor Syndrome that resembles mononucleosis (fatigue, mild hepatitis, splenomegaly, adenopathy), chorioretinitis | CMV IgM antibody titers Possibly polymerase chain reaction testing | |
Sore throat, adenopathy, right upper quadrant tenderness, splenomegaly, fatigue Usually occurring in adolescents and young adults In older adults, typical findings possibly absent | Serologic testing | |
History of high-risk behaviors (eg, unprotected sex, sharing needles) Weight loss, night sweats, fatigue, adenopathy, opportunistic infections | Fourth-generation combination immunoassay Sometimes testing for HIV RNA (for acute HIV infection) | |
Often history of risk factors (eg, structural heart disease, prosthetic heart valve, periodontal disease, IV catheter, illicit drug injection) Usually a heart murmur, sometimes extracardiac manifestations (eg, splinter hemorrhages, petechiae, Roth spots, Osler nodes, Janeway lesions, joint pain or effusion, splenomegaly) | Serial blood cultures, echocardiography | |
Visiting or living in an endemic area Erythema migrans rash, headache, fatigue, Bell palsy, meningitis, radiculopathy, heart block, joint pain and swelling | Serologic testing | |
Localized pain, swelling, erythema | Radiographs (if subacute or chronic) Sometimes MRI (most accurate test), radionuclide scanning with indium-111, bone scanning | |
Prolonged congestion, headache, facial pain | CT of sinuses | |
Tuberculosis (pulmonary and disseminated) | History of high-risk exposure Cough, weight loss, fatigue Use of immunosuppressants History of HIV infection | Chest radiograph, tuberculin skin test (PPD), interferon-gamma release assay Sputum smear for acid-fast bacilli, nucleic acid amplification testing (NAAT), culture of body fluids (eg, gastric aspirates, sputum, cerebrospinal fluid) |
Uncommon infections (eg, brucellosis, malaria, Q fever, toxoplasmosis, trichinosis, typhoid fever) | History of travel to endemic areas Exposure to or ingestion of certain animal products | Serologic testing for individual causes Peripheral blood smear for malaria |
Systemic rheumatic | ||
Adult Still disease | Evanescent salmon-pink rash, arthralgias, arthritis, myalgias, cervical adenopathy, sore throat, cough, chest pain | ANA, RF, serum ferritin concentration, radiographs of affected joints |
Unilateral headache, visual disturbances Often symptoms of polymyalgia rheumatica, sometimes jaw claudication Tenderness of temporal artery when palpated | Erythrocyte sedimentation rate, temporal artery biopsy | |
Fever, weight loss, myalgias, arthralgias, purpura, hematuria, abdominal pain, testicular pain, angina, livedo reticularis, new-onset hypertension | Biopsy of involved tissues or angiography | |
History of morning stiffness in shoulders, hips, and neck Malaise, fatigue, anorexia Possibly synovitis, bursitis, pitting edema of extremities | Creatine kinase, ANA, RF, erythrocyte sedimentation rate Possibly MRI of extremities | |
Sometimes recent history of infection with Chlamydia, Salmonella, Yersinia, Campylobacter, or Shigella Asymmetric oligoarthritis, urethritis, conjunctivitis, genital ulcerations | ANA, RF, serologic testing for causative pathogens | |
Symmetric peripheral polyarthritis, prolonged morning stiffness, subcutaneous rheumatoid nodules in pressure sites (extensor surface of ulna, sacrum, back of head, Achilles tendon) | ANA, RF, anticyclic citrullinated peptide (anti-CCP) antibody, radiographs (to identify bone erosions) | |
Fatigue, arthralgia, pleuritic chest pain, malar rash, tender swollen joints, mild peripheral edema, Raynaud syndrome, serositis, nephritis, alopecia | Clinical criteria, ANA, antibodies to double-stranded DNA | |
Neoplastic | ||
Atrial myxoma | Dyspnea, occasional emboli causing neurologic symptoms | Echocardiography |
Castleman disease | Enlarged lymph nodes | Biopsy of lymph node |
Abdominal pain, change in bowel habits, hematochezia, weakness, nausea, vomiting, weight loss, fatigue | Colonoscopy, biopsy | |
History of chronic liver disease, abdominal pain, weight loss, early satiety, palpable mass in right upper quadrant | Abdominal ultrasound and CT, liver biopsy | |
Sometimes history of myelodysplastic disorder Fatigue, weight loss, bleeding, pallor, petechiae, ecchymoses, anorexia, splenomegaly, bone pain | Complete blood count, bone marrow examination | |
Painless adenopathy, weight loss, malaise, night sweats, splenomegaly, hepatomegaly | Lymph node biopsy | |
Symptoms dependent on the site of metastasis (eg, cough and shortness of breath for lung metastasis, headache and dizziness for brain metastasis) Often asymptomatic, discovered during a routine medical evaluation | Biopsy of suspicious mass or node, imaging tests appropriate for area of concern | |
Frequently asymptomatic, abnormal indices incidentally detected during screening complete blood count | Testing based on the suspected disorder | |
Adnexal mass, pelvic pain | Ultrasound | |
Weight loss, night sweats, flank pain, hematuria, palpable flank mass, hypertension | Serum calcium (to check for hypercalcemia), urinalysis, CT of kidneys | |
Miscellaneous | ||
Long history of alcohol use Sometimes ascites, jaundice, small or enlarged liver, gynecomastia, Dupuytren contracture, testicular atrophy | Prothrombin time/partial thromboplastin time, alkaline phosphatase, transaminases, albumin, bilirubin Sometimes abdominal ultrasound and CT | |
Pain, swelling, sometimes redness of leg | Ultrasound Sometimes D-dimer assay | |
Drug fever | Fever coincident with administration of a drug (usually within 7–10 days) Sometimes a rash | Withdrawal of drug |
Dramatic, atypical presentation, vague and inconsistent details, knowledge of textbook descriptions, compulsive or habitual lying (pseudologia fantastica) | Diagnosis of exclusion | |
Abdominal pain, diarrhea (sometimes bloody), weight loss, guaiac-positive stools Sometimes fistulas, perianal and oral ulcerations, arthralgias | Upper gastrointestinal endoscopy with small-bowel follow-through or CT enterography (Crohn disease) Colonoscopy (ulcerative colitis or Crohn colitis) | |
Thyroiditis | Nervousness, palpitations, increased sweating, heat hypersensitivity, fatigue, increased appetite, weight loss, and infiltrative ophthalmopathy and dermopathy (Graves disease) | T4, TSH, thyroid autoantibodies |
* Patients with FUO may lack typical findings, but such findings should be sought. | ||
ANA = antinuclear antibodies; CMV = cytomegalovirus; RF = rheumatoid factor; T4 = thyroxine; TSH = thyroid-stimulating hormone. | ||