Fever of unknown origin resident survival guide

Fever of Unknown Origin

Diagnostic Criteria

Causes Common Causes Age-Specific Considerations

Complete Diagnostic Approach Focused History Physical Examination Laboratory Workup Imaging Study Other Investigation

Management

Main article: Fever of unknown origin

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Gerald Chi, M.D.

Overview

Management of fever of unknown origin should generally be withheld until the etiology is ascertained so that treatment can be targeted toward a specific pathology.

Diagnostic Criteria

Fever of unknown origin (FUO) may be considered providing all the following criteria are fulfilled:

• Fever higher than 38.3°C (100.9°F) on several occasions
• Persisting without diagnosis for at least 3 weeks
• At least 1 week's investigation in hospital

Minimum diagnostic evaluation to qualify as FUO includes:

• Comprehensive history
• Repeated physical examination
• Complete blood count, including differential and platelet count
• Routine blood chemistry, including lactate dehydrogenase, bilirubin, and liver enzymes
• Urinalysis, including microscopic exmination
• Chest radiograph
• Erythrocyte sedimentation rate
• Antinuclear antibodies
• Rheumatoid factor
• Three or more sets of blood cultures while not receiving antibiotics
• Cytomegalovirus IgM antibodies or virus detection in blood
• Heterophile antibody test in children and young adults
• Tuberculin skin test
• CT of abdomen or radionuclide scan
• HIV antibodies or virus detection assay
• Further evaluation of any abnormalities detected by above tests

Causes

Common Causes

Common causes of fever of unknown origin are as follows:

• Infections

Localized

– Endocarditis

– Intra-abdominal infections

– Urinary tract infections

– Osteomyelitis

– Upper respiratory tract infections

– Infected peripheral vessels

Generalized

– Bacterial

– Mycobacterial

– Fungal

– Viral

– Parasitic

• Neoplasia

– Lymphoproliferative disorders

– Leukemia

– Myelodysplastic syndrome

– Solid tumors

• Rheumatic disorders

– Adult onset Still's disease

– Giant cell arteritis

– Polymyalgia rheumatica

– Other forms of vasculitis (e.g., polyarteritis nodosa, Wegener's granulomatosis, Takayasu's arteritis)

– Other rheumatologic disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, Sjogren's syndrome)

• Endocrine disorders

– Hyperthyroidism

– Thyroiditis

– Adrenocortical insufficiency

• Hereditary disorders (e.g., familial Mediterranean fever)
• Factitious fever
• Miscellaneous

– Granulomatous disorders

– Hepatitis

– Vascular disorders (e.g., pulmonary embolism, hematoma)

– Drug fever

Age-Specific Considerations

Respiratory tract infections cause FUO in infants more often than in children older than 12 months, whereas connective tissue diseases predominate as the cause of FUO in children and adults. For patients older than 65 years, non-infectious inflammatory disorders including polymyalgia rheumatica and temporal arteritis are identified as the major causes of FUO in developed countries. Intra-abdominal abscesses, complicated urinary tract infections, tuberculosis, and endocarditis are the most common infectious causes of FUO in the elderly.

Complete Diagnostic Approach

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CBC, complete blood count; CMV, cytomegalovirus; DC, differential count; HIV, human immunodeficiency virus; PET, positron emission tomography; s/o, suggestive of; SMA-7, sequential multiple analysis-7.

Suspected Fever of Unknown Origin Fever higher than 38.3°C (100.9°F) on several occasions Persisting without diagnosis for at least 3 weeks At least 1 week's investigation in hospital
Focused History Verify the presence of fever and its pattern Sustained fever (s/o brucellosis, drug fever, Gram-negative pneumonia, tularemia, typhoid, typhus) Remittent fever (s/o tuberculosis, mycoplasma pneumonia, malaria, legionellosis) Intermittent fever (s/o malaria, kala-azar, pyaemia) Double quotidian fever (s/o Still's disease, legionellosis, miliary tuberculosis, kala-azar) Quotidian fever (s/o Plasmodium falciparum or Plasmodium knowlesi malaria) Tertian fever (s/o Plasmodium vivax or Plasmodium ovale malaria) Quartan fever (s/o Plasmodium malariae malaria) Alternate-day fever (s/o response to antipyretic dosage schedule) Hyperpyrexia (s/o intracranial hemorrhage, septicemia, Kawasaki disease, thyroid storm, drug fever) Hectic or spiking pattern (s/o biliary or urinary tract infection, endocarditis) Morning temperature spikes (s/o typhoid fever, tuberculosis, polyarteritis nodosa) Relapsing pattern (s/o Borrelia recurrentis, typhoid fever, malaria, brucellosis, rat-bite fever) Irregular pattern (s/o factitious fever) Pel-Ebstein pattern (s/o Hodgkin's lymphoma) Picket fence pattern (s/o acute mastoiditis complicated by transverse sinus thrombosis) Saddleback (dromedary) pattern (s/o dengue fever, leptospirosis, poliomyelitis, ehrlichiosis) Wunderlich curve pattern (s/o typhoid fever) History of previous surgeries or procedures History of malignancy and related therapy History of previously treated infections History of sick or animal contacts History of psychiatric illness History of recent traveling History of comorbidities History of medications History of transfusions Social and family history
Physical Examination Vitals A fever is often present. The periodicity of fever may have clinical significance in selected contexts. Weak or absent pulse may be present in Takayasu's arteritis. Physiologically, fever is accompanied by tachycardia. Relative bradycardia (Faget's sign) may be present in legionellosis, brucellosis, psittacosis, leptospirosis, drug fever, or factitious fever. Skin Janeway lesions may be present in infective endocarditis. Petechiae may be present in Rocky Mountain spotted fever. maculopapular, vesicular, or petechial rash may be present in typhus. An eschar at the site of the tick bite may be present in tick-borne diseases. Swollen lymph nodes may be present. Lymphadenopathy may represent reactive lymphoid hyperplasia (suggestive of inflammation or infection) or underlying malignant processes such as lymphoma. Rose spots (blanching pink papules 2–3 mm in diameter) may be present on the trunk in salmonellosis. Macules, papules, and nodules may be present on the trunk and extremities in meningococcemia. Macules or petechiae evolving into vesicles and pustules on a hemorrhagic base may be present in disseminated gonococcal infection. Diffuse hyperpigmentation may be present in Whipple's disease. Papules and nodules evolving into crusted, verrucous growths may be present in blastomycosis. Warty nodules and subcutaneous abscesses may be present in coccidioidomycosis. Erythematous papules, pustules, subcutaneous nodules, or cellulitis may be present in cryptococcosis. Sister Mary Joseph nodule (palpable nodule bulging into the umbilicus) may be present in metastasis of a malignant tumor in the pelvis or abdomen. Multiple purplish papules, nodules, and plaques may be present on the scalp, face, and neck in lymphoma. Multiple erythematous, painful plaques with small bumps, pustules, and vesicles may be present in Sweet's syndrome. Palpable purpura may be present on the lower extremities and other areas of dependency in cutaneous vasculitis. Head Temporal artery tenderness with weak pulse may be present in temporal arteritis. Sinus tenderness may be present in sinusitis. Eyes Roth's spots or conjunctival hemorrhage may be present in infective endocarditis. Photophobia or ocular pain on palpation suggestive of uveitis may be present in Wegener's granulomatosis, Behcet syndrome, Vogt-Koyanagi-Harada syndrome, or infections. Mouth Oral thrush caused by candidiasis may be present in patients with HIV/AIDS. Oral ulcers may be present in systemic lupus erythematosis, disseminated histoplasmosis, and Behcet syndrome. Tenderness with a palpable abscess may be present in periodontal disease. Petechiae on the palate may be present in infective endocarditis. Parotid gland enlargement and tenderness may be present in infections (e.g., Staphylococcus aureus, tuberculosis, mumps, HIV), Sjogren's syndrome, or sarcoidosis. Neck Cervical lymph nodes may be present in inflammation, infection, lymphoma, or Kikuchi disease. Enlargement of the thyroid gland may be present in thyroiditis. Lungs Rales or rhonchi may be present in pneumonia. Fremitus with diminished breath sounds may be present in pneumonia. Heart Heart murmurs may be present in endocarditis secondary to infections (infective endocarditis), systemic lupus erythematosus (Libman-Sacks endocarditis), or chronic diseases (marantic endocarditis). Abdomen Abdominal tenderness may be present in intra-abdominal infections. Rebound tenderness may be present in intra-abdominal infections. An acute abdomen may be present in intra-abdominal infections. Guarding may be present in intra-abdominal infections. Flank pain may be present in psoas muscle abscess, perinephric abscess, or pyelonephritis. An inguinal mass may be present in psoas muscle abscess. Splenomegaly may be present in infectious mononucleosis, splenic abscess, or hepatitis. Genitourinary Prostatic enlargement may be present in prostatic abscess. Epididymal nodule may be present in epididymitis. Testicular nodule may be present in polyarteritis nodosa. Extremities Osler's nodes may be present in infective endocarditis. Swollen joints with effusion may be present in infectious arthritis or rheumatic diseases. Splinter hemorrhage in the nail beds may be present in infective endocarditis. Limb tenderness along deep veins may be present in deep vein thrombosis or thrombophlebitis. Neurologic Altered mental status may be present. Cranial nerve deficits may be present in cerebral vasculitis associated with systemic lupus erythematosus.
Laboratory Workup CBC with DC SMA-7 AST, ALT, LDH, bilirubin, and ALP Creatine kinase Blood cultures, at least 2 sets Urinalysis with microscopic examination Urine cultures Erythrocyte sedimentation rate C-reactive protein Gamma-glutamyl transferase Coombs test Cold agglutinins Ferritin Angiotensin-converting enzyme Thyroid peroxidase and anti-thyroglobulin antibodies Antinuclear antibodies Rheumatoid factor Cryoglobulins CMV serology and heterophile antibody test if ⊕ atypical lymphocytes Q fever serology if ⊕ exposure to livestocks HIV serology Serum protein electrophoresis Tuberculin skin test Fecal occult blood test
Imaging Study Chest Radiograph Chest radiograph should be considered as a part of the initial diagnostic workup. Echocardiography Echocardiography should be considered when suspecting endocarditis. Abdominal Ultrasonography Abdominal ultrasonography should be considered when suspecting hepatobiliary pathology. Chest CT Scan Chest CT scan may detect nodular lesions (s/o malignancy or fungal/mycobacterial/nocardial infection) or mediastinal adenopathy (s/o lymphoma, histoplasmosis, or sarcoidosis). Abdominal CT Scan Abdominal CT scan should be considered when suspecting intra-abdominal abscess or malignancy. Positron Emission Tomography PET may be useful in localizing the nidus of fever of unknown origin.
Other Investigation Lymph Node Biopsy Lymph node biopsy may be useful when suspecting lymphoma, lymphogranuloma venereum, toxoplasmosis, and Kikuchi disease. Granuloma may indicate disorders associated with granulomatous inflammation (eg, tuberculosis, sarcoidosis) or lymphoma. Bone Marrow Biopsy Bone marrow biopsy may be considered when suspecting intracellular infectious pathogens or hematologic malignancies. Discontinuation of Nonessential Medications Nonessential medications should be discontinued. Defervescence in less than 72 hours after discontinuing the culprit medication suggests drug fever. Rechallenge with the offending agent usually results in recurrence of drug fever. Trial of Empiric Antibiotics Therapeutic trials of antimicrobial agents may be considered if other techniques fail to disclose the etiology. An infectious etiology is likely if abatement of fever occurs after the administration of empiric antibiotics. Naproxen Test Naproxen test (375 mg twice daily) can be used to distinguish neoplastic fever from other etiologies. Naproxen test is considered positive when there is a rapid or sustained abatement of fever during the 3 days of the trial period. Defervescence within 12 hours occurs in almost all patients with neoplastic fever. Fever recurs after discontinuation of naproxen in patients with neoplasms. Naproxen demonstrated no antipyretic activity against fever in patients with occult infection.

Management

• Management should be withheld until the etiology is ascertained so that treatment can be directed toward a specific pathology.
• Empiric corticosteroids may be appropriate in patients with suspected temporal arteritis to prevent vascular complications.
• Patients with febrile neutropenia should receive broad-spectrum antipseudomonal antibiotics immediately after specimens for cultures have been obtained.

FUO

D/C nonessential Rx

Defervescence in 72h

Fever persists

Drug fever

CT or nuclear scan

Focus identified

Focus undetermined

Verify with tissue biopsy

IE suspected?

Duke criteria fulfilled

IE unlikely

Treat as IE

GCA suspected?

GCA likely

GCA unlikely

Treat as GCA

ANC < 500?

Febrile neutropenia

Normal ANC

Antipseudomonal abx

Follow up

References