Fever of unknown origin

• Definition: 10 days of febrile illness (T>38.3 or 38.5 depending on what article) on multiple occasions despite thorough workup
• more often an unusual presentation of a common disease
  1. Infections (30-40%)
  2. Neoplasms (20-30%)
  3. Collagen vascular diseases (10-20%),
  4. miscellaneous diseases (15-20%).
  5. 5-15% of FUO cases defy diagnosis, despite exhaustive studies. Patients with undiagnosed FUOs (5-15%) generally have a benign long-term course, especially when the fever is not accompanied by substantial weight loss or other signs of a serious underlying disease. These findings suggest that an intensive and rational diagnostic evaluation usually results in the identification of the most serious diseases that initially manifest as FUOs
• In patients with FUOs lasting more than 1 year, infections and neoplasms decline in frequency, and granulomatous diseases become the most frequent etiology.

Ask about:

• exposure to animals (cat-scratch, brucellosis, tularemia, leptospirosis)
  • brucellosis: cattle, swine, goats, and sheep or in patients who consume raw milk products.
  • Birds: chlamydia psittacosis
• travel history (malaria, coccidiomycosis, blastomycosis, tuberculosis, esp tb of kidney or mesenteric lymph nodes)
• diet: raw meat, fish, unpasteurized milk (trichinosis, hepatitis); well-water (giardiasis)
• pica (fungal infection)
• change in behavior (brain tumor, Tb, EBV, RMSF); psych/behaviour problems (factitious fever ie twirls thermometer under tongue)
• pattern of fever (periodic fever syndromes)
• medications (OTC meds, eye drops also. Atropine induced fever)
• hx of previous intraabdominal surgeries (abscess)
• constitutional sx may suggest more serious underlying disease (growth failure, developmental arrest)
• arthritis/bony tenderness (JRA, IBD, leukemia, osteomyelitis)
• if has episodes of FUO and delayed dentition, consider anhidrotic ectodermal dysplasia. (abnormal sweat glands, unable to sweat and regulate temperature)

Think

• Bacterial:
  • sinusitis, UTI, Tb, abscess (liver/pelvic), osteomyelitis, cat scratch disease, salmonellosis, neisseri, toxoplasmosis, atypical mycobacterial
  • borrelia (B. recurrentis - relapsing fever, Lyme dz, syphilis)
  • rickettsia (RMSF, Coxiella burnetii, chronic Q fever, or Q fever endocarditis
  • uncommon causes: tularemia, brucellosis, leptospirosis, rat-bite fever, malaria, babesiosis, endocarditis (Culture-negative endocarditis is reported in 5-10% of endocarditis cases. Prior antibiotic therapy is the most frequent reason for negative blood cultures)
• Viral: CMV, EBV, Viral hepatitis, HIV, adenovirus
• fungal: uncommon causes include disseminated histoplasmosis, coccidiomycosis, blastomycosis
• Other ID considerations: Kawasaki, drug fever
• Collagen vascular disease: SLE, JRA, rheumatic fever, serum sickness, uncommon causes: sarcoidosis, hypersensitivity vasculitis, polyarteritis nodosa
• Malignancy:  leukemia/lymphoma, neuroblastoma, hodgkin;s, of solid tumors, renal cell carcinoma is most common (fever being the only presenting symptom in 10% of cases); uncommon causes: atrial myxoma, brain tumor
• Endocrine: DI, thyroiditis
• Immunologic: familial mediterranean fever, cyclic neutropenia
• Psych: factitious fever
• in hospital on TPN? malassezia furfur

Workup as indicated

Labs

1. CBC/diff, look at WBC morphology: infection, kawasaki, cyclic neutropenia, cancer
2. Serum electrolyes, LFT's
3. blood cx, aerobic and anarobic: endocarditis, salmonellosis
4. Fungal studies as indicated: histoplasmosis, coccidiomycosis, blastomycosis
5. Stool cx/O&P: salmonella, giardia
6. Cultures: Obtain cultures for bacteria, mycobacteria, and fungi in all normally sterile tissues and liquids that are sampled during further workup. These tissues and fluids include cerebrospinal fluid (CSF), pleural or peritoneal fluid, and fluid from the liver, bone marrow, and lymph nodes
7. UA/urine cx: UTI, kawasaki
8. CRP/ESR: infection, kawasaki, collagen-vascular disease, IBD
9. PPD
10. Serologies are most helpful if paired samples show a significant, usually 4-fold, increase of antibodies specific to an infectious microorganism. Brucellosis, CMV, infectious mononucleosis, HIV, amebiasis, toxoplasmosis, and chlamydial diseases are diagnosed by serology.
11. Hepatitis/viral serologies: CMV, EBV, Hep panel
12. ANA, Rheumatoid factor, thyroxine level (T4)

Imaging

1. CXR/sinus Xray: sinusitis, TB, histoplasmosis
2. Abdominal US to screen for abscess
3. Chest/abd CT scan: Tb, liver abscess
4. Gallium scan/bone scan: osteo
5. MRI for osteo
6. GI radioimaging or endoscopy for IBD, etc
7. Echo for endocarditis

Indications for transfer

• The current facility is unable to arrive at a diagnosis.
• Diagnostic tests are unavailable at the existing facility.
• Clinical deterioration of the patient occurs.

Emedicine.com, last update March 8, 2005
The 5 minute pediatric consult, 3rd ed.