Fever of unknown origin (2 mo - 18 years)

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Fever of unknown origin (2 mo - 18 years)

Treat appropriately

Recent international travel

Suspected specific infection?

Specific serologic testing

Cause identified?

Treat appropriately

Consider Kawasaki disease pathway

Purified Protein Derivative (PPD) skin test


Suspected Kawasaki disease?

  • Infectious disease and/or rheumatology and/or hematology-oncology consult
  • IgG, IgA, and IgM if not previously done
  • Consider further imaging
  • Positron emission tomography - PET
  • Abdominal US (if GI symptoms present)
  • Full body MRI (utility not established)

IgM, Serum
IgG, Serum
IgA, Serum

Consider infectious disease or other subspecialty consult

Concerning signs for osteomyelitis/septic arthritis

  • Non-weight-bearing/decreased mobility
  • Joint effusion
  • Unilaterality
  • Acute onset (2 - 5 days)
  • CRP > 2 mg/dL or ESR > 40 mm/hr
  • Serum WBC > 12k
  • History of surgery or other complex medical disorder

Interferon Gamma Release Assay (QuantiFERON)

Antibiotics are NOT routinely indicated for FUO unless the patient is ill-appearing or there is strong suspicion for a specific infection. Empiric antibiotics may mask or delay the diagnosis of serious infections.

Gastroenteritis PCR, Stool
C.diff toxin B PCR, Stool
Guaiac, Stool

Relevant testing for areas visited


Gastrointestinal complaints?

Cause identified?

Family to start fever diary(date/time, measurement, method of measurement, duration, associated symptoms, response to medications), re-evaluation in 3-7 days

Family history of rheumatologic disease?

Bone/joint pain or swelling?

X-rays or affected area

Kawasaki Disease primary criteria:

  1. Oral mucous membrane changes (injected/cracked lips, injected pharynx, strawberry tongue)
  2. Polymorphous rash
  3. Peripheral extremity changes (palmar erythema, hand or feet edema, periungual desquamation)
  4. Cervical lymphadenopathy (one lymph node >1.5 cm in diameter)
  5. Bilateral bulbar conjunctival injection without exudate

4-5 criteria -> Likely KD

2-3 criteria -> Possible atypical KD

Antinuclear Antibody (ANA), Serum

Complete Blood Count, Serum
Complete Metabolic Panel, Serum
Blood Culture (Aerobic and Anaerobic), Serum
C-Reactive Protein (CRP), Serum
Erythrocyte Sedimentation Rate (ESR), Serum
Peripheral Smear, Serum
HIV Antigen/Antibody Rapid, Serum
Urinalysis with micro, Urine
Urine Culture, Urine
X-ray Chest, 2 view

Discontinue non-essential medications

Inclusion Criteria
  • Fever >38.3C (101F) at least once per day for ≥ 8 days
  • No apparent diagnosis after initial evaluation that includes a detailed history and thorough physical examination
Exclusion Criteria
  • Immunosuppressed, transplant recipient, history of cancer
  • Ill appearing or signs of SIRS
  • Pregnancy

Infectious causes of FUO


Exposure to animals or animal products (raw cheese/mild, meat)



Testicular pain


Exposure to cats/kittens

Localized lymphadenopathy

Hepato/splenomegaly & pain

Nodule at infective site


Cardiac risk factor

New murmur


Splinter hemorrhages

Conjunctival hemorrhage


Intraabdominal abscess

Previous abdominal surgery or infection

Abdominal pain


Exposure to animal urine or infected tissue

HA, myalgia, rigors, cough

Relative bradycardia


Liver abscess



Abdominal pain


Exposure to malaria area

Relapsing fevers


Osteomyelitis/septic arthritis

Bone/joint pain



Exposure to Eggs, reptiles

GI symptoms, diarrhea

HA, fatigue, urinary symptoms


Exposure to feline feces



Exposure to endemic area

Intermittent fevers



Exposure/ingestion to animal meat (rabbits, squirrels)

HA, fatigue, chills, myalgias


Exposure to endemic area

HA, diarrhea, abdominal pain

Relative bradycardia

Urinary tract infection

Dysuria, urgency, frequency, incontinence

Abdominal pain

Suprapubic tenderness

Other causes of FUO

Diabetes insipidus

  • Polyuria
  • Polydipsia
  • Weight loss

Drug fever

  • Rash

Familial dysautonomia

  • Lack of sweat during fever
  • Ashkenazi Jewish descent
  • Abnormal vital signs

Hemophagocytic lymphohistiocytosis

  • History of immunologic disorder, malignancy, drugs
  • Lymphadenopathy
  • Hepato/splenomegaly
  • Skin lesions

Inflammatory bowel disease

  • Abdominal pain, diarrhea
  • Weight loss
  • Short stature
  • Oral ulcers
  • Perianal fistulae
  • Erythema nodosum

Juvenile idiopathic arthritis

  • Intermittent fevers
  • Arthralgias
  • Rash
  • Erythema nodosum
  • Lymphadenopathy
  • Hepato/splenomegaly


  • Bone pain
  • Hepato/splenomegaly
  • Lymphadenopathy
  • Testicular enlargement


  • Intermittent fevers
  • Fatigue
  • Night sweats
  • Hepato/splenomegaly
  • Lymphadenopathy
  • Weight loss

Periodic fever disorders

  • Recurrent fevers

Systemic lupus erythematosus

  • Weight loss
  • HA, fatigue, dyspnea
  • Oral ulcers
  • Malar rash
  • Erythema nodosum