Fever of unknown origin (peds)

This page is for pediatric patients. For adult patients, see: fever of unknown origin

Background

• Fever of unknown origin (FUO) in children accounts for approximately 3% of pediatric hospitalizations
• Most commonly represents an atypical presentation of a common disease rather than a rare condition
• Prolonged fever of unknown origin without identified cause generally has a favorable prognosis — the majority of undiagnosed cases self-resolve
• No standardized diagnostic algorithm has been fully validated in pediatric populations; workup should be guided by potential diagnostic clues (PDCs) from history and exam

• The ED role is to:
  • Identify life-threatening causes: sepsis, leukemia, macrophage activation syndrome, Kawasaki disease (especially incomplete)
  • Initiate a focused workup based on clinical clues
  • Determine safe disposition (admit vs. close outpatient follow-up)
  • Recognize fever patterns that suggest specific diagnoses

Definition

• Original definition (Petersdorf and Beeson, 1961):
  • Fever >38.3°C on several occasions
  • Lasting for at least 3 weeks
  • No clear diagnosis after 1 week inpatient workup
• Newer definition (Durack and Street, 1991): "Prolonged fever" with:
  • 3 outpatient visits without identifying a cause OR
  • 3 inpatient days without identifying a cause OR
  • 1 week of "intelligent and invasive" ambulatory investigation
• Many pediatric centers now use a shorter threshold of ≥8 days of fever without diagnosis after initial evaluation

Etiologic Distribution in Children

• Infections: 40-60% (most common cause — higher proportion than in adults)
• Non-infectious inflammatory diseases: 10-20% (Systemic JIA is the most common rheumatic cause)
• Malignancy: 5-10% (lower proportion than adults, but leukemia and lymphoma must always be excluded)
• Miscellaneous: 5-10%
• Undiagnosed: 10-25% (prognosis is generally favorable; most self-resolve)

• True classic FUO is uncommonly diagnosed in a single ED visit — most children with prolonged fever are seen multiple times before a diagnosis is made

Clinical Features

History — Key Questions

• Duration and pattern of fever:
  • Quotidian (daily spikes returning to baseline) → Systemic JIA
  • Periodic/recurrent (stereotyped episodes separated by well intervals) → PFAPA syndrome, familial Mediterranean fever, other autoinflammatory syndromes
  • Continuous high fever → leukemia, lymphoma, Kawasaki disease, tuberculosis
• Associated symptoms:
  • Joint pain or swelling → sJIA, reactive arthritis, leukemia, Lyme disease, septic arthritis
  • Rash → sJIA (evanescent, salmon-pink), Kawasaki disease, viral exanthem, SLE, drug reaction
  • Weight loss → malignancy, inflammatory bowel disease, tuberculosis
  • Night sweats → lymphoma, tuberculosis
  • Sore throat (culture-negative) → sJIA, PFAPA
  • Oral ulcers → PFAPA, Behçet disease, SLE
  • Abdominal pain → inflammatory bowel disease, intra-abdominal abscess, mesenteric lymphadenitis
  • Bone/limb pain → leukemia, osteomyelitis, neuroblastoma
• Exposures:
  • Animal contact (cats → cat scratch disease; farm animals → Q fever, brucellosis; ticks → Lyme disease, tularemia)
  • Travel history (malaria, typhoid, tuberculosis, endemic fungi)
  • Unpasteurized dairy (brucellosis)
  • Sick contacts, daycare attendance
• Immunization status (incomplete vaccination broadens the infectious differential)
• Medications (including recent antibiotics that may mask infection)
• Family history: periodic fever syndromes, autoimmune disease, consanguinity (primary HLH, primary immunodeficiency)

Physical Exam — High-Yield Findings

Finding	Consider
Evanescent salmon-colored rash (with fever)	Systemic JIA
Conjunctival injection, mucous membrane changes, hand/foot edema	Kawasaki disease (even if incomplete criteria)
Diffuse lymphadenopathy	Leukemia, lymphoma, EBV, CMV, cat scratch disease, tuberculosis, sJIA
Hepatomegaly and/or splenomegaly	Leukemia, lymphoma, sJIA, EBV, CMV, malaria, HLH/MAS
Bone/joint tenderness (out of proportion to exam)	Leukemia, osteomyelitis, neuroblastoma
Heart murmur (new)	Endocarditis, acute rheumatic fever, atrial myxoma (rare)
Pharyngitis (culture-negative, recurrent)	PFAPA, sJIA
Oral ulcers	PFAPA, Behçet disease, SLE
Skin nodules, petechiae, purpura	Vasculitis, leukemia, endocarditis, MAS
Perianal disease (fissures, tags, fistula)	Inflammatory bowel disease (Crohn's)
Abdominal mass	Neuroblastoma, Wilms tumor, lymphoma, abscess
Uveitis/iridocyclitis	sJIA, sarcoidosis, tuberculosis

• ED Pearl: Repeated and careful physical exams over time are more valuable than exhaustive lab panels — findings may not be present on the first visit
• Rule out factitious/fabricated fever: Consider when fever is documented only by caregivers, pattern is atypical, no objective cause despite extensive workup, or temperature exceeds 41°C without corresponding tachycardia or skin warmth

Differential Diagnosis

Infections (~40-60%, most common cause in children)

• Bacterial
  • UTI/pyelonephritis (especially in infants and young children)
  • Occult abscess (intra-abdominal, hepatic, pelvic, perinephric, retropharyngeal, dental)
  • Osteomyelitis
  • Endocarditis
  • Cat scratch disease (Bartonella henselae) — one of the most common causes of pediatric FUO
  • Brucellosis (exposure to unpasteurized dairy, travel)
  • Tuberculosis (pulmonary and extrapulmonary, especially miliary)
  • Sinusitis (chronic/occult)
  • Mastoiditis
  • Lyme disease
  • Q fever
  • Rat-bite fever
  • Salmonella (enteric fever/typhoid)
  • Tularemia
  • Leptospirosis
• Viral
  • EBV (mononucleosis)
  • CMV
  • HIV (acute seroconversion or perinatal)
  • Hepatitis A, hepatitis B
  • Adenovirus
  • COVID-19
  • Parvovirus B19
• Fungal
  • Histoplasmosis
  • Coccidioidomycosis
  • Blastomycosis
  • Cryptococcosis (immunocompromised)
  • Aspergillosis (immunocompromised)
• Parasitic
  • Malaria (travel history)
  • Toxoplasmosis
  • Visceral leishmaniasis
  • Toxocara (visceral larva migrans)

Autoimmune/Inflammatory (~10-20%)

• Rheumatic
  • Systemic JIA (sJIA / Still's disease) — most common rheumatic cause of FUO in children
  • Systemic lupus erythematosus (SLE) — more common in adolescents
  • Juvenile dermatomyositis
  • Polyarteritis nodosa
  • Reactive arthritis
• Vasculitis
  • Kawasaki disease — important to consider in any child <5 years with prolonged fever; may be "incomplete Kawasaki" without classic features
  • Henoch-Schönlein purpura (IgA vasculitis)
  • Takayasu arteritis (rare in children)
• Inflammatory
  • Inflammatory bowel disease (Crohn's disease > ulcerative colitis; may present with fever and weight loss before GI symptoms)
  • Sarcoidosis (rare in young children)
• Autoinflammatory/Periodic Fever Syndromes
  • PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis) — most common periodic fever syndrome in children; benign
  • Familial Mediterranean fever (FMF)
  • TNF receptor-associated periodic syndrome (TRAPS)
  • Hyper-IgD syndrome (HIDS/mevalonate kinase deficiency)
  • Cryopyrin-associated periodic syndromes (CAPS)
  • Chronic recurrent multifocal osteomyelitis (CRMO)
• Hemophagocytic
  • Macrophage activation syndrome (MAS) — especially complicating sJIA
  • Hemophagocytic lymphohistiocytosis (HLH) — primary (familial) or secondary

Malignancy (~5-10%)

• Hematologic (most common malignant cause of FUO in children)
  • Leukemia (ALL most common, AML) — most important malignancy to exclude
  • Lymphoma (Hodgkin > non-Hodgkin in older children/adolescents)
  • Langerhans cell histiocytosis
• Solid Tumors
  • Neuroblastoma (especially in children <5 years)
  • Wilms tumor
  • Ewing sarcoma / osteosarcoma (with bone involvement)
  • Hepatoblastoma

Drug Fever

• Antibiotics (beta-lactams, sulfonamides)
• Anticonvulsants (phenytoin, carbamazepine, lamotrigine)
• Atropine, anticholinergics
• DRESS syndrome
• Chemotherapy agents
• Immunizations (post-vaccination fever — usually self-limited and brief)

Central/Neurogenic Fever

• Hypothalamic dysfunction (tumor, trauma, surgery, hemorrhage)
• Autonomic dysreflexia (spinal cord injury)
• Post-neurosurgical

Factitious/Fabricated

• Fabricated or induced illness (Munchausen syndrome by proxy / medical child abuse) — consider when fever is documented only by caregiver, pattern is atypical, and no objective cause is identified
• Self-induced (older children/adolescents)

Miscellaneous

• Hemolytic anemia (sickle cell crisis, autoimmune hemolytic anemia)
• Hematoma resorption (after trauma)
• Ectodermal dysplasia (anhidrotic — impaired heat regulation, not true fever)
• Thyrotoxicosis (rare in children)
• Diabetes insipidus (dehydration-related hyperthermia)
• Infantile cortical hyperostosis (Caffey disease)
• Castleman disease (rare)
• Chronic granulomatous disease (recurrent infections)
• Cyclic neutropenia
• Idiopathic (~10-20% of pediatric FUO remains undiagnosed; most self-resolve)

Evaluation

Workup should be guided by potential diagnostic clues (PDCs) from history and exam. A stepwise approach avoids unnecessary invasive testing.

Workup

Initial Workup (ED and Early Inpatient)

Laboratories

• CBC with differential and peripheral blood smear
  • Leukocytosis → infection, sJIA, Kawasaki disease
  • Leukopenia, blasts, or unexplained cytopenias → leukemia (most important to exclude)
  • Eosinophilia → parasitic infection, drug reaction, Hodgkin lymphoma
  • Atypical lymphocytes → EBV, CMV
  • Falling platelets → MAS/HLH
• ESR, CRP
  • ESR >100 mm/hr narrows differential significantly (endocarditis, abscess, malignancy, sJIA, Kawasaki disease)
  • Paradoxically falling ESR with rising CRP → MAS (fibrinogen consumption)
• Ferritin
  • Markedly elevated (>500-1,000 ng/mL) → sJIA, MAS/HLH
  • >10,000 ng/mL → strongly suggestive of MAS
• LFTs (AST, ALT, LDH, albumin)
• BMP (renal function, electrolytes, glucose)
• Urinalysis with culture (UTI is a common cause in young children)
• Blood cultures (×2 sets, before antibiotics)
• Lactate if concern for sepsis
• Procalcitonin — may help differentiate bacterial infection from inflammatory/autoimmune causes
• Uric acid — elevated in tumor lysis (leukemia, lymphoma)

Serology (Initial)

• EBV (VCA IgM, heterophile/MonoSpot)
• CMV (IgM or PCR)
• HIV (4th-generation Ag/Ab)
• Tuberculosis testing: QuantiFERON-Gold or T-SPOT (preferred over PPD in children ≥2 years)

Imaging

• CXR — baseline for infiltrates, mediastinal mass (lymphoma), hilar lymphadenopathy

Other

• Echocardiography — if ≥5 days of fever and Kawasaki disease is being considered (even without full criteria); also to evaluate for endocarditis, pericardial effusion, or coronary artery abnormalities

Extended Workup (Guided by PDCs or Non-Diagnostic Initial Workup)

Laboratories

• Fibrinogen, D-dimer, coagulation studies — if MAS/HLH or DIC suspected
• Triglycerides — elevated in HLH/MAS
• LDH — markedly elevated in malignancy, HLH/MAS, hemolysis
• ANA — screening for SLE (more relevant in adolescents)
• ASLO / Anti-DNase B — if acute rheumatic fever suspected
• Immunoglobulins (IgG, IgA, IgM, IgD) — elevated IgD in hyper-IgD syndrome (HIDS); low immunoglobulins in primary immunodeficiency
• sIL-2R (soluble CD25) — elevated in HLH/MAS and lymphoma (if available)

Directed Serologies/Cultures (based on exposure history)

• Bartonella henselae (cat scratch disease) — serology or PCR
• Brucella serology
• Lyme disease (two-tier testing)
• Toxoplasmosis IgM/IgG
• Hepatitis A, Hepatitis B
• Parvovirus B19 IgM
• Tularemia, Leptospirosis, Q fever serologies
• Histoplasma/Coccidioides antigens and serologies (endemic areas or travel)
• Stool cultures, ova and parasites (if GI symptoms or travel)

Imaging

• Abdominal ultrasound — evaluate for hepatosplenomegaly, abdominal abscess, lymphadenopathy, renal abscess
• CT chest/abdomen/pelvis with contrast — if ultrasound non-diagnostic; assess for occult abscess, lymphadenopathy, mass
• FDG-PET/CT — emerging role in pediatric FUO when standard imaging is non-diagnostic; useful for identifying occult infection, vasculitis, and malignancy
• CT sinuses/mastoids — if chronic sinusitis or mastoiditis suspected
• MRI — for suspected osteomyelitis, epidural abscess, CNS involvement
• Bone scan (technetium) — if multifocal bone pain or suspected osteomyelitis

Ophthalmologic

• Slit-lamp examination — for uveitis/iridocyclitis (sarcoidosis, sJIA, tuberculosis)

Tissue Biopsy (Targeted)

• Bone marrow biopsy: if concern for leukemia, HLH/MAS, or disseminated infection (granulomatous disease, TB, fungal)
  • Particularly important before starting corticosteroids (steroids can mask leukemia)
• Lymph node biopsy: excisional preferred over FNA; if significant persistent lymphadenopathy without a clear infectious cause (lymphoma, cat scratch disease, tuberculosis, sarcoidosis)
• LP: if CNS infection, meningeal leukemia, or CNS vasculitis suspected

Diagnosis

• FUO diagnosis is iterative — often requires serial evaluations over days to weeks
• No single test is diagnostic for most causes of FUO
• Key diagnostic patterns to recognize in the ED:
  • Quotidian fever + evanescent rash + arthritis + leukocytosis + very high ferritin + negative ANA/RF → Systemic JIA
  • Fever ≥5 days + conjunctivitis + mucous membrane changes + rash + extremity swelling + cervical lymphadenopathy (even if incomplete) → Kawasaki disease
  • Bone pain out of proportion + cytopenias or blasts on smear → Leukemia
  • Falling platelets + falling ESR + ferritin >10,000 → MAS/HLH
  • Recurrent stereotyped febrile episodes with well intervals + aphthous stomatitis + pharyngitis + cervical adenitis → PFAPA
  • Fever + weight loss + perianal disease + abdominal pain → Inflammatory bowel disease

Management

• Treat the underlying cause once identified
• Empiric antibiotics are generally NOT recommended in hemodynamically stable children with FUO — they obscure cultures, delay diagnosis, and promote resistance
• Exceptions where empiric treatment IS appropriate:
  • Hemodynamically unstable / septic: empiric broad-spectrum antibiotics per sepsis guidelines (see Sepsis (Peds))
  • Febrile neutropenia: empiric antipseudomonal beta-lactam within 1 hour
  • Suspected Kawasaki disease: IVIG 2 g/kg + high-dose aspirin — do not delay if clinical suspicion is high, even with incomplete criteria (risk of coronary artery aneurysm increases with treatment delay)
  • Suspected MAS/HLH: high-dose IV methylprednisolone (30 mg/kg, max 1g) ± anakinra or cyclosporine; emergent rheumatology/hematology consultation (see Macrophage activation syndrome)
  • Suspected tuberculosis: empiric anti-TB therapy if clinical suspicion high (especially immunocompromised)
• Avoid empiric corticosteroids in undiagnosed FUO — may mask leukemia, worsen infection, or cause diagnostic confusion
  • Exception: MAS/HLH with life-threatening features (do not delay for bone marrow results)
• Antipyretics (acetaminophen, ibuprofen) for symptomatic relief are appropriate in all patients
• Drug fever: If suspected, discontinue all non-essential medications; fever typically resolves within 48-72 hours

Disposition

Admit

• Hemodynamically unstable or septic-appearing
• Suspicion for leukemia or other malignancy requiring urgent biopsy
• Suspicion for MAS/HLH
• Kawasaki disease (for IVIG administration and echocardiographic monitoring)
• Immunocompromised (febrile neutropenia, HIV, transplant recipient)
• Significant cytopenias, coagulopathy, or end-organ dysfunction
• Failure to thrive / significant weight loss
• Need for invasive workup (bone marrow biopsy, lymph node biopsy)
• Unable to ensure close outpatient follow-up
• Young infants (<3 months) with prolonged fever

Consider Discharge with Close Follow-Up (24-72 hours)

• Hemodynamically stable, well-appearing, immunocompetent
• Initial workup (labs, cultures, imaging) has been initiated and pending results are being tracked
• No red flags for malignancy, MAS, or Kawasaki disease
• Reliable family with clear return precautions
• Follow-up arranged with pediatrician, infectious disease, or rheumatology within 2-3 days
• Document pending labs and the diagnostic plan — communicate clearly to the follow-up provider

Prognosis

• 10-25% of pediatric FUO cases remain undiagnosed even after thorough workup
• Undiagnosed pediatric FUO generally carries a favorable prognosis — most self-resolve without serious sequelae
• Prognosis is better in children than adults with undiagnosed FUO
• Children with FUO lasting >6 months without a diagnosis most commonly have periodic fever syndromes, factitious fever, or habitual hyperthermia — serious infection and malignancy become less likely with time

See Also

• Fever
• Fever of unknown origin
• Pediatric fever of uncertain source
• Systemic JIA
• Kawasaki disease
• Macrophage activation syndrome
• Hemophagocytic lymphohistiocytosis
• Leukemia
• Sepsis (Peds)

External Links

• PMC - Update on FUO in Children: Focus on Etiologies and Clinical Approach (2024)
• StatPearls - Fever of Unknown Origin
• MDCalc - HScore for MAS/HLH