Fever of unknown origin (peds): Difference between revisions

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==Background==
==Background==
*Fever of unknown origin (FUO) in children accounts for approximately 3% of pediatric hospitalizations<ref name="Trapani2024">Trapani S, Fiordelisi A, Stinco M, Resti M. Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach. Children. 2024;11(1):20.</ref>
*Fever of unknown origin (FUO) in children accounts for approximately 3% of pediatric hospitalizations<ref name="Trapani2024">Trapani S, Fiordelisi A, Stinco M, Resti M. Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach. Children. 2024;11(1):20.</ref>
*Most commonly represents an '''atypical presentation of a common disease''' rather than a rare condition
*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
*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<ref name="Trapani2024"/>
*No standardized diagnostic algorithm has been fully validated in pediatric populations; workup should be guided by potential diagnostic clues (PDCs) from history and exam<ref name="Trapani2024"/>


*The ED role is to:
*The ED role is to:
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**No clear diagnosis after 1 week inpatient workup
**No clear diagnosis after 1 week inpatient workup
*Newer definition (Durack and Street, 1991):<ref name="Durack">Durack DT, Street AC. Fever of unknown origin--reexamined and redefined. Curr Clin Top Infect Dis. 1991;11:35-51.</ref> "Prolonged fever" with:
*Newer definition (Durack and Street, 1991):<ref name="Durack">Durack DT, Street AC. Fever of unknown origin--reexamined and redefined. Curr Clin Top Infect Dis. 1991;11:35-51.</ref> "Prolonged fever" with:
**3 outpatient visits without identifying a cause '''OR'''
**3 outpatient visits without identifying a cause OR
**3 inpatient days without identifying a cause '''OR'''
**3 inpatient days without identifying a cause OR
**1 week of "intelligent and invasive" ambulatory investigation
**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<ref name="Antoon2015">Antoon JW, Potisek NM, Lohr JA. Pediatric Fever of Unknown Origin. Pediatr Rev. 2015;36(9):380-391.</ref>
*Many pediatric centers now use a shorter threshold of ≥8 days of fever without diagnosis after initial evaluation<ref name="Antoon2015">Antoon JW, Potisek NM, Lohr JA. Pediatric Fever of Unknown Origin. Pediatr Rev. 2015;36(9):380-391.</ref>


===Etiologic Distribution in Children===
===Etiologic Distribution in Children===
*'''Infections:''' 40-60% (most common cause — higher proportion than in adults)<ref name="Trapani2024"/>
*Infections: 40-60% (most common cause — higher proportion than in adults)<ref name="Trapani2024"/>
*'''Non-infectious inflammatory diseases:''' 10-20% ([[Systemic JIA]] is the most common rheumatic cause)
*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)
*'''Malignancy:''' 5-10% (lower proportion than adults, but [[leukemia]] and [[lymphoma]] must always be excluded)
*'''Miscellaneous:''' 5-10%
*Miscellaneous: 5-10%
*'''Undiagnosed:''' 10-25% (prognosis is generally favorable; most self-resolve)<ref name="Trapani2024"/>
*Undiagnosed: 10-25% (prognosis is generally favorable; most self-resolve)<ref name="Trapani2024"/>


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


===Physical Exam — High-Yield Findings===
===Physical Exam — High-Yield Findings===
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|}
|}


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


;Serology (Initial):
;Serology (Initial):
*'''[[EBV]]''' (VCA IgM, heterophile/MonoSpot)
*[[EBV]] (VCA IgM, heterophile/MonoSpot)
*'''[[CMV]]''' (IgM or PCR)
*[[CMV]] (IgM or PCR)
*'''[[HIV]]''' (4th-generation Ag/Ab)
*[[HIV]] (4th-generation Ag/Ab)
*'''Tuberculosis testing:''' QuantiFERON-Gold or T-SPOT (preferred over PPD in children ≥2 years)
*Tuberculosis testing: QuantiFERON-Gold or T-SPOT (preferred over PPD in children ≥2 years)


;Imaging:
;Imaging:
*'''[[CXR]]''' — baseline for infiltrates, mediastinal mass (lymphoma), hilar lymphadenopathy
*[[CXR]] — baseline for infiltrates, mediastinal mass (lymphoma), hilar lymphadenopathy


;Other:
;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
*[[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)====
====Extended Workup (Guided by PDCs or Non-Diagnostic Initial Workup)====
;Laboratories:
;Laboratories:
*'''Fibrinogen, D-dimer, coagulation studies''' — if MAS/HLH or DIC suspected
*Fibrinogen, D-dimer, coagulation studies — if MAS/HLH or DIC suspected
*'''Triglycerides''' — elevated in HLH/MAS
*Triglycerides — elevated in HLH/MAS
*'''LDH''' — markedly elevated in malignancy, HLH/MAS, hemolysis
*LDH — markedly elevated in malignancy, HLH/MAS, hemolysis
*'''ANA''' — screening for [[SLE]] (more relevant in adolescents)
*ANA — screening for [[SLE]] (more relevant in adolescents)
*'''ASLO / Anti-DNase B''' — if [[acute rheumatic fever]] suspected
*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
*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)
*sIL-2R (soluble CD25) — elevated in HLH/MAS and lymphoma (if available)


;Directed Serologies/Cultures (based on exposure history):
;Directed Serologies/Cultures (based on exposure history):
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;Imaging:
;Imaging:
*'''Abdominal [[ultrasound]]''' — evaluate for hepatosplenomegaly, abdominal abscess, lymphadenopathy, renal abscess
*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
*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<ref name="Trapani2024"/>
*FDG-PET/CT — emerging role in pediatric FUO when standard imaging is non-diagnostic; useful for identifying occult infection, vasculitis, and malignancy<ref name="Trapani2024"/>
*'''CT sinuses/mastoids''' — if chronic sinusitis or mastoiditis suspected
*CT sinuses/mastoids — if chronic sinusitis or mastoiditis suspected
*'''MRI''' — for suspected osteomyelitis, epidural abscess, CNS involvement
*MRI — for suspected osteomyelitis, epidural abscess, CNS involvement
*'''Bone scan''' (technetium) — if multifocal bone pain or suspected osteomyelitis
*Bone scan (technetium) — if multifocal bone pain or suspected osteomyelitis


;Ophthalmologic:
;Ophthalmologic:
*'''Slit-lamp examination''' — for uveitis/iridocyclitis ([[sarcoidosis]], sJIA, [[tuberculosis]])
*Slit-lamp examination — for uveitis/iridocyclitis ([[sarcoidosis]], sJIA, [[tuberculosis]])


====Tissue Biopsy (Targeted)====
====Tissue Biopsy (Targeted)====
*'''Bone marrow biopsy:''' if concern for [[leukemia]], [[hemophagocytic lymphohistiocytosis|HLH]]/MAS, or disseminated infection (granulomatous disease, TB, fungal)
*Bone marrow biopsy: if concern for [[leukemia]], [[hemophagocytic lymphohistiocytosis|HLH]]/MAS, or disseminated infection (granulomatous disease, TB, fungal)
**Particularly important '''before starting corticosteroids''' (steroids can mask leukemia)
**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]])
*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
*[[LP]]: if CNS infection, meningeal leukemia, or [[CNS vasculitis]] suspected


===Diagnosis===
===Diagnosis===
*FUO diagnosis is '''iterative''' — often requires serial evaluations over days to weeks
*FUO diagnosis is iterative — often requires serial evaluations over days to weeks
*'''No single test''' is diagnostic for most causes of FUO
*No single test is diagnostic for most causes of FUO
*Key diagnostic patterns to recognize in the ED:
*Key diagnostic patterns to recognize in the ED:
**'''Quotidian fever + evanescent rash + arthritis + leukocytosis + very high ferritin + negative ANA/RF''' → [[Systemic JIA]]
**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]]
**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]]
**Bone pain out of proportion + cytopenias or blasts on smear → [[Leukemia]]
**'''Falling platelets + falling ESR + ferritin >10,000''' → [[Macrophage activation syndrome|MAS]]/[[Hemophagocytic lymphohistiocytosis|HLH]]
**Falling platelets + falling ESR + ferritin >10,000 → [[Macrophage activation syndrome|MAS]]/[[Hemophagocytic lymphohistiocytosis|HLH]]
**'''Recurrent stereotyped febrile episodes with well intervals + aphthous stomatitis + pharyngitis + cervical adenitis''' → '''PFAPA'''
**Recurrent stereotyped febrile episodes with well intervals + aphthous stomatitis + pharyngitis + cervical adenitis → PFAPA
**'''Fever + weight loss + perianal disease + abdominal pain''' → [[Inflammatory bowel disease]]
**Fever + weight loss + perianal disease + abdominal pain → [[Inflammatory bowel disease]]


==Management==
==Management==
*'''Treat the underlying cause''' once identified
*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
*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:'''
*Exceptions where empiric treatment IS appropriate:
**'''Hemodynamically unstable / [[sepsis|septic]]:''' empiric broad-spectrum antibiotics per sepsis guidelines (see [[Sepsis (Peds)]])
**Hemodynamically unstable / [[sepsis|septic]]: empiric broad-spectrum antibiotics per sepsis guidelines (see [[Sepsis (Peds)]])
**'''[[Febrile neutropenia]]:''' empiric antipseudomonal beta-lactam within 1 hour
**[[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 [[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 [[macrophage activation syndrome|MAS]]/[[hemophagocytic lymphohistiocytosis|HLH]]:''' high-dose IV [[methylprednisolone]] (30 mg/kg, max 1g) ± [[anakinra]] or [[cyclosporine]]; emergent rheumatology/hematology consultation (see [[Macrophage activation syndrome]])
**Suspected [[macrophage activation syndrome|MAS]]/[[hemophagocytic lymphohistiocytosis|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)
**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
*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)
**'''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
*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
*Drug fever: If suspected, discontinue all non-essential medications; fever typically resolves within 48-72 hours


==Disposition==
==Disposition==
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*Reliable family with clear return precautions
*Reliable family with clear return precautions
*Follow-up arranged with pediatrician, infectious disease, or rheumatology within 2-3 days
*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
*Document pending labs and the diagnostic plan — communicate clearly to the follow-up provider


===Prognosis===
===Prognosis===
*10-25% of pediatric FUO cases remain undiagnosed even after thorough workup<ref name="Trapani2024"/>
*10-25% of pediatric FUO cases remain undiagnosed even after thorough workup<ref name="Trapani2024"/>
*Undiagnosed pediatric FUO generally carries a '''favorable prognosis''' — most self-resolve without serious sequelae
*Undiagnosed pediatric FUO generally carries a favorable prognosis — most self-resolve without serious sequelae
*Prognosis is better in children than adults with undiagnosed FUO
*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
*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

Latest revision as of 09:31, 22 March 2026

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[1]
  • 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[1]
  • The ED role is to:

Definition

  • Original definition (Petersdorf and Beeson, 1961):[2]
    • 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):[3] "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[4]

Etiologic Distribution in Children

  • Infections: 40-60% (most common cause — higher proportion than in adults)[1]
  • 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)[1]
  • 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

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)

Autoimmune/Inflammatory (~10-20%)

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

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.[1][4]

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

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)
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[1]
  • 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

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:
  • 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[1]
  • 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

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Trapani S, Fiordelisi A, Stinco M, Resti M. Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach. Children. 2024;11(1):20.
  2. ↑ Kaya A, Ergul N, Kaya SY, et al. The management and the diagnosis of fever of unknown origin. Expert Rev Anti Infect Ther. 2013 Aug;11(8):805-15.
  3. ↑ Durack DT, Street AC. Fever of unknown origin--reexamined and redefined. Curr Clin Top Infect Dis. 1991;11:35-51.
  4. ↑ 4.0 4.1 Antoon JW, Potisek NM, Lohr JA. Pediatric Fever of Unknown Origin. Pediatr Rev. 2015;36(9):380-391.
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