View source for Fever of unknown origin (peds)

{{PediatricPage|fever of unknown origin}}
==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>
*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<ref name="Trapani2024"/>

*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):<ref name="Kaya">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.</ref>
**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):<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 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<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===
*'''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)
*'''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)<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


==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 [[hemophagocytic lymphohistiocytosis|HLH]], primary immunodeficiency)

===Physical Exam — High-Yield Findings===
{| {{table}}
| align="center" style="background:#f0f0f0;"|'''Finding'''
| align="center" style="background:#f0f0f0;"|'''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]], [[hemophagocytic lymphohistiocytosis|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==
{{FUO Peds DDX}}

==Evaluation==
''Workup should be guided by potential diagnostic clues (PDCs) from history and exam. A stepwise approach avoids unnecessary invasive testing.''<ref name="Trapani2024"/><ref name="Antoon2015"/>

===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''' → [[macrophage activation syndrome|MAS]]/[[hemophagocytic lymphohistiocytosis|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<ref name="Trapani2024"/>
*'''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]], [[hemophagocytic lymphohistiocytosis|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''' → [[Macrophage activation syndrome|MAS]]/[[Hemophagocytic lymphohistiocytosis|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 / [[sepsis|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 [[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)
*'''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 [[macrophage activation syndrome|MAS]]/[[hemophagocytic lymphohistiocytosis|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<ref name="Trapani2024"/>
*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==
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC10814770/ PMC - Update on FUO in Children: Focus on Etiologies and Clinical Approach (2024)]
*[https://www.ncbi.nlm.nih.gov/books/NBK532265/ StatPearls - Fever of Unknown Origin]
*[https://www.mdcalc.com/calc/4053/hscore-reactive-hemophagocytic-syndrome MDCalc - HScore for MAS/HLH]

==References==
{{reflist|2}}

[[Category:Pediatrics]]
[[Category:ID]]