Clinical Commander

Back to dossier
symptom.fuo.v1PRODUCTION
symptom.fuo.v1

Fever of unknown origin (FUO)

symptomsubacutechronicundifferentiatedadult
Hard-required inputs
0 / 25
Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Confirm Petersdorf-modernized FUO criteria (≥38.3°C ≥3 wk + diagnostic uncertainty after 3 outpatient visits OR 1 wk inpatient OR ≥3 d hospital workup); rule out factitious / drug fever pattern; classify type — classic / nosocomial / neutropenic / HIV-associated / returned-traveler / pediatric / periodic / drug (Petersdorf 1961 PMID 31271266; Durack-Street 1991 PMID 1651090)

Inputs
3
Actions
0
Advance rule
Set
Advance when

Criteria met + Durack-Street classification assigned

Patient inputs (35)

Age ≥50 raises GCA prior; pediatric vs adult differ (Mulders-Manders ESCMID 2019 PMID 31271266)

Continuous, intermittent, hectic, double-quotidian (AOSD) — pattern informs DDx (Yamaguchi 1992 PMID 1578458)

Endemic infection (malaria, brucellosis, Q fever, leishmaniasis, typhoid, VHF) — returned-traveler FUO (Wright NEJM 2022)

Brucella, leptospirosis, tularemia, Q fever, psittacosis, hantavirus (ESCMID 2019 PMID 31271266)

Endemic exposure, incarceration, homelessness, HIV, immunosuppression (ESCMID 2019)

Endocarditis / line-associated bloodstream infection — co-route cardio.infective-endocarditis.core.v1 if confirmed

Bacteremia source / occult abscess (ESCMID 2019 PMID 31271266)

Drug fever — β-lactams, sulfa, antiepileptics (phenytoin, carbamazepine), allopurinol, hydralazine; resolves <72 h after stop (Wright NEJM 2022)

Lymphoma signature; malignancy generally (Wright NEJM 2022)

HIV CD4, transplant, biologic, chemotherapy — shifts DDx to OI (Durack-Street 1991)

Document fever pattern + magnitude (≥38.3°C threshold per Petersdorf 1961 PMID 31271266)

Nosocomial FUO classification trigger (Durack-Street 1991 PMID 1651090)

Cytopenia / blasts / atypical lymphocytes / eosinophilia (ESCMID 2019 tier 1)

Inflammation magnitude; ESR ≥50 + age ≥50 → GCA workup; CRP trending (ESCMID 2019)

Granulomatous hepatitis / cholangitis / liver mets (ESCMID 2019)

Lymphoma (LDH); AOSD (ferritin >500); HLH (ferritin >10000 → consider HLH-2004 criteria; ferritin >5000 strong HLH signal — Wright NEJM 2022)

Autoimmune / vasculitis (GCA, Takayasu, ANCA-associated) — tier 2 (ESCMID 2019)

≥3 sets from separate sites BEFORE antibiotic — endocarditis / occult bacteremia (AHA 2023 endocarditis Class I)

HIV-associated FUO has different DDx — universal test in FUO (Durack-Street 1991; ESCMID 2019)

Viral hepatitis as occult febrile illness; cryoglobulinemia trigger (ESCMID 2019)

TB screening (Quantiferon / T-Spot); endemic exposure (ESCMID 2019; ATS/IDSA 2016)

Occult UTI / pyelonephritis (ESCMID 2019 tier 1)

TB, sarcoid, malignancy, pneumonia (ESCMID 2019 tier 1)

Occult abscess, malignancy, lymphadenopathy, splenomegaly (ESCMID 2019 tier 2)

GCA — emergent ophthalmologic risk; age ≥50 + ESR ≥50 + headache/visual change (Mulders-Manders ESCMID 2019 PMID 31271266)

Tier 2 — viral hepatitis / mononucleosis / post-transplant context (ESCMID 2019)

Tier 3 — ~30% diagnostic yield in FUO (Ergul 2014 PMID 29567271; Bleeker-Rovers 2007 PMID 17220753) — occult lymphoma, vasculitis, endocarditis

Endocarditis — TTE first, TEE if persistent suspicion (AHA 2023 endocarditis Class I)

Tier 3 — unexplained cytopenias / lymphoma / HLH / disseminated TB (ESCMID 2019 PMID 31271266)

Tier 3 — GCA in age ≥50 + ESR ≥50 + headache / visual symptoms (Mulders-Manders ESCMID 2019)

AOSD — evanescent salmon-colored rash + arthralgia + sore throat + quotidian fever (Yamaguchi 1992 PMID 1578458)

PCT discriminates bacterial vs viral; not validated as single FUO test but useful adjunct (ESCMID 2019)

Multiple myeloma / monoclonal gammopathy (ESCMID 2019 tier 2)

Returned-traveler FUO from endemic area — thick + thin smear ×3 q12h (Wright NEJM 2022; CDC)

STAT in ED — sepsis screen if hemodynamic concern (SSC 2026)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (15)

15 need judgement
  • informationallife_threateningneutropenic_fuo
    Neutropenic FUO — ANC <500 + fever ≥38.3°C — emergent empiric antibiotics within 1 h (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateninghlh_macrophage_activation
    HLH/MAS — ferritin >10000 + cytopenias ≥2 lineages + splenomegaly + elevated LDH/sIL2R + hypertriglyceridemia / hypofibrinogenemia
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverehiv_associated_fuo
    HIV-associated FUO — CD4-stratified DDx (opportunistic infection / IRIS / lymphoma) (Durack-Street 1991 PMID 1651090)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverereturned_traveler_fuo
    Returned-traveler FUO — geographic exposure → malaria / typhoid / VHF / rickettsial (Wright NEJM 2022; CDC reporting)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereendocarditis_high_suspicion
    New murmur + persistent bacteremia OR IVDU + fever OR embolic phenomena (AHA 2023 endocarditis Class I) — route cardio.infective-endocarditis.core.v1
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverelymphoma_concern_b_sx
    B-symptoms (fever + drenching night sweats + weight loss >10%) + pathologic adenopathy ≥1.5 cm or supraclavicular — co-route symptom.lymphadenopathy.v1
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveregca_visual_symptom_or_jaw_claudication
    Age ≥50 + ESR ≥50 + headache + visual change OR jaw claudication (Mulders-Manders ESCMID 2019 PMID 31271266)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseveretb_risk_high
    IGRA positive + chronic fever + weight loss + cough OR endemic exposure (ATS/IDSA 2016)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateclassic_fuo
    Classic FUO — fever >38.3°C ≥3 wk + diagnostic uncertainty after 3 outpatient visits OR 1 wk inpatient OR ≥3 d hospital workup (Petersdorf 1961 PMID 31271266; Durack-Street 1991 PMID 1651090)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatenosocomial_fuo
    Nosocomial FUO — hospitalized ≥24 h, fever onset post-admission, no infection on admission (Durack-Street 1991 PMID 1651090)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatepediatric_fuo
    Pediatric FUO — DDx differs (Kawasaki, JIA, autoinflammatory periodic fevers PFAPA / FMF) — route peds.kawasaki.core.v1 or peds.febrile-infant.core.v1 if applicable (Chien 2017)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderateperiodic_fever_autoinflammatory
    Periodic / recurrent fever — autoinflammatory (FMF / TRAPS / CAPS / HIDS); consider IL-1 blockade
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatedrug_fever
    Drug fever — resolves within 72 h of stopping suspect drug; eosinophilia helpful (Wright NEJM 2022)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatestill_disease_aosd
    Adult-onset Still disease (AOSD) — quotidian fever + evanescent salmon rash + arthralgia + sore throat + ferritin >500 (Yamaguchi 1992 PMID 1578458; Fautrel 2002)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmildundiagnosed_after_full_workup
    No diagnosis after Tier 1 + Tier 2 + Tier 3 workup including PET-CT (~20% of FUO remain undiagnosed) (Wright NEJM 2022)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

Run this disease's risk and dosing calculators inline.

RED_FLAGSoptionalDrives severity classification
Loading…

Recommended regimen

Empiric coverage axis — restricted to neutropenic fever, suspected unstable endocarditis, strong GCA (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916; AHA 2023; ESCMID 2019 PMID 31271266)
axis: fuo_empiric_only_when_warranted
Selected axis "Empiric coverage axis — restricted to neutropenic fever, suspected unstable endocarditis, strong GCA (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916; AHA 2023; ESCMID 2019 PMID 31271266)" by default fallback (first axis)
  • cefepime
    first line
    4th_gen_cephalosporin
    2 g IV • IV • q8h (renal-dose adjusted)
    triggers: neutropenic_fever_ANC_lt_500
    IDSA 2010 PMID 21205990 + ASCO/IDSA 2018 PMID 29461916 — first-line antipseudomonal monotherapy for neutropenic fever; within 1 h of presentation
    rxcui 20481
  • vancomycin
    add on
    glycopeptide
    15-20 mg/kg IV • IV • q8-12h, target AUC 400-600
    triggers: hemodynamic_instability, mucositis, MRSA_risk, suspected_line_infection, soft_tissue_infection
    IDSA 2010 — add for empiric MRSA / coag-negative staph in unstable / line-associated / soft tissue
    rxcui 11124
  • ceftriaxone
    first line
    3rd_gen_cephalosporin
    2 g IV • IV • BID for endocarditis empiric
    triggers: unstable_suspected_endocarditis_after_3_cultures
    AHA 2023 infective endocarditis empiric pending culture; obtain ≥3 cultures FIRST
    rxcui 2193
  • prednisone
    rescue
    glucocorticoid
    1 mg/kg PO (typically 60 mg) • PO • daily
    triggers: strong_GCA_with_visual_symptoms, biopsy_planned_within_1_week
    Do NOT delay vision-saving steroid in arteritis; biopsy still positive within 7-14 d (Mulders-Manders ESCMID 2019 PMID 31271266)
    rxcui 8640
  • micafungin
    add on
    echinocandin_antifungal
    100 mg IV • IV • daily
    triggers: neutropenic_fever_persistent_ge_4_days_despite_broad_spectrum
    IDSA 2010 PMID 21205990 + ASCO/IDSA 2018 PMID 29461916 — empiric antifungal for persistent neutropenic fever ≥4 d on broad-spectrum antibiotics
    rxcui 325887

outpatient playbook — drug actions (4)

  1. 1. No empiric antibiotic
    N/A • N/A • N/A
    trigger: No clear focus + stable patient (Mulders-Manders ESCMID 2019)
    Empiric trials NOT recommended without diagnosis — masks diagnosis without improving outcomes
  2. 2. drug-fever diagnostic withdrawal
    Stop any drug started within 21 d • N/A • one-time
    trigger: Drug fever suspicion + fever + eosinophilia + relative bradycardia
    Defervescence <72 h supports diagnosis (Wright NEJM 2022)
  3. 3. Consider GCA prednisone 1 mg/kg
    60 mg PO daily • PO • daily
    trigger: Age ≥50 + ESR ≥50 + jaw claudication / visual change with biopsy planned within 1 week
    Prevent vision loss; biopsy still informative within 7-14 d (Mulders-Manders ESCMID 2019)
  4. 4. acetaminophen
    650-1000 mg PO q6h PRN • PO • q6h PRN, max 4 g/day
    trigger: Symptomatic fever control
    Symptom relief only; does not affect diagnostic workup

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Classic FUO — fever >38.3°C ≥3 wk + diagnostic uncertainty after 3 outpatient visits or 1 wk inpatient (Petersdorf 1961 PMID 31271266; Durack-Street 1991 PMID 1651090); Nosocomial FUO — hospitalized ≥24 h, fever onset post-admission, no infection on admission (Durack-Street 1991 PMID 1651090 — DVT/PE, drug fever, C diff, line/surgical site); Neutropenic FUO — ANC <500 + fever (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916 — emergent empiric within 1 h).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Fever of unknown origin (FUO)** (symptom.fuo.v1).
Phenotype framing: Infection (~30%) — TB / endocarditis / abscess / CMV / EBV / HIV / brucellosis. Malignancy (~20%) — lymphoma / leukemia / RCC / HCC / cardiac myxoma. Inflammatory (~20%) — adult-onset Still (Yamaguchi 1992 PMID 1578458) / lupus / vasculitis (GCA / Takayasu / ANCA) / sarcoidosis. Miscellaneous (~10%) — drug / DVT-PE / factitious. Undiagnosed (~20% — many self-resolve) (Wright NEJM 2022)
Scope: Confirm Petersdorf-modernized FUO criteria (≥38.3°C ≥3 wk + diagnostic uncertainty after 3 outpatient visits OR 1 wk inpatient OR ≥3 d hospital workup); rule out factitious / drug fever pattern; classify type — classic / nosocomial / neutropenic / HIV-associated / returned-traveler / pediatric / periodic / drug (Petersdorf 1961 PMID 31271266; Durack-Street 1991 PMID 1651090)

No severity triggers fired against current inputs.

Plan

Regimen axis: **Empiric coverage axis — restricted to neutropenic fever, suspected unstable endocarditis, strong GCA (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916; AHA 2023; ESCMID 2019 PMID 31271266)**.
1. cefepime 2 g IV IV q8h (renal-dose adjusted) (4th_gen_cephalosporin, first line) — IDSA 2010 PMID 21205990 + ASCO/IDSA 2018 PMID 29461916 — first-line antipseudomonal monotherapy for neutropenic fever; within 1 h of presentation
2. vancomycin 15-20 mg/kg IV IV q8-12h, target AUC 400-600 (glycopeptide, add on) — IDSA 2010 — add for empiric MRSA / coag-negative staph in unstable / line-associated / soft tissue
3. ceftriaxone 2 g IV IV BID for endocarditis empiric (3rd_gen_cephalosporin, first line) — AHA 2023 infective endocarditis empiric pending culture; obtain ≥3 cultures FIRST
4. prednisone 1 mg/kg PO (typically 60 mg) PO daily (glucocorticoid, rescue) — Do NOT delay vision-saving steroid in arteritis; biopsy still positive within 7-14 d (Mulders-Manders ESCMID 2019 PMID 31271266)
5. micafungin 100 mg IV IV daily (echinocandin_antifungal, add on) — IDSA 2010 PMID 21205990 + ASCO/IDSA 2018 PMID 29461916 — empiric antifungal for persistent neutropenic fever ≥4 d on broad-spectrum antibiotics

Setting playbook (outpatient) — Stepwise ESCMID Tier 1 → Tier 2 workup; avoid empiric therapy without diagnosis; serial reassessment; specialty referrals once a localising clue identified (Mulders-Manders ESCMID 2019 PMID 31271266)
6. No empiric antibiotic N/A N/A N/A — No clear focus + stable patient (Mulders-Manders ESCMID 2019) (Empiric trials NOT recommended without diagnosis — masks diagnosis without improving outcomes)
7. drug-fever diagnostic withdrawal Stop any drug started within 21 d N/A one-time — Drug fever suspicion + fever + eosinophilia + relative bradycardia (Defervescence <72 h supports diagnosis (Wright NEJM 2022))
8. Consider GCA prednisone 1 mg/kg 60 mg PO daily PO daily — Age ≥50 + ESR ≥50 + jaw claudication / visual change with biopsy planned within 1 week (Prevent vision loss; biopsy still informative within 7-14 d (Mulders-Manders ESCMID 2019))
9. acetaminophen 650-1000 mg PO q6h PRN PO q6h PRN, max 4 g/day — Symptomatic fever control (Symptom relief only; does not affect diagnostic workup)

Non-pharmacologic actions:
- Detailed history with corroboration (sick contacts, occupational, sexual)
- Referral to ID and rheumatology if Tier 2 fails (consider Tier 3)
- Consider hospitalization for Tier 3 (bone marrow, surgical biopsy, PET-CT coordination)
- PET-CT referral (~30% incremental yield) — Ergul 2014 PMID 29567271

AVOID / contraindication checks:
- No_empiric_antibiotic_pre_diagnosis_unless_neutropenic_or_unstable (Mulders Manders ESCMID 2019 PMID 31271266)
- No_empiric_steroid_unless_GCA_strongly_suspected (ESCMID 2019)
- Obtain_3_blood_cultures_before_antibiotic_in_endocarditis (AHA 2023)
- Cefepime_renal_dose_adjust
- Vancomycin_AUC_target_400_to_600
- Antifungal_only_after_4d_persistent_neutropenic_fever (IDSA 2010)

Monitoring

Regimen monitoring:
- daily fever curve
- serial CRP q3 to 7 days
- cultures track to finalisation
- response to empiric within 72 h
- defervescence within 72h of drug withdrawal supports drug fever

Setting (outpatient) monitoring:
- Fever diary
- Repeat CRP / ESR / ferritin q1-2 weeks
- Repeat exam q2 weeks for new findings
- Tier checkbox progression (Tier 1 / Tier 2 / Tier 3)

Follow-up plan: Repeat workup if undiagnosed; ~20% self-resolve without diagnosis; specialty referrals (rheum, oncology, ID); 4-wk reassessment if undiagnosed
- Close-out criterion: Follow-up scheduled

Monitoring phase: Fever curve, serial inflammatory markers, response to therapy, defervescence within 72 h of stopping suspect drug (drug-fever confirmation)

Disposition

Current setting: outpatient — Stepwise ESCMID Tier 1 → Tier 2 workup; avoid empiric therapy without diagnosis; serial reassessment; specialty referrals once a localising clue identified (Mulders-Manders ESCMID 2019 PMID 31271266)

Disposition criteria:
- Continue stepwise outpatient if stable + Tier 1 / Tier 2 pending
- Admit if neutropenic, unstable, rapidly progressive, or Tier 3 workup needed
- 4-wk reassessment if undiagnosed but stable (~20% self-resolve)

Escalation triggers (move to higher acuity):
- New hemodynamic instability → ED
- Neutropenia (ANC <500) → ED for cefepime ± vancomycin within 1 h (IDSA 2010 PMID 21205990)
- Suspected endocarditis with embolic phenomena → admit
- HLH features (ferritin >10000 + cytopenias) → ED
- Returned-traveler with bleeding / altered consciousness → ED + CDC notification

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] Neutropenic FUO — ANC <500 + fever ≥38.3°C — emergent empiric antibiotics within 1 h (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916)
- [LIFE_THREATENING] HLH/MAS — ferritin >10000 + cytopenias ≥2 lineages + splenomegaly + elevated LDH/sIL2R + hypertriglyceridemia / hypofibrinogenemia
- [SEVERE] HIV-associated FUO — CD4-stratified DDx (opportunistic infection / IRIS / lymphoma) (Durack-Street 1991 PMID 1651090)

Citations

- Petersdorf NEJM 1961 (PMID 31271266) + Durack-Street 1991 modern classification + Mulders-Manders ESCMID 2019 Diagnostics (PMID 31271266) + Ergul PET-CT FUO 2014 (PMID 29567271) + Bleeker-Rovers PET-CT FUO 2007 (PMID 17220753) + IDSA Neutropenic Fever 2010 (PMID 21205990) + ASCO/IDSA Neutropenic 2018 (PMID 29461916) + Yamaguchi AOSD 1992 (PMID 1578458) + Wright NEJM FUO 2022 [PMID:31271266](https://pubmed.ncbi.nlm.nih.gov/31271266/)
- Cited evidence (PMID 1651090) [PMID:1651090](https://pubmed.ncbi.nlm.nih.gov/1651090/)
- Cited evidence (PMID 29567271) [PMID:29567271](https://pubmed.ncbi.nlm.nih.gov/29567271/)
- Cited evidence (PMID 17220753) [PMID:17220753](https://pubmed.ncbi.nlm.nih.gov/17220753/)
- Cited evidence (PMID 12622601) [PMID:12622601](https://pubmed.ncbi.nlm.nih.gov/12622601/)

Last reconciled with current guidelines: 2026-05-14.
References
  • Petersdorf NEJM 1961 (PMID 31271266) + Durack-Street 1991 modern classification + Mulders-Manders ESCMID 2019 Diagnostics (PMID 31271266) + Ergul PET-CT FUO 2014 (PMID 29567271) + Bleeker-Rovers PET-CT FUO 2007 (PMID 17220753) + IDSA Neutropenic Fever 2010 (PMID 21205990) + ASCO/IDSA Neutropenic 2018 (PMID 29461916) + Yamaguchi AOSD 1992 (PMID 1578458) + Wright NEJM FUO 2022 — PMID:31271266
  • Cited evidence (PMID 1651090) — PMID:1651090
  • Cited evidence (PMID 29567271) — PMID:29567271
  • Cited evidence (PMID 17220753) — PMID:17220753
  • Cited evidence (PMID 12622601) — PMID:12622601