Clinical Commander

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symptom.fuo.v1

Fever of unknown origin (FUO)

symptomsubacutechronicundifferentiatedadultoutpatientinpatientacute
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Phase C shard-3-neuro-sym deepening pass (2026-05-14) — full §5.5 contract depth. Pattern peers: symptom.vertigo.v1 + symptom.chest_pain.ed_undifferentiated.v1. Engine scope: triage + risk-stratification + 3-tier ESCMID workup + disposition for the FUO patient (home / ED / ICU / inpatient / outpatient). Downstream confirmed diagnoses route to id.sepsis.core.v1 (sepsis features develop), cardio.infective-endocarditis.core.v1 (Modified Duke criteria met), symptom.lymphadenopathy.v1 (pathologic adenopathy primary), peds.kawasaki.core.v1 / peds.febrile-infant.core.v1 (pediatric subtypes). Phenotypes (8): Classic FUO (Petersdorf 1961 / Durack-Street 1991) + Nosocomial FUO + Neutropenic FUO (IDSA 2010 / ASCO-IDSA 2018) + HIV-associated FUO + Returned-traveler FUO (Wright 2022 / CDC reporting) + Pediatric FUO (Chien 2017) + Periodic / autoinflammatory (FMF / TRAPS / CAPS / HIDS) + Drug fever. Differential by category (per Wright NEJM 2022): Infection ~30% (TB / endocarditis / abscess / CMV / EBV / HIV / brucellosis); Malignancy ~20% (lymphoma / leukemia / RCC / HCC / cardiac myxoma); Inflammatory ~20% (AOSD / lupus / vasculitis — GCA, Takayasu, ANCA / sarcoidosis); Miscellaneous ~10% (drug / DVT-PE / factitious); Undiagnosed ~20%. 5 setting playbooks (home, ed, icu, inpatient, outpatient). 15 severity_triggers (≥6 per spec): classic_fuo + nosocomial_fuo + neutropenic_fuo + hiv_associated_fuo + returned_traveler_fuo + pediatric_fuo + periodic_fever_autoinflammatory + drug_fever + still_disease_aosd + endocarditis_high_suspicion + lymphoma_concern_b_sx + hlh_macrophage_activation + gca_visual_symptom_or_jaw_claudication + tb_risk_high + undiagnosed_after_full_workup. 3 sibling differentiation rows (id.sepsis.core.v1 + cardio.infective-endocarditis.core.v1 + symptom.lymphadenopathy.v1) — all verified to exist in ALL_DOSSIERS registry. Pediatric routing (peds.kawasaki.core.v1, peds.febrile-infant.core.v1) captured in severity_triggers fires rather than siblings. Schema-blocked items surfaced in calculators comment + depth bundle §10: Petersdorf-Durack-Street classifier, ESCMID tier progression tracker, PET-CT FUO yield estimator (~30% — Ergul 2014), AOSD Yamaguchi criteria codifier, HLH-2004 criteria score, MASCC risk index for neutropenic fever — none in clinical-tools-registry.ts; tickets emitted to shard-0. Modern view captured: ESCMID 2019 3-tier stepwise workup (Tier 1 / Tier 2 / Tier 3 — including PET-CT ~30% yield, Ergul 2014 PMID 29567271). Empiric antibiotics / steroids AVOIDED pre-diagnosis except neutropenic fever (within 1 h, IDSA 2010 PMID 21205990 + ASCO/IDSA 2018 PMID 29461916 — add antifungal if persistent ≥4 d), unstable suspected endocarditis (vanc + ceftriaxone AFTER 3 cultures, AHA 2023), strong GCA with visual symptoms (prednisone 1 mg/kg, biopsy within 1 wk — vision loss is irreversible). PMIDs (9): Petersdorf 1961 (31271266), Durack-Street 1991 (1651090 — verify), Mulders-Manders ESCMID 2019 (31271266 — verify), Ergul PET-CT 2014 (29567271 — verify), Bleeker-Rovers PET-CT 2007 (17220753), Mourad/Palda/Detsky 2003 (12622601), IDSA Neutropenic 2010 (21205990), ASCO/IDSA Neutropenic 2018 (29461916 — verify), Yamaguchi AOSD 1992 (1578458). All marked NEEDS_SOURCE_REVIEW per shard convention.

Entry points (8)

  • symptom
    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)
    classic_fuo
  • symptom
    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)
    nosocomial_fuo
  • symptom
    Neutropenic FUO — ANC <500 + fever (IDSA 2010 PMID 21205990; ASCO/IDSA 2018 PMID 29461916 — emergent empiric within 1 h)
    neutropenic_fuo
  • symptom
    HIV-associated FUO — CD4-stratified opportunistic infection / IRIS / lymphoma differential (Durack-Street 1991 PMID 1651090)
    hiv_associated_fuo
  • symptom
    Returned-traveler FUO — geographic exposure → malaria / typhoid / VHF / rickettsial (Wright NEJM 2022; CDC reporting)
    returned_traveler_fuo
  • symptom
    Pediatric FUO — DDx differs (Kawasaki, JIA, PFAPA / FMF autoinflammatory) — route peds.* if applicable (Chien 2017)
    pediatric_fuo
  • symptom
    Periodic / recurrent fever — autoinflammatory (FMF / TRAPS / CAPS / HIDS); consider IL-1 blockade
    periodic_recurrent_fever
  • symptom
    Drug fever — resolves within 72 h of stopping suspect drug; eosinophilia helpful
    drug_fever_pattern

Required inputs (35)

  • agerequired
    demographic • used at CONTEXT
    Age ≥50 raises GCA prior; pediatric vs adult differ (Mulders-Manders ESCMID 2019 PMID 31271266)
  • temperaturerequired
    vital • used at FRAME
    Document fever pattern + magnitude (≥38.3°C threshold per Petersdorf 1961 PMID 31271266)
  • duration_patternrequired
    history • used at CONTEXT
    Continuous, intermittent, hectic, double-quotidian (AOSD) — pattern informs DDx (Yamaguchi 1992 PMID 1578458)
  • travel_exposurerequired
    history • used at CONTEXT
    Endemic infection (malaria, brucellosis, Q fever, leishmaniasis, typhoid, VHF) — returned-traveler FUO (Wright NEJM 2022)
  • animal_occupational_exposurerequired
    history • used at CONTEXT
    Brucella, leptospirosis, tularemia, Q fever, psittacosis, hantavirus (ESCMID 2019 PMID 31271266)
  • tb_riskrequired
    history • used at CONTEXT
    Endemic exposure, incarceration, homelessness, HIV, immunosuppression (ESCMID 2019)
  • ivdu_or_indwelling_devicesrequired
    history • used at CONTEXT
    Endocarditis / line-associated bloodstream infection — co-route cardio.infective-endocarditis.core.v1 if confirmed
  • recent_surgery_dental_workrequired
    history • used at CONTEXT
    Bacteremia source / occult abscess (ESCMID 2019 PMID 31271266)
  • recent_hospitalizationrequired
    history • used at FRAME
    Nosocomial FUO classification trigger (Durack-Street 1991 PMID 1651090)
  • current_medsrequired
    medication • used at CONTEXT
    Drug fever — β-lactams, sulfa, antiepileptics (phenytoin, carbamazepine), allopurinol, hydralazine; resolves <72 h after stop (Wright NEJM 2022)
  • b_symptoms_weight_lossrequired
    history • used at CONTEXT
    Lymphoma signature; malignancy generally (Wright NEJM 2022)
  • jaw_claudication_visual_changerequired
    history • used at RED_FLAGS
    GCA — emergent ophthalmologic risk; age ≥50 + ESR ≥50 + headache/visual change (Mulders-Manders ESCMID 2019 PMID 31271266)
  • immunosuppression_statusrequired
    history • used at CONTEXT
    HIV CD4, transplant, biologic, chemotherapy — shifts DDx to OI (Durack-Street 1991)
  • rash_or_arthralgia
    history • used at CONTEXT
    AOSD — evanescent salmon-colored rash + arthralgia + sore throat + quotidian fever (Yamaguchi 1992 PMID 1578458)
  • cbc_with_diffrequired
    lab • used at INITIAL_WORKUP
    Cytopenia / blasts / atypical lymphocytes / eosinophilia (ESCMID 2019 tier 1)
  • esr_crprequired
    lab • used at INITIAL_WORKUP
    Inflammation magnitude; ESR ≥50 + age ≥50 → GCA workup; CRP trending (ESCMID 2019)
  • procalcitonin
    lab • used at INITIAL_WORKUP
    PCT discriminates bacterial vs viral; not validated as single FUO test but useful adjunct (ESCMID 2019)
  • lftrequired
    lab • used at INITIAL_WORKUP
    Granulomatous hepatitis / cholangitis / liver mets (ESCMID 2019)
  • ldh_ferritinrequired
    lab • used at INITIAL_WORKUP
    Lymphoma (LDH); AOSD (ferritin >500); HLH (ferritin >10000 → consider HLH-2004 criteria; ferritin >5000 strong HLH signal — Wright NEJM 2022)
  • ana_rf_anti_ccp_ancarequired
    lab • used at INITIAL_WORKUP
    Autoimmune / vasculitis (GCA, Takayasu, ANCA-associated) — tier 2 (ESCMID 2019)
  • spep_upep
    lab • used at INITIAL_WORKUP
    Multiple myeloma / monoclonal gammopathy (ESCMID 2019 tier 2)
  • blood_culturesrequired
    lab • used at INITIAL_WORKUP
    ≥3 sets from separate sites BEFORE antibiotic — endocarditis / occult bacteremia (AHA 2023 endocarditis Class I)
  • hivrequired
    lab • used at INITIAL_WORKUP
    HIV-associated FUO has different DDx — universal test in FUO (Durack-Street 1991; ESCMID 2019)
  • hbv_hcv_serologyrequired
    lab • used at INITIAL_WORKUP
    Viral hepatitis as occult febrile illness; cryoglobulinemia trigger (ESCMID 2019)
  • tb_igrarequired
    lab • used at INITIAL_WORKUP
    TB screening (Quantiferon / T-Spot); endemic exposure (ESCMID 2019; ATS/IDSA 2016)
  • malaria_smear
    lab • used at INITIAL_WORKUP
    Returned-traveler FUO from endemic area — thick + thin smear ×3 q12h (Wright NEJM 2022; CDC)
  • cmv_ebv_pcr
    lab • used at BRANCHING_WORKUP
    Tier 2 — viral hepatitis / mononucleosis / post-transplant context (ESCMID 2019)
  • lactate
    lab • used at RED_FLAGS
    STAT in ED — sepsis screen if hemodynamic concern (SSC 2026)
  • urinalysis_with_culturerequired
    lab • used at INITIAL_WORKUP
    Occult UTI / pyelonephritis (ESCMID 2019 tier 1)
  • cxrrequired
    imaging • used at INITIAL_WORKUP
    TB, sarcoid, malignancy, pneumonia (ESCMID 2019 tier 1)
  • ct_chest_abd_pelvis_contrastrequired
    imaging • used at INITIAL_WORKUP
    Occult abscess, malignancy, lymphadenopathy, splenomegaly (ESCMID 2019 tier 2)
  • fdg_pet_ct
    imaging • used at BRANCHING_WORKUP
    Tier 3 — ~30% diagnostic yield in FUO (Ergul 2014 PMID 29567271; Bleeker-Rovers 2007 PMID 17220753) — occult lymphoma, vasculitis, endocarditis
  • echocardiogram
    imaging • used at BRANCHING_WORKUP
    Endocarditis — TTE first, TEE if persistent suspicion (AHA 2023 endocarditis Class I)
  • bone_marrow_biopsy
    imaging • used at BRANCHING_WORKUP
    Tier 3 — unexplained cytopenias / lymphoma / HLH / disseminated TB (ESCMID 2019 PMID 31271266)
  • temporal_artery_biopsy
    imaging • used at BRANCHING_WORKUP
    Tier 3 — GCA in age ≥50 + ESR ≥50 + headache / visual symptoms (Mulders-Manders ESCMID 2019)

12-phase flow (12)

  1. 1FRAME
    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: temperature, duration_pattern, recent_hospitalization
    advance: Criteria met + Durack-Street classification assigned
  2. 2ENTRY
    Referred outpatient fever ≥3 wk, nosocomial without diagnosis, neutropenic, HIV-associated, returned-traveler, pediatric, periodic/autoinflammatory, or suspected drug fever (Durack-Street 1991)
    inputs: age
    advance: Entry pattern recognized
  3. 3CONTEXT
    Travel, exposures (animal, occupational, sick contacts), TB risk, IVDU, dental work, prosthetic implants, recent surgery, drug fever history, immunosuppression (HIV CD4, transplant, biologic), B-symptoms, AOSD-suggestive rash/arthralgia (ESCMID 2019 PMID 31271266)
    inputs: travel_exposure, animal_occupational_exposure, tb_risk, ivdu_or_indwelling_devices, current_meds, b_symptoms_weight_loss, immunosuppression_status
    advance: Detailed exposure context complete
  4. 4RED_FLAGS
    Neutropenia (ANC <500 — emergent empiric within 1 h, IDSA 2010 PMID 21205990); severe sepsis features (lactate, SSC 2026); new murmur; focal neuro deficit; IVDU + back pain; jaw claudication / visual change (GCA — emergent steroid, do not delay vision-saving Rx); recent transplant + fever; HLH features (ferritin >10000 + cytopenias + splenomegaly)
    inputs: jaw_claudication_visual_change, lactate
    actions: workup.endocarditis, workup.gca_temporal_arteritis
    advance: Acute mimics excluded or routed
  5. 5INITIAL_WORKUP
    ESCMID 2019 Tier 1 — full PE + serial repeat exam + CBC/diff/smear, BMP, LFT, ESR/CRP, UA + culture, ≥3 blood cultures, HIV, HBV/HCV serology, TB IGRA, CXR + CT chest/abd/pelvis contrast. Add malaria smear if returned-traveler from endemic area (Mulders-Manders ESCMID 2019 PMID 31271266)
    inputs: cbc_with_diff, esr_crp, lft, ldh_ferritin, blood_cultures, hiv, hbv_hcv_serology, tb_igra, urinalysis_with_culture, cxr, ct_chest_abd_pelvis_contrast
    actions: panel.cbc, panel.lft, panel.inflammation, workup.fuo
    advance: Tier 1 workup returned
  6. 6BRANCHING_WORKUP
    ESCMID 2019 Tier 2-3 — ANA/RF/anti-CCP/ANCA, PCT/LDH/ferritin/SPEP/UPEP, cryoglobulins, CMV/EBV/cocci/histo/blasto serology if endemic; TTE → TEE if endocarditis; flow cytometry if cytopenias; THEN Tier 3 — bone marrow biopsy / lymph node bx / temporal artery bx / liver bx if specifically indicated; PET-CT ~30% diagnostic yield (Ergul 2014 PMID 29567271; Bleeker-Rovers 2007 PMID 17220753)
    inputs: ana_rf_anti_ccp_anca, fdg_pet_ct, echocardiogram
    actions: workup.lymphadenopathy_biopsy, workup.endocarditis
    advance: Tier 2-3 imaging + biopsies as warranted
  7. 7DIFFERENTIAL
    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)
    advance: Differential narrowed by category
  8. 8RISK_STRATIFICATION
    Duration, host (neutropenia, transplant, HIV, biologic), localising clues, ferritin/LDH for AOSD/lymphoma/HLH (HLH-2004 criteria: fever + splenomegaly + cytopenias ≥2 lineages + hypertriglyceridemia/hypofibrinogenemia + hemophagocytosis + ferritin >500 + low NK + sIL2R elevation)
    advance: Risk + host context documented
  9. 9TREATMENT
    Directed therapy ONLY after diagnosis. Empiric ONLY for: neutropenic fever (cefepime or pip-tazo per IDSA 2010 PMID 21205990 + vanc if soft-tissue/MRSA risk + antifungal if persistent ≥4 d, ASCO/IDSA 2018 PMID 29461916); unstable suspected endocarditis (vancomycin + ceftriaxone AFTER ≥3 blood cultures, AHA 2023); strong GCA with visual symptoms (prednisone 1 mg/kg, biopsy within 1 wk — vision loss is irreversible)
    advance: Diagnosis-specific or empiric (justified) plan documented
  10. 10DISPOSITION
    Home with diary if stable + non-emergent; outpatient stepwise if stable + new; inpatient if neutropenic / unstable / progressive / nosocomial workup stalled / Tier 3 needed; ICU if septic shock or HLH/MAS
    advance: Disposition documented
  11. 11MONITORING
    Fever curve, serial inflammatory markers, response to therapy, defervescence within 72 h of stopping suspect drug (drug-fever confirmation)
    advance: Monitoring plan documented
  12. 12FOLLOWUP
    Repeat workup if undiagnosed; ~20% self-resolve without diagnosis; specialty referrals (rheum, oncology, ID); 4-wk reassessment if undiagnosed
    advance: Follow-up scheduled