12-phase flow (12)

1. 1FRAME
   Adult endemic-mycosis engine covering histoplasmosis (Ohio/Mississippi River valleys + bird/bat exposure), coccidioidomycosis (SW US Arizona/California Central Valley + Mexico/Central America), blastomycosis (SE/NC US + Great Lakes + St. Lawrence River), and paracoccidioidomycosis (rural Latin America). Talaromycosis (SE Asia AIDS) noted as sibling but routed separately. Pediatric-isolated forms and isolated chronic-pulmonary subforms flagged for siblings.
   inputs: geographic_travel_or_residence, immunocompromise_substrate
   advance: host + exposure + scope confirmed (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017)
2. 2ENTRY
   CAP / pneumonia-mimic + endemic exposure, OR fever + weight loss + hepatosplenomegaly + pancytopenia (disseminated histo), OR mucocutaneous ulcer (paracocci, blasto), OR subacute basilar meningitis in SW-US traveler (cocci), OR positive urine histo antigen / cocci serology / BAL fungal stain.
   inputs: geographic_travel_or_residence, temperature
   advance: entry trigger validated
3. 3CONTEXT
   Document travel detail (specific region, season, activity — spelunking, construction, dust storms, soil disruption, agricultural work, archaeology, biology field work), exposure intensity, immunocompromise (HIV with CD4, transplant type + time-from-transplant, biologic class, chronic-steroid dose-duration, malignancy + chemo schedule), comorbidities (DM2 — severe cocci risk; pregnancy — alters drug choice and trimester windows), prior antifungal exposure (azole-resistance), drug-drug interactions (rifampin / ART / calcineurin inhibitors / warfarin / statins), and African-American / Filipino / Hispanic ancestry for severe cocci risk (IDSA cocci 2016 PMID 27470238).
   inputs: immunocompromise_substrate, pregnancy_status
   advance: host risk + exposure detail + DDI profile documented
4. 4RED_FLAGS
   Disseminated disease, CNS involvement (cocci meningitis with hydrocephalus, blasto brain abscess, histo CNS encephalitis), respiratory failure / hypoxic ARDS, septic shock (rare; usually fungemia in profound immunosuppression), pancytopenia with bone-marrow involvement, mucocutaneous lesions threatening airway (paracocci), pregnancy in 1st trimester (azole teratogenicity), HIV CD4 < 150 with disseminated histo (highest mortality) — life-threatening features require L-AmB induction + ICU (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107).
   inputs: spo2
   actions: calc.qsofa
   advance: life-threatening features triggered if present; L-AmB induction planned if severe
5. 5INITIAL_WORKUP
   CBC + diff (cytopenias / eosinophilia), CMP + LFTs (baseline for azoles + AmB), inflammation panel (CRP / ESR / procalcitonin if pneumonia overlap), urine Histoplasma antigen (high sens for disseminated histo and progressive disease; cross-reactive with blasto ~80%, paracocci variable), serum Histo antigen + serum Blasto antigen if available, cocci immunodiffusion (IgM + IgG) + complement fixation, blood fungal cultures (rule out fungemia in disseminated phenotype), sputum / BAL fungal stains (GMS + PAS) and culture, CXR + CT chest, HIV testing if status unknown + CD4 + VL if HIV+, pregnancy test in reproductive-age females (Hage ATS 2019 PMID 31469325; IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008).
   inputs: urine_histo_antigen, cocci_serology, fungal_culture, cbc_with_diff, chest_imaging, creatinine
   actions: panel.cbc, panel.renal, panel.lft, panel.inflammation
   advance: organism / phenotype documented; empiric L-AmB not delayed in unstable disseminated patient
6. 6BRANCHING_WORKUP
   MRI brain with contrast if CNS phenotype (cocci meningitis suspected, blasto brain abscess, histo CNS encephalitis); LP with opening pressure + CSF cell count / glucose / protein / fungal culture / cocci CF titer for suspected cocci meningitis; tissue biopsy for histology + culture when serology + antigen non-diagnostic (lymph node, bone marrow, mucocutaneous lesion); ophthalmology consult if cocci endophthalmitis variant; HIV + transplant team consult; ID consult mandatory for all severe / disseminated / CNS cases (IDSA histo 2007; IDSA cocci 2016 PMID 27470238).
   inputs: mri_brain_with_contrast
   actions: workup.hiv_initial, workup.fuo
   advance: CNS / extrapulmonary extent + species confirmed
7. 7DIFFERENTIAL
   TB (separate engine; can co-infect histo / blasto), cryptococcosis (separate engine; HIV / immunocompromised, basilar meningitis with CrAg LFA), pneumocystis jirovecii (HIV CD4 < 200; β-glucan + bilateral GGO), aspergillosis (immunocompromised, halo sign + galactomannan), bacterial CAP / atypical pneumonia, sarcoidosis (mediastinal LAD + non-caseating granulomas), lymphoma (B-symptoms + adenopathy + tissue diagnosis), lung cancer (cavitary mass mimicking chronic histo / blasto), tularemia (rabbit exposure + ulceroglandular). Endemic-mycosis differential resolved by antigen + serology + culture + histology trajectory (IDSA histo 2007 PMID 17806045; IDSA cocci 2016 PMID 27470238; IDSA blasto 2008 PMID 18462107; Shikanai-Yasuda 2017 PMID 28746570).
   advance: endemic mycosis vs alternative resolved or empiric coverage strategy set
8. 8RISK_STRATIFICATION
   Severity tiering: (a) mild-moderate ambulatory pulmonary — itraconazole or fluconazole or observation; (b) severe pulmonary (hypoxic, ARDS) or disseminated — L-AmB induction; (c) CNS — L-AmB + lifelong azole maintenance (cocci meningitis); (d) immunocompromised — extend induction + lifelong / immune-recovery maintenance; (e) pregnancy — L-AmB, avoid azoles in 1st trimester. Coccidioidal risk amplifiers: African-American / Filipino / Hispanic / pregnancy / DM2 / chronic steroid / TNF-α blocker / HIV / lymphoma / SOT (IDSA cocci 2016 PMID 27470238).
   inputs: spo2, immunocompromise_substrate, pregnancy_status
   actions: calc.qsofa
   advance: severity tier assigned + induction regimen selected
9. 9TREATMENT
   Drug selection by organism × severity × host × site: HISTOPLASMOSIS — mild-moderate pulmonary itraconazole 200 mg PO TID × 3 d → BID × 6-12 mo (acute pulmonary self-limited if symptoms < 4 wk); severe / disseminated L-AmB 3-5 mg/kg/d IV × 1-2 wk → itraconazole 200 mg PO BID × ≥ 12 mo (Johnson Ann Intern Med 2002 PMID 12118965); CNS L-AmB 5 mg/kg/d × 4-6 wk → itraconazole 200 mg PO BID-TID × ≥ 12 mo with TDM trough > 1 µg/mL. COCCIDIOIDOMYCOSIS — mild-moderate pulmonary often observation OR fluconazole 400-800 mg/d × 3-6 mo; severe / disseminated fluconazole 400-1200 mg/d or itraconazole 200 mg BID-TID; L-AmB if respiratory failure or 1st-trimester pregnancy; CNS meningitis fluconazole 400-1200 mg/d PO LIFELONG (no taper — relapse on withdrawal); intrathecal AmB for refractory. BLASTOMYCOSIS — mild-moderate itraconazole 200 mg PO TID × 3 d → BID × 6-12 mo; severe L-AmB × 1-2 wk → itraconazole 200 mg BID × ≥ 12 mo; CNS L-AmB longer ± fluconazole 800 mg/d or voriconazole. PARACOCCIDIOIDOMYCOSIS — itraconazole 200 mg/d × 6-12 mo (mild-moderate, preferred); TMP-SMX as resource-limited alternative × 12-24 mo; severe / juvenile-form L-AmB then itraconazole maintenance (Shikanai-Yasuda 2017 PMID 28746570). Voriconazole / posaconazole / isavuconazole = rescue for azole-resistance or intolerance. ART deferred 4-6 wk in HIV-associated severe disseminated histo to avoid IRIS (extrapolated from COAT cryptococcal data). Itraconazole + rifampin = absolute contraindication (CYP3A4 enzyme induction destroys levels); transplant patients require calcineurin-inhibitor dose reduction 40-60% on azoles.
   inputs: creatinine, lft
   advance: organism-specific regimen running + DDI screen done + TDM plan in place
10. 10DISPOSITION
    ICU for hypoxic respiratory failure / disseminated with shock / CNS herniation risk; ward for stable disseminated on L-AmB; outpatient for stable mild-moderate pulmonary / mucocutaneous on oral azole; OPAT for residual L-AmB doses after 1-2 wk inpatient induction (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008).
    inputs: spo2
    advance: level of care set + outpatient transition plan documented
11. 11MONITORING
    CBC + BMP + LFT q48h during L-AmB induction; itraconazole trough at steady-state (~14 d) target > 1 µg/mL HPLC; LFT monthly during 6-12 mo azole maintenance; cocci CF titer q3 mo (rising titer = progression / relapse); urine histo antigen q3 mo during therapy (clearance marks resolution); HIV CD4 + VL q3 mo for ART efficacy / IRIS surveillance; pregnancy test repeat if azole switch from L-AmB attempted; symptom + functional recovery q1-3 mo. Cocci meningitis lifelong fluconazole — annual neurology + imaging surveillance (Galgiani Dewsnup withdrawal data).
    inputs: creatinine, cbc_with_diff, lft, itraconazole_trough
    actions: panel.renal, panel.cbc, panel.lft
    advance: TDM in target + tolerating regimen + cocci CF titer trending down or histo antigen clearing
12. 12FOLLOWUP
    ID outpatient q1-3 mo through 6-12 mo of therapy + lifelong for cocci meningitis; HIV / transplant clinic concurrent; vaccinations per ACIP after immune-recovery; exposure-avoidance counselling (no spelunking / dusty soil disruption in endemic areas while immunocompromised); fertility / pregnancy planning if azole maintenance ongoing; mental-health screening for post-critical-illness sequelae; pulmonary rehab for fibrotic / cavitary sequelae; relapse vigilance — return of fever / cough / weight loss / mucocutaneous lesion → re-evaluation (IDSA histo 2007; IDSA cocci 2016; IDSA blasto 2008; Shikanai-Yasuda 2017).
    advance: maintenance plan + relapse-precaution counselling + immune-recovery threshold documented