12-phase flow (12)

1. 1FRAME
   Adult cerebral toxoplasmosis in HIV (CD4 < 100, especially < 50) and non-HIV immunocompromised hosts (SOT — heart D+/R- highest; alloHSCT; biologic + CAR-T). Congenital + isolated ocular toxoplasmosis out of scope (DHHS 2024 OI; Robert-Gangneux PMID 22491772)
   inputs: immunocompromise_substrate
   advance: immunocompromise substrate + scope confirmed
2. 2ENTRY
   Focal neurologic deficit / AMS / seizure / new ring-enhancing brain lesion in immunocompromised adult — subacute (2-3 wk) presentation typical; Toxo IgG+ + CD4 < 100 + multifocal ring-enhancing lesions has > 90% predictive value for toxoplasmosis (Luft/Remington PMID 1520757; DHHS 2024 OI)
   inputs: immunocompromise_substrate
   advance: one entry trigger present in immunocompromised host
3. 3CONTEXT
   Document immune substrate — HIV (CD4 + VL + ART history + Toxo IgG + prophylaxis history) vs SOT (organ + D/R serostatus + time-from-transplant) vs alloHSCT (donor + engraftment + GVHD + IS regimen) vs biologic/CAR-T; pregnancy status; sulfa-allergy; current IS regimen (DHHS 2024 OI; AST IDCOP transplant ID)
   inputs: cd4_count, current_art_or_immunosuppression, sulfa_allergy_status
   advance: host risk profile + immune substrate documented
4. 4RED_FLAGS
   Mass effect + impending herniation (Cushing reflex, asymmetric pupils, posturing) → emergent neurosurgery + dexamethasone + osmotherapy; status epilepticus → neuro.status-epilepticus.core.v1; sepsis-pattern + altered consciousness → id.sepsis.core.v1 cross-route (DHHS 2024 OI; IDSA neurocritical care)
   inputs: mass_effect_or_herniation_features
   advance: life-threatening intracranial complications addressed if present
5. 5INITIAL_WORKUP
   Toxoplasma IgG (qualitative); MRI brain with contrast (ring-enhancing lesions characterization — number, size, location, midline shift); CBC + LFT + creatinine baseline; HIV serology + CD4 + VL if not yet established; ophthalmology consult to evaluate for ocular toxoplasmosis (frequent co-existence in CNS disease); CSF only if no mass effect — CSF Toxoplasma PCR sensitivity ~50-65% (LR+ high when positive but negative does not rule out); blood Toxoplasma PCR adjunctive (DHHS 2024 OI; Luft/Remington PMID 1520757; Robert-Gangneux PMID 22491772)
   inputs: toxoplasma_igg_serology, mri_brain_with_contrast, cbc, creatinine
   actions: workup.hiv_initial, panel.cbc, panel.lft, panel.renal
   advance: IgG + MRI + baseline labs in hand; CSF if obtained
6. 6BRANCHING_WORKUP
   Empiric treatment trial (default for HIV + Toxo IgG+ + CD4 < 100 + multifocal ring-enhancing lesions; Luft/Remington > 90% response) vs upfront stereotactic biopsy (single lesion + Toxo IgG-negative + atypical imaging + transplant recipient — Cibickova PMID 17428279 lower threshold; lack of clinical/radiographic improvement at 10-14 d of appropriate empiric → biopsy); FDG-PET / SPECT to differentiate primary CNS lymphoma (hot on PET/SPECT) from toxoplasmosis (cold) when biopsy risky (DHHS 2024 OI)
   inputs: toxoplasma_igg_serology, mri_brain_with_contrast
   actions: workup.first_seizure
   advance: empiric-trial-vs-biopsy decision made
7. 7DIFFERENTIAL
   Toxoplasmosis vs primary CNS lymphoma (single lesion + Toxo IgG-negative + hot on FDG-PET / Th-201 SPECT / EBV-positive CSF → lymphoma) vs tuberculoma (TB-endemic exposure + basal enhancement + chest findings) vs cryptococcoma (CrAg + India ink) vs bacterial brain abscess (acute course + parameningeal source) vs PML (no enhancement typically, white matter) vs HIV encephalopathy (DHHS 2024 OI; Luft/Remington PMID 1520757; Atreya Int J STD AIDS 2013 PMID 24108450)
   advance: differential mapped + alternative diagnosis sufficiently excluded
8. 8RISK_STRATIFICATION
   Severity tier per lesion burden + mass effect + CD4 (severe if CD4 < 50 + multifocal + mass effect) + transplant status (transplant recipients have higher mortality and lower threshold for biopsy + ICU); empiric trial response is dichotomous (responder vs non-responder at 10-14 d) — non-responders must escalate to biopsy (DHHS 2024 OI)
   inputs: cd4_count, mass_effect_or_herniation_features
   actions: calc.ckd_epi_2021
   advance: severity tier + empiric-trial-response milestone defined
9. 9TREATMENT
   Induction × ≥6 wk (longer if not improving): First-line Pyr-Sdz-leucovorin = pyrimethamine 200 mg PO load → 75-100 mg PO daily + sulfadiazine 1.5 g PO q6h (1.0 g if < 60 kg) + leucovorin 10-25 mg PO daily; Sulfa-allergy alternative Pyr-Cm-leucovorin = pyrimethamine same + clindamycin 600 mg PO/IV q6h + leucovorin (Katlama PMID 8838183 — Pyr-Cm acceptable but higher relapse rate at maintenance); Pyrimethamine-unavailable / resource-limited alternative = TMP-SMX 5 mg/kg TMP IV/PO BID; Atovaquone-based regimens for salvage / intolerance (atovaquone 1500 mg PO BID with food + pyrimethamine + leucovorin OR atovaquone + sulfadiazine); Adjunctive dexamethasone ONLY when mass effect/edema/herniation — avoid otherwise (confounds response assessment); seizure prophylaxis with levetiracetam if seized; ART continuation (or initiation within ~2 wk of induction in ART-naive — DHHS 2024 OI); reduce IS in SOT/HSCT where feasible (DHHS 2024 OI; Dannemann PMID 1727093; Katlama PMID 8838183; Caumes PMID 8527561; Luft/Remington PMID 1520757)
   inputs: sulfa_allergy_status, creatinine, cbc
   advance: pathogen-specific induction regimen started; renal + hematologic monitoring scheduled; sulfa-allergy + steroid-indication addressed
10. 10DISPOSITION
    Inpatient for IV induction in severe / mass-effect / NPO / transplant-recipient; outpatient PO induction acceptable for stable HIV ambulatory patient + reliable follow-up + no mass effect; transition (post-hospital) for IV-to-PO switch + arranging maintenance + secondary prophylaxis + ART optimization (DHHS 2024 OI)
    advance: level of care + transition plan set
11. 11MONITORING
    Clinical response (resolution of focal deficit + AMS) at d 7-14; repeat MRI at 2-4 wk for radiographic response (lesion regression, enhancement decrease); CBC weekly (myelosuppression — anemia/neutropenia/thrombocytopenia — leucovorin titrate up to 25-50 mg daily if cytopenia); creatinine weekly (sulfadiazine crystalluria + AKI); LFT every 2 wk; CD4 + VL trending (HIV); IRIS surveillance ~2-8 wk after ART start (DHHS 2024 OI; Dannemann PMID 1727093)
    inputs: cbc, creatinine
    actions: panel.cbc, panel.renal, panel.lft, panel.inflammation
    advance: clinical + radiographic improvement at 10-14 d documented OR escalation to biopsy / regimen change triggered
12. 12FOLLOWUP
    Maintenance / secondary prophylaxis after ≥6 wk induction: pyrimethamine 25-50 mg PO daily + sulfadiazine 2-4 g/day (in divided doses) + leucovorin 10-25 mg daily (OR pyrimethamine + clindamycin + leucovorin for sulfa-allergic) OR atovaquone 750-1500 mg PO BID; Discontinue secondary prophylaxis when CD4 > 200 × 6 mo on suppressive ART + clinically asymptomatic (DHHS 2024 OI); Primary prophylaxis re-initiate / continue when HIV CD4 < 100 + Toxo IgG+ — TMP-SMX 1 SS PO daily (same as PJP prophylaxis); Transplant recipients: prophylaxis per protocol (TMP-SMX is standard PJP + toxo + Nocardia prophylaxis post-SOT/HSCT). Lifelong ophtho + neurology surveillance for sequelae (DHHS 2024 OI; Luft/Remington PMID 1520757)
    advance: maintenance + prophylaxis plan + ART optimization documented; CD4 + VL trending; sequelae surveillance scheduled