id.cryptococcal-meningitis.v1

Cryptococcal meningitis (HIV-associated and non-HIV)

infectious_diseaseacutesubacuteadultacuteinpatientoutpatienttransition

Start encounter →Print handoutPRODUCTION

Cryptococcal meningitis dossier built end-to-end as INTEGRATED for Lane F id-neuro-acute wave (2026-05-26). Covers HIV-associated (dominant global burden) and non-HIV (SOT, biologic, idiopathic CD4 lymphopenia, C. gattii in immunocompetent). Evidence anchors: WHO 2022 + IDSA 2010 Perfect (PMID 20047480) + AMBITION 2022 (Jarvis NEJM 35320642) + ACTA 2018 (Molloy NEJM 29539274) + COAT 2014 (Boulware NEJM 24963568) + Day 2013 (NEJM 23550668) + Graybill 2000 (CID 10619732) + Rajasingham 2017 burden (Lancet ID 28483415). All 7 PMIDs PubMed-live-verified 2026-05-26. RxNav live-verified 2026-05-26 catches: amphotericin B 596 (=alprazolam) -> 732; flucytosine 4493 (=fluoxetine) -> 4451; voriconazole 313802 (empty) -> 121243; isavuconazonium 1664757 (empty) -> 1608322. liposomal-amphotericin 236594, fluconazole 4450, acetazolamide 167, dexamethasone 3264 verified correct from prompt seeds. Adjunctive dexamethasone explicitly NOT used in induction per CRYPTODEX Beardsley NEJM 2016 harm signal — listed only as contraindication_substitute with carve-out for severe IRIS. Acetazolamide / mannitol / hypertonic saline also explicitly NOT used per IDSA 2010 Perfect — therapeutic LP is the evidence-based intervention. AMBITION 2022 single-dose L-AmB regimen is the WHO 2022 preferred induction when flucytosine available; 2-wk L-AmB + flucytosine is the alternative; ACTA all-oral fluconazole 1200 + flucytosine is the resource-limited fallback. Each is encoded as a distinct drug action / regimen tier. COAT NEJM 2014 ART deferral 4-6 wk is encoded as a severity-trigger-driven rule (life_threatening if violated by earlier ART start) and as a transition setting playbook decision point. Cryptococcal IRIS is its own severity trigger with NSAIDs-first guidance. Phenotype matrix (host × organism × severity × pregnancy × C. gattii vs C. neoformans × complications) encoded indirectly via severity_triggers (severely_elevated_opening_pressure, high_csf_crag_titer_or_fungal_burden, altered_mental_status_or_focal_deficit, non_hiv_non_immunocompromised_c_gattii, cryptococcal_iris_post_art, pregnancy_in_cryptococcal_meningitis, crag_screen_positive_no_meningitis). First-class TS field is schema-blocked. Cross-dossier routing: id.opportunistic-infection.hiv-transplant.v1 (parent overlay, surfaces CrAg+ trigger here); id.hiv-initial.chronic.v1 (concurrent for ART decisions); id.bacterial-meningitis.core.v1 (initial co-cover when CD4 < 100 + AMS); id.candidemia.core.v1 / id.invasive-aspergillosis.core.v1 (sibling fungal engines for differential). Gaps still open (post-INTEGRATED → PRODUCTION): manifest is a 5-line scaffold stub; protocol-runner test ladder not yet authored (single contract-depth test only); first-class phenotype + Bayesian linkage fields schema-blocked.

Entry points (7)

symptom
Subacute headache + fever in HIV / immunocompromised host (1-2 wk evolution) (WHO 2022; IDSA 2010 Perfect)
subacute_headache_with_fever
symptom
AMS over days-weeks in CD4 < 100 or transplant recipient (WHO 2022; DHHS 2024 OI)
altered_mental_status_in_immunocompromised
symptom
Visual obscurations / diplopia / papilledema / CN VI palsy — elevated ICP phenotype (Graybill CID 2000 PMID 10619732)
visual_changes_papilledema_cn_vi_palsy
lab_abnormality
Serum CrAg LFA positive in CD4 < 100 — reflex LP (WHO 2022; DHHS 2024 OI)
serum_crag_positive
lab_abnormality
CSF lymphocytic pleocytosis with low glucose in immunocompromised host (IDSA 2010 Perfect)
csf_lymphocytic_pleocytosis_in_immunocompromised
imaging
Cryptococcoma / basilar enhancement on MRI brain (IDSA 2010 Perfect)
cryptococcoma_on_mri
problem_list
New HIV diagnosis with CD4 < 200 — eligible for CrAg screening and pre-emptive fluconazole (WHO 2022 CrAg screen-and-treat)
cd4_below_100_no_crag_screening

Required inputs (14)

hiv_status_and_cd4required
history • used at CONTEXT
CD4 < 100 defines highest-risk host and drives CrAg screening + maintenance discontinuation thresholds (WHO 2022; DHHS 2024 OI)
immunocompromise_substraterequired
history • used at CONTEXT
Non-HIV hosts: SOT, malignancy, biologic-DMARD, chronic steroids, idiopathic CD4 lymphopenia, C. gattii environmental exposure — alters induction choice and ART carve-out (IDSA 2010 Perfect)
temperaturerequired
vital • used at CONTEXT
Fever is commonly subtle / absent in advanced HIV; presence supports active infection vs colonisation (WHO 2022)
gcsrequired
symptom • used at RED_FLAGS
GCS < 14 portends raised ICP / impending herniation; mandates CT before LP and ICU disposition (IDSA 2010 Perfect; Graybill CID 2000)
serum_crag_lfarequired
lab • used at INITIAL_WORKUP
Serum CrAg LFA sensitivity ~95-99% — positive in nearly all HIV-associated cryptococcal meningitis; lower in non-HIV (WHO 2022; IDSA 2010 Perfect)
csf_opening_pressurerequired
lab • used at INITIAL_WORKUP
Opening pressure ≥ 250 mmH2O (25 cmH2O) defines severely-elevated ICP — single most important predictor of survival; therapeutic LP indicated (Graybill CID 2000 PMID 10619732)
csf_crag_titerrequired
lab • used at INITIAL_WORKUP
CSF CrAg titer > 1:1024 / 1:1280 marks high fungal burden and severe disease (IDSA 2010 Perfect; WHO 2022)
csf_culture_fungalrequired
lab • used at INITIAL_WORKUP
Gold standard; quantitative culture (CFU/mL) drives sterilisation assessment at 2-wk repeat LP (IDSA 2010 Perfect)
csf_india_ink
lab • used at INITIAL_WORKUP
India ink sens 60-80% (lower than CrAg LFA) — rapid bedside support when LFA unavailable (WHO 2022)
creatininerequired
lab • used at TREATMENT
Amphotericin B nephrotoxicity (especially deoxycholate); flucytosine renal dosing; tenofovir co-exposure compounds risk (IDSA 2010 Perfect; AMBITION Jarvis NEJM 2022)
cbc_with_diffrequired
lab • used at MONITORING
Flucytosine TDM target peak 30-80 µg/mL; toxicity > 100 → bone-marrow suppression; AmB also myelosuppressive (IDSA 2010 Perfect)
lft
lab • used at MONITORING
Fluconazole hepatotoxicity monitoring during 8-wk consolidation + maintenance (IDSA 2010 Perfect)
ct_head_pre_lp
imaging • used at INITIAL_WORKUP
Required before LP if GCS < 14, focal deficit, papilledema, new seizure, or immunocompromise (IDSA 2010 Perfect)
mri_brain_with_contrast
imaging • used at BRANCHING_WORKUP
Cryptococcoma, hydrocephalus, basilar enhancement, infarct from cryptococcal vasculopathy (IDSA 2010 Perfect)

12-phase flow (12)

1FRAME
Adult cryptococcal meningitis covering HIV-associated (dominant burden in sub-Saharan Africa) and non-HIV (SOT, malignancy, biologic-DMARD, idiopathic CD4 lymphopenia, C. gattii in immunocompetent). Paediatric and pulmonary-only cryptococcosis are out of scope — flag for siblings.
inputs: immunocompromise_substrate
advance: host substrate + scope confirmed (WHO 2022; IDSA 2010 Perfect)
2ENTRY
Subacute headache + fever + AMS in immunocompromised host, OR positive serum CrAg LFA, OR visual obscurations / CN VI palsy from raised ICP. CrAg pre-emptive screen-and-treat pathway when CD4 < 200 (WHO 2022 CrAg screening Strong recommendation)
inputs: hiv_status_and_cd4, temperature
advance: entry trigger validated (WHO 2022)
3CONTEXT
Document CD4, HIV viral load, ART history, transplant type / time-from-transplant, current immunosuppression, prior cryptococcal disease, prior fluconazole exposure (azole-resistance risk), travel / environmental exposures (C. gattii in PNW / Vancouver Island), pregnancy status (alters AmB choice + fluconazole teratogenicity)
inputs: hiv_status_and_cd4, immunocompromise_substrate
advance: host risk profile + prior antifungals documented
4RED_FLAGS
Raised ICP / impending herniation (Cushing reflex, papilledema, CN VI palsy, GCS drop, OP ≥ 250 mmH2O), septic shock (rare but described), refractory seizure, vision loss from optic neuropathy; severe CrAg titer > 1:1280 + AMS predict early mortality (Graybill CID 2000 PMID 10619732; IDSA 2010 Perfect)
inputs: gcs, csf_opening_pressure
actions: calc.qsofa
advance: life-threatening features triggered if present; therapeutic LP planned if OP ≥ 250 mmH2O
5INITIAL_WORKUP
Serum CrAg LFA + CT head (if GCS < 14 / focal / papilledema / new seizure / immunocompromise) → LP with opening pressure + CSF CrAg + India ink + fungal culture + cell count + glucose + protein; CBC + BMP + LFT baseline for AmB / flucytosine toxicity. HIV testing if status unknown; CD4 + VL if HIV+.
inputs: serum_crag_lfa, csf_opening_pressure, csf_crag_titer, csf_culture_fungal, creatinine
actions: panel.csf, panel.cbc, panel.renal
advance: CSF CrAg / culture / opening pressure documented; empiric induction not delayed for results in unstable patient
6BRANCHING_WORKUP
MRI brain with contrast for cryptococcoma / hydrocephalus / basilar enhancement / infarct; HIV testing reflex if status unknown; CD4 + VL + ART history; immunoglobulin levels + lymphocyte subsets in apparently immunocompetent (idiopathic CD4 lymphopenia, GM-CSF autoantibodies); C. gattii speciation in non-HIV / immunocompetent
inputs: mri_brain_with_contrast
actions: workup.hiv_initial
advance: species + host profile + complications mapped
7DIFFERENTIAL
TB meningitis (subacute, lymphocytic, basilar enhancement, GeneXpert MTB/RIF, ADA), bacterial meningitis (acute, neutrophilic — separate engine), viral encephalitis (HSV PCR), neurocysticercosis (endemic, cysts on MRI), CNS lymphoma (ring-enhancing, EBV+ in HIV), cerebral toxoplasmosis (multiple ring-enhancing, Toxo-IgG+ in HIV CD4 < 100), neurosyphilis (RPR + CSF VDRL), Nocardia (immunocompromised, slow-growing). Cryptococcoma vs lymphoma vs toxoplasmosis distinction may require empiric trial + biopsy (WHO 2022; IDSA 2010 Perfect)
advance: cryptococcal vs alternative dx resolved by CrAg / culture / imaging trajectory
8RISK_STRATIFICATION
Severe disease markers: opening pressure ≥ 250 mmH2O, CSF CrAg titer ≥ 1:1024, CD4 < 50, altered mental status, cryptococcoma, focal neurologic deficit, positive blood culture (fungaemia), non-HIV non-immunocompromised C. gattii (more virulent), pregnancy. Severe → ICU + aggressive therapeutic LP + AMBITION or 2-wk L-AmB + flucytosine induction (IDSA 2010 Perfect; AMBITION Jarvis NEJM 2022; Graybill CID 2000)
inputs: gcs, csf_opening_pressure, csf_crag_titer
actions: calc.qsofa
advance: severity tier assigned + induction regimen selected
9TREATMENT
Induction → consolidation → maintenance. Preferred induction (HIV with flucytosine available): AMBITION — single-dose liposomal AmB 10 mg/kg IV × 1 + flucytosine 100 mg/kg/d PO × 14 d + fluconazole 1200 mg/d PO × 14 d (Jarvis NEJM 2022 PMID 35320642 — non-inferior, less toxic, cheaper; preferred by WHO 2022). Alternative induction: L-AmB 3-4 mg/kg/d IV × 2 wk + flucytosine 100 mg/kg/d × 2 wk OR AmB deoxycholate 0.7-1 mg/kg/d + flucytosine. ACTA-style oral induction (fluconazole 1200 mg/d + flucytosine 100 mg/kg/d × 2 wk) where no AmB available (Molloy NEJM 2018 PMID 29539274). Consolidation: fluconazole 800 mg/d × 8 wk. Maintenance: fluconazole 200 mg/d until CD4 > 200 × 12 mo sustained on ART (HIV) or per host immune-recovery. ART deferred 4-6 wk in HIV+ to avoid IRIS (COAT NEJM 2014 PMID 24963568). Therapeutic LP daily-q48h until OP < 200 mmH2O or 50% reduction (Graybill CID 2000 PMID 10619732). Acetazolamide / mannitol / steroids NOT effective for cryptococcal ICP and may worsen outcomes (IDSA 2010 Perfect)
inputs: creatinine, csf_opening_pressure
advance: induction regimen running + therapeutic LP plan in place + ART timing addressed
10DISPOSITION
ICU for GCS ≤ 12, refractory raised ICP needing q24h LP / EVD, septic shock, respiratory failure; ward for stable HIV-associated with OP < 250 mmH2O and good response; OPAT-eligible for consolidation phase oral fluconazole only after sterile follow-up CSF + clinical improvement (IDSA 2010 Perfect; AST IDCOP 2024 for transplant)
inputs: gcs, csf_opening_pressure
advance: level of care set; consolidation transition plan documented
11MONITORING
Daily-q48h therapeutic LP until OP < 200 mmH2O; CBC + BMP + LFT q48h during AmB induction (AmB-deoxycholate Cr / K / Mg; L-AmB CBC); flucytosine TDM peak 30-80 µg/mL (avoid > 100); fluconazole CBC + LFT during consolidation; repeat LP at 2 wk for CSF sterilisation (negative culture marks transition to consolidation); CrAg titer trajectory during maintenance; IRIS surveillance 1-4 wk after ART initiation (DHHS 2024 OI; IDSA 2010 Perfect; AMBITION Jarvis NEJM 2022)
inputs: creatinine, cbc_with_diff, lft
actions: panel.renal, panel.cbc, panel.lft
advance: 2-wk CSF sterile + clinical improvement + no acute toxicity → consolidation
12FOLLOWUP
Outpatient ID + HIV / transplant clinic q1-2 wk during consolidation, q monthly during maintenance; serial neurologic + visual + audiologic exam; ART initiation at 4-6 wk if HIV (COAT NEJM 2014); discontinue maintenance fluconazole when CD4 > 200 × 12 mo + VL suppressed on ART; vaccinations per ACIP; counsel C. gattii / pigeon-droppings exposure avoidance; relapse risk highest in first 6 mo — re-LP if clinical change (WHO 2022; IDSA 2010 Perfect; DHHS 2024 OI)
advance: maintenance plan + ART timing + outpatient surveillance documented