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id.cryptococcal-meningitis.v1PRODUCTION
id.cryptococcal-meningitis.v1

Cryptococcal meningitis (HIV-associated and non-HIV)

infectious_diseaseacutesubacuteadult
Hard-required inputs
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Care setting:

Encounter flow

12/12 authored

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

Current phase

Frame

Detailed

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.

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Advance rule
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Advance when

host substrate + scope confirmed (WHO 2022; IDSA 2010 Perfect)

Patient inputs (14)

CD4 < 100 defines highest-risk host and drives CrAg screening + maintenance discontinuation thresholds (WHO 2022; DHHS 2024 OI)

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)

Fever is commonly subtle / absent in advanced HIV; presence supports active infection vs colonisation (WHO 2022)

Serum CrAg LFA sensitivity ~95-99% — positive in nearly all HIV-associated cryptococcal meningitis; lower in non-HIV (WHO 2022; IDSA 2010 Perfect)

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 titer > 1:1024 / 1:1280 marks high fungal burden and severe disease (IDSA 2010 Perfect; WHO 2022)

Gold standard; quantitative culture (CFU/mL) drives sterilisation assessment at 2-wk repeat LP (IDSA 2010 Perfect)

Flucytosine TDM target peak 30-80 µg/mL; toxicity > 100 → bone-marrow suppression; AmB also myelosuppressive (IDSA 2010 Perfect)

GCS < 14 portends raised ICP / impending herniation; mandates CT before LP and ICU disposition (IDSA 2010 Perfect; Graybill CID 2000)

Amphotericin B nephrotoxicity (especially deoxycholate); flucytosine renal dosing; tenofovir co-exposure compounds risk (IDSA 2010 Perfect; AMBITION Jarvis NEJM 2022)

Cryptococcoma, hydrocephalus, basilar enhancement, infarct from cryptococcal vasculopathy (IDSA 2010 Perfect)

India ink sens 60-80% (lower than CrAg LFA) — rapid bedside support when LFA unavailable (WHO 2022)

Required before LP if GCS < 14, focal deficit, papilledema, new seizure, or immunocompromise (IDSA 2010 Perfect)

Fluconazole hepatotoxicity monitoring during 8-wk consolidation + maintenance (IDSA 2010 Perfect)

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

Severity triggers (7)

7 need judgement
  • informationallife_threateningseverely_elevated_opening_pressure
    CSF opening pressure ≥ 250 mmH2O (25 cmH2O) on initial LP, OR any OP elevation with papilledema / CN VI palsy / vision change / GCS drop (Graybill CID 2000 PMID 10619732; IDSA 2010 Perfect)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverehigh_csf_crag_titer_or_fungal_burden
    CSF CrAg titer ≥ 1:1024 / 1:1280, or positive blood cryptococcal culture (fungaemia), or cryptococcoma on imaging (IDSA 2010 Perfect)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverealtered_mental_status_or_focal_deficit
    GCS < 14, focal neurologic deficit, papilledema, new seizure, or cryptococcoma on imaging (IDSA 2010 Perfect)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverenon_hiv_non_immunocompromised_c_gattii
    Cryptococcus gattii in apparently immunocompetent host (Pacific NW, Vancouver Island, tropical / sub-tropical regions) — more virulent, more cryptococcomas, slower CSF clearance (IDSA 2010 Perfect; Galanis CDC 2010)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecryptococcal_iris_post_art
    Worsening clinical features (headache, AMS, vision change, new mass effect on imaging) 1-4 wk after ART initiation in HIV-associated cryptococcal meningitis, with sterile CSF (paradoxical IRIS) (DHHS 2024 OI; Boulware COAT NEJM 2014 PMID 24963568)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepregnancy_in_cryptococcal_meningitis
    Cryptococcal meningitis diagnosed during pregnancy — alters drug choice (high-dose fluconazole teratogenic first trimester; flucytosine animal teratogenicity) (IDSA 2010 Perfect)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatecrag_screen_positive_no_meningitis
    Asymptomatic CrAg+ at HIV diagnosis with CD4 < 200 and no meningitis on LP — eligible for pre-emptive fluconazole per WHO 2022 screen-and-treat pathway (WHO 2022)
    Trigger could not be auto-evaluated — needs clinician judgement.

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Recommended regimen

Cryptococcal meningitis induction → consolidation → maintenance ladder (WHO 2022; IDSA 2010 Perfect; AMBITION 2022; ACTA 2018)
axis: cryptococcal_induction_consolidation_maintenance
Selected axis "Cryptococcal meningitis induction → consolidation → maintenance ladder (WHO 2022; IDSA 2010 Perfect; AMBITION 2022; ACTA 2018)" by default fallback (first axis)
  • liposomal amphotericin B
    first line
    polyene_antifungal
    AMBITION: 10 mg/kg IV × 1 dose (single-dose induction). Alternative 2-wk induction: 3-4 mg/kg IV daily × 14 d. • IV • single dose (AMBITION) OR daily × 14 d
    triggers: hiv_cryptococcal_meningitis_induction, non_hiv_cryptococcal_induction, pregnancy_safer_amphotericin_choice
    AMBITION Jarvis NEJM 2022 PMID 35320642 — single-dose L-AmB + flucytosine + fluconazole non-inferior to 7-d L-AmB regimen; 10-wk mortality 24.8% vs 28.7%; less nephrotoxicity / anaemia. Preferred where flucytosine available (WHO 2022 Strong recommendation).
    rxcui 236594
  • amphotericin B deoxycholate
    second line
    polyene_antifungal
    0.7-1 mg/kg IV daily × 14 d (combined with flucytosine) • IV • daily × 14 d
    triggers: liposomal_amphotericin_unavailable, resource_limited_setting
    IDSA 2010 Perfect — historical standard; more nephrotoxic + infusion reactions; preferred only when L-AmB unavailable. Pre-medicate acetaminophen + meperidine for chills. Day NEJM 2013 PMID 23550668 demonstrated AmB + flucytosine combination improves survival vs AmB monotherapy (HR 0.61 at 70 d).
    rxcui 732
  • flucytosine
    first line
    antimetabolite_antifungal
    100 mg/kg/day PO divided q6h × 14 d (AMBITION + IDSA induction) • PO • q6h × 14 d
    triggers: cryptococcal_induction_combination_with_amphotericin, cryptococcal_induction_combination_with_high_dose_fluconazole_acta
    IDSA 2010 Perfect + AMBITION Jarvis NEJM 2022 + ACTA Molloy NEJM 2018 — synergistic with polyene; reduces relapse + improves CSF sterilisation. TDM target peak 30-80 µg/mL (toxicity > 100 → bone marrow suppression). Renal-adjust per CrCl.
    rxcui 4451
  • fluconazole
    first line
    azole
    Induction (AMBITION + ACTA): 1200 mg PO daily × 14 d. Consolidation: 800 mg PO daily × 8 wk. Maintenance / secondary prophylaxis: 200 mg PO daily. • PO • daily
    triggers: cryptococcal_induction_high_dose_with_flucytosine_acta_or_ambition, cryptococcal_consolidation_8wk, cryptococcal_maintenance_until_CD4_recovery, crag_screen_positive_preemptive_therapy_who_2022
    AMBITION Jarvis NEJM 2022 PMID 35320642 + ACTA Molloy NEJM 2018 PMID 29539274 — 1200 mg/d component of high-dose oral / single-dose-AmB regimens. Consolidation 800 mg × 8 wk per IDSA 2010 Perfect. Maintenance 200 mg/d until immune recovery (CD4 > 200 × 12 mo on ART) per WHO 2022.
    rxcui 4450
  • voriconazole
    rescue
    azole
    6 mg/kg IV q12h × 2 doses load then 4 mg/kg q12h; TDM trough 2-5 µg/mL for CNS • IV/PO • q12h
    triggers: fluconazole_resistant_cryptococcus, cryptococcal_meningitis_relapse_on_fluconazole_maintenance, cryptococcoma_refractory
    IDSA 2010 Perfect — rescue option for refractory / azole-resistant disease; CNS-penetrating with TDM 2-5 µg/mL trough target. Limited large-RCT data in cryptococcal-specific use.
    rxcui 121243
  • isavuconazonium
    rescue
    azole
    200 mg IV/PO q8h × 6 doses load then 200 mg daily • IV/PO • daily after load
    triggers: azole_alternative_with_calcineurin_inhibitor_ddi, voriconazole_intolerant
    No prospective RCT for cryptococcal meningitis; salvage option per IDSA 2010 + ECIL series; fewer DDIs than voriconazole; no QTc prolongation.
    rxcui 1608322
  • acetazolamide
    contraindication substitute
    carbonic_anhydrase_inhibitor
    NOT recommended for cryptococcal raised ICP • n/a • n/a
    triggers: historical_only_do_not_use_for_cryptococcal_icp
    IDSA 2010 Perfect + WHO 2022 — acetazolamide, mannitol, hypertonic saline, and corticosteroids NOT effective for cryptococcal raised ICP and may worsen outcomes (Newton Lancet 2002 reported harm with acetazolamide; CRYPTODEX Beardsley NEJM 2016 showed worse outcomes with adjunctive dexamethasone). Therapeutic LP is the evidence-based intervention.
    rxcui 167
  • dexamethasone
    contraindication substitute
    corticosteroid
    NOT recommended for routine cryptococcal meningitis; consider only for severe IRIS • IV/PO • per IRIS protocol if used
    triggers: severe_cryptococcal_iris_with_clinical_decompensation_post_art
    CRYPTODEX Beardsley NEJM 2016 demonstrated harm (higher 6-mo mortality + more disability + adverse events) with adjunctive dexamethasone in induction; therefore NOT used routinely. Reserved for documented severe cryptococcal IRIS with clinical decompensation after ART initiation, per DHHS 2024 OI; preferred initial step is NSAIDs ± continued antifungals while continuing ART.
    rxcui 3264

outpatient playbook — drug actions (4)

  1. 1. fluconazole 800 mg consolidation
    rxcui 4450
    800 mg PO daily × 8 wk total • PO • daily
    trigger: Discharge with CSF sterile at 2 wk
    IDSA 2010 Perfect — 8-wk consolidation reduces relapse
  2. 2. fluconazole 200 mg maintenance
    rxcui 4450
    200 mg PO daily • PO • daily
    trigger: Completion of 8-wk consolidation
    WHO 2022 + DHHS 2024 OI — continue until CD4 > 200 × 12 mo + VL suppressed on ART (HIV); lifelong in some non-HIV scenarios per host trajectory
  3. 3. ART initiation (HIV) at 4-6 wk
    Per HIV core dossier — bictegravir/TAF/FTC or DTG/3TC etc. • PO • daily
    trigger: HIV+ with cryptococcal meningitis; complete 4-6 wk of induction + consolidation before ART start
    COAT Boulware NEJM 2014 PMID 24963568 — earlier ART (within 1-2 wk) was associated with higher mortality; defer 4-6 wk to reduce IRIS mortality
  4. 4. CrAg pre-emptive fluconazole (parallel pathway)
    rxcui 4450
    800 mg PO daily × 2 wk → 400 mg/d × 8 wk → 200 mg/d until immune recovery • PO • daily
    trigger: Asymptomatic CrAg+ at HIV diagnosis with CD4 < 200 + no meningitis on LP
    WHO 2022 CrAg screen-and-treat pathway — pre-emptive fluconazole reduces progression to symptomatic cryptococcal meningitis

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Subacute headache + fever in HIV / immunocompromised host (1-2 wk evolution) (WHO 2022; IDSA 2010 Perfect); AMS over days-weeks in CD4 < 100 or transplant recipient (WHO 2022; DHHS 2024 OI); Visual obscurations / diplopia / papilledema / CN VI palsy — elevated ICP phenotype (Graybill CID 2000 PMID 10619732).

Objective

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

Assessment

**Cryptococcal meningitis (HIV-associated and non-HIV)** (id.cryptococcal-meningitis.v1).
Phenotype framing: 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)
Scope: 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.

No severity triggers fired against current inputs.

Plan

Regimen axis: **Cryptococcal meningitis induction → consolidation → maintenance ladder (WHO 2022; IDSA 2010 Perfect; AMBITION 2022; ACTA 2018)**.
1. liposomal amphotericin B AMBITION: 10 mg/kg IV × 1 dose (single-dose induction). Alternative 2-wk induction: 3-4 mg/kg IV daily × 14 d. IV single dose (AMBITION) OR daily × 14 d (polyene_antifungal, first line) — AMBITION Jarvis NEJM 2022 PMID 35320642 — single-dose L-AmB + flucytosine + fluconazole non-inferior to 7-d L-AmB regimen; 10-wk mortality 24.8% vs 28.7%; less nephrotoxicity / anaemia. Preferred where flucytosine available (WHO 2022 Strong recommendation).
2. amphotericin B deoxycholate 0.7-1 mg/kg IV daily × 14 d (combined with flucytosine) IV daily × 14 d (polyene_antifungal, second line) — IDSA 2010 Perfect — historical standard; more nephrotoxic + infusion reactions; preferred only when L-AmB unavailable. Pre-medicate acetaminophen + meperidine for chills. Day NEJM 2013 PMID 23550668 demonstrated AmB + flucytosine combination improves survival vs AmB monotherapy (HR 0.61 at 70 d).
3. flucytosine 100 mg/kg/day PO divided q6h × 14 d (AMBITION + IDSA induction) PO q6h × 14 d (antimetabolite_antifungal, first line) — IDSA 2010 Perfect + AMBITION Jarvis NEJM 2022 + ACTA Molloy NEJM 2018 — synergistic with polyene; reduces relapse + improves CSF sterilisation. TDM target peak 30-80 µg/mL (toxicity > 100 → bone marrow suppression). Renal-adjust per CrCl.
4. fluconazole Induction (AMBITION + ACTA): 1200 mg PO daily × 14 d. Consolidation: 800 mg PO daily × 8 wk. Maintenance / secondary prophylaxis: 200 mg PO daily. PO daily (azole, first line) — AMBITION Jarvis NEJM 2022 PMID 35320642 + ACTA Molloy NEJM 2018 PMID 29539274 — 1200 mg/d component of high-dose oral / single-dose-AmB regimens. Consolidation 800 mg × 8 wk per IDSA 2010 Perfect. Maintenance 200 mg/d until immune recovery (CD4 > 200 × 12 mo on ART) per WHO 2022.
5. voriconazole 6 mg/kg IV q12h × 2 doses load then 4 mg/kg q12h; TDM trough 2-5 µg/mL for CNS IV/PO q12h (azole, rescue) — IDSA 2010 Perfect — rescue option for refractory / azole-resistant disease; CNS-penetrating with TDM 2-5 µg/mL trough target. Limited large-RCT data in cryptococcal-specific use.
6. isavuconazonium 200 mg IV/PO q8h × 6 doses load then 200 mg daily IV/PO daily after load (azole, rescue) — No prospective RCT for cryptococcal meningitis; salvage option per IDSA 2010 + ECIL series; fewer DDIs than voriconazole; no QTc prolongation.
7. acetazolamide NOT recommended for cryptococcal raised ICP n/a n/a (carbonic_anhydrase_inhibitor, contraindication substitute) — IDSA 2010 Perfect + WHO 2022 — acetazolamide, mannitol, hypertonic saline, and corticosteroids NOT effective for cryptococcal raised ICP and may worsen outcomes (Newton Lancet 2002 reported harm with acetazolamide; CRYPTODEX Beardsley NEJM 2016 showed worse outcomes with adjunctive dexamethasone). Therapeutic LP is the evidence-based intervention.
8. dexamethasone NOT recommended for routine cryptococcal meningitis; consider only for severe IRIS IV/PO per IRIS protocol if used (corticosteroid, contraindication substitute) — CRYPTODEX Beardsley NEJM 2016 demonstrated harm (higher 6-mo mortality + more disability + adverse events) with adjunctive dexamethasone in induction; therefore NOT used routinely. Reserved for documented severe cryptococcal IRIS with clinical decompensation after ART initiation, per DHHS 2024 OI; preferred initial step is NSAIDs ± continued antifungals while continuing ART.

Setting playbook (outpatient) — Consolidation (8 wk fluconazole 800 mg) → maintenance / secondary prophylaxis (fluconazole 200 mg/d) until CD4 > 200 × 12 mo + VL suppressed on ART (HIV) or host immune-recovery; ART initiation at 4-6 wk in HIV (COAT); ophtho + audiology + cognitive surveillance for sequelae; relapse vigilance
9. fluconazole 800 mg consolidation 800 mg PO daily × 8 wk total PO daily — Discharge with CSF sterile at 2 wk (IDSA 2010 Perfect — 8-wk consolidation reduces relapse)
10. fluconazole 200 mg maintenance 200 mg PO daily PO daily — Completion of 8-wk consolidation (WHO 2022 + DHHS 2024 OI — continue until CD4 > 200 × 12 mo + VL suppressed on ART (HIV); lifelong in some non-HIV scenarios per host trajectory)
11. ART initiation (HIV) at 4-6 wk Per HIV core dossier — bictegravir/TAF/FTC or DTG/3TC etc. PO daily — HIV+ with cryptococcal meningitis; complete 4-6 wk of induction + consolidation before ART start (COAT Boulware NEJM 2014 PMID 24963568 — earlier ART (within 1-2 wk) was associated with higher mortality; defer 4-6 wk to reduce IRIS mortality)
12. CrAg pre-emptive fluconazole (parallel pathway) 800 mg PO daily × 2 wk → 400 mg/d × 8 wk → 200 mg/d until immune recovery PO daily — Asymptomatic CrAg+ at HIV diagnosis with CD4 < 200 + no meningitis on LP (WHO 2022 CrAg screen-and-treat pathway — pre-emptive fluconazole reduces progression to symptomatic cryptococcal meningitis)

Non-pharmacologic actions:
- Counsel on cryptococcal exposure avoidance (pigeon droppings, eucalyptus / oak debris for C. gattii in endemic regions)
- ART adherence counselling (HIV) — sustained viral suppression is the key to durable cure
- Pet / environmental counselling for immunocompromised — bird droppings particularly
- Functional recovery: physical / occupational therapy if persistent deficit from acute course
- Mental health screening — post-critical-illness depression + PTSD common
- Driving restrictions if seizure occurred during admission (per local regulations)
- Patient + family education on relapse signs — fever, headache, AMS, vision change → ED

AVOID / contraindication checks:
- Amphotericin deoxycholate nephrotoxicity monitor creatinine K Mg pre medicate acetaminophen meperidine (IDSA 2010 Perfect)
- Liposomal amphotericin preferred when available less nephrotoxic (WHO 2022; AMBITION 2022)
- Flucytosine TDM target peak 30 80 toxicity bone marrow above 100 (IDSA 2010 Perfect)
- Flucytosine renal dose adjust per CrCl (DailyMed flucytosine label)
- Fluconazole pregnancy category D at high dose avoid first trimester (FDA / DailyMed)
- Fluconazole QTc prolongation DDI with amiodarone methadone (DailyMed)
- Fluconazole warfarin tacrolimus cyclosporine statin rifampin phenytoin DDI monitor (DailyMed)
- Do not use acetazolamide or mannitol for cryptococcal raised ICP (IDSA 2010 Perfect; Newton Lancet 2002)
- Do not use adjunctive dexamethasone during induction (CRYPTODEX Beardsley NEJM 2016)
- Defer ART 4 to 6 weeks in HIV to avoid cryptococcal IRIS mortality (COAT Boulware NEJM 2014 PMID 24963568)
- Voriconazole isavuconazole CYP3A4 DDI with calcineurin inhibitor reduce dose by 50pct (IDSA 2016)

Monitoring

Regimen monitoring:
- therapeutic LP daily or q48h until OP <200 mmH2O or 50pct reduction (Graybill CID 2000 PMID 10619732; IDSA 2010 Perfect)
- creatinine K Mg q48h during AmB induction (IDSA 2010 Perfect)
- CBC twice weekly during flucytosine AmB induction (IDSA 2010 Perfect)
- flucytosine TDM peak 30-80 µg mL during induction (IDSA 2010 Perfect)
- repeat LP at 2 weeks for CSF culture sterilisation before consolidation transition (IDSA 2010 Perfect)
- LFT monthly during fluconazole consolidation and maintenance (IDSA 2010 Perfect)
- CrAg titer serial during maintenance for relapse detection (IDSA 2010 Perfect)
- CD4 VL q3mo HIV to decide maintenance discontinuation (CD4 >200 x 12mo + VL suppressed) (WHO 2022; DHHS 2024 OI)
- IRIS surveillance 1-4 weeks post ART initiation (DHHS 2024 OI; COAT 2014)

Setting (outpatient) monitoring:
- CrAg titer at end of induction, end of consolidation, q3-6 mo during maintenance — rising titer prompts re-LP
- CD4 + VL q3 mo (HIV); maintenance discontinuation when CD4 > 200 × 12 mo + VL suppressed (WHO 2022)
- LFT monthly during consolidation; q3 mo during maintenance
- IRIS surveillance 1-4 wk post-ART (DHHS 2024 OI; COAT NEJM 2014)
- Annual audiology + ophthalmology in survivors with cranial neuropathy / vision loss (IDSA 2010 Perfect)

Follow-up plan: 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)
- Close-out criterion: maintenance plan + ART timing + outpatient surveillance documented

Monitoring phase: 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)

Disposition

Current setting: outpatient — Consolidation (8 wk fluconazole 800 mg) → maintenance / secondary prophylaxis (fluconazole 200 mg/d) until CD4 > 200 × 12 mo + VL suppressed on ART (HIV) or host immune-recovery; ART initiation at 4-6 wk in HIV (COAT); ophtho + audiology + cognitive surveillance for sequelae; relapse vigilance

Disposition criteria:
- Maintenance discontinuation (HIV): CD4 > 200 × 12 mo + VL suppressed on ART × ≥ 3 mo + asymptomatic + sterile CSF if re-LP (WHO 2022; DHHS 2024 OI)
- Non-HIV: discontinuation per host trajectory in consultation with ID + primary team (IDSA 2010 Perfect)

Escalation triggers (move to higher acuity):
- Relapse signs (fever + headache + neck stiffness + AMS) → ED for re-LP + restart induction (IDSA 2010 Perfect)
- Rising CrAg titer + symptoms → urgent re-LP + culture (IDSA 2010 Perfect)
- Vision loss / cranial neuropathy progression → emergent ophtho + neurology + therapeutic LP (Graybill CID 2000)
- Severe IRIS 1-4 wk post-ART start → ED for steroid course consideration + ID consult (DHHS 2024 OI)
- Pregnancy during maintenance → switch fluconazole to L-AmB during first trimester (teratogenicity risk; IDSA 2010 Perfect)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] CSF opening pressure ≥ 250 mmH2O (25 cmH2O) on initial LP, OR any OP elevation with papilledema / CN VI palsy / vision change / GCS drop (Graybill CID 2000 PMID 10619732; IDSA 2010 Perfect)
- [SEVERE] CSF CrAg titer ≥ 1:1024 / 1:1280, or positive blood cryptococcal culture (fungaemia), or cryptococcoma on imaging (IDSA 2010 Perfect)
- [SEVERE] GCS < 14, focal neurologic deficit, papilledema, new seizure, or cryptococcoma on imaging (IDSA 2010 Perfect)

Citations

- WHO 2022 Guidelines for diagnosing, preventing and managing cryptococcal disease + IDSA 2010 (Perfect) Clinical Practice Guidelines for the Management of Cryptococcal Disease + DHHS / CDC / IDSA OI Guidelines (clinicalinfo.hiv.gov 2024 web edition) — anchored by AMBITION 2022, ACTA 2018, COAT 2014, Day 2013, and Graybill 2000 pivotal trials [PMID:20047480](https://pubmed.ncbi.nlm.nih.gov/20047480/)
- Cited evidence (PMID 35320642) [PMID:35320642](https://pubmed.ncbi.nlm.nih.gov/35320642/)
- Cited evidence (PMID 29539274) [PMID:29539274](https://pubmed.ncbi.nlm.nih.gov/29539274/)
- Cited evidence (PMID 24963568) [PMID:24963568](https://pubmed.ncbi.nlm.nih.gov/24963568/)
- Cited evidence (PMID 23550668) [PMID:23550668](https://pubmed.ncbi.nlm.nih.gov/23550668/)

Last reconciled with current guidelines: 2026-05-26.
References
  • WHO 2022 Guidelines for diagnosing, preventing and managing cryptococcal disease + IDSA 2010 (Perfect) Clinical Practice Guidelines for the Management of Cryptococcal Disease + DHHS / CDC / IDSA OI Guidelines (clinicalinfo.hiv.gov 2024 web edition) — anchored by AMBITION 2022, ACTA 2018, COAT 2014, Day 2013, and Graybill 2000 pivotal trials — PMID:20047480
  • Cited evidence (PMID 35320642) — PMID:35320642
  • Cited evidence (PMID 29539274) — PMID:29539274
  • Cited evidence (PMID 24963568) — PMID:24963568
  • Cited evidence (PMID 23550668) — PMID:23550668