Multisystem Processes & Disorders

Cryptococcosis in immunocompromised hosts

Clinical Overview and When to Suspect Cryptococcosis

— Advanced HIV/AIDS with CD4 <100 (especially <50) — most classic

— Solid organ transplant recipients (kidney > liver > heart), typically 1–6 months post-transplant

— Chronic glucocorticoid use (prednisone ≥20 mg/day for >2 weeks)

— Hematologic malignancy, biologics (TNF-α inhibitors, ibrutinib, alemtuzumab), idiopathic CD4 lymphopenia

— Cirrhosis, ESRD on dialysis, sarcoidosis

— Subacute (1–4 weeks) headache, fever, malaise, personality change in a host with any of the above

— New focal neuro deficit, cranial neuropathy (especially CN VI from elevated ICP), or unexplained visual loss in HIV

— Indolent pneumonia with nodules/cavities not responding to standard antibacterials in a transplant patient

— Fungemia or skin lesions resembling molluscum contagiosum in AIDS

Cryptococcus neoformans (worldwide, pigeon droppings, immunocompromised) and C. gattii (Pacific Northwest, eucalyptus, can affect immunocompetent) are encapsulated yeasts acquired by inhalation

Spectrum: asymptomatic pulmonary colonization → pneumonia → disseminated disease → cryptococcal meningoencephalitis (the dominant Step 3 presentation)

High-risk hosts to memorize:

When to suspect on the wards/clinic:

Board pearl: In a patient with AIDS and CD4 <100 presenting with 2–4 weeks of headache plus low-grade fever and normal CT head, do an LP — cryptococcal meningitis classically has a bland CSF (few cells) but markedly elevated opening pressure

Step 3 management: Before initiating ART in newly diagnosed HIV with CD4 <100, current guidelines recommend serum cryptococcal antigen (CrAg) screening; if positive without meningitis, treat preemptively and delay ART to prevent unmasking IRIS

Mortality remains 15–30% even with treatment; early recognition is the single most modifiable factor

Presentation Patterns and Key History

— Insidious onset over 2–4 weeks (not hours like bacterial meningitis)

— Headache (75–90%), fever (often low-grade or absent), nausea, malaise

— Altered mentation, behavioral change, memory loss — families notice "he's just not himself"

— Neck stiffness present in only ~25% — absence of meningismus does not exclude diagnosis

— Visual changes, diplopia, hearing loss → reflect raised ICP and cranial nerve involvement

— Cough, dyspnea, pleuritic pain, low-grade fever; may be asymptomatic and found incidentally

— In transplant recipients, often presents as nodules or cavitary lesions; in AIDS, more diffuse interstitial infiltrates mimicking PCP

— Skin: umbilicated papules resembling molluscum contagiosum (highly suggestive in AIDS)

— Bone, prostate (a reservoir for relapse), eye (chorioretinitis), adrenals

— HIV status and most recent CD4; ART adherence

— Transplant date and immunosuppressive regimen (tacrolimus, MMF, prednisone)

— Recent steroid course, biologic agents, chemotherapy

— Exposure to pigeon roosts, eucalyptus (C. gattii regions: PNW, British Columbia, Australia)

— Cirrhosis, sarcoid, prior PCP/CMV

Cryptococcal meningoencephalitis — the dominant syndrome

Pulmonary cryptococcosis

Disseminated disease

Cryptococcemia — fungemia in profoundly immunosuppressed; high mortality

Key history elements to anchor the diagnosis:

Key distinction: Bacterial meningitis = hours to a few days, neutrophil-predominant CSF, very ill. Cryptococcal meningitis = weeks, lymphocyte-predominant or paucicellular CSF, deceptively well-appearing

Board pearl: A renal transplant recipient 4 months post-op with new headache and personality change — order serum CrAg and LP; do not wait for fever or meningismus

Step 3 management: Document baseline visual acuity and mental status on admission — these are the metrics you'll trend to detect rising ICP and IRIS

Physical Exam Findings (and Neurologic Assessment)

— Often deceptively well despite serious CNS infection — a Step 3 trap

— Low-grade fever or afebrile; weight loss if chronic

— Cachexia, oral thrush, Kaposi sarcoma → clues to underlying AIDS

— Mental status: subtle inattention, slowed processing, disorientation; frank obtundation = severe disease

— Meningismus often absent or mild — do not be falsely reassured

— Cranial nerve deficits: CN VI palsy (false localizing sign of ↑ICP), CN VII, CN VIII (hearing loss), optic nerve involvement

— Papilledema on fundoscopy → reflects elevated intracranial pressure; predicts worse outcome

— Visual field defects, decreased visual acuity → optic nerve sheath compression

— Focal motor deficits if cryptococcomas or hydrocephalus

— Umbilicated, flesh-colored papules on face/scalp/trunk — molluscum-like lesions in AIDS = cryptococcosis until proven otherwise

— Cellulitis-like plaques in transplant patients

— Crackles, decreased breath sounds; often surprisingly normal exam despite imaging findings

— Chorioretinitis, papilledema, ophthalmoplegia — get formal ophthalmology eval if any visual complaint

— Usually stable; hypotension/sepsis physiology suggests fungemia or alternative diagnosis

General appearance

Neurologic exam (the highest-yield portion)

Skin

Pulmonary

Ocular

Hemodynamic assessment

CCS pearl: On the CCS case, order funduscopic exam, mental status, and cranial nerve exam on every encounter with suspected or confirmed cryptococcal meningitis — these track ICP and treatment response

Board pearl: A CD4 of 30, headache for 3 weeks, mild confusion, papilledema, normal CT head, opening pressure 40 cm H₂O on LP — classic. High opening pressure (>25 cm H₂O) is found in ~50–75% of cases and is the most important modifiable prognostic factor

Key distinction: Focal deficits or seizures should prompt MRI to look for cryptococcomas (more common with C. gattii)

Diagnostic Workup — Initial Labs, Imaging, and CSF

— Lateral flow assay: rapid, sensitivity and specificity >95% for disseminated/meningeal disease

— First test of choice when cryptococcosis is suspected, especially in HIV with CD4 <100

— Positive serum CrAg in HIV mandates LP to rule out meningitis regardless of symptoms

— CT head without contrast prior to LP if focal deficit, altered mentation, papilledema, or immunocompromised (almost always indicated here)

— CT often normal; MRI may show leptomeningeal enhancement, dilated Virchow-Robin spaces, gelatinous pseudocysts, hydrocephalus, or cryptococcomas

— Measure and record opening pressure with patient in lateral decubitus — non-negotiable

— Send: cell count + differential, glucose, protein, India ink, CSF CrAg, fungal culture, Gram stain, bacterial culture, AFB

— Typical CSF: opening pressure ↑↑, lymphocytic pleocytosis (often <50 cells), elevated protein, low–normal glucose

— In severe AIDS, CSF can be nearly acellular despite heavy fungal burden — do not exclude based on cell count

— India ink: 60–80% sensitive in AIDS (high burden); CSF CrAg ~95% sensitive

— CD4 count and HIV viral load

— CBC, BMP, LFTs (baseline for amphotericin/flucytosine toxicity)

— Blood cultures (fungemia common in AIDS); urine culture (prostatic reservoir)

— Chest imaging — CT chest if pulmonary symptoms; nodules, cavities, infiltrates

Step 1 — Serum cryptococcal antigen (CrAg)

Step 2 — Neuroimaging before LP

Step 3 — Lumbar puncture (the diagnostic centerpiece)

Supporting labs

Board pearl: Opening pressure ≥25 cm H₂O drives both therapeutic LPs and prognosis — explicitly document it

Step 3 management: A positive serum CrAg without symptoms in HIV still requires LP; if LP is negative for meningitis, treat as isolated cryptococcal antigenemia with fluconazole and delay ART 2–4 weeks

CCS pearl: Order "LP with opening pressure" — the simulator rewards explicit pressure measurement

Diagnostic Workup — Advanced and Confirmatory Studies

— Sabouraud dextrose agar, grows in 3–7 days

— Quantitative cultures track treatment response; early fungicidal activity (EFA) is the rate of CSF sterilization and predicts outcomes

— Repeat LP at 2 weeks of induction therapy to document culture sterility before stepping down

— Titers correlate with fungal burden at diagnosis (≥1:1024 = high burden, worse prognosis)

— Titers do NOT reliably track treatment response — culture is the metric. Don't follow CrAg titers to decide therapy duration

— Indicated for focal deficits, seizures, persistent symptoms despite therapy, or C. gattii suspicion

— Findings: cryptococcomas (ring-enhancing), dilated perivascular spaces with gelatinous pseudocysts, basilar meningeal enhancement, hydrocephalus

— Nodules (single or multiple), cavities, consolidation, mediastinal lymphadenopathy

— Biopsy with mucicarmine, Fontana-Masson, or GMS stain — shows narrow-based budding yeast with thick capsule

— Mucicarmine stains capsule pink (pathognomonic); India ink shows halo around organism

— Skin biopsy of molluscum-like lesions confirms cutaneous dissemination

— HIV testing if status unknown; if HIV+, start ART planning (delayed initiation)

— Screen for co-infections: TB, syphilis (RPR), toxoplasma IgG, CMV

— Ophthalmology consult for any visual symptom or papilledema

CSF fungal culture — gold standard

CSF and serum CrAg titers

MRI brain with contrast

Chest CT

Histopathology

Ancillary workup

Key distinction: C. gattii is more likely to cause cryptococcomas, hydrocephalus, and prolonged therapy in immunocompetent hosts — geography (PNW, BC) and imaging hint at it

Board pearl: Persistently positive CSF cultures at 2 weeks define treatment failure and prompt extended induction

Step 3 management: Always recheck LP at 2 weeks before transitioning from induction to consolidation — exam loves this milestone

Risk Stratification and First-Line Management Logic

— Induction (≥2 weeks): liposomal amphotericin B + flucytosine

— Consolidation (8 weeks): high-dose fluconazole

— Maintenance/secondary prophylaxis (≥1 year and until immune reconstitution): low-dose fluconazole

— Altered mental status, opening pressure ≥25 cm H₂O, CSF CrAg ≥1:1024, or CSF WBC <20 → high-risk disease, higher mortality

— Pulmonary-only without CNS or fungemia and asymptomatic → fluconazole alone may suffice

— All CNS cryptococcosis = inpatient admission for IV induction

— Severe disease, altered mentation, or rising ICP → consider ICU

— Mild pulmonary cryptococcosis in non-CNS, non-fungemic, non-immunocompromised host → outpatient fluconazole 400 mg/day for 6–12 months with close follow-up

— Therapeutic LPs daily until opening pressure normalizes (<20 cm H₂O) and remains stable

— Remove enough CSF to reduce pressure by ~50% or to <20 cm H₂O

— Persistent elevation despite daily LPs → lumbar drain or VP shunt (neurosurgery consult)

— Avoid steroids and mannitol as routine ICP measures — steroids worsen outcomes in non-IRIS cryptococcal meningitis (COAT trial)

— Delay ART by 4–6 weeks after starting antifungals to reduce IRIS mortality

— Starting ART early (within 1–2 weeks) increases mortality — landmark teaching point

Three-phase antifungal strategy (memorize cold):

Risk stratification at presentation:

Triage decisions:

ICP management — equally important as antifungals

ART timing in HIV

Board pearl: The single most actionable intervention to reduce mortality is aggressive ICP control with serial LPs, not antifungal escalation

Step 3 management: On admission, order: IV amphotericin + flucytosine, daily neuro checks, daily fundoscopy, baseline LP with opening pressure, repeat LP for ICP control, hold ART for 4–6 weeks

CCS pearl: Advance the clock 14 days, then repeat LP to confirm CSF culture sterility before stepping down to fluconazole

Pharmacotherapy — First-Line Antifungal Regimen

— Liposomal amphotericin B 3–4 mg/kg/day IV + flucytosine (5-FC) 100 mg/kg/day PO divided q6h

— Liposomal preferred over amphotericin B deoxycholate — much less nephrotoxic, equally effective

— Continue until clinical improvement AND negative CSF culture at 2-week LP

— Extend induction to 4–6 weeks if: cryptococcoma, persistent positive culture, neurologic deterioration, C. gattii

— Single high-dose liposomal amphotericin 10 mg/kg ×1 + flucytosine + fluconazole (AMBITION-cm regimen) — preferred in resource-limited settings, non-inferior, now endorsed by WHO; appearing in US guidelines

— If flucytosine unavailable: amphotericin + fluconazole 800–1200 mg/day (inferior but acceptable)

— Fluconazole 400–800 mg PO daily ×8 weeks after successful induction

— Fluconazole 200 mg PO daily for ≥12 months

— Continue in HIV patients until CD4 >100 (some say >200) for ≥3 months AND undetectable viral load on ART for ≥3 months

— In transplant patients, continue 6–12 months with reduction in immunosuppression

— Amphotericin: daily BMP, magnesium, potassium; pre-hydrate with 1 L NS; expect nephrotoxicity, infusion reactions, hypokalemia/hypomagnesemia

— Flucytosine: CBC every 2–3 days (myelosuppression); check 5-FC levels (target peak 30–80 mcg/mL) — toxicity rises with renal impairment

— Fluconazole: LFTs, QTc, drug interactions (warfarin, tacrolimus, sulfonylureas)

Induction therapy (minimum 2 weeks)

Alternative induction regimens

Consolidation (weeks 3–10)

Maintenance/secondary prophylaxis

Key monitoring

Board pearl: Flucytosine + amphotericin clears CSF faster than either alone and reduces 10-week mortality — a classic exam fact

Step 3 management: Renally dose flucytosine; check 5-FC trough if Cr rising; never use flucytosine monotherapy (resistance develops rapidly)

Adjunctive Management — ICP Control, Surgery, and Reduction of Immunosuppression

— Therapeutic LPs: daily if opening pressure ≥25 cm H₂O; remove CSF to halve the pressure or bring it <20 cm H₂O

— Continue daily LPs until pressures stable for several days

— Lumbar drain if frequent LPs needed but pressure remains uncontrolled

— Ventriculoperitoneal (VP) shunt for refractory hydrocephalus or persistent ICP elevation — neurosurgery consult

— Steroids: avoid routinely; reserved for confirmed IRIS or cerebral edema from cryptococcoma

— Acetazolamide and mannitol: not effective and may worsen outcomes

— Coordinate with transplant team; typically taper calcineurin inhibitors and reduce prednisone

— Beware graft rejection and cryptococcal IRIS from rapid taper

— Calcineurin inhibitors paradoxically have anti-cryptococcal activity — abrupt withdrawal worsens disease

— Defer ART 4–6 weeks after antifungal initiation; abrupt early ART → IRIS, mortality ↑

— Once started, monitor for paradoxical IRIS at 1–2 months

— Cryptococcomas usually managed medically; surgery reserved for mass effect or diagnostic uncertainty

— Large pulmonary nodules/cavities may require resection for diagnosis

— Aggressive hydration during amphotericin; pre-meds (acetaminophen, diphenhydramine) for infusion reactions

— Electrolyte repletion — magnesium and potassium daily

— DVT prophylaxis, nutrition, glycemic control

Intracranial pressure management (mortality-defining)

Reduction of immunosuppression (transplant patients)

ART in HIV

Surgical drainage

Supportive care

CCS pearl: Order "therapeutic LP" as a recurring order with opening pressure measurement; the case rewards iterative ICP control

Board pearl: A patient on induction therapy whose mental status worsens at week 1 — first action is repeat LP to measure ICP, not antifungal change

Step 3 management: In transplant cryptococcosis, taper immunosuppression slowly and watch for IRIS unmasking when prednisone drops

Special Populations — Elderly and Renal/Hepatic Impairment

— Often present with subtle confusion or "failure to thrive" rather than classic headache/fever

— Lower threshold for LP in elderly immunosuppressed (chronic steroids for PMR, GCA, IBD, RA on biologics)

— Polypharmacy raises drug-interaction risk with fluconazole (warfarin INR ↑, sulfonylurea hypoglycemia, statin myopathy, QTc prolongation with antiarrhythmics)

— Increased baseline renal impairment → strict liposomal amphotericin (not deoxycholate), close electrolyte monitoring, dose-adjust flucytosine

— Flucytosine dose adjustment is critical:

– CrCl 20–40: reduce to q12h

– CrCl 10–20: q24h

– CrCl <10 or dialysis: dose after HD

— Check 5-FC serum levels (target 30–80 mcg/mL, peak 2 hr post-dose); levels >100 → marrow toxicity

— Liposomal amphotericin preferred — much less nephrotoxicity than deoxycholate; still monitor Cr daily

— Hold amphotericin if Cr doubles; alternative: amphotericin lipid complex

— Fluconazole: reduce by 50% if CrCl <50; supplemental dose after HD

— Fluconazole hepatotoxicity uncommon but check baseline and weekly LFTs

— Hold/reduce if AST/ALT >5× ULN or symptomatic hepatitis

— Cirrhotic patients are themselves at increased risk for cryptococcosis (often misdiagnosed as SBP or hepatic encephalopathy initially)

— ↑ Warfarin (bleed) — recheck INR

— ↑ Tacrolimus, cyclosporine, sirolimus levels — reduce dose 30–50%

— ↑ Statins (rhabdomyolysis with simvastatin)

— QTc prolongation with methadone, ondansetron, antipsychotics

Elderly patients

Renal impairment

Hepatic impairment

Drug interactions to memorize (fluconazole, a CYP3A4 and CYP2C9 inhibitor)

Board pearl: Cirrhotic patient with headache, lymphocytic CSF, normal CT — check serum CrAg; cryptococcosis in cirrhosis is high-mortality and often missed

Step 3 management: When starting fluconazole in a transplant patient, reduce tacrolimus dose and check trough in 3–5 days

Special Populations — Pregnancy and Pediatrics

— Cryptococcal meningitis in pregnancy is rare but high mortality if missed

— Amphotericin B (liposomal preferred) is the antifungal of choice — Category B, no teratogenicity reported

— Flucytosine: avoid in first trimester (teratogenic in animals); use cautiously in 2nd/3rd if benefit outweighs risk; discuss with MFM and ID

— Fluconazole: avoid in first trimester (associated with craniofacial, cardiac, skeletal anomalies at high doses); can use in 2nd/3rd trimester at lowest effective dose for consolidation

— Practical approach: amphotericin monotherapy (induction) during first trimester; add flucytosine if essential after week 14; defer fluconazole to postpartum if possible

— Postpartum: complete maintenance therapy; breastfeeding generally avoided on flucytosine

— Most pediatric cases occur in HIV-infected children, congenital immunodeficiencies (CD40L, idiopathic CD4 lymphopenia), or hematologic malignancy

— Same three-phase regimen, weight-based dosing:

– Liposomal amphotericin 3–6 mg/kg/day

– Flucytosine 100 mg/kg/day divided q6h

– Fluconazole 10–12 mg/kg/day for consolidation, 6 mg/kg/day for maintenance

— Higher relative ICP burden — aggressive LP-based management

— Newly diagnosed HIV with CD4 <100: screen with serum CrAg before starting ART

— Positive CrAg without meningitis → preemptive fluconazole 800 mg/day ×2 weeks → 400 mg ×8 weeks → 200 mg maintenance; delay ART 2–4 weeks

— Positive CrAg + meningitis → full induction regimen, delay ART 4–6 weeks

— Onset usually >1 month post-transplant; lung transplant patients have highest pulmonary involvement

— Manage in conjunction with transplant team

Pregnancy

Pediatrics

HIV-specific subgroup

Solid organ transplant

Board pearl: CrAg screening before ART initiation in CD4 <100 is now standard of care (IDSA, WHO)

Step 3 management: Pregnant patient with cryptococcal meningitis — liposomal amphotericin alone during first trimester; reintroduce flucytosine after week 14, fluconazole postpartum

Complications and Adverse Outcomes

— Visual loss (often permanent if not promptly relieved), hearing loss, cranial neuropathies

— Herniation if pressure unrelieved

— Requires aggressive serial LPs ± shunting

— Paradoxical IRIS: clinical worsening after starting ART or reducing immunosuppression despite microbiologic response; presents as recurrent meningitis, lymphadenitis, cryptococcomas

— Unmasking IRIS: previously undiagnosed cryptococcosis emerges after immune restoration

— Occurs 1–10 months after ART initiation; risk highest with low CD4 + high fungal burden + rapid ART start

— Management: continue antifungals, continue ART, add corticosteroids (prednisone 1 mg/kg) for severe IRIS only

— Defined as persistently positive CSF cultures at ≥2 weeks or clinical deterioration

— Action: extend induction, ensure flucytosine therapeutic levels, look for cryptococcoma/hydrocephalus, consider C. gattii

— Usually from prostatic or CNS reservoir; from inadequate maintenance therapy or premature discontinuation

— Re-induce with full course

— Amphotericin: nephrotoxicity, hypokalemia, hypomagnesemia, anemia, infusion reactions

— Flucytosine: cytopenias (esp. with high levels), hepatitis, GI upset, enterocolitis

— Fluconazole: hepatitis, QTc, rash (rare SJS), alopecia at high cumulative doses

— Cognitive impairment, deafness, blindness, cranial neuropathies

— Hydrocephalus requiring chronic shunt

Elevated intracranial pressure (most common, most lethal)

Immune reconstitution inflammatory syndrome (IRIS)

Treatment failure

Relapse

Drug toxicities

Permanent neurologic sequelae

Mortality: 10-week mortality 15–30% even with best therapy; up to 70% in resource-limited settings

Key distinction: Worsening symptoms during induction = uncontrolled ICP or treatment failure; worsening after ART start = IRIS (cultures negative, inflammation +)

Board pearl: Don't stop antifungals during IRIS — treat with steroids and continue both ART and antifungals

Step 3 management: Visual changes during therapy → urgent LP for pressure, ophthalmology, neurosurgery for possible optic nerve fenestration or shunt

When to Escalate Care — ICU, Consultation, and Triage

— Confirmed or suspected CNS cryptococcosis

— Disseminated disease or fungemia

— Need for IV amphotericin induction

— Inability to take PO, hemodynamic concern, or social barriers to outpatient care

— Altered mental status with GCS ≤12

— Opening pressure >40 cm H₂O or refractory to therapeutic LP

— Need for frequent neuro checks, lumbar drain, or imminent shunt

— Hemodynamic instability, fungemia with septic physiology

— Respiratory failure from cryptococcal pneumonia

— Seizures or focal deficits

— Infectious Diseases: every case — confirms regimen, manages duration

— Neurosurgery: for refractory ICP, lumbar drain placement, VP shunt

— Neurology: status changes, seizures, IRIS

— Ophthalmology: any visual symptom or papilledema

— Transplant medicine: SOT patients — manage immunosuppression taper

— HIV/ART clinic: timing of ART initiation, drug interactions

— Pharmacy: amphotericin/flucytosine TDM, drug interaction review

— If lacking ID, neurosurgery, or amphotericin formulary → transfer to tertiary center

— Hemodialysis access if amphotericin nephrotoxicity progresses

— Negative CSF culture at 2 weeks

— Clinical improvement, stable ICP without daily LP

— Tolerating PO fluconazole consolidation

— Reliable follow-up arranged

Admit to inpatient (all of the following at minimum)

ICU triage criteria

Consult services to call early (CCS-style)

Transfer considerations

Discharge readiness

Board pearl: A patient on induction who develops new lethargy + opening pressure 45 cm H₂O — ICU + neurosurgery for lumbar drain or shunt, not antifungal escalation

CCS pearl: Order ID consult on day 1 of every cryptococcosis case; the simulator credits early consultation

Step 3 management: Coordinate transitions — communicate antifungal regimen, monitoring plan, and ART timing in the handoff

Key Differentials — Other Opportunistic CNS Infections

— Similar subacute timeline, basilar meningeal enhancement, lymphocytic CSF

— Distinguish: very low CSF glucose (often <40), markedly elevated protein, AFB smear/PCR/culture, history of TB exposure or positive IGRA

— More common in foreign-born, alcohol use, malnutrition

— AIDS with CD4 <100, focal deficits, multiple ring-enhancing lesions on MRI (vs. single in lymphoma)

— Toxoplasma IgG positive, serum CrAg negative

— Empiric treatment with sulfadiazine + pyrimethamine + leucovorin

— AIDS with CD4 <50, single periventricular ring-enhancing lesion, EBV PCR positive in CSF

— Diagnostic challenge vs. toxo: thallium SPECT or response to empiric toxo therapy

— JC virus, AIDS, multifocal non-enhancing white matter lesions; subacute focal deficits without fever

— CD4 <50, periventricular enhancement, CMV PCR in CSF

— Cognitive decline without focal infection; diagnosis of exclusion

— Acute, neutrophilic CSF; Listeria in immunosuppressed/elderly

— RPR/VDRL, FTA-ABS; CSF VDRL; can mimic chronic meningitis

— Geographic clues (SW US, Mississippi/Ohio valley); urine/serum antigens

Tuberculous meningitis

Toxoplasmosis (CNS)

Primary CNS lymphoma

Progressive multifocal leukoencephalopathy (PML)

CMV encephalitis / ventriculitis

HIV-associated dementia / encephalopathy

Bacterial meningitis (Listeria, S. pneumoniae)

Neurosyphilis

Coccidioidomycosis / Histoplasmosis meningitis

Key distinction: Multiple ring-enhancing lesions in AIDS + Toxo IgG+ → empiric toxoplasmosis; single lesion + EBV PCR → lymphoma; subacute meningitis + lymphocytic CSF + ↑opening pressure → cryptococcus

Board pearl: Always send serum and CSF CrAg in any AIDS patient with neurologic symptoms — it's cheap, fast, and sensitive

Step 3 management: Don't anchor — workup for cryptococcosis runs in parallel with toxo serology, TB PCR, and syphilis testing

Key Differentials — Non-Infectious and Pulmonary Mimics

— Lung cancer (especially in transplant or smoker): solitary pulmonary nodule, PET-avid; biopsy required to distinguish

— TB: cavitary upper lobe, AFB, history of exposure

— Pneumocystis (PCP): diffuse bilateral ground-glass in AIDS; LDH ↑, exertional desaturation; bronchoscopy with silver stain

— Histoplasmosis/coccidioidomycosis: regional exposure, urine antigens

— Sarcoidosis: bilateral hilar adenopathy, non-caseating granulomas; cryptococcosis can complicate sarcoid on steroids

— Carcinomatous meningitis: malignancy history, multiple cranial neuropathies, malignant cells on CSF cytology

— Sarcoid neurologic involvement: basilar meningitis, cranial neuropathies, lymphocytic CSF

— Behçet, vasculitis, NMO: imaging clues, autoimmune serologies

— Drug-induced aseptic meningitis (NSAIDs, IVIG, TMP-SMX): temporal association, normal cultures

— Cryptococcomas vs. lymphoma, abscess, glioma — biopsy when in doubt

— Adrenal insufficiency from cryptococcal adrenalitis presenting as fatigue, hypotension, hyponatremia

— Always check cortisol in disseminated cryptococcosis with hemodynamic instability

— Subacute personality change in elderly or immunosuppressed → exclude cryptococcal meningitis before attributing to depression or dementia

Pulmonary cryptococcosis mimics

CNS mimics — non-infectious

Mass lesions

Endocrine and metabolic confounders

Psychiatric mimics

Key distinction: A transplant patient with a solitary pulmonary nodule — must distinguish cryptococcoma from malignancy and TB; serum CrAg + biopsy with mucicarmine clinch it

Board pearl: Cryptococcal adrenalitis is a rare but board-favorite cause of adrenal insufficiency in AIDS with disseminated disease

Step 3 management: A subacute headache in any immunocompromised patient warrants serum CrAg even if the working diagnosis is something else — it's a cheap test that changes management

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Fluconazole 200 mg PO daily after completing 8 weeks of consolidation

— Duration in HIV: minimum 12 months AND CD4 >100 (some sources >200) sustained ≥3 months AND HIV RNA suppressed ≥3 months

— Duration in SOT: 6–12 months with reduction of net immunosuppression

— Duration in non-HIV, non-transplant: 6–12 months; longer if persistent immunosuppression

— Fluconazole (correct phase: consolidation 400 mg vs. maintenance 200 mg)

— ART regimen — start at 4–6 weeks post-antifungal initiation in HIV

— TMP-SMX for PCP prophylaxis if CD4 <200

— Azithromycin for MAC prophylaxis if CD4 <50

— Electrolyte repletion (K, Mg) tapered as amphotericin discontinued

— Antiemetics PRN; PPI if GI intolerance to flucytosine residual

— Pneumococcal (PCV15/PCV20 + PPSV23), influenza annually, hepatitis B, HPV

— Avoid live vaccines in active immunosuppression

— Optimize HIV: ensure ART adherence, achieve viral suppression

— Taper steroids to lowest effective dose; minimize biologics where possible

— Counsel SOT patients on avoidance of pigeon droppings, soil exposure (gardening with mask/gloves)

— Fluconazole interactions: warfarin, statins, sulfonylureas, tacrolimus — reconcile and educate

— Baseline CBC, BMP, LFTs; recheck at 2 and 4 weeks, then monthly

Maintenance antifungal therapy (secondary prophylaxis)

Discharge medications checklist

Vaccinations and prevention

Risk factor modification

Drug interactions on discharge

Monitoring labs at discharge

Board pearl: Stopping fluconazole maintenance too early → relapse from prostatic reservoir; reinforce minimum 12 months in HIV

Step 3 management: Document the stop date for fluconazole maintenance in the chart with the criteria (CD4 + viral load + time) — this is a transitions-of-care safety net

CCS pearl: Order "fluconazole 200 mg daily" as a recurring outpatient prescription on the discharge orders

Follow-Up, Monitoring, and Counseling

— ID clinic: 1–2 weeks post-discharge, then monthly for the first 6 months, then quarterly

— HIV clinic: 2 weeks for ART initiation/adjustment, then monthly until viral suppression, then every 3–6 months

— Transplant clinic: per transplant team, typically weekly initially

— Ophthalmology: if any visual symptoms or papilledema, monthly until resolved

— Neurology: as needed for sequelae

— CBC, BMP, LFTs at 2 and 4 weeks, then monthly while on fluconazole maintenance

— CD4 and HIV viral load every 3 months

— Fluconazole TDM not routine; consider if persistent symptoms or interactions

— Do not routinely follow serum or CSF CrAg titers — they remain positive for months despite cure and do not reliably guide therapy decisions

— Repeat MRI if persistent symptoms, suspicion of cryptococcoma, or IRIS

— Chest CT for pulmonary cryptococcosis at 3–6 months to confirm resolution

— Repeat LP only if new symptoms, suspicion of relapse, or IRIS — not routine

— Symptoms of relapse: recurrent headache, fever, mental status change, vision changes — return immediately

— Medication adherence is the single most important predictor of relapse prevention

— Avoid pigeon droppings, soil disturbance, eucalyptus dust where possible

— Pregnancy planning: avoid fluconazole in first trimester; coordinate with OB

— Mental health support: chronic illness, neurologic sequelae often co-occur with depression

— Visual rehabilitation if persistent deficits; vestibular and audiology if CN VIII involved

— Cognitive rehab for residual deficits

Follow-up cadence

Monitoring labs

Imaging follow-up

LP follow-up

Counseling points

Rehabilitation

Key distinction: Persistent positive CrAg ≠ active infection; culture is the gold standard for active disease

Board pearl: A patient at 6 months on fluconazole with new headache — repeat LP with culture, not just CrAg titer

Step 3 management: Build a calendar-based follow-up plan with explicit milestones (CD4 check, fluconazole stop criteria, ART labs) — transition-of-care safety

Ethical, Legal, and Patient Safety Considerations

— LP with opening pressure measurement: explain risks (post-LP headache, infection, bleeding) and benefits (diagnosis + ICP reduction)

— VP shunt / lumbar drain: full surgical consent, alternatives, prognosis

— In altered mental status patients, identify a surrogate decision-maker per state hierarchy; document capacity assessment

— Newly diagnosed HIV at cryptococcosis presentation is common

— Mandatory reporting of HIV diagnosis to public health varies by state; partner notification programs (PNS) help with disclosure

— Confidentiality of HIV status is protected — discuss with patient before disclosure to family

— Common errors:

– Premature ART initiation (<2 weeks) → fatal IRIS

– Stopping fluconazole maintenance too early → relapse

– Failure to communicate amphotericin nephrotoxicity to outpatient PCP → missed AKI

– Missed drug interactions (warfarin, tacrolimus) on discharge

— Closed-loop communication at discharge: written plan, scheduled labs, named follow-up provider, medication reconciliation

— Daily medication review for amphotericin nephrotoxicity, flucytosine cytopenias, fluconazole-driven QTc

— Fall precautions in patients with visual loss, altered mentation, vestibular dysfunction

— DVT prophylaxis in immobile patients with elevated ICP (mechanical preferred if neurosurgical procedures planned)

— Liposomal amphotericin and flucytosine availability varies; verify formulary on admission

— Insurance coverage for prolonged fluconazole; assist with patient assistance programs

— Coordinate with HIV linkage-to-care services for newly diagnosed patients

— In advanced disease with poor prognosis (refractory ICP, multiorgan failure), goals-of-care conversation with patient/family; palliative care consult

Informed consent for procedures

HIV disclosure and partner notification

Transitions of care — high-risk topic on Step 3

Patient safety in inpatient phase

Health systems and access

End-of-life considerations

Board pearl: Delayed ART (4–6 weeks) is both a clinical and a safety/ethics issue — counsel the patient on the rationale to avoid the perception of withholding care

Step 3 management: Document capacity, surrogate, and code status on every admission; do not rely on verbal handoffs alone

High-Yield Associations and Rapid-Fire Clinical Facts

C. neoformans = pigeon droppings, immunocompromised hosts worldwide

C. gattii = eucalyptus trees, Pacific Northwest/British Columbia/Australia, can affect immunocompetent, more cryptococcomas

CD4 <100 = main risk threshold in HIV; <50 highest risk

Mucicarmine stain = pink capsule — pathognomonic histology

India ink = clear halo around yeast on CSF — classic image

Narrow-based budding distinguishes Cryptococcus from Blastomyces (broad-based)

Polysaccharide capsule (glucuronoxylomannan) = basis of CrAg test

Serum CrAg = first screen; CSF CrAg = confirms meningitis

Opening pressure ≥25 cm H₂O = serial therapeutic LPs

Induction: liposomal amphotericin + flucytosine ×2 weeks minimum

Consolidation: fluconazole 400–800 mg ×8 weeks

Maintenance: fluconazole 200 mg daily ≥12 months

ART deferral: 4–6 weeks after antifungal start

Steroids: not routine; reserve for IRIS (COAT trial — early steroids worsen outcome)

IRIS: 1–10 months after ART, paradoxical worsening, treat with steroids while continuing both ART and antifungals

AMBITION-cm regimen: single high-dose liposomal amphotericin + flucytosine + fluconazole — non-inferior, WHO-endorsed

Don't follow CrAg titers to guide therapy duration — follow cultures

Prostate = sanctuary site for relapse

Adrenal involvement in disseminated disease → check cortisol

Skin lesions look like molluscum contagiosum in AIDS

Pulmonary nodule + transplant + serum CrAg+ = pulmonary cryptococcosis

Cirrhosis is an underrecognized risk factor — high mortality

Idiopathic CD4 lymphopenia = HIV-negative patient with low CD4 and cryptococcal meningitis — board favorite

Fluconazole drug interactions: warfarin ↑, tacrolimus ↑, statins ↑, sulfonylureas ↑, QTc ↑

Flucytosine TDM target: 30–80 mcg/mL; >100 = marrow toxicity

Board pearl: AIDS + headache + normal CT + lymphocytic CSF + ↑opening pressure = cryptococcal meningitis until proven otherwise

Step 3 management: Screen all newly diagnosed HIV with CD4 <100 with serum CrAg before ART

Board Question Stem Patterns

— "32-year-old man, HIV CD4 25, 3 weeks of headache, low-grade fever, mild confusion, no neck stiffness, normal CT head, LP opening pressure 38 cm H₂O, lymphocytic CSF."

— Best next step: CSF cryptococcal antigen (or India ink). Treatment: liposomal amphotericin + flucytosine

— Newly diagnosed HIV, cryptococcal meningitis on day 5 of induction. When start ART?

— Answer: Defer 4–6 weeks to reduce IRIS mortality

— Patient on appropriate antifungals develops worsening headache and visual blurring on day 4. Next step?

— Answer: Repeat LP with opening pressure measurement and CSF drainage, not antifungal change

— HIV patient 6 weeks into ART after cryptococcal meningitis develops new headache, fever, lymphadenopathy; CSF cultures negative.

— Diagnosis: paradoxical IRIS. Action: continue ART and antifungals; add corticosteroids for severe cases

— Newly diagnosed HIV, CD4 60, asymptomatic. Pre-ART workup?

— Answer: Serum cryptococcal antigen screening; if positive, LP before ART

— Renal transplant 4 months ago, subacute headache, low-grade fever. Next step?

— Answer: Serum CrAg + LP; treat with liposomal amphotericin + flucytosine; reduce immunosuppression in conjunction with transplant team

— Asymptomatic lung transplant patient with solitary pulmonary nodule, biopsy shows narrow-based budding yeast with capsule. Next?

— Answer: Serum CrAg + LP to rule out CNS disease; if isolated pulmonary, fluconazole; if CNS, full regimen

— Image: budding yeast with mucicarmine-pink capsule on lung biopsy → Cryptococcus

— Cryptococcal meningitis post-transplant on tacrolimus, started fluconazole. Action?

— Answer: Reduce tacrolimus dose 30–50%, recheck trough in 3–5 days

— When can fluconazole 200 mg be stopped in HIV?

— Answer: ≥12 months therapy AND CD4 >100 sustained ≥3 months AND HIV RNA suppressed ≥3 months

Stem 1 — Classic AIDS meningitis

Stem 2 — ART timing

Stem 3 — ICP management

Stem 4 — IRIS

Stem 5 — Screening

Stem 6 — Transplant patient

Stem 7 — Pulmonary cryptococcosis

Stem 8 — Stain identification

Stem 9 — Drug interaction

Stem 10 — Maintenance discontinuation

Board pearl: Distractors often include "give corticosteroids" — wrong unless IRIS; "start ART immediately" — wrong, defer; "stop antifungals during IRIS" — wrong, continue both

Step 3 management: Recognize the question's phase of care — induction vs. consolidation vs. maintenance vs. follow-up — to pick the right action

One-Line Recap

Cryptococcosis in immunocompromised hosts (especially HIV with CD4 <100, transplant recipients, and chronic-steroid users) classically presents as subacute meningoencephalitis with elevated opening pressure; diagnose with serum/CSF CrAg and India ink, treat with induction liposomal amphotericin B + flucytosine ×2 weeks, consolidation fluconazole 400–800 mg ×8 weeks, and maintenance fluconazole 200 mg for ≥12 months, while aggressively controlling ICP with serial therapeutic LPs and deferring ART 4–6 weeks to prevent IRIS.

Diagnostic anchor: serum CrAg first → LP with opening pressure → CSF CrAg, India ink, fungal culture; do not rely on meningismus or fever

Therapeutic anchor: three-phase regimen (induction-consolidation-maintenance); flucytosine + amphotericin combination beats monotherapy

Pressure anchor: opening pressure ≥25 cm H₂O = daily therapeutic LPs; refractory ICP = lumbar drain or VP shunt; steroids are not for ICP (they're for IRIS)

Timing anchor: defer ART 4–6 weeks; screen all CD4 <100 patients with serum CrAg before ART; never stop maintenance fluconazole until CD4 >100 sustained, viral load suppressed, ≥12 months completed

Safety anchor: monitor amphotericin nephrotoxicity daily, flucytosine cytopenias every 2–3 days, fluconazole drug interactions (warfarin, tacrolimus, statins, QTc) at every transition of care

Board pearl: The two highest-yield mortality-modifying interventions are aggressive ICP control with serial LPs and delayed ART initiation — get both right and you've answered most Step 3 cryptococcosis questions correctly