Encapsulated yeast Cryptococcus neoformans causing subacute meningoencephalitis in HIV/AIDS; C. gattii causes disease in immunocompetent hosts.
Also known as: Cryptococcus neoformans, Cryptococcus gattii, cryptococcal meningitis, crypto meningitis
Overview
Infection caused by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii, acquired by inhalation. Most clinically significant manifestation is subacute or chronic meningoencephalitis, especially in patients with HIV/AIDS. Pulmonary, cutaneous, and disseminated disease also occur.
Epidemiology
C. neoformans is distributed worldwide, classically associated with pigeon droppings, and primarily infects immunocompromised hosts (especially HIV with CD4 <100). C. gattii is endemic to tropical and subtropical regions and the Pacific Northwest of North America and infects immunocompetent hosts. Cryptococcal meningitis remains a major cause of HIV-related mortality globally.
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Question 1Infectious DiseaseMedium
A 35-year-old man with HIV infection who is not receiving antiretroviral therapy or prophylaxis presents with a 1-week history of fever, headache, and neck stiffness. His most recent CD4 count is 180 cells/mm^3. On examination he has nuchal rigidity. Lumbar puncture shows a lymphocytic pleocytosis, and India ink staining of the cerebrospinal fluid is positive. Which of the following is the most likely diagnosis?
ACryptococcal meningitis
BBacterial meningitis
CTuberculous meningitis
DCoccidioidal meningitis
ECMV encephalitis
Reveal answer & full explanation
Correct answer: A — Cryptococcal meningitis
ACryptococcal meningitis✓
BBacterial meningitis
CTuberculous meningitis
DCoccidioidal meningitis
ECMV encephalitis
Why Cryptococcal meningitis is correct
A positive India ink stain of CSF reveals encapsulated budding yeast and is characteristic of Cryptococcus neoformans
Cryptococcal meningitis is an AIDS-defining illness that typically occurs once the CD4 count falls below 100-200 cells/mm^3, as in this untreated patient
A subacute lymphocytic pleocytosis, often with elevated opening pressure, fits cryptococcal rather than pyogenic infection
Confirm with CSF and serum cryptococcal antigen; treat with amphotericin B plus flucytosine induction, then fluconazole consolidation and maintenance
Why the others are wrong
Bacterial meningitis — produces a neutrophilic (not lymphocytic) pleocytosis with low glucose and is India ink negative; buzzword-matching nuchal rigidity to pyogenic meningitis while ignoring the CSF profile
CMV encephalitis — causes altered mentation and periventricular changes in advanced AIDS and is not detected by India ink; premature closure on a viral CNS process
Tuberculous meningitis — also gives a lymphocytic pleocytosis with very low glucose but is India ink negative; the CSF AFB smear is usually negative as well because the infection is paucibacillary, so diagnosis relies on CSF mycobacterial culture and nucleic acid amplification testing
Coccidioidal meningitis — another fungal meningitis with a lymphocytic (sometimes eosinophilic) pleocytosis in an immunocompromised host, but Coccidioides forms spherules rather than encapsulated budding yeast and is India ink negative; diagnosis relies on CSF complement-fixing antibody, and it usually follows residence in or travel to the desert Southwest
Question 2Infectious DiseaseMedium
A 35-year-old man who recently emigrated from sub-Saharan Africa was diagnosed with HIV and cryptococcal meningitis 8 weeks ago, when his CD4 count was 28 cells/mm^3, CSF opening pressure was 32 cmH2O, CSF white cell count was 6/mm^3, and CSF cryptococcal antigen titer was 1:2048. His symptoms resolved with 2 weeks of liposomal amphotericin B plus flucytosine, and he has continued fluconazole with confirmed adherence. Antiretroviral therapy (ART) was started 5 weeks after antifungal therapy began. Three weeks later he returns with fever, recurrent headache, and neck stiffness. His CD4 count is now 118 cells/mm^3, and his HIV RNA has fallen from 310,000 to 420 copies/mL. Repeat lumbar puncture shows an opening pressure of 30 cmH2O, 95 white cells/mm^3 (80% lymphocytes), glucose 56 mg/dL (serum 98 mg/dL), and protein 88 mg/dL. CSF cryptococcal antigen titer is 1:128, and CSF fungal culture shows no growth. Which of the following is the most likely diagnosis?
AParadoxical cryptococcal IRIS
BActive tuberculous meningitis
CDrug-induced aseptic meningitis
DRelapsed cryptococcal infection
EUnmasking cryptococcal IRIS
Reveal answer & full explanation
Correct answer: A — Paradoxical cryptococcal IRIS
AParadoxical cryptococcal IRIS✓
BActive tuberculous meningitis
CDrug-induced aseptic meningitis
DRelapsed cryptococcal infection
EUnmasking cryptococcal IRIS
Why Paradoxical cryptococcal IRIS is correct
Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory response against pathogen antigen as immunity recovers on ART; the paradoxical form is a flare of an opportunistic infection that was already diagnosed and improving on treatment
This patient improved on induction therapy, then deteriorated 3 weeks after ART began, in step with a CD4 rise from 28 to 118 cells/mm^3 and a nearly 3-log fall in HIV RNA; paradoxical cryptococcal IRIS typically appears within the first 1-3 months of ART
The CSF now shows far more inflammation than at diagnosis (95 vs 6 white cells/mm^3) with raised opening pressure, yet the fungal culture is sterile: inflammation without viable organisms. The antigen is still detectable because cryptococcal antigen clears slowly after successful therapy, so its presence does not signal live yeast
He carried the classic risk factors: very low CD4 count and high HIV RNA before ART, a high baseline antigen titer, and a scant CSF white cell response at diagnosis
Why the others are wrong
Active tuberculous meningitis — TB often surfaces in the first months of ART in patients from high-burden regions and also gives a lymphocytic CSF, but tuberculous meningitis usually lowers CSF glucose (CSF:serum ratio <0.5) and raises protein markedly (often 100-500 mg/dL); here the ratio is 0.57 and protein is only 88 mg/dL. Timing cannot separate the two, because TB that appears on ART also flares as the CD4 count recovers; what tips the balance is that a flare of the cryptococcal meningitis already diagnosed, in a patient who carried the classic IRIS risk factors, explains the return of the same syndrome with the same raised opening pressure more simply than a second central nervous system pathogen. Mycobacterial studies are still sent because the two can coexist (the trap is chasing a new pathogen suggested by the patient's origin instead of the infection already diagnosed)
Relapsed cryptococcal infection — relapse means viable Cryptococcus has returned, proven by a positive CSF culture; this culture is sterile and adherence to fluconazole is confirmed. Cryptococcal antigen clears slowly and stays detectable for months after successful therapy, so a positive titer does not diagnose relapse and serial titers are not used to judge treatment response (the trap is reading persistent antigen as active infection)
Drug-induced aseptic meningitis — a sterile meningitis after a new drug is tempting, but antiretrovirals are not among the classic culprits (NSAIDs, trimethoprim-sulfamethoxazole, intravenous immunoglobulin, and lamotrigine); onset is usually within hours to days of starting or restarting the drug and the CSF is often neutrophil-predominant. A flare at the site of a treated infection that tracks CD4 recovery is immune reconstitution, not drug toxicity (the trap is blaming the newest medication)
Unmasking cryptococcal IRIS — both forms of IRIS track immune recovery on ART, but unmasking IRIS is the first presentation of an opportunistic infection that was subclinical and untreated when ART began; this meningitis was diagnosed and treated before ART was started, so a flare now is the paradoxical form (the trap is mixing up the two IRIS subtypes)
Additional high-yield points
IRIS is a diagnosis of exclusion: repeat the CSF fungal culture and send mycobacterial studies (such as Xpert MTB/RIF Ultra) before settling on it; tuberculosis first diagnosed in the first 3 months of ART is termed ART-associated TB, and unmasking TB IRIS when it presents with an exaggerated inflammatory picture
Management: continue ART and fluconazole (do not stop ART), relieve intracranial pressure with therapeutic lumbar punctures when opening pressure is 25 cmH2O or higher, and reserve a short corticosteroid course for severe or life-threatening IRIS; steroids are not routine adjuncts for cryptococcal meningitis itself (harm in the CryptoDex trial)
Prevention: defer ART for several weeks after antifungal therapy begins; starting ART 1-2 weeks after diagnosis raised mortality in the COAT trial, and WHO advises a 4-6 week delay
If the culture is positive (true relapse), restart induction therapy and test the isolate for fluconazole susceptibility
Fluconazole maintenance (200 mg daily) continues for at least 1 year in total and until the CD4 count is 100 cells/mm^3 or higher with suppressed HIV RNA for at least 3 months on ART
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HIV/AIDS with CD4 <100 cells/microL (especially <50)
Solid organ transplantation, hematopoietic stem cell transplant
Chronic corticosteroid therapy
Idiopathic CD4 lymphopenia
Sarcoidosis, hematologic malignancy
Cirrhosis
C. gattii: outdoor exposure in endemic regions (eucalyptus trees, Pacific Northwest)
Pathophysiology
Inhaled yeast cells deposit in alveoli; the polysaccharide capsule (glucuronoxylomannan) inhibits phagocytosis and complement activation. In immunocompromised hosts, the organism disseminates hematogenously with predilection for the central nervous system, causing meningoencephalitis with cryptococcomas and elevated intracranial pressure. The capsular polysaccharide also drives much of the pathology by blocking CSF outflow.
Clinical presentation
Symptoms
Subacute headache, fever, malaise progressing over days to weeks
Visual changes (papilledema, cranial nerve VI palsy from increased ICP)
Nausea, vomiting from elevated intracranial pressure
Seizures (less common)
Pulmonary cryptococcosis: cough, chest pain, dyspnea, often subclinical
Cutaneous: umbilicated papules resembling molluscum contagiosum in advanced HIV
C. gattii in immunocompetent hosts: more cryptococcomas (brain or lung) and slower clinical course
Signs / physical exam
Often minimal meningismus despite extensive CNS involvement
Papilledema, cranial nerve palsies (VI most common)
Skin lesions: umbilicated, flesh-colored papules
Focal neurologic deficits from cryptococcomas
Pulmonary findings often minimal on exam
Classic findings
HIV patient with CD4 <100, subacute headache, and a positive serum CrAg. India ink staining of CSF reveals encapsulated yeast with a clear halo against a dark background. Elevated CSF opening pressure (>25 cm H2O) is the most important prognostic factor.
Differential diagnosis
Tuberculous meningitis — Subacute lymphocytic meningitis, low CSF glucose, elevated protein; AFB testing and TB-specific PCR; both can coexist in advanced HIV
Bacterial meningitis — Acute onset, neutrophilic CSF, very low glucose; gram stain and bacterial culture
Viral (HIV) aseptic meningitis — Lymphocytic CSF, normal glucose, milder course; PCR for HSV/enteroviruses
Toxoplasmosis (CNS) — Multiple ring-enhancing lesions on MRI in HIV with CD4 <100; positive Toxo IgG; response to empirical pyrimethamine-sulfadiazine
CNS lymphoma — Solitary periventricular lesion, EBV DNA in CSF; biopsy if not improving on empirical treatment
Neurosyphilis — Reactive RPR with CSF VDRL, cranial nerve abnormalities; treat with IV penicillin
Carcinomatous meningitis — Known malignancy, malignant cells on CSF cytology
Diagnostic workup
Diagnostic criteria
Diagnosis established by positive CSF cryptococcal antigen, India ink stain, or culture. Serum CrAg supports diagnosis and is used for screening in advanced HIV.
Labs
Serum cryptococcal antigen (CrAg) — highly sensitive and specific lateral flow assay; recommended screening in HIV patients with CD4 <100
Lumbar puncture with opening pressure measurement — CSF CrAg, India ink, culture, cell count, glucose, protein
Typical CSF: lymphocytic pleocytosis, low glucose, elevated protein, very high opening pressure (often >30 cm H2O); in advanced AIDS the CSF white count is often minimal or even normal, so a bland CSF does not exclude cryptococcal meningitis
Fungal blood cultures (positive in 30-70% of HIV-associated cases)
HIV testing and CD4 count if not known
BMP, LFTs, CBC
Imaging
MRI brain with contrast: may show meningeal enhancement, dilated Virchow-Robin spaces, cryptococcomas, hydrocephalus
Chest x-ray or CT for pulmonary involvement: nodules, infiltrates, cavities
Imaging should not delay lumbar puncture unless focal deficits, papilledema, or altered mental status suggest mass lesion
Diagnostic algorithm
flowchart TD
A["HIV CD4 <100<br/>headache, fever"] --> B[Serum CrAg]
B -->|Positive| C[Lumbar puncture<br/>measure opening pressure]
C --> D["CSF CrAg, India ink, culture"]
D --> E[Confirmed cryptococcal meningitis]
E --> F["Induction:<br/>Liposomal ampho B + flucytosine x 2 wk"]
F --> G["Consolidation:<br/>Fluconazole 400-800 mg x 8 wk"]
G --> H["Maintenance:<br/>Fluconazole 200 mg daily for at least 1 year<br/>stop once CD4 >=100 with suppressed<br/>viral load on ART for 3 months"]
C --> I{"Opening pressure<br/>>=25 cm H2O?"}
I -->|Yes| J["Therapeutic LPs<br/>daily until controlled<br/>no steroids, acetazolamide, or mannitol"]
E --> K[Delay ART start<br/>4-6 weeks<br/>to avoid IRIS]
Cryptococcal meningitis in HIV: diagnosis, induction-consolidation-maintenance therapy, ICP management, and ART timing.
Treatment
First-line
HIV-associated cryptococcal meningitis — Induction: liposomal amphotericin B 3-4 mg/kg/day IV plus flucytosine 100 mg/kg/day PO divided QID for 2 weeks (combination superior to monotherapy)
WHO 2022 preferred induction, used mainly in resource-limited settings (AMBITION-cm trial): single high-dose liposomal amphotericin B 10 mg/kg once plus 14 days of flucytosine 100 mg/kg/day and fluconazole 1,200 mg/day
Consolidation: fluconazole 400-800 mg PO daily for at least 8 weeks
Maintenance / secondary prophylaxis: fluconazole 200 mg PO daily for at least 1 year in total; stop once asymptomatic with CD4 ≥100 and suppressed viral load on ART for at least 3 months; restart if CD4 falls below 100
Aggressive management of elevated ICP — therapeutic LPs (drain to <20 cm H2O or to half the opening pressure), repeat daily until pressure controlled; consider lumbar drain or VP shunt for persistent hydrocephalus
Delay ART initiation by 4-6 weeks after starting antifungal therapy to reduce risk of cryptococcal IRIS
Non-HIV / non-transplant host: liposomal amphotericin B + flucytosine x 4 weeks, then fluconazole 400 mg daily 8 weeks, then 200 mg daily 6-12 months
Second-line / adjunct
Amphotericin B deoxycholate if liposomal unavailable (more nephrotoxicity)
Echinocandins are INACTIVE against Cryptococcus and should not be used
Fluconazole monotherapy only when amphotericin and flucytosine unavailable (inferior outcomes)
Cryptococcal antigen screening in HIV: preemptive fluconazole if positive without overt meningitis
Complications
Elevated intracranial pressure with permanent neurologic damage, blindness, or death — single most important determinant of outcome
Paradoxical cryptococcal IRIS, most often when ART is started too early: meningitis symptoms return, typically within the first weeks to 3 months of ART, as CD4 rises and viral load falls; CSF is more inflamed with high opening pressure but fungal culture is sterile (a positive culture means relapse instead), and CrAg stays positive for months so it cannot judge response; continue ART and fluconazole, relieve pressure with therapeutic LPs, and give corticosteroids only for severe IRIS
Hydrocephalus requiring shunting
Drug toxicity: amphotericin B nephrotoxicity and electrolyte wasting, flucytosine marrow suppression (monitor levels, target 25-100 microg/mL), fluconazole hepatotoxicity
Relapse if maintenance therapy stopped before immune recovery
PANCE pearls
Opening pressure management is at least as important as antifungal therapy in cryptococcal meningitis — drain CSF aggressively.
Echinocandins do NOT cover Cryptococcus — this is a high-yield exam point.
Delay ART by 4-6 weeks after antifungal initiation in HIV to reduce IRIS mortality (COAT trial).
Beta-D-glucan is typically NEGATIVE in cryptococcosis — use cryptococcal antigen instead.
C. gattii infects immunocompetent hosts and is endemic to the Pacific Northwest of the US and Canada.
Do NOT use dexamethasone (worse outcomes in the CryptoDex trial), acetazolamide, or mannitol to lower intracranial pressure in cryptococcal meningitis; repeated therapeutic lumbar puncture is the effective measure, and corticosteroids are reserved for severe IRIS.
References
IDSA 2010 — Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America (Perfect et al., Clin Infect Dis 2010)
WHO 2022 — WHO Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease among Adults, Adolescents and Children Living with HIV (2022)
AIDSinfo — Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV — Cryptococcosis section
AMBITION-cm 2022 — Jarvis JN et al., Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis (N Engl J Med 2022;386(12):1109-20)
CryptoDex 2016 — Beardsley J et al., Adjunctive Dexamethasone in HIV-Associated Cryptococcal Meningitis (N Engl J Med 2016;374(6):542-54)
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