Cryptococcosis Flashcards
What is the most common cause of HIV-associated cryptococcal infections?
Cryptococcus neoformans
Occasionally, Cryptococcus gattii may also be a cause.
Where is Cryptococcus gattii most often found?
Australia and similar subtropical regions, and in the U.S. Pacific Northwest.
What percentage of people with advanced HIV had disseminated cryptococcosis before effective antiretroviral therapy (ART)?
5% to 8%.
How many cases of cryptococcal infection in people with AIDS occur worldwide each year?
Approximately 280,000 cases.
What percentage of AIDS-related deaths is accounted for by cryptococcal disease?
15%.
What CD4 T lymphocyte cell count is associated with 90% of cryptococcal cases in people with HIV?
CD4 counts <100 cells/mm3.
What are common clinical manifestations of cryptococcosis in people with HIV?
Subacute meningitis or meningoencephalitis with fever, malaise, and headache.
What is the median duration for the development of symptoms in cryptococcosis?
2 weeks.
True or False: Classic meningeal symptoms occur in most people with cryptococcosis.
False.
What are some encephalopathic symptoms associated with cryptococcosis?
- Lethargy
- Altered mentation
- Personality changes
- Memory loss.
How can isolated pulmonary infection from cryptococcosis present?
Cough and dyspnea with abnormal chest radiograph.
What does analysis of cerebrospinal fluid (CSF) usually show in cryptococcosis?
- Mildly elevated protein levels
- Low-to-normal glucose concentrations
- Variable pleocytosis.
What is the significance of a positive cryptococcal antigen (CrAg) test?
It indicates the presence of cryptococcal infection.
What is the preferred method for detecting cryptococcal disease?
Culture, CSF microscopy, cryptococcal antigen detection, or CSF polymerase chain reaction (PCR).
What is the sensitivity of the BioFire FilmArray Meningitis/Encephalitis Panel PCR assay?
It performs well in infections with a moderate-to-high fungal burden.
What are the three methods for antigen detection in cryptococcosis?
- Latex agglutination
- Enzyme immunoassay (EIA)
- Lateral flow assay (LFA).
What should be done if a patient with HIV has a negative CSF PCR?
Perform CrAg testing of CSF and blood simultaneously.
What is the recommended action for patients with HIV and CD4 counts ≤200 cells/mm3?
Routine surveillance testing for serum CrAg.
What prophylactic treatment can reduce the frequency of primary cryptococcal disease?
Fluconazole or itraconazole.
What is the duration of induction therapy for treating cryptococcosis?
2 weeks.
What is the preferred regimen for induction therapy in the United States?
Liposomal amphotericin B 3–4 mg/kg IV once daily plus flucytosine 25 mg/kg PO four times a day.
What is the duration for consolidation therapy after induction therapy?
At least 8 weeks.
What is the preferred regimen for maintenance therapy?
Fluconazole 200 mg PO once daily for ≥1 year.
What is the criterion for stopping maintenance therapy?
At least 1 year from initiation of antifungal therapy and CD4 count ≥100 cells/mm3.
What are the alternative regimens for treating cryptococcosis?
- Amphotericin B lipid complex 5 mg/kg IV daily
- Itraconazole 200 mg PO twice a day.
What should be done if a patient’s CD4 count declines to <100 cells/mm3?
Restart maintenance therapy.
What is the recommended treatment for Non-CNS extrapulmonary disease with cryptococcal antigenemia?
Administer the same treatment as for cryptococcal meningitis
This includes cases with normal CSF and serum CrAg titer ≥1:640 by LFA (or ≥1:160 by EIA or latex agglutination) (BIII)
What is the treatment for Non-CNS focal pulmonary infiltrates with mild symptoms and negative serum CrAg?
Fluconazole 400 mg daily for 6 to 12 months
Duration is guided by symptom resolution (BIII)
What is the treatment regimen for isolated asymptomatic cryptococcal antigenemia with serum CrAg titer <1:640?
Fluconazole 800–1,200 mg PO daily for 2 weeks, followed by fluconazole 400–800 mg PO daily for 10 weeks, then 200 mg PO daily for a total of 6 months plus effective ART (BIII)
Lower risk patients with serum CrAg titer <1:80 by LFA can be treated without lumbar puncture (AI)
What is the preferred therapy for cryptococcal disease during the first trimester of pregnancy?
Amphotericin B deoxycholate 0.7–1.0 mg/kg IV daily or lipid formulation amphotericin B 3–4 mg/kg IV daily (AIII)
Flucytosine addition should be considered only when benefits outweigh risks, ideally delayed until after the first trimester (AIII)
What are the three phases of treatment for CNS and disseminated cryptococcal disease?
Induction, consolidation, and maintenance
Each phase has specific treatment protocols and monitoring requirements.
What is the recommended induction therapy for cryptococcal meningitis in resource-available settings?
Amphotericin B formulation IV plus oral flucytosine for 2 weeks (AII)
Lipid formulations are preferred due to lower toxicity.
What is the recommended induction therapy in resource-limited health care settings?
Single dose of liposomal amphotericin B (10 mg/kg) followed by 2 weeks of flucytosine and fluconazole (AI)
This regimen aims for effective treatment with fewer resources.
What monitoring is required during induction therapy for cryptococcal meningitis?
Patients must be monitored in the hospital for at least 7 days and ideally 14 days (AII)
Lumbar punctures should be performed on Day 7 and Day 14.
What is the recommended consolidation therapy after successful induction therapy?
Fluconazole 800 mg daily for at least 8 weeks (AII)
This is to prevent breakthrough infections during consolidation.
What should be done if a patient shows no clinical improvement after 2 weeks of induction therapy?
Continue or start amphotericin B plus flucytosine until CSF fungal cultures are confirmed negative (BIII)
This ensures effective treatment is maintained.
What alternatives can be used for consolidation therapy if fluconazole is not available?
Itraconazole 200 mg twice per day (CI)
Itraconazole is inferior to fluconazole.
What is the maintenance therapy for cryptococcal disease?
Fluconazole 200 mg per day until at least 1 year from initiation of antifungal treatment
This helps prevent recurrence of the disease.
True or False: Echinocandins are recommended for the clinical management of cryptococcosis.
False
Echinocandins have no clinical activity against Cryptococcus spp.
What should be monitored closely when using flucytosine?
Therapeutic drug monitoring, particularly in patients with renal impairment
Serum peak concentrations should be between 25 mg/L and 100 mg/L.
What is the significance of CSF culture results after induction therapy?
Successful induction is defined by substantial clinical improvement and a negative CSF culture
Positive CSF CrAg may not indicate treatment failure at Week 2.
What is the recommended initial management for cryptococcosis?
Posaconazole, voriconazole, and isavuconazole are not recommended for initial management or maintenance therapy
Echinocandins have no clinical activity against Cryptococcus spp. and are not recommended.
What is the maintenance therapy for cryptococcosis?
Fluconazole 200 mg per day for at least 1 year from initiation of antifungal therapy
Assumes immune reconstitution on ART and patient is asymptomatic.
How should non-CNS extrapulmonary cryptococcosis be treated?
Same as CNS disease
Mild symptoms with focal pulmonary infiltrates may be treated with fluconazole 400 mg per day for 6 to 12 months.
What should be done for patients with non-CNS extrapulmonary symptoms and cryptococcal antigenemia?
CSF should be sampled to rule out CNS disease
If serum CrAg titer is ≥1:640, treat as patients with cryptococcal meningitis.
When should CSF be sampled in patients with asymptomatic cryptococcal antigenemia?
Dependent on underlying risk and serum CrAg titer
Lower risk patients with serum CrAg <1:80 can be treated without lumbar puncture.
What is the recommended fluconazole regimen for fully asymptomatic cryptococcal antigenemia?
Fluconazole 800 to 1,200 mg per day for 2 weeks, followed by 400 to 800 mg per day for 10 weeks, then 200 mg daily for a total of 6 months
Should be combined with effective ART.
When should ART be initiated in patients with CNS cryptococcosis?
Generally deferred for 4 to 6 weeks after starting antifungal therapy
Early ART can increase mortality in some cases.
What was the outcome of the trial comparing early versus delayed ART initiation?
Greater increase in 6-month mortality in the early ART group (45% vs. 30%)
Most pronounced in the first 8 to 30 days.
What is the recommended approach for ART initiation in patients with non-CNS cryptococcosis?
Delay ART initiation for 2 weeks after starting antifungal therapy
Risk of symptomatic IRIS appears to be lower.
What are common side effects of higher dose fluconazole therapy?
Dry skin (17%), alopecia (16%)
Increased liver transaminases are rare at doses of 400 to 800 mg.
What is the risk of IRIS in patients with cryptococcal meningitis after starting ART?
10 to 30% may experience IRIS
Both unmasking and paradoxical IRIS may occur.
How can the risk of IRIS be minimized in patients with cryptococcal meningitis?
Achieving CSF culture sterility before starting ART and deferring ART initiation for 4 to 6 weeks
Using fluconazole 800 mg per day as consolidation therapy also helps.
What is the management strategy for IRIS?
Continue both ART and antifungal therapy, reduce elevated ICP if present
Difficult to distinguish IRIS from treatment failure.
What should be done if a patient’s CSF opening pressure is ≥25 cm CSF?
Immediate clinical intervention to reduce ICP is required
Increased ICP is associated with high mortality rates.
What is recommended for initial management of elevated ICP in cryptococcal meningitis?
Drainage of CSF via lumbar puncture
Aim to reduce opening pressure by at least 50%.
What are the recommendations for therapeutic lumbar punctures in cryptococcal meningitis?
Repeat daily until symptoms improve and opening pressure normalizes to <20 cm CSF
Strong consideration for repeating within 72 hours if initial pressure was <25 cm CSF.
What should be monitored in patients treated with amphotericin B?
Nephrotoxicity and electrolyte disturbances
Pre-infusion saline administration reduces nephrotoxicity risk.
What are the side effects associated with flucytosine?
Concentration-dependent bone marrow toxicity, hepatotoxicity, gastrointestinal toxicities
Monitoring is necessary for dosage adjustments.
What should be done for patients experiencing amphotericin B infusion reactions?
Administer acetaminophen and diphenhydramine or hydrocortisone before infusion
Meperidine can be used for amphotericin B–associated rigors.
What does a negative PCR test indicate in the context of CSF cultures?
A negative PCR test has a high predictive value for sterile CSF cultures and can help distinguish between paradoxical IRIS and culture-positive relapse.
What is the recommended management strategy for IRIS?
Continue both ART and antifungal therapy, reduce elevated ICP, and consider escalating antifungal therapy.
What corticosteroid dosage is commonly recommended for severe symptoms of IRIS?
Starting at 1.0 mg/kg per day of prednisone.
What does elevated serum C-reactive protein (CRP) indicate at the time of IRIS development?
CRP is generally elevated and will decrease with corticosteroid therapy if IRIS is present.
How does the risk of IRIS differ among various forms of cryptococcosis?
The risk of IRIS is much lower and less severe with forms like lymphadenitis, cutaneous abscesses, and bony lesions compared to cryptococcal meningitis.
Define treatment failure in the context of cryptococcal therapy.
Treatment failure is defined by lack of clinical improvement and continued positive cultures after 2 weeks of therapy or relapse after initial clinical response.
What should be done if treatment failure or relapse occurs with Cryptococcus?
Cryptococcus isolates should undergo antifungal susceptibility testing.
What is the preferred regimen for patients with treatment failure after induction?
Start preferred regimens or continue amphotericin B until clinical response occurs.
What is the recommended outpatient consolidation therapy after achieving CSF sterility?
Fluconazole at a higher dose of 1,200 mg per day and optimization of ART.
What is the recommended chronic maintenance therapy after completing induction for cryptococcal meningitis?
Fluconazole 200 mg per day for at least 1 year.
When can maintenance therapy for cryptococcosis be discontinued?
After at least 1 year from initiation if CD4 counts are ≥100 cells/mm3 with undetectable viral loads.
What is the risk associated with fluconazole use during the first trimester of pregnancy?
Fluconazole has teratogenic potential and may lead to congenital malformations.
What should be the approach for pregnant individuals with cryptococcal infections?
Treatment should be initiated promptly, with attention to management of increased ICP.
What is the recommendation regarding ART initiation in pregnant individuals with CNS cryptococcal infection?
Start ART as expeditiously as possible to reduce the risk of perinatal transmission of HIV.
What is the preferred therapy for cryptococcosis in the first trimester of pregnancy?
Amphotericin B deoxycholate is preferred and has not been associated with teratogenicity.
What should be considered when using flucytosine during pregnancy?
Flucytosine should be delayed until after the first trimester when feasible due to teratogenic potential.
What is the recommendation regarding azole antifungals during the first trimester of pregnancy?
Azole antifungals should generally be avoided unless the benefits outweigh the risks.
What findings have been reported regarding fluconazole exposure during pregnancy?
Increased prevalence of heart defects and other congenital malformations.
What is the recommendation for switching to oral fluconazole after the first trimester?
Switching to oral fluconazole may be considered if appropriate clinically for consolidation or maintenance therapy.
What is the conclusion about itraconazole exposure during pregnancy?
No significant difference in overall risk of birth defects compared to non-exposed groups.
What is the recommendation for voriconazole, posaconazole, and isavuconazole during pregnancy?
They are not recommended, especially in the first trimester.
