Amita Gupta, M.D. and Karen Wendel, M.D.
Cryptococcus is a ubiquitous fungus and considered endemic in Zambia.
- Epidemiology of cryptococcosis unclear in Zambia, but generally reported as significantly more prevalent in sub-Saharan Africa vs. developing world.
- One Zambian study of patients with cryptococcal meningitis at University Teaching Hospital in Lusaka reported that it was AIDS -defining illness in 91% of patients and 4th most common reason for medical admission. Mortality rate was 100%, despite use of fluconazole monotherapy in approximately half of pts (given at lower than currently recommended doses).
- Recommendations for Dx and management of cryptococcal meningitis in Zambia largely similar to those in developed world.
- Azole (fluconazole) primary prophylaxis generally not recommended in developed world, may be beneficial in areas where cryptococcosis is common and could be considered for patients in severely immunocompromised in Zambia (WHO Stage 4 or CD4 <100) whether or not they are on ART.
- Clinical trials and more definitive recommendations for primarily azole prophylaxis in Africa currently in progress.
- Liposomal amphotericin preparations, voriconazole, posaconazole, and 5-FC not readily available in Zambia.
- Clinical role of cryptococcal antigen screening still being defined, but in patients with CD4<100, it appears to identify those at risk of meningitis, allowing an opportunity for targeted preemptive therapy.
Zambia Information Author: Larry William Chang, MD, MPH
Cryptococcus neoformans var. neoformans (serotypes A and D).
Cryptococcus neoformans var. gattii (serotypes B and C, rare in HIV).
Cryptococcus neoformans var. grubii (has been used to designate serotype A).
- Yeast-like round fungus, 5-10 µm with polysaccharide capsule
- Epidemiology: found worldwide in soil; major OI in sub-saharan Africa,Thailand, India. In US pre-HAART era5-8% of HIV+ pts developed cryptococcosis. Dramatically reduced incidence in HAART era.
- Infection via inhalation of fungus. Most common clinical syndrome in HIV is meningitis or meningoencephalitis. Less common pulmonary presentation with pneumonia can occur (focal infiltrates, nodules or rarely, cavitary lesions accompanied by low grade fever). Most pts with meningitis have no history of pneumonia and usually have CD4 <100.
- Less commonly can disseminate to other organs (skin, bone, prostate, eye). Skin lesions resembling molluscum contagiosum can occur in the setting of disseminated cryptococcosis.
- Sx of cryptococcal meningitis include gradually increasing headache with low grade fever (subacute meningitis). However, may also present without fever, with seizure, confusion, lethargy, progressive dementia, fever without localizing signs, or bizarre behavior. Evidence of meningeal irritation often absent.
- Reported mortality rate of meningitis 6-25%.
- CNS mass lesions or cryptococcomas usually accompanied by meningitis. Neck stiffness and photophobia only in 25-33% pts
- Elevated intracranial pressure (>200 mm H20) common and may be accompanied by evidence of cerebral edema: blurred vision, diplopia, hearing loss, severe headaches, confusion, and papilledema.
- Hydrocephalus can occur in more indolent cases and may require placement of CSF shunt.
- Pts who initiate HAART are at risk for cryptococcal IRIS (either unmasking type or exacerbation of partly treated disease). Presentations can be atypical, such as lymphadenitis.
- Cx for fungus: sputum, skin Bx, blood, and CSF. Blood Cx + in 50-70% with meningitis.
- Serum cryptococcal antigen (CrAg) positive in >99% of HIV+ pts with cryptococcal meningitis, less often with isolated pulmonary disease.
- CSF CrAg important tool to diagnose meningeal disease but can be negative in nonmeningeal cryptococcosis.
- Pts with evidence of pulmonary or systemic cryptococcosis by CrAg or Cx should undergo LP to rule out meningitis. Pts with focal signs or evidence of cerebral edema should have a head CT or MRI prior to LP to assure no mass effect or risk of herniation.
- CSF evaluation should include: opening pressure (up to 75% have >200 mm, fungal Cx, CrAg, glucose, protein, cell count and differential. CSF typically shows mild increase in protein, low-nl glucose, pleocytosis with lymphocytes, although some pts have no cells, which can be associated with more severe disease. CSF CrAg and fungal Cx positive in >95%. India ink less sensitive (60-80%).
- Pulmonary: positive sputum Cx or serum CrAg, clinical and CXR/CT findings
- In U.S., routine screening of asymptomatic pts with serum CrAg not recommended.
- First line: fluconazole 400 mg PO once-daily x10 wks followed by 200 mg PO once-daily lifelong or until CD4 >200 x 6 mos.
- Second line: itraconazole (liquid formulation preferred) 400 mg PO once-daily for 10 wks then 200 mg once-daily lifelong or until CD4 >200 x 6 mos; fluconazole 400 mg PO once-daily with flucytosine 100-150 mg/kg/d PO divided over 4 doses for 10 wks (toxicity limits utility of this regimen).
- First line: amphotericin B 0.7-1.0 mg/kg/day IV; lipid formulation of amphotericin 5mg/kg/day IV. Continue until pt improved clinically and stable for conversion to oral azole.
- Second line: In pts who can not tolerate amphotericin, fluconazole 400 mg PO once-daily x 10 wks followed by 200 mg PO once-daily lifelong; itraconazole (liquid formulation preferred) 400 mg PO once-daily for 10 wks then 200 mg once-daily lifelong; fluconazole 400 mg PO once-daily with flucytosine100-150 mg/kg/d PO divided over 4 doses for 10 wks (toxicity limits utility of this regimen).
- First line: amphotericin B 0.7-1 mg/kg/d IV OR lipid formulation 4-6 mg/kg/d IV (consider for pts with renal dysfunction or at high risk for renal failure) +/- flucytosine (5-FC) 100 mg/kg/d PO divided over 4 doses x 2 wks, then fluconazole 400 mg/d x8 wks or until CSF sterile. Addition of 5-FC associated with more rapid sterilization and decreased risk for subsequent relapse but often not well tolerated; monitor CBC and 5-FC levels.
- Second line: amphotericin B 0.7-1 mg/kg/d IV plus 5-FC100 mg/kg/d PO divided over 4 doses for 6-10 wks; amphotericin B (or lipid formulation, dose as first line) plus fluconazole 400 mg PO or IV daily; amphotericin B 0.7-1 mg/kg/d for 6-10 wks; fluconazole 400-800 mg/d PO for 10-12 wks; fluconazole 400-800 mg/d PO with 5-FC 100-150 mg/kg/d PO divided over 4 doses for 6 wks; lipid formulation of amphotericin B 4-5 mg/kg/d IV for 6-10 wks. Itraconazole 400 mg/d PO (liquid formulation preferred) for 10-12 wks can be given but is less effective than fluconazole.
- Combination of amphotericin B with fluconazole 400 mg PO once-daily inferior to amphotericin + 5-FC but more effective than amphotericin B alone for clearing crypto from CSF.
- First line: fluconazole 200 mg PO once-daily.
- Second line: itraconazole 200 mg PO twice-daily; amphotericin B 1 mg/kg IV 1-3 times/wk. Intermittent amphotericin therapy associated with higher rate of relapse and greater toxicity compared to fluconazole.
- ART may improve immunology control and decrease rates of relapse. See follow-up section regarding recommendations for discontinuing maintenance therapy.
- Elevated ICP is most common cause of death or neurologic sequelae with cryptococcal meningitis, and should be managed aggressively.
- If ICP >250 mm and signs of cerebral edema present, do daily LP to reduce pressure until pt is improved. One approach is to remove volume of CSF that halves opening pressure (typically 20-30 ml) .
- If clinical signs of cerebral edema do not improve after about 2 wks of daily LPs, consider placement of lumbar drain or VP shunt.
- Pts with hydrocephalus may or may not have increased ICP and rarely have cerebral edema.
- Corticosteroids, mannitol and acetazolamide not recommended.
- Primary prevention with azoles not recommended due to relative infrequency of infection, low attributable mortality, risk of toxicity and resistance, and no evidence of survival benefit.
| Amphotericin B ||Gold standard for initial therapy. Intrathecal amphotericin should only be used in cases refractory to standard IV amphotericin +/- flucytosine.
| Fluconazole ||Drug of choice for maintenance therapy. Fluconazole superior to itraconazole in preventing relapse. All azoles should be avoided during pregnancy. If a women has active cryptococcosis during pregnancy, consider a switch to IV amphotericin B.
| Flucytosine ||Can be used in combination with amphotericin for initial therapy. Favor use of this drug in severe cases characterized by increased ICP or change in mental status. Therapy should be monitored with peak levels drawn 2 hrs after oral dose (50-100 mcg/mL), should not exceed 75 mcg/ml. No IV formulation.
| Itraconazole ||Uncommonly used in place of fluconazole for maintenance therapy. Multiple drug interactions require caution when prescribing this medication. Liquid formulation preferred due to improved bioavailability. Liquid formulation should be taken on empty stomach. Capsule formulation should be taken with food. Drug levels should be monitored with peak level drawn 2 hrs after dosing after >5 days of therapy with goal of >1 ug/mL (native drug).
|Voriconazole ||In vitro activity. Limited data specific to cryptococcal meningitis. Given substantial risk of drug interactions with ART and lack of data to support use over fluconazole for this indication; would avoid its use.
|Posaconazole ||In vitro activity. May have a role for complex, refractory CNS fungal infections but data supporting its use for this indication are limited. Other options are cheaper and better studied.
|echinocandins ||No in vitro activity; should not be used.
- In pre-HAART era, risk of relapse was 4% in on maintenance therapy but up to 37-60% in those who discontinued therapy.
- Pts should remain on maintenance therapy until they are asymptomatic, have had >6 mos with CD4 >200 on HAART and have completed initial course of antifungal therapy.
- If after discontinuation of maintenance therapy, the CD4 falls to <100-200, reinitiate maintenance therapy.
- Monitor for treatment related toxicity on bi-weekly schedule during induction phase and every other wk on consolidation phase.
5-FC: severe colitis, leukopenia, thrombocytopenia, rash, or hepatitis. Dosage should be reduced for cytopenias or colitis and levels monitored to limit toxicity. Addition of 5-FC to amphotericin B provides only marginal benefit at most. 5-FC may be held if toxicity encountered that cannot be controlled with dosing changes.
- Azoles: liver toxicity.
Amphotericin B: electrolyte imbalances, renal insufficiency, anemia, acute infusion-related toxicity and may require close monitoring. Liposomal formulation less toxic.
- Perform fungal Cx. Serum CrAg not reliable to evaluate pts for relapse of cryptococcal disease. If convalescence CSF CrAg titer available for comparison, an increase in titer of 2 dilutions suggests relapse.
- Fungal Cx may help differentiate between relapse and IRIS. IRIS after initiation of ART can include worsening meningitis with elevated ICP, lymphadenitis, sterile abscess, or cavitation of pulmonary lesions.
- Treatment failure defined as either lack of clinical improvement after 2 wks of appropriate therapy, relapse after initial response (positive CSF Cx and/or compatible clinical picture with rising CSF CrAg). Optimal therapy not defined. If started on fluconazole switch to amphotericin B +/- 5-FC. Consider liposomal amphotericin or higher doses of fluconazole or addition of flucytosine.
- After initial 2 wks of treatment, repeat LP should be performed to ensure organism has been cleared from CSF. Positive Cx at 2 wks predictve of future relapse and can be associated with less favorable outcomes.
- When to start ART in setting of cryptococcal meningitis unknown. Some data from US with small number of cases (ACTG 5164) favor early ART, but data from Uganda suggest increased mortality with early initiation (within 2 wks of Dx). 2009 OI guidelines suggest delaying initiation at least until completion of induction of therapy, especially with elevated ICP.
- IRIS can occur in up to 30%. With severe symptoms, consider cocorticosteroids.
- Antifungal resistance testing should be limited to pts with multiple recurrences or disease in setting of adherence to standard therapy, as fluconazole or amphotericin resistance is rare.