Clinical Guide > Comorbidities and Complications > Cryptococcal Disease

# Cryptococcal Disease

January 2011

### Chapter Contents

      - Background 
      - S: SubjectiveO: ObjectiveA: AssessmentP: PlanPatient Education
ReferencesPotential ARV Interactions
Background 
Cryptococcosis is a systemic or central nervous system (CNS) fungal infection caused by the yeast *Cryptococcus neoformans*. The organism is ubiquitous, and is particularly plentiful in soils enriched with bird droppings. It also may be present in fruit skins or juices, and in unpasteurized milk. In immunocompetent patients, cryptococcal infection usually is asymptomatic, self-limited, and confined to the lungs. In persons with advanced HIV infection (e.g., those with CD4 counts of <100 cells/µL), *Cryptococcus* may cause life-threatening illness, either from a new exposure or through reactivation of a previously acquired latent infection.

In HIV-infected patients, *Cryptococcus* can infect almost all organs in the body, but most commonly causes meningitis or meningoencephalitis. Disseminated disease, pneumonia, and skin lesions also may be seen.
S: Subjective
Symptoms depend upon the locus of infection. In the case of meningitis, the patient typically experiences subacute onset of fever, headaches, and malaise, which worsen over the course of several weeks. These symptoms may be accompanied by nausea with or without vomiting. Classic meningeal signs, nuchal rigidity, and photophobia are present in only about 25% of cases. Cryptococcal meningitis may cause confusion, personality or behavior changes, blindness, deafness, and, if left untreated, coma and death. If the disease involves the lungs, patients may experience cough or shortness of breath, pleuritic chest pain, and fever. Skin lesions may be present.
O: Objective
Perform a thorough physical examination with particular attention to the following:
- Vital signs, hydration status
-  Funduscopic findings
- Neck (for nuchal rigidity, which is uncommon)
-  Lungs, especially if respiratory symptoms are present
-  Neurologic evaluation, including cranial nerves, visual acuity, and mental status
-  Skin
Cryptococcal Meningitis
Physical examination may reveal papilledema with loss of visual acuity and cranial nerve deficits (particularly in cranial nerves III and VI).
Cryptococcal Pulmonary Disease
Examination may reveal tachypnea or fine rales.
Cutaneous Infection
Skin lesions are variable and may appear as papules, nodules, or ulcers; they often resemble molluscum lesions.
A: Assessment
The differential diagnosis for cryptococcal meningitis or meningoencephalitis is broad and includes other infectious causes of meningitis (fungal, mycobacterial, bacterial, viral), syphilis, lymphoma, mass lesions, intoxication, HIV encephalopathy, and trauma. (See chapter *Neurologic Symptoms*.)

The differential diagnosis for cryptococcal pneumonia is broad and includes other infectious causes of pneumonia (fungal, mycobacterial, bacterial, viral), malignancy, and congestive heart failure. (See chapter *Pulmonary Symptoms*.)
P: PlanDiagnostic Evaluation
The workup should include serum cryptococcal antigen (CrAg), which usually is very sensitive, and blood cultures, including bacterial, acid-fast bacilli (AFB), and fungal cultures. Patients with symptoms of disseminated or pulmonary infection should be evaluated by chest X ray (which may show diffuse or focal infiltrates, sometimes appearing as nodular or miliary; intrathoracic adenopathy; or pleural effusions), sputum culture (including fungal and AFB cultures), and AFB stain. Bronchoscopy and bronchoalveolar lavage may be necessary for diagnosis. For cutaneous lesions, consider biopsy and histopathologic evaluation or culture. As part of the general fever workup, urinalysis and urine cultures should be checked.

Patients with a positive serum CrAg, another positive test for *Cryptococcus*, or signs or symptoms of meningitis should undergo analysis of the cerebrospinal fluid (CSF). If neurologic symptoms or signs are present, obtain a computed tomography (CT) scan of the brain before performing a lumbar puncture (LP) to rule out a mass lesion or increased intracranial pressure (ICP), which could cause herniation upon LP. Always measure the CSF opening pressure; a high ICP contributes to morbidity and mortality and determines the need for serial LP to manage the increased ICP. Send the CSF for the following:
- CrAg (usually positive at high titer in meningitis)
- Fungal culture
- India ink stain (less sensitive than CSF CrAg; perform if CSF CrAg is not available)
- Cell count
- Glucose
- Protein

For exclusion of other etiologies, perform CSF Venereal Disease Research Laboratory (VDRL) test, bacterial culture, AFB smear and culture, or polymerase chain reaction (PCR), if tuberculosis is suspected, and other tests as indicated by the patient's symptoms and exposures.
TreatmentCryptococcal meningitis
Acute treatment of cryptococcal meningitis consists of two phases: induction and consolidation. Acute treatment is followed by chronic maintenance (suppressive) therapy.
Induction
Patients with cryptococcal meningitis should be hospitalized to start 2 weeks of induction therapy with amphotericin B (0.7 mg/kg/day) IV plus flucytosine (25 mg/kg) PO Q6H.

Amphotericin B causes many adverse effects, including fever, rigors, hypotension, nausea, nephrotoxicity and electrolyte disturbances, anemia, and leukopenia. The patient's hemoglobin, white blood cell (WBC) count, platelets, electrolytes, magnesium, and creatinine must be monitored closely during treatment. Note that liposomal forms of amphotericin (AmBisome and Abelcet) cause fewer adverse effects and appear to be effective, although data on use for treatment of cryptococcal meningitis are limited. These liposomal forms should be considered for patients who have difficulty tolerating standard amphotericin B and for those who are at high risk of renal failure. Flucytosine is associated with bone marrow toxicity, and complete blood counts should be monitored during induction therapy. If available, flucytosine levels can be evaluated 3-5 days after the start of therapy, with a target 2 hour post-dose level of 30-80 mg/mL; a level of >100 mg/mL should be avoided. Note that the dosage of flucytosine must be adjusted for patients with renal insufficiency.

If amphotericin is not available, is contraindicated, or is not tolerated by the patient, alternative induction therapies may be considered. The primary alternative to amphotericin-based therapy is high-dose fluconazole (800-1,200 mg PO once daily), with or without flucytosine. Among the newer antifungal agents, echinocandins have no activity against *Cryptococcus*. Voriconazole and posaconazole have good in vitro activity and may be considered for treatment of relapsed disease but not as first-line agents. The efficacy of alternative regimens is not well defined. See "Potential ARV Interactions," below, regarding drug-drug interactions between these antifungals and ARVs.

Resistance testing may be considered for patients who have relapsed and for those for whom fluconazole failed to sterilize the CSF.
Consolidation
After clinical improvement with 2 weeks of induction therapy, and a negative CSF culture on repeat LP, treatment can be switched to fluconazole (400 mg PO once daily to complete 8 weeks of acute treatment). Itraconazole (200 mg PO BID) sometimes is used as an alternative for patients who cannot take fluconazole. It should be noted that itraconazole is less effective than fluconazole and has significant drug interactions with commonly used medications.
Maintenance
After completing acute treatment, the patient should receive chronic maintenance therapy with fluconazole (200 mg PO once daily) to prevent recurrence of cryptococcosis. An alternative treatment is itraconazole (200 mg PO once daily or BID)--with the caution indicated above.

Maintenance therapy should be continued for life, unless the patient has sustained CD4 cell recovery in response to effective antiretroviral therapy (ART) (CD4 count >200 cells/µL for at least 6 months during ART). Maintenance therapy should be restarted if the CD4 count declines to <200 cells/µL.
Management of elevated ICP
Elevated ICP significantly increases the morbidity and mortality of cryptococcal meningitis and should be treated by the removal of CSF. The CSF opening pressure should be checked on the initial LP. If the initial opening pressure is >250 mm H2O, remove up to 30 mL of CSF to lower the ICP by 50%, if possible. LP and CSF removal should be repeated daily as needed for ICP reduction. A lumbar drain or ventriculoperitoneal shunt may be needed if the initial opening pressure is >400 mm H2O, or in refractory cases. There is no role for acetazolamide, mannitol, or steroids in the treatment of elevated ICP.

A repeat LP is not required for patients who did not have elevated ICP at baseline and are responding to treatment. If new symptoms develop, a repeat LP is indicated. Serum CrAg titers are not useful in monitoring response to treatment.
Cryptococcal pulmonary disease, with negative CSF CrAg and culture results
After CSF cryptococcal disease has been excluded, treat with fluconazole if symptoms are mild or moderate, 400 mg PO once daily for 6-12 months, then 200 mg once daily for maintenance. Otherwise, consider amphotericin induction, as described above with CNS disease. Monitor fungal blood cultures and CrAg to verify the effectiveness of therapy. Itraconazole may be used as an alternative (200 mg PO BID for capsules; 100-200 mg once daily for oral suspension). Therapy should be continued for life, unless the patient has sustained CD4 cell recovery in response to effective ART (CD4 count of >200 cells/µL for at least 6 months during ART) and with a minimum of 12 months of antifungal therapy. Therapy should be restarted if the CD4 count declines to <200 cells/µL.
Cutaneous infection, with negative CSF CrAg and culture results
Treat with fluconazole 400 mg PO once daily for 6-12 months, then continue with 200 mg once daily for chronic maintenance therapy, as discussed above.
Asymptomatic antigenemia
Data are limited for management of asymptomatic antigenemia, which can be associated with development of subsequent disease. Fungal cultures of CSF and blood should be obtained; if either result is positive for cryptococcal growth, treatment should be initiated for symptomatic meningoencephalitis or disseminated disease. If no meningoencephalitis is found, fluconazole 400 mg PO once daily should be given until immune reconstitution occurs; treatment may be discontinued per maintenance guidelines described above.
Cryptococcus IRIS
Immune reconstitution through ART is effective for preventing recurrence of cryptococcal infections. However, initiating ART within the first 1-2 months after cryptococcal infection may result in worsening or recurrence of symptoms because of immune reconstitution inflammatory syndrome (IRIS). IRIS can be life-threatening in cryptococcal meningeal disease. IRIS and relapse of cryptococcal disease (e.g., treatment failure) must be differentiated; in IRIS, the serum and CSF cultures are negative. (See chapter *Immune Reconstitution Inflammatory Syndrome*.)

Optimal timing of ART initiation in cryptococcal CNS disease is unknown. Some experts recommend treating cryptococcosis with effective antifungal therapy for 1-2 months before starting ART, to decrease the risk of IRIS.
Other treatment notesPregnancy
Fluconazole and other azole drugs are not recommended for use during pregnancy, especially in the first trimester. During the first trimester, pregnant women should be treated with amphotericin for both induction and consolidation therapy. Flucytosine is teratogenic at high doses in rats and class C in humans; it should be used during pregnancy only if the benefits clearly outweigh the risks.
Preventive therapy
Studies have suggested that routine primary prophylaxis for cryptococcal disease in patients with CD4 counts of <100 cells/µL is effective at preventing cryptococcal infection but is not cost efficient. Therefore, it is not routinely recommended.
Potential ARV Interactions
There may be significant drug-drug interactions between certain systemic antifungals, particularly itraconazole, voriconazole, and posaconazole, and ritonavir-boosted protease inhibitors (PIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), or maraviroc. Some combinations are contraindicated and others require dosage adjustment of the ARV, the antifungal, or both. Check for adverse drug interactions before prescribing. For example, voriconazole use is not recommended for patients taking ritonavir-boosted PIs, and dosage adjustment of both voriconazole and NNRTIs may be required when voriconazole is used concurrently with NNRTIs. See Tables 15a-e of the U.S. Department of Health and *Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents*, or consult with an expert.
Patient Education- Cryptococcosis is not curable in persons with low CD4 cell counts and may require lifelong treatment. Patients should be instructed to take their treatment without interruptions.
- Even with therapy, disease may recur. Patients should report fevers or recurrence of other symptoms immediately.
- Patients should avoid pregnancy while taking any oral antifungal drug. Fetal craniofacial and skeletal abnormalities have been reported.
References- Bicanic T, Harrison TS.  Cryptococcal meningitis . Br Med Bull. 2005 Apr 18;72:99-118.
- Brouwer AE, Rajanuwong A, Chierakul W, et al.  Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial . Lancet. 2004 May 29;363(9423):1764-7.
- Centers for Disease Control and Prevention.  Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America . April 10, 2009.
- McNicholl I.  Database of Antiretroviral Drug Interactions . In: Coffey S, Volberding PA, eds. HIV InSite. San Francisco: UCSF Center for HIV Information.Accessed June 30, 2010.
- Nussbaum JC, Jackson A, Namarika D, et al.  Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi . Clin Infect Dis. 2010 Feb 1;50(3):338-44.
- Perfect JR, Dismukes WE, Dromer F, et al.  Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America . Clin Infect Dis. 2010 Feb 1;50(3):291-322.