Cryptococcal Disease

Background

Cryptococcosis usually presents as 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: Plan

Diagnostic 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.

Treatment

Cryptococcal 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 at least 2 weeks of induction therapy.

Preferred therapy:

  • Liposomal amphotericin B 3-4 mg/kg IV QD + flucytosine 25 mg/kg PO QID

Lipid formulations of amphotericin B are less nephrotoxic than amphotericin B deoxycholate and appear to be equally effective. Amphotericin-based therapy, in combination with flucytosine, is recommended. If these are not available, are contraindicated, or are not tolerated by the patient, the other indicated induction therapies may be considered.

Alternative therapy:

  • Amphotericin B lipid complex 5 mg/kg IV QD + flucytosine 25 mg/kg PO QID
  • Amphotericin B deoxycholate 0.7-1.0 mg/kg IV QD + flucytosine 25 mg/kg PO QID
  • Liposomal amphotericin B 3-4 mg/kg IV QD + fluconazole 800 mg PO or IV QD
  • Amphotericin B deoxycholate 0.7-1.0 mg/kg IV QD + fluconazole 800 mg PO or IV QD
  • Liposomal amphotericin B 3-4 mg/kg IV QD alone
  • Fluconazole 400-800 mg PO or IV QD + flucytosine 25 mg/kg PO QID
  • Fluconazole 1,200 mg PO or IV QD alone

The primary alternative to amphotericin-based therapy is high-dose fluconazole (800-1,200 mg PO QD), 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.

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. Liposomal forms of amphotericin cause fewer adverse effects. These should be should be used particularly for patients who have difficulty tolerating standard amphotericin B and for those who are at high risk of renal failure. Electrolytes and creatinine should be monitored. Flucytosine is associated with bone marrow and liver toxicity, and complete blood counts and liver function tests 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.

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 QD for at least 8 weeks). Itraconazole (200 mg PO BID) is 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 QD) to prevent recurrence of cryptococcosis.

Maintenance therapy should be continued for life, unless the patient has completed induction and consolidation therapy followed by at least 1 year of maintenance therapy, and has sustained CD4 cell recovery in response to effective antiretroviral therapy (ART) (CD4 count ≥100 cells/µL for at least 3 months during ART). Maintenance therapy should be restarted if the CD4 count declines to <100 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 and chest imaging shows focal infiltrates: 400 mg PO QD for 12 months, then 200 mg QD for maintenance. Otherwise, consider amphotericin induction, as described above with CNS disease. Maintenance therapy should be continued for life, unless the patient has sustained CD4 cell recovery in response to effective ART (CD4 count of ≥100 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 <100 cells/µL.

Cutaneous infection, with negative CSF CrAg and culture results

Treat with fluconazole 400 mg PO QD for 6-12 months, then continue with 200 mg QD 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 QD 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 starting treatment for 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 not known. Some experts recommend treating severe cryptococcosis with effective antifungal therapy for 2-10 weeks before starting ART, to decrease the risk of IRIS. On the other hand, if the CD4 count is very low (e.g., <50 copies/µL), it is important to initiate ART as soon as possible.

Other treatment notes

Pregnancy

Fluconazole and other azole drugs should be avoided during the first trimester of pregnancy, and voriconazole and posaconazole should be avoided throughout pregnancy. During the first and second trimesters, pregnant women should be treated with amphotericin for both induction and consolidation therapy. Flucytosine is teratogenic at high doses in rats and is classified as a pregnancy class C drug; 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), elvitegravir/cobicistat, 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 relevant tables in the U.S. Department of Health and Human Services 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.
  • Antiretroviral therapy and improvement in immune system health are essential for prevention of recurrence.
  • Patients should avoid pregnancy while taking any oral antifungal drug. Fetal craniofacial and skeletal abnormalities have been reported.

References

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly