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Management Recommendations > Cryptococcosis

Ward 86 Management Recommendations

Diagnosis and Management of AIDS-Related Cryptococcal Infection

updated August 2018

Contributors: Mark Jacobson, MD
Elvin H. Geng, MD

  1. A serum cryptococcal antigen (CrAg) assay should be ordered for any patient with a CD4 count of <100 cells/µL who has unexplained fever, headache, altered mental status, or signs of pneumonia.

    Invasive cryptococcal disease is one of the most common life-threatening opportunistic infections associated with advanced HIV disease, both in the United States and in resource-limited settings around the world. It occurs almost exclusively in patients who have a CD4 count of <100 cells/µL and are not taking antiretroviral therapy. It can present as meningitis, pneumonia, granulomatous skin lesions with an "apple-jelly" or molluscum-like appearance, or fungemia without specific end-organ involvement. Diagnosis can be simply and rapidly confirmed with a positive serum or cerebrospinal fluid (CSF) CrAg test result. Serum CrAg is a highly sensitive and specific test (>98%) for invasive cryptococcal disease, including meningitis, but it is not specific for meningitis. CSF CrAg is approximately 90% sensitive and 100% specific for cryptococcal meningitis, with fungal culture positivity being the gold standard.(1)

  2. The CrAg assay should be used only for diagnosis, not for evaluating response to antifungal treatment. Fungal culture is the gold standard for confirming the success or failure of therapy.

    Because the CrAg assay detects a fungal polysaccharide antigen that cannot be metabolized by mammalian enzymes, neither serum nor CSF CrAg is useful in monitoring patients' response to therapy.(2) Similarly, the appearance of yeast in stained biopsied specimens or CSF obtained after treatment has been initiated is not informative about the viability of organisms or the efficacy of treatment. Culture of cryptococcus is the only gold standard for cure or relapse.

    Serum CrAg screening of asymptomatic patients with low CD4 counts, as well as fluconazole prophylaxis for this fungal infection, have been demonstrated to lack clinical utility in the United States, primarily because of the low incidence of this opportunistic infection. However, in resource-limited settings that have higher incidences of invasive cryptococcal disease among patients with AIDS, serum CrAg screening of antiretroviral-naive HIV-infected adults with CD4 counts of <100 cells/µL has become standard of care, and preemptive fluconazole therapy is given to those who test positive. A recent metaanalysis of this issue in such settings reported the pooled prevalence of serum CrAg positivity was 6% in such patients with advanced HIV disease, and asymptomatic cryptococcal meningitis was present in 33% of such serum CrAg-positive patients. Among those who were serum CrAg positive but had CSF analysis showing no evidence of meningitis, preemptive fluconazole appeared effective in preventing meningitis and prolonging survival.(3)

  3. Any patient with a new positive serum CrAg result should have a lumbar puncture performed to rule out meningitis. CSF should be sent for CrAg testing as well as fungal culture, and the CSF opening pressure should be measured.

    The clinical presentation of cryptococcal meningitis can be subtle. Only half of patients with proven cryptococcal meningitis are febrile and less than half have altered mental status or a stiff neck.(1) Most morbidity and mortality resulting from cryptococcal meningitis is caused by elevated intracerebral pressure; this may be amenable to CSF drainage procedures.

  4. Antifungal therapy for invasive cryptococcal disease

    1. All patients with cryptococcal meningitis and abnormal neurologic findings or elevated CSF pressure should receive a 14-day induction regimen of amphotericin and flucytosine followed by consolidation with high-dose fluconazole therapy for 8 weeks, then suppressive low-dose fluconazole for at least 1 year (see Table 1, below). Lipid formulations of amphotericin are preferred to amphotericin deoxycholate as the former are equally effective and less toxic.

    2. It is not clear whether initial combination fungicidal therapy with amphotericin and flucytosine is necessary for those patients who will be initiating antiretroviral therapy and who, despite a positive CSF CrAg result, have a normal neurologic examination, normal CSF pressure, and no symptoms of meningitis. Amphotericin alone may suffice for such patients.

    3. An alternative induction regimen of fluconazole plus flucytosine, or even fluconazole alone in rare circumstances, may be adequate for certain patients depending on existing comorbidities that may limit amphotericin tolerance (eg, renal insufficiency, neutropenia, thrombocytopenia).

    4. We consider using high-dose fluconazole, with or without flucytosine (see Table 1 for dosing recommendations), as initial therapy for patients who have isolated cryptococcal pneumonia or cryptococcemia (ie, meningitis has been ruled out by a negative CSF CrAg result) and who are not severely ill.

    5. In resource-limited settings where lipid formulations of amphotericin are unavailable and safety monitoring for amphotericin deoxycholate toxicity and management of such toxicity are more challenging, clinical trials have demonstrated an optimal outcome with just 1 week of amphotericin deoxycholate, combined with flucytosine, compared with other combinations and durations of antifungal therapy for treatment of HIV-associated cryptococcal meningitis.(4,5)

  5. Cryptococcal meningitis patients who have elevated CSF pressure (ie, >200 mm H2O) should have lumbar punctures repeated every 12-24 hours, and sufficient fluid should be drained to lower the CSF pressure by 50% or at least to <200 mm H2O.

    1. Frequent lumbar punctures should be repeated until the opening CSF pressure is in the normal range and symptoms and signs attributable to high CSF pressure have resolved or stabilized.

    2. If, after 2-3 days, frequent lumbar punctures are ineffective in lowering pressure and neurologic deficits or uncontrolled discomfort owing to high CSF pressure (ie, refractory headache or nausea/vomiting) persist or progress, placement of a temporary lumbar spinal fluid drain should be considered. There is substantial variability among those who can perform this procedure (neurologists, anesthesiologists, or neurosurgeons) in their willingness to place such a drain. Some consider a high CSF protein and patient agitation to be relative contraindications. The decision to pursue a lumbar drain must be undertaken with an infectious disease or HIV consultant as well.

    3. A shunt from the ventricle to the peritoneum should be considered only in the exceedingly rare situation when high CSF pressure cannot be controlled after 2-4 weeks of maximal therapy. A shunt is accompanied by much higher morbidity, and furthermore, cannot be removed without risk of significant neurological damage.

  6. Adjunctive corticosteroids: Although adjunctive corticosteroid therapy, dexamethasone in particular, has been demonstrated to be beneficial in the treatment of bacterial and tuberculous meningitis, a multicenter, international, randomized trial reported no improvement in mortality among patients with AIDS-associated cryptococcal meningitis. More adverse events and disability occurred in those assigned to adjunctive dexamethasone compared with those who received placebo.(6)

  7. Timing of ART initiation after diagnosis of cryptococcal meningitis is discussed in the section Initiating Antiretroviral Therapy in Hospitalized HIV-Infected Patients.


  1. Chuck SL, Sande MA. Infections with Cryptococcus neoformans in the acquired immunodeficiency syndrome. N Engl J Med. 1989 Sep 21;321(12):794-9.
  2. Powderly WG, Cloud GA, Dismukes WE, et al. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis. 1994 May;18(5):789-92.
  3. Temfack E, Bigna JJ, Luma HN, et al. Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral na´ve HIV-infected adults with less than 100 CD4 cells/?L: a systematic review and meta-analysis. Clin Infect Dis. 2018 Jul 18. doi: 10.1093/cid/ciy567. [Epub ahead of print]
  4. Molloy SF, Kanyama C, Heyderman RS, et al; ACTA Trial Study Team. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018 Mar 15;378(11):1004-17.
  5. Tenforde MW, Shapiro AE, Rouse B, et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018 Mar 15;378(11):1004-17.
  6. Beardsley J, Wolbers M, Kibengo FM, et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N Engl J Med. 2016;374:542-54.

Table 1. Antifungal Regimens Recommended for the Treatment of Invasive Cryptococcal Disease

1. Initial induction therapy (2 weeks duration)
(regimens listed in order of preference)

a. Liposomal amphotericin B 3-4 mg/kg IV daily + flucytosine 25 mg/kg PO QID*; alternatives for liposomal amphotericin are amphotericin B lipid complex 5 mg/kg or amphotericin B deoxycholate 0.7-1.0 mg/kg IV daily

b. Fluconazole 400-800 mg PO daily + flucytosine 25 mg/kg PO QID*

c. Fluconazole 1,200 mg PO daily

2. Consolidation therapy (8 weeks duration) to immediately follow induction therapy

a. Fluconazole 400 mg PO once daily

3. Suppressive therapy to continue until CD4 cell count is ≥100 cells/µL and patient has completed 1 year of suppressive therapy

a. Fluconazole 200 mg PO daily

4. Suppressive therapy should be reinitiated if CD4 count subsequently decreases to <100 cells/µL
* Flucytosine dosage should be adjusted if estimated creatinine clearance is ≤40 mL/min