Category Archives: Cryptococcosis

Cryptococcosis

– Christian Hoffmann –

Infection with the yeast Cryptococcus neoformans is a rare AIDS-defining illness in Europe. In the US and especially in Southeast Asia, cryptococcosis occurs much more frequently and is considerably one of the more prominent AIDS-defining illnesses worldwide. Presumably transmitted via inhalation, bird droppings are a key reservoir for C. neoformans. This pulmonary infection may remain subclinical in immunocompetent patients, but is almost always followed by disseminated disease in HIV patients. Apart from the lungs, the main manifestation after hematogenic spread is in the CNS. For this reason, a CSF examination is obligatory in every suspected case. However, isolated skin manifestations and lymphadenitis can also occur. Organ involvement, such as in the urogenital or gastrointestinal tract, is rare.

Cryptococcosis almost always occurs with severe immunodeficiency. In a collection of 114 cases, 87% had less than 100 CD4 T cells/µl; the median CD4 count was 30/µl (Weitzel 1999). Cryptococcosis is fatal if untreated. Treatment is lengthy, complicated and should managed only on an inpatient basis. Relapses were frequent in the pre-HAART era and occurred in at least 15% of cases. In addition, cryptococcosis occurs relatively frequently in the presence of an immune reconstitution inflammatory syndrome. Prognosis has much improved over the last years. In one study from France, the mortality rate per 100 person-years was 15.3 in 1996-2000, compared with 63.8% in the pre-HAART era although early mortality did not differ between the two periods (Lortholary 2006).

Signs and symptoms

The CNS manifestation with encephalitis is the most frequent manifestation (ca. 80%). Patients complain mainly of headaches, fever and confusion or clouding of consciousness which progresses rapidly over a few days. Disorders of gait, hearing, and vision may occur, as well as paresis, particularly of the cranial nerves, in such cases intracranial pressure is almost always increased. However, meningeal symptoms are usually absent. In the course of an immune reconstitution syndrome, clinical symptoms are often atypical and characterized by extensive abscesses (Manfredi 1999).

Pulmonary disease leads to symptoms of atypical pneumonia with unproductive cough and chest pain. Skin lesions can initially resemble molluscum contagiosum, and later become confluent in the form of larger, ulcerative lesions.

Diagnosis

Cryptococcosis is life threatening, and the mortality rate in larger studies is between 6 and 25% (Saag 2000). There is no time to lose during diagnostic testing. Rapid examination of the lungs (HR-CT) and CNS in particular (MRI) should be initiated in every suspected case (e.g. positive cryptococcal antigen test).

The chest x-ray usually does not reveal much; therefore, an HRCT scan must be performed if pulmonary involvement is suspected. The spectrum of morphology on the image is very variable. Diffuse, small lesions similar to tuberculosis may occur, but there can also be sharply defined infiltrates reminiscent of bronchopneumonia. Cavitation and bronchiectasis may also be present. Every attempt should therefore be made to clearly identify the causative organism by BAL.

An MRI scan of the head should always be performed if there are neurological symptoms. However, in contrast to toxoplasmosis and primary CNS lymphoma, it usually does not reveal much, and isolated or multiple mass lesions (cryptococcomas) are very rare. Nevertheless, intracranial pressure is often increased and a fundoscopy (papillary edema) should be performed.

The most important test for cryptococcosis is lumbar puncture after a fundoscopy and/or an MRI. Diagnosis can be made via India ink stain in almost all cases. CSF must be examined even in cases with pulmonary or other manifestation to exclude CNS involvement. Cryptococcal antigen in the blood (titer > 1:8) is a good parameter and should always be determined. Blood cultures are also often positive. With cutaneous involvement, the diagnosis is usually made from a biopsy.

Treatment

In cases of CNS involvement an immediate combination of antimycotics is urgently recommended followed by maintenance therapy with fluconazole (Saag 2000). Fluconazole alone is not sufficient, as recently shown by two randomized trials from Africa. In these trials, mortality of cryptococcal meningitis was unacceptable high. Within the first weeks, 54-59% of the patients died (Longley 2008, Makadzange 2009).

Combination prevents resistance and allows reduction of acute therapy to 4-6 weeks. The choice of combination is not clearly defined. In some countries, combination therapy with the three antimycotics amphotericin B, flucytosine and fluconazole is often used for meningitis. The triple therapy leads to complete remission of meningitis in around 80% of cases (Weitzel 1999), and consequently the possibility of a slightly higher rate than under dual therapy with amphotericin B and flucytosine as favored in the United States (van der Horst 1997).

However, other data is raising questions as to the superiority of triple therapy. According to the measurements of cryptococcal clearance in the CSF, in a small, randomized study of 64 patients in Thailand, the combination of amphotericin B and flucytosine was the most effective treatment (Brouwer 2004). It was even significantly better than triple therapy and also amphotericin B and fluconazole. Amphotericin B at a dosage of 1 mg/kg plus is possibly more rapidly fungicidal than is standard-dose Amphotericin B (Bicanic 2008). If amphotericin B should not be available, the combination of flucytosine and fluconazole is better than fluconazole alone (Nussbaum 2010).

Nevertheless, in view of the toxicity of flucytosine which is only available in many countries for infusion and not in tablet form, the combination of amphotericin B and fluconazole is preferable. In a phase II study the high doses of 800 mg fluconazole daily was most effective (Pappas 2009). A newer study showed the efficacy of high dose fluconazole is equivalent to flucytosine (Loyse 2011).

In addition to having significantly lower toxicity, liposomal amphotericin (Ambisome®) is slightly more effective than conventional amphotericin B (Lenders 1997, Hamill 1999). However even Ambisome®-containing combinations are highly toxic. Daily monitoring of kidney- and liver enzymes, blood count and electrolytes are recommended. Fluconazol should be administered as an infusion, particularly if patients seem confused.

In untreated patients, ART is typically started during the acute phase of treatment. Caution should be taken with tenofovir, given an observed case of renal failure requiring dialysis after treatment with tenofovir and amphotericin B. Since there is also a higher risk for the development of IRIS, the optimal time for initiation of ART is still under debate. In ACTG 5164, early start of ART was of advantage (Zolopa 2009). In a small African study on seriously ill patients, however, mortality was increased in patients starting ART immediately after diagnosis (Makadzange 2010).

In cases of isolated pulmonary involvement (CSF negative) or other extracerebral manifestations, treatment without flucytosine can be completed the acute therapy with amphotericin B and fluconazole within two instead of four weeks. If there is a positive cryptococcal antigen test without evidence of CNS, pulmonary or other infection, then treatment can consist of fluconazole alone.

Treatment success is monitored based on the clinical course and repeated lumbar punctures. CSF is negative in approximately 60% of cases after two weeks (Saag 2000). When this is the case, maintenance therapy or secondary prophylaxis can be started, though not sooner than after four weeks of acute therapy. The quicker the CSF shows to be negative, the better the prognosis (Bicanic 2009). If there is increased intracranial pressure, then CSF drainage may become necessary (Graybill 2000). Steroids are ineffective (Saag 2000).

Prophylaxis

Exposure can presumably also not be prevented. As survival benefit was not demonstrated, primary prophylaxis against Cryptococcus neoformans is not recommended even in endemic areas such as Thailand (McKinsey 1999, Chariyalertsak 2002). Fluconazole is given as secondary prophylaxis or maintenance therapy. It is significantly more effective than itraconazole. For example, in a large randomized study, the relapse rate in the fluconazole arm was only 4% compared to 23% in the itraconazole arm, resulting in discontinuation of the study before completion (Saag 1999). Fluconazole can probably be discontinued with sufficient immune reconstitution (above 200 CD4 cells/µl, undetectable viral load for three to six months), as demonstrated in several studies (Aberg 2002, Kirk 2002, Vibhagool 2003, Mussini 2004), and after at least six months of maintenance therapy. It is prudent to check for cryptococcal antigen before stopping (Mussini 2004). Positive antigen tests require continuation of treatment as the risk of relapses is high, especially in patients with high antigen titres (Lortholary 2006).

Treatment/prophylaxis of cryptococcosis (daily doses, unless specified otherwise), see also Drugs section for further details!
Acute therapy   Duration: always at least six weeks
Treatment of choice Amphotericin B

 

 
+ fluconazole

+ flucytosine *

Amphotericin B  0.5-0.75 mg/kg qd or

liposomal amphotericin B 3 mg/kg qd (preparation by pharmacy) plus

fluconazole 1 bottle at 200 mg i.v. bid or

fluconazole 1 cap. at 200 mg bid  plus

flucytosine 1 bottle at 250 ml (2.5 g) i.v. qid

(= 100-150 mg/kg distributed in four separate doses)

Maintenance therapy Discontinuation possible from > 200 CD4 cells/µl > 3-6 months
Treatment of choice Fluconazole Fluconazole 1-2 cap. at 200 mg qd

 

Alternative Itraconazole Itraconazole 2 cap. at 100 mg bid
Primary prophylaxis Not recommended
*Note: We usually omit flucytosine. In this case the daily doses of fluconazole should be 800 mg. Instead, we begin with ART during the acute therapy phase in those patients, who are almost always ART naive.

References

Aberg JA, Price RW, Heeren DM, Bredt B. A pilot study of the discontinuation of antifungal therapy for disseminated cryptococcal disease in patients with AIDS, following immunologic response to ART. J Infect Dis 2002, 185:1179-82.

Bicanic T, Muzoora C, Brouwer AE, et al.  Independent association between rate of clearance of infection and clinical outcome of HIV-associated cryptococcal meningitis: analysis of a combined cohort of 262 patients. Clin Infect Dis 2009, 49:702-9.

Bicanic T, Wood R, Meintjes G, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008, 47:123-30.

Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004, 363:1764-7.

Chariyalertsak S, Supparatpinyo K, Sirisanthana T, et al. A controlled trial of itraconazole as primary prophylaxis for systemic fungal infections in patients with advanced HIV infection in Thailand. Clin Infect Dis 2002, 34:277-84.

Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. Clin Infect Dis 2000;30:47-54.

Hamill RJ, Sobel J, El-Sadr W, et al. Randomized double blind trial of Ambisome and amphotericin B in acute cryptococcal meningitis in AIDS patients. 39th ICAAC 1999, San Francisco; Abstract 1161.

Kirk O, Reiss P, Uberti-Foppa C, et al. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Ann Intern Med 2002, 137:239-50.

Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 1997, 11:1463-71.

Longley N, Muzoora C, Taseera K, et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556-61.

Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 2006, 20:2183-91.

Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose 5-FC, voriconazole, and flucytosine, as second drugs given in combination with amphotericin b, to treatment of hiv-associated cryptococcal meningitis. Abstract 893, 18th CROI 2011, Boston.

Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010, 50:1532-8.

Manfredi R, Pieri F, Pileri SA, Chiodo F. The changing face of AIDS-related opportunism: cryptococcosis in the HAART era. Case reports and literature review. Mycopathologia 1999, 148:73-8.

McKinsey DS, Wheat LJ, Cloud GA, Itraconazole prophylaxis for fungal infections in patients with advanced HIV infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999, 28:1049-56.

Mussini C, Pezzotti P, Miro JM, et al. Discontinuation of maintenance therapy for cryptococcal meningitis in patients with AIDS treated with HAART: an international observational study. Clin Infect Dis 2004, 38:565-71.

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, 50:338-44.

Pappas PG, Chetchotisakd P, Larsen RA, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis 2009, 48:1775-83.

Saag MS, Cloud GA, Graybill JR, et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999, 28:291-6.

Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Infectious Diseases Society of America. Clin Infect Dis 2000, 30:710-8.

van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the AIDS. N Engl J Med 1997, 337:15-21.

Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients treated with HAART: a prospective, multicenter, randomized study. Clin Infect Dis 2003, 36:1329-31.

Weitzel A, Arasteh K, Mertenskötter T, et al. Kryptokokkosen bei HIV-positiven Patienten in Deutschland – eine Auswertung 24 deutscher Zentren. In: Brockmeyer NH et al. HIV-Infekt, Springer-Verlag; 1999.

Zolopa A, Andersen J, Komarow L, et al. Immediate vs deferred ART in the setting of acute AIDS-related opportunistic infection: final results of a randomized strategy trial, ACTG A5164. 15th CROI 2008, Boston.

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Filed under 11. Opportunistic Infections, Cryptococcosis, Part 3 - AIDS