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Articles

Cryptococcosis In HIV And Non-HIV Infected Patients

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Rongpong Plongla, MD, MSc, D(ABMM)
Clinical Instructor
Division of Infectious Diseases, Department of Medicine
Faculty of Medicine, Chulalongkorn University and
King Chulalongkorn Memorial Hospital
Thai Red Cross Society
Bangkok, Thailand

A 43-year-old female presented with progressively worsening headache, subtle fever, nausea and vomiting that developed over a few weeks. Oral candidiasis, bilateral papilledema and meningeal irritation signs without focal neurologic deficits were revealed during physical examination. Computed tomography of the brain was normal. Lumbar puncture results were: opening pressure, 30 cmH2O; cerebrospinal fluid (CSF) sugar, 48 mg/dL; protein, 50 mg/dL; and white blood cell count, 40 cells/mm3 with 100% mononuclear cells. India ink examination showed numerous encapsulated yeasts. Her blood and CSF cultures grew Cryptococcus neoformans. She also had reactive anti-HIV test, and positive CSF and serum cryptococcal antigen tests with titers of >1:5,120.

Physicians are familiar with the above scenario of cryptococcal meningitis or disseminated cryptococcal infections as AIDS-defining illnesses. Infections caused by Cryptococcus species can affect other populations and have a wide spectrum of clinical presentations, ranging from colonization to dissemination into any organ, with a predilection for the central nervous system (CNS) and the lungs. However, a decrease in cryptococcosis may be expected in the era of combination antiretroviral therapy (cART). This article aims to summarize the key features and treatment of cryptococcosis in HIV- and non–HIV-infected patients.

Table. Antifungal therapy and minimum durations of treatment for patients with cryptococcal infections7,8

MeningoencephalitisInductionConsolidationMaintenance
HIV-infected [AmBd or LAMB] plus flucytosine, 2 weeksFluconazole 400 mg/day,
8 weeks
Fluconazole 200 mg/day, 1 year
Transplant recipients [LAMB or ABLC] plus flucytosine, 2 weeksFluconazole 400-800 mg/day, 8 weeksFluconazole 200-400 mg/day, 6-12 months
Non-HIV, non-transplant [AmBd or LAMB or ABLC] plus flucytosine, 4 weeks; or
AmBd, 6 weeks
Fluconazole 400-800 mg/day, 8 weeksFluconazole 200 mg/day, 6-12 months
Non-meningeal cryptococcosis
  • HIV-infected
Extrapulmonary and diffuse pulmonary diseaseSame as CNS disease
Focal pulmonary disease and isolated cryptococcal antigenemiaFluconazole 400 mg/day, 12 months
  • Non–HIV-infected: immunosuppressed and immunocompetent patients
Mild-moderate pulmonary disease Fluconazole 400 mg/day, 6-12 months
Severe pulmonary disease Same as CNS disease, 12 months
Cryptococcemia Same as CNS disease, 12 months
Single site of infection, no fungemia, no CNS disease, no immunosuppressive risk factors Fluconazole 400 mg/day, 6-12 months
AmBd, amphotericin B deoxycholate 0.7-1.0 mg/kg per day; LAMB, liposomal amphotericin B 3-4 mg/kg per day; ABLC, amphotericin B lipid complex 5 mg/kg per day; CNS, central nervous system


C. neoformans
and C. gattii are two major pathogenic Cryptococcus species. Both species cause infections either in immunocompromised or immunocompetent hosts, but C. gattii is the cause of the majority of cryptococcosis in immunocompetent patients.1 Besides HIV infection, other risk factors for cryptococcosis include: solid organ transplantation; corticosteroid/immunosuppressive therapy; lymphoproliferative disorders; sarcoidosis; idiopathic CD4+ lymphopenia; cirrhosis; hyper-IgE syndrome; hyper-IgM syndrome; anti–granulocyte-macrophage colony-stimulating factor (anti–GM-CSF) antibodies; rheumatic diseases; and treatment with monoclonal antibodies (eg, infliximab, alemtuzumab, adalimumab).1 However, about one fifth of patients with cryptococcosis have no apparent risk factors.2

Several studies have shown that HIV-related cryptococcosis tends to affect younger patients (between 30 and 40 years) and males.3-6 With a higher burden of yeasts and a greater degree of immunosuppression, patients with HIV infection present with headache and have higher proportions of CNS disease, cryptococcemia and extrapulmonary diseases than non–HIV-infected individuals.3-6 Higher serum and CSF polysaccharide antigen titers, lower CSF pleocytosis and higher positive CSF India ink examination (up to 80% vs 30-50%) are more common in AIDS-related cryptococcal meningitis than in non–AIDS-related disease.1 In HIV-infected patients with cryptococcal meningitis, there may be slower sterilization of CSF, a higher incidence of increased intracranial pressure (ICP), co-infections with other organisms, and immune reconstitution inflammatory syndrome (IRIS). Pulmonary manifestations are different in HIV-infected and in non–HIV-infected patients. One third of normal hosts present with an asymptomatic isolated lung mass or multiple nodules, while alveolar and interstitial infiltrates mimicking Pneumocystis infection are common in HIV-infected patients.1

Treatment of cryptococcosis includes antifungal therapy, management of increased ICP and hydrocephalus, and regaining host immune status. Current antifungal treatment recommendations from the Infectious Diseases Society of America and the Department of Health and Human Services for treatment of cryptococcosis in HIV- and non–HIV-infected patients are summarized in the Table.7,8 Reduction of immunosuppressive therapy helps control cryptococcosis in non–HIV-infected patients; however, caregivers should consider deferring initiation of cART in HIV-infected patients until 2 to 10 weeks or later after the initiation of antifungal therapy and monitor carefully for increased ICP as a presentation of IRIS.8 At least 1 year of suppressive therapy with fluconazole 200 mg is recommended for HIV-infected patients, until a CD4 count ≥100 cells/μL for at least 3 months and suppressed HIV-RNA are acheived.8 The prognosis of non-HIV, non-transplant patients is, unfortunately, poorer than that of other groups, which is likely due to delayed diagnosis and the severity of comorbid diseases, such as malignancy.3-5

In conclusion, cryptococcosis has different manifestations, treatment and prognosis in HIV-infected- and non–HIV-infected patients. In the era of cART, early recognition of cryptococcosis may improve patient outcomes.

References:

  1. Maziarz EK, Perfect JR. Infect Dis Clin North Am 2016;30:179-206.
  2. Pappas PG, et al. Clin Infect Dis 2001;33:690-699.
  3. Bratton EW, et al. PloS One 2012;7:e43582.
  4. Brizendine KD, et al. PloS One 2013;8:e60431.
  5. Jongwutiwes U, et al. Jpn J Infect Dis 2008;61:111-115.
  6. Lee Y-C, et al. J Microbiol Immunol Infect 2011;44:338-345.
  7. Perfect JR, et al. Clin Infect Dis 2010;50:291-322.
  8. Cryptococcosis. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. AIDSinfo website. Available at: aidsinfo.nih.gov/guidelines/html/4/adult-andadolescent-oi-prevention-and-treatment-guidelines/333/cryptococcosis. Accessed October 2, 2016.
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