Cryptococcosis

Etiology and PathogenesisTop

1. Etiologic agent: Yeast from the Cryptococcus genus that are considered human pathogens were historically divided into 2 species, C neoformans (serotypes A [variant grubii] and D [variant neoformans]) and C gattii (serotypes B and C). These different serotypes are now defined as belonging to the C neoformans species complex (CNSC) and C gattii species complex (CGSC), with multiple different molecular types and species being defined by molecular taxonomy within each of the complexes. CNSC occurs almost exclusively in individuals with impaired cellular and type 1 helper T-cell (Th1)–dependent immune response, while infection due to CGSC can occur in apparently immunocompetent hosts.

2. Reservoir and transmission: CNSC occurs around the world, and the infection is associated with contact with bird droppings or contaminated soil. CGSC was initially associated with eucalyptus trees in Australia, but now it is linked to a wide range of trees, including coniferous trees in North America. The geographic range of CGSC continues to expand.

The infection is most frequently acquired through inhalation and rarely by direct inoculation of the skin. Human-to-human transmission does not occur, except in rare instances of organ transplant. Infection usually occurs early in childhood as a latent infection of intrapulmonary lymph nodes and is reactivated by immunosuppression. The disease can also occur by primary inhalation in a vulnerable host.

3. Risk factors: The most common risk factors are immunodeficiency due to HIV infection (CD4+ T-cell count <100/microL) and solid organ transplant (SOT). Additional risk factors include receipt of glucocorticoid therapy, ibrutinib, Janus kinase (JAK) inhibitors, and other biologic therapies, as well as lymphoproliferative neoplasms, sarcoidosis, idiopathic CD4+ T-cell lymphocytopenia (without HIV infection), cirrhosis, and rare primary immunodeficiencies such as hyper-IgM syndrome, anticytokine antibodies, and Job syndrome.

4. Incubation period: The incubation period depends on the patient’s immune status, pathogenicity of the strain, and inoculum. In severe immunodeficiency incubation may last several days. The incubation period of CNSC is estimated to be 110 months and that of CGSC, from 6 to 35 months. Reactivation can occur years after initial infection.

Clinical Features and Natural HistoryTop

1. CNS cryptococcosis: CNSC and CGSC are neurotropic pathogens. Meningoencephalitis is the most common presentation of cryptococcosis.

2. Pulmonary cryptococcosis: Asymptomatic infection may occur in 30% to 40% of immunocompetent patients. Symptomatic infection typically develops slowly (over weeks) after primary colonization via inhalation; faster progression is observed in patients with severe immunodeficiency.

The clinical picture is dominated by cough, expectoration of large amounts of sputum, chest pain, weight loss, and headache. An isolated pulmonary nodule occurs more frequently in immunocompetent patients with concomitant extrapulmonary disease (10%-15%). In immunocompromised patients extrapulmonary disease is seen in up to 75% of cases. Cavitation of nodules occurs more frequently in immunocompromised individuals compared with the immunocompetent ones. Other pulmonary features include airspace consolidation and rarely a reticulonodular pattern. Pleural effusion is not common, occurring in <10% of patients, but it can be the only pulmonary finding.

All patients with pulmonary cryptococcosis should be carefully evaluated for immunosuppression. A careful evaluation for CNS and extrapulmonary disease should be performed, with lumbar puncture, cultures of blood, and examination of any other potential extrapulmonary site of infection.

3. Cutaneous cryptococcosis may manifest with papules, nodules, maculopapular lesions, subcutaneous abscesses, vesicles, scales, erythema, and herpes-like and molluscum contagiosum−like lesions. Skin lesions frequently indicate disseminated disease; primary skin involvement may result from skin injury or direct contact with the pathogen (bird droppings).

4. Nonpulmonary, non–central nervous system (CNS) disease: Hematogenous dissemination can lead to disease in any organ. Involvement of the liver, skin, spleen, kidney, and prostate gland can occur. Bone and joint involvement is less common. Rarely patients may have pericarditis, myocarditis, endocarditis, fungal aneurysm, vascular graft or valve infection, esophagitis, or paranasal sinusitis. The kidneys, thyroid gland, stomach, and intestines may also be involved. Cryptococcal peritonitis may occur in patients on hemodialysis and those with chronic liver disease.

5. Prostate gland involvement: Asymptomatic infection of the prostate gland is common—it is considered a sanctuary site for HIV-infected patients on antifungal therapy. Relapse due to persistent prostatitis can occur. Positive results of urine (with and without prostatic massage) and semen cultures may also indicate systemic infection.

6. Ocular cryptococcosis: Signs and symptoms were observed in early reports in up to 45% of patients with CNS cryptococcosis. Visual changes are frequently due to raised intracranial pressure (ICP; increased ICP may cause compression of the ophthalmic artery, leading to optic nerve injury). Direct ocular involvement with keratitis, retinitis, and endophthalmitis can occur and ophthalmologic examination is required.

DiagnosISTop

Diagnostic Tests

1. Identification of the etiologic agent:

1) Microbiologic studies:

a) Direct microscopic examination: Identification of the pathogen by Gram staining, direct fungal stains such as KOH/calcofluor, or both. Detection of the capsule using India ink stain in cerebrospinal fluid (CSF) specimens is a rapid test, but its sensitivity is significantly lower than that of antigen detection methods and therefore it is not the preferred method in resource-rich settings.

b) Culture is considered the gold standard, but growth can take 48 to 72 hours. Cryptococcus can be detected using routine bacterial blood culture media and can be grown on standard agar plates. Accurate identification as CNSC or CGSC can be performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS).

c) Susceptibility testing: Standardized methods are available for antifungal susceptibility testing. However, clinical breakpoints are not currently available. Susceptibility testing should be considered for relapsed infection, lack of treatment response, or if the infection is caused by specific genotypes known to be associated with reduced susceptibility. Results should be interpreted in cooperation with a microbiologist or infectious diseases physician.

2) Serologic tests: Detection of the cryptococcal capsular polysaccharide antigen (CrAg) from CSF or serum. The sensitivity and specificity using cryptococcal lateral flow assay (LFA) from CSF are 97% to 100% and 95% to 99%, respectively. LFA is preferred to latex agglutination tests and enzyme immunoassays (EIAs). Antibody testing is not recommended.

3) Histopathology: Yeast are usually sized 4 to 20 microm in diameter, with narrow-based budding. Gomori methenamine and periodic acid–Schiff (PAS) are fungal-specific stains that stain the cell wall and capsule. Mucicarmine is a capsule-specific stain that detects the polysaccharide capsule, while Fontana-Masson stain is used to detect melanin in the cell wall.

4) Molecular studies: Molecular detection of cryptococcus in CSF is not routinely recommended, as available assays are not as sensitive as LFA or culture. Direct detection of Cryptococcus from tissue using DNA sequencing is not routinely available, but it can help confirm the identification of yeast in histopathologic assays (differentiate them from other yeast forms).

2. Other studies:

1) CSF analysis: Mononuclear pleocytosis with increased protein concentration.

2) Imaging studies:

a) Pulmonary cryptococcosis: Chest radiography and computed tomography (CT) show nonspecific pulmonary lesions, local and disseminated densities, intraparenchymal lesions, cavities, atelectasis, pleural exudate, and parahilar lymphadenopathy.

b) CNS cryptococcosis: Magnetic resonance imaging (MRI) is recommended (see Central Nervous System (CNS) Infections).

Differential Diagnosis

1) Pulmonary involvement: Typical and atypical pneumonia, pulmonary tuberculosis (TB), non-TB mycobacterioses, Nocardia spp infection, Rhodococcus spp infection, histoplasmosis, blastomycosis, aspergillosis, Pneumocystis jirovecii pneumonia, Chlamydia psittaci infection. In the setting of pulmonary nodules, noninfectious etiologies such as malignancy and sarcoidosis should be considered.

2) CNS involvement: Neurotoxoplasmosis, lymphomas, CNS TB, nocardiosis, other neurotropic fungi including Aspergillus spp, Scedosporium spp, Lomentospora, Fusarium spp.

3) Intestinal inflammatory lesions: Crohn disease.

4) Retinitis: Cytomegalovirus, Candida endophthalmitis, toxoplasmosis, HIV infection.

TreatmentTop

Antifungal Treatment

Consultation with an infectious diseases specialist is recommended for the management of cryptococcosis.

1. CNS cryptococcosis (cryptococcal meningitis/meningoencephalitis) and disseminated cryptococcosis (non-CNS/nonpulmonary):

1) Adult patients living with HIV infection:

a) Induction: Liposomal amphotericin B 3 to 4 mg/kg daily plus 5-fluorocytosine 25 mg/kg qid for 2 weeks; or single-dose liposomal amphotericin B 10 mg/kg, 5-fluorocytosine 25 mg/kg qid, and fluconazole 1200 mg once daily for 2 weeks. Consider prolonging the induction therapy if CSF culture results are positive at 2 weeks.

If fluorocytosine is not available: liposomal amphotericin B 3 to 4 mg/kg daily plus oral fluconazole 1200 mg once daily for 14 days.

b) Consolidation: Oral fluconazole 400 to 800 mg once daily for 8 weeks.

c) Maintenance: Oral fluconazole 200 mg once daily until immune reconstitution (CD4+ T-cell count >200/microL) and suppression of viral load for patients living with HIV infection receiving antiretroviral treatment (ART).

2) SOT recipients without HIV infection and patients who are not SOT recipients:

a) Induction: Liposomal amphotericin B 3 to 4 mg/kg/d plus 5-fluorocytosine 25 mg/kg qid for 2 weeks. 

b) Consolidation: Oral fluconazole 400 to 800 mg once daily for 8 weeks.

c) Maintenance: Oral fluconazole 200 mg once daily for 12 months.

2. Isolated pulmonary cryptococcosis (CNS disease excluded):

1) Asymptomatic disease: In immunocompetent individuals consider observation without treatment or use fluconazole 400 to 800 mg/d for 6 to 12 months. In immunocompromised individuals use fluconazole 400 to 800 mg/d for 6 to 12 months.

2) Mild disease: Fluconazole 400 to 800 mg/d for 6 to 12 months.

3) Moderate to severe disease: Liposomal amphotericin B 3 to 4 mg/kg/d plus 5-fluorocytosine 25 mg/kg qid for 2 weeks (induction); followed by oral fluconazole 400 to 800 mg once daily for 8 weeks (consolidation); and then fluconazole 200 mg once daily for 6 to 12 months (maintenance).

3. Direct skin inoculation: Oral fluconazole 400 mg once daily for 3 to 6 months.

Other Treatment Modalities

1. Management of raised ICP in CNS cryptococcosis: All patients should have the opening pressure (OP) measured when any lumbar puncture is performed. If the OP is ≥20 cm, therapeutic lumbar puncture is recommended and should be performed daily until the OP is ≤20 cm, has been reduced by 50%, or both. Consultation with a neurosurgeon is recommended if therapeutic lumbar puncture is not successful.

2. ART initiation in patients living with HIV: Immediate or early commencement of ART is not recommended. However, timing depends on the induction therapy that is being used, patient response to therapy, and whether CSF sterility is obtained. Consultation with an infectious diseases specialist is recommended.

3. Monitoring for clinical relapse:

1) Consider both infective and noninfective causes when clinical relapse is being considered. At a minimum, perform brain MRI and repeat lumbar puncture.

2) Guiding treatment decisions based on CrAg titers from CSF and blood is not recommended.

ComplicationsTop

1. Brain involvement: Hydrocephalus and complications of increased ICP such as cranial nerve palsy, cognitive disorders, dementia, blindness.

2. Pulmonary involvement: Acute respiratory distress syndrome (ARDS).

3. Immune reconstitution inflammatory syndrome (IRIS) associated with cryptococcal meningitis and ART.

PrognoSisTop

Prognosis depends on the possibility of treating immunodeficiency. In patients living with HIV, survival is longer than in those with lymphoproliferative neoplasms; mortality reported in patients after organ transplant reached ~42%. Prognosis in CNS cryptococcosis has been related to 2 factors: infection severity (number of fungal cells visualized by ink staining and CrAg titer) at diagnosis and the level of consciousness. In high-income countries mortality from cryptococcal meningitis is 20% to 30%, compared with 70% in low-income countries.

PreventionTop

Specific Prevention

1. Vaccination: None available.

2. Pharmacoprophylaxis: Consider fluconazole in patients with severe immunodeficiency who are at high risk of developing cryptococcosis. Fluconazole is recommended for patients living with HIV who are positive for CrAg and asymptomatic.

3. Screening: For patients living with HIV, blood CrAg measurement using LFA is recommended. Patients with CD4+ count <200/microL (ART-naive ones or following ART discontinuation) should be investigated for cryptococcosis.

Nonspecific Prevention

Patients with immunodeficiency should avoid areas contaminated with bird droppings.