Approach

Isolation of the fungus together with typical clinical and/or radiologic findings forms the basis of the diagnosis.

Inhalation of spores is considered the primary route of inoculation, resulting in pulmonary involvement with the potential for subsequent systemic dissemination. In immunosuppressed patients, hematogenous dissemination can occur to multiple organs including the central nervous system (CNS) and meninges, skin, prostate, eyes, bone, urinary tract, and blood.[1] Extrapulmonary infection, especially that involving the CNS, is life-threatening and must always be considered, particularly in immunodeficient patients, even if there are no specific clinical signs of disseminated infection.

Clinical presentation

The clinical presentation of cryptococcosis varies from asymptomatic infection to life-threatening pneumonia and is different in HIV-infected and non-HIV-infected patients.[1][2]

Presenting features

  • Patients with acute pulmonary cryptococcosis present with pyrexia, a productive cough, dyspnea, chest pain, weight loss, and fatigue. They may also present with acute respiratory failure.

  • Headache, fever, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent CNS involvement and can present over several days or over months. A high index of suspicion should be maintained in HIV-infected patients and immunocompromised patients, even with headache alone, due to the subacute onset and nonspecific presentation of meningoencephalitis in these patients. Seizures may be a presenting factor in 15% of patients with HIV-related cryptococcal meningitis.[34]

  • HIV-associated cryptococcosis is characterized by more CNS and extrapulmonary involvement and presents with a higher burden of organisms.[1] It is also associated with a poor inflammatory reaction at the site of infection.[1]

  • In HIV-positive patients, symptoms typically occur over a period of 1 to 2 weeks or more. Patients without HIV infection have symptoms for a longer period of time, usually several months, prior to diagnosis.

Obtain past medical and drug history, as symptomatic disease usually develops in immunocompromised patients and those with severe comorbidities.

  • HIV infection, organ transplantation, idiopathic CD4 lymphocytopenia, liver disease, systemic lupus erythematosus, diabetes mellitus, hematologic malignancies, and immunosuppressant medication such as corticosteroids or monoclonal antibodies (e.g., alemtuzumab and infliximab) can all allow reactivation of a cryptococcal infection.[1]

Physical exam

Dullness to percussion, diminished breath sounds, and crackles on the affected side represent pleural effusion, diffuse alveolar and interstitial infiltrates, or endobronchial lesions.

Meningeal irritation characterized by neck stiffness, photophobia, and vomiting is seen in one quarter to one third of HIV-positive patients with meningoencephalitis.[1][2][4][35] Cranial nerve palsies can also occur.

Papilledema is a sign of increased intracranial pressure, which may result from meningeal inflammation, cryptococcoma, or hydrocephalus. It occurs in almost 50% of both HIV-negative and HIV-positive patients with cryptococcal meningitis, and it complicates management, leading to visual or hearing loss.[35]

The most common ocular manifestations include retinal and peripapillary hemorrhages, and other retinal lesions, all of which can result in visual loss.[1]

Cutaneous infections resulting from direct inoculation or secondary to disseminated disease are the third most common clinical site of cryptococcosis, especially in immunocompromised patients. Common skin lesions in HIV-positive patients are molluscum contagiosum-like and acneiform lesions. Purpura, vesicles, nodules, abscesses, ulcers, granulomas, draining sinuses, and cellulitis have also been described.[1]

Cryptococcal capsular polysaccharide antigen (CrAg) and cultures

Direct exam of the Cryptococcus fungus in body fluids along with cytology, histopathology of infected tissues, serologic studies, and culture are necessary for the diagnosis of cryptococcosis and should be carried out in all patients.

CrAg can be detected in blood, cerebrospinal fluid (CSF), and pleural fluid using rapid antigen tests. Rapid diagnosis is facilitated by the cryptococcal antigen (CrAg) lateral flow assay (LFA) for serum and CSF, complementing traditional microscopy (India ink staining) and culture techniques.[32][36]

  • A lateral flow assay (LFA) is a point-of-care rapid diagnostic test that provides results within 10 minutes. Plasma, serum, whole blood, or CSF can be tested.[37] Validation of one available CrAg LFA has shown sensitivity of 99.3% and specificity of 99.1%.[38]

  • Latex agglutination (latex particles coated with polyclonal cryptococcal capsular antibodies), a direct antigen detection assay, is performed on blood, CSF, or body fluids such as pleural fluid and bronchoalveolar lavage samples. Latex agglutination sensitivity ranges from 97.0% to 97.8%, and specificity ranges from 85.9% to 100%.[38] False-positive results may occur due to the presence of rheumatoid factor or infections with Trichosporon beigelii, Stomatococcus mucilaginosus, Capnocytophaga canimorsus, or Klebsiella pneumoniae.[39][40][41] False-negative results are caused by a low fungal burden.

  • Serum CrAg is generally universally positive in patients with HIV infection and cryptococcal meningitis, and CSF involvement becomes increasingly probable as serum CrAg titers increase above 1:160 (LFA). At a serum titer of >1:1280, or >1:640 (LFA) in patients with HIV, even if CSF is CrAg negative, CNS brain parenchymal involvement should be assumed.[20][42] In pulmonary cryptococcosis, serum CrAg is usually negative if the infection is confined to the lung with ≤1 cm nodule. A positive result may indicate disseminated disease. Serial fluctuations in serum CrAg titers should not be used to guide treatment as the kinetics of CrAg elimination remain unclear.[1][43]

  • A rise in CSF CrAg titers during suppressive therapy is associated with relapse in HIV-positive patients with cryptococcal meningitis.[1] There is a correlation between initial CSF antigen titers and the burden of yeast in the CNS in quantitative cultures.[1][2][4] The presence of CrAg in the pleural fluid can be useful when cultures are negative.[44]

  • CrAg titers, in general, cannot be followed over time to monitor treatment response. CrAg may remain positive for years.[43]

Cultures

  • Cryptococcus neoformans and Cryptococcus var. gattii can be grown from biologic samples, and colonies are observed on solid agar plates after 48 to 72 hours incubation at 86°F (30°C) to 95°F (35°C) in aerobic conditions.[1] Samples from patients treated with systemic antifungal therapy may require more time to produce visible colonies.

  • Blood cultures may be positive in up to 50% of patients with HIV-associated cryptococcal meningitis.[20] Negative CSF cultures in patients with cryptococcal meningitis may be caused by a low fungal burden. Bronchial secretions and urine can be contaminated by many microorganisms that may mask the growth of cryptococci, especially in patients with AIDS. Prostatic massage can improve fungal detection on urine culture.

  • Although Cryptococcus species is not considered normal respiratory flora in humans, it can occasionally colonize the respiratory tract of patients with lung disease, and sputum cultures may be positive. In immunocompromised patients, all isolates must be considered significant as they have the potential to cause dissemination.

HIV antibodies

As de novo cryptococcal meningitis or disseminated disease usually occurs in HIV-positive patients, testing for HIV antibodies in patients with unknown HIV status who present with cryptococcal meningitis or disseminated disease is recommended.[32]

Chest x-ray and CT chest

Radiologic features of pulmonary cryptococcosis vary widely according to the immune state of the patient and include nodules, consolidation, cavitation, lobar infiltrates, hilar lymphadenopathy, mediastinal lymphadenopathy, pleural effusions, and collapse. Chest computed tomography (CT) reveals the radiologic features in more detail and may be indicated in all patients, but especially in immunocompromised patients suspected for pulmonary cryptococcosis. Immunocompetent patients present with discrete nodules, whereas alveolar and interstitial infiltrates, cavitations, pleural disease, and collapse are more commonly seen in immunocompromised patients.[1][4][45][46][Figure caption and citation for the preceding image starts]: Bilateral cannonball lesions secondary to Cryptococcus neoformansFrom the collection of the radiology department, The Prince Charles Hospital, Chermside, Brisbane, Australia; used with permission [Citation ends].com.bmj.content.model.Caption@f0ed15[Figure caption and citation for the preceding image starts]: Pulmonary nodules in right lower lobe and left lower lobe secondary to Cryptococcus neoformansFrom the collection of the radiology department, The Prince Charles Hospital, Chermside, Brisbane, Australia; used with permission [Citation ends].com.bmj.content.model.Caption@75df311[Figure caption and citation for the preceding image starts]: Bibasal pneumonic consolidation secondary to Cryptococcus neoformansFrom the collection of the radiology department, The Prince Charles Hospital, Chermside, Brisbane, Australia; used with permission [Citation ends].com.bmj.content.model.Caption@51269d2c[Figure caption and citation for the preceding image starts]: Bilateral patchy opacification in mid-to-lower zones secondary to Cryptococcus neoformansFrom the collection of the radiology department, The Prince Charles Hospital, Chermside, Brisbane, Australia; used with permission [Citation ends].com.bmj.content.model.Caption@6cebf0e6

Neuroimaging

Magnetic resonance imaging of the brain detects significantly more cryptococcosis-related lesions than CT.[47][48]

Radiologic features include single or multiple focal mass lesions in cryptococcoma, granulomas without significant mass effect, cysts (gelatinous pseudocysts), hydrocephalus, dilated Virchow-Robin spaces, and enhancing cortical nodules. Cryptococcus var. gattii has a predilection to cause disease in the brain parenchyma rather than the meninges, resulting in cerebral cryptococcomas (represented by single or multiple focal mass lesions) or hydrocephalus.[1]

Lumbar puncture

Direct microscopic exam of the CSF for the presence of encapsulated yeasts with India ink is a rapid and inexpensive diagnostic test for cryptococcal meningitis.[1][2][4] However, many laboratories no longer perform the India ink test, and its usefulness in the management of cryptococcal meningitis is limited.[20] India ink staining allows detection of yeasts in a CSF specimen when more than 10³ yeasts/mL are present, and shows encapsulated yeast in 60% to 80% of cases.[20] In non-HIV cryptococcal meningitis, the sensitivity is 30% to 50%, while in HIV-associated cryptococcal meningitis it is up to 80%.[20] Myelin globules, fat droplets, lysed lymphocytes, and lysed tissue cells can cause false-positive results.[1]

Laboratory analysis of the CSF generally reveals slightly elevated protein levels, low-to-normal glucose levels, and sometimes leukocytosis.[20] 

Radiographic imaging of the brain with CT or MRI should be undertaken before lumbar puncture in patients with focal neurologic signs or papilledema to identify mass lesions that may contraindicate lumbar puncture.[1][2]

Asymptomatic immunocompetent patients with pulmonary cryptococcosis and a negative serum CrAg do not necessarily require a lumbar puncture to rule out CNS disease. Immunocompromised patients should undergo a lumbar puncture regardless of symptoms, particularly when the serum CrAg titer is ≥1:160, and have the CSF tested for CrAg to rule out concomitant CNS infection.[42]

Elevated intracranial pressure, defined as an opening pressure of >20 cm H₂O, measured with the patient in the lateral decubitus position, occurs in up to 80% of patients with cryptococcal meningitis and is associated with a poorer clinical response.[23]​​[49][50][51] Opening pressures ≥25 cm H₂O may be detected in 60% to 80% of HIV-positive patients with cryptococcal meningitis.[20] US guidelines recommend measuring opening pressure at diagnosis in all patients with suspected cryptococcal meningitis.[20]

Bronchoscopy

CrAg testing and cultures of bronchoalveolar lavage samples and washings may be positive in pulmonary cryptococcosis.[4]

CrAg testing in bronchoalveolar lavage samples is highly effective in diagnosing cryptococcal pneumonia with a titer >1:8, having 100% sensitivity and 98% specificity.[4]

Biopsy

Histologic exam of lung, skin, bone marrow, brain, or prostatic tissue can also be undertaken to detect systemic dissemination. Fine-needle aspiration (FNA) specimens obtained from the lymph nodes and adrenal glands can be used for cytologic study. Percutaneous transthoracic FNA of pulmonary nodules or infiltrative lesions, under ultrasound or CT guidance, can be performed to diagnose pulmonary cryptococcosis. Other specimens for cytologic exam include bronchoalveolar lavage fluid, centrifuged CSF, vitreous aspiration fluid, and seminal fluid.[1][2][4][36]​

Emerging investigations

The BioFire® FilmArray® polymerase chain reaction (PCR) assay is available in the US for the detection of cryptococcal infection in the CSF.[20] The assay may give false-negative results if fungal burden is low, so it should not be used as a diagnostic test in isolation.[20]

PCR is likely to be most useful in differentiating a second episode of cryptococcal meningitis (PCR positive) from immune reconstitution inflammatory syndrome (PCR negative) in patients with HIV.[20]

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