CONTENTS

• Epidemiology
• Cryptococcal pneumonia
  • Clinical presentation
  • Thoracic radiology
• Extrapulmonary dissemination:
  • Cryptococcal meningitis & brain imaging
  • Other sites of dissemination
• Laboratory tests
• Management
• Questions & discussion

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epidemiology

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Cryptococcus neoformans: general epidemiology

• Cryptococcus neoformans is a widespread opportunistic fungus found in soil and bird droppings.
• Most clinically evident infections might actually represent latent infection that reactivates in the context of depressed immunity. (Murray 2022)

at-risk groups for Cryptococcus neoformans include: 

• HIV:
  • CD4 count is usually <100-200/uL.
  • Most common fungal infection in HIV patients.
• Solid organ transplantation
  • Cryptococcosis is the third most common invasive fungal pathogen in solid organ transplant patients (after Candida and Aspergillus). (Murray 2022)
  • Cryptococcus causes 8% of invasive fungal infections among solid organ transplant patients but only 0.6% among stem cell transplant patients. This may result from the transfer of latent infection harbored within solid organs. (Murray 2022)
  • Cryptococcus is often a relatively late complication of solid organ transplantation, occurring a median of ~1.5 years post-transplant. (26540422)
• Immunosuppressive medications, including:
  • Chronic steroid use.
  • TNF-inhibitors.
  • Azathioprine.
  • Calcineurin inhibitors (e.g., cyclosporine, tacrolimus).
  • Fingolimod (an S1P receptor modulator used for multiple sclerosis).
  • Tyrosine kinase inhibitors (e.g., ibrutinib). (33516057, 33896533)
• Malignancy (especially hematological).
• Cirrhosis.
• Diabetes.
• Chronic renal failure.
• Sickle cell disease.
• Sarcoidosis.
• 💡 ~15-50% of patients have no underlying immunocompromising condition (especially patients with pulmonary cryptococcosis). (30329097) 

epidemiology of Cryptococcus gattii

• Cryptococcus gattii causes infection in immunocompetent patients but is restricted to specific geographic locales (British Columbia and the Pacific Northwest; figure below). Clinical presentations are similar to C. neoformans, but C. gattii may be more likely to cause large pulmonary and brain mass lesions (cryptococcomas). (de Moraes 2024)
• The incubation period of C. gatti may be long (often 2-12 months), so remote travel history may be relevant. (de Moraes 2024)

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cryptococcal pneumonia: clinical presentation

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general

• Among immunocompetent patients, pneumonia is usually asymptomatic or minimally symptomatic.
• Among immunocompromised patients, the outcome is unpredictable:
  • Severe pneumonia may cause respiratory failure and ARDS.
  • In most immunocompromised patients, infection may progress to dissemination without substantial pneumonic symptoms (e.g., leading to an initial neurological presentation).

symptoms are nonspecific and variable

• The most common symptom is cough (which may be productive).
• Pleuritic chest pain or dyspnea may occur.
• Constitutional symptoms are somewhat less common (fever, weight loss).
• Hemoptysis may rarely occur. (34016288)

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thoracic radiology of cryptococcus

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usual findings on thoracic radiology

• Nodules are the most common finding:
  • Well-defined nodules are usually <1 cm, but may range from ~0.7 – 3 cm. (29518379)
  • May be solitary or multiple (potentially mimicking lung cancer).
  • Often in a subpleural distribution. (36354923)
  • Halo sign may occur in ~20% of nodules (although this is more common in immunocompromise). (32000285)
  • Cavitation can occur (although this more often occurs among patients with marked immunosuppression).
• Consolidation:
  • Ill-defined areas of consolidation may occur.
  • Segmental or lobar consolidation may occur, most often in the lower lobes.
• Not usually seen among immunocompetent patients:
  • Lymphadenopathy.
  • Pleural effusion.

thoracic radiology in HIV-positive patients

• A wider range of radiographic patterns may be seen. In addition to the patterns listed above, other findings may include: (32000285)
  • Cryptococcus may present as ground glass opacities that can radiographically mimic pneumocystis.
  • Hilar lymphadenopathy (~1/3 of patients).
  • Miliary pattern: 1-2 mm miliary nodules may occur due to hematogenous spread.

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cryptococcal meningitis

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basics

• Cryptococcus has a proclivity for causing meningitis. Identification of Cryptococcus anywhere in the body should lead to a consideration of the possibility of simultaneous cryptococcal meningitis.

pathophysiology

• Pneumonia is the primary focus of infection, with secondary dissemination to other sites (especially the brain). However, patients may present initially with neurological abnormalities.
• A hallmark of cryptococcal meningitis is communicating hydrocephalus, with markedly elevated intracranial pressure.
• Meningeal inflammation may affect blood vessels, leading to ischemic strokes (figure below).

clinical features of cryptococcal meningitis

• Usually patients present with subacute or chronic onset of mild symptoms, including headache, malaise, and fever. Symptoms may be insidious and may fluctuate over time.
• (1) Meningeal findings:
  • Headache and fever are often present.
  • Frank meningeal irritation is uncommon (e.g., nuchal rigidity).
  • Basilar meningitis may cause cranial nerve abnormalities (e.g., mimicking Meniere's disease). (26633781)
• (2) Elevated intracranial pressure:
  • Nausea and vomiting.
  • Visual loss and abducens nerve palsy.
  • Examination may reveal papilledema.
  • Confusion, behavior changes, and eventually stupor/coma may occur.
• (3) Clinical effects of cryptococcomas:
  • Invasion of the brain parenchyma may lead to focal lesions in the basal ganglia, thalamus, and subcortical white matter. (28466277) 
  • Symptoms may include seizures and other focal findings (e.g., weakness, sensory abnormalities).

CSF studies in cryptococcal meningitis

• Opening pressure is often extremely elevated, but it is also frequently normal. Opening pressure is >25 cm water in only half of patients with cryptococcal meningitis. (32000285) Measuring the opening pressure is essential because this dictates the management of intracranial pressure, as discussed below: ⚡️
• Basic CSF profile:
  • HIV-negative patients:
    • Moderate lymphocytic pleocytosis is usually seen. However, cell counts can be extremely elevated in patients able to mount an immune response (e.g., >1,000/uL). (30273244)
    • Protein is often highly elevated.
    • Glucose is usually reduced.
  • Patients with HIV may have essentially normal laboratories (or only mild elevation of white blood cell count or protein). Normal CSF chemistries don't exclude cryptococcal meningitis in the context of AIDS. Low cell count is actually a poor prognostic sign among patients with cryptococcal meningitis. (26633781)
• CrAG (cryptococcal antigen) testing in the CSF is highly specific and sensitive (>97%). (34623105)
• Fungal culture has a high yield but takes several days.
• (Multiplex PCR platforms such as BioFire 📖 have limited sensitivity for Cryptococcus spp.  Therefore, CrAG should be tested to exclude Cryptococcus.)

imaging: CT scan

• CT scan is often normal. (33516057) 
• Hydrocephalus may be seen in some patients.
• Parenchymal cryptococcomas may be seen, most often in the basal ganglia.

imaging: MRI

• Hydrocephalus is the most common radiological abnormality (which may be communicating or noncommunicating). (Tang 2015)
• Nodular leptomeningeal enhancement is sometimes seen, especially involving the basal meninges. Ventriculitis may also be seen. However, this may be less likely in patients with more severe immunocompromise.
• Infarcts may be seen due to perivascular inflammation, most commonly in the basal ganglia and less often in the thalamus, frontal, temporal, parietal, and occipital lobes. (33516057)
• Pseudocysts may occur, especially in HIV:(34623100)
  • Gelatinous pseudocysts develop within dilated Virchow-Robin spaces surrounding penetrating blood vessels near the basal ganglia and the corticomedullary junction. Similar patterns may occur in coccidiomycosis or candidiasis. (31964490) Although the basal ganglia are most often involved, pseudocysts may be seen in the cerebral white matter, brainstem, and cerebellum.
  • Cysts often lack vasogenic edema or enhancement. This may produce a “soap bubble” appearance. (bottom figure, below)
• Parenchymal cryptococcomas may be seen, typically within the basal ganglia.
  • Unlike pseudocysts, cryptococcomas reflect parenchymal brain invasion that incites granulomatous inflammation.
  • Lesions are hyperintense on T2 and hypointense on T1, with surrounding vasogenic edema.
  • Contrast enhancement may occur.

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other sites of dissemination

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most common

• Skin and mucous membranes:
  • Lesions may have variable appearance (e.g., papular lesions that may become pedunculated, plaques, ulcers, abscesses, pustules, or nodules.) (34016288)
  • Skin lesions usually reflect hematogenous dissemination, but may occasionally represent the primary site of infection following cutaneous inoculation. (32000285)
  • There should be a low threshold to obtain skin biopsy with staining and culture for fungal organisms.
• Osteomyelitis.

less common

• Hepatitis.
• Pericarditis, endocarditis.
• Renal abscess, prostatitis.
• Adrenal involvement.
• Liver, spleen, or lymph node involvement.
• Endophthalmitis.
• Arthritis.

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laboratory tests

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cytology

• Yeast forms can sometimes be seen in cytologic examination of pleural fluid or bronchoalveolar lavage fluid. Cryptococcus appears as a narrow-based budding yeast 4-10 uM large, with a prominent mucoid capsule.
• (Cytologic features of Cryptococcus are discussed here: 📖)

culture

• Cryptococcus grows readily in most laboratory media. Growth usually occurs within one week, but incubation for up to two weeks is recommended. (36354923, 34246386)
• Thoracic infection:
  • Sputum cultures have ~10% sensitivity. Cryptococcus may rarely be isolated from the sputum of immunocompetent patients without symptoms, in whom treatment may not be necessary. (34016288)
  • Bronchoalveolar lavage may have a sensitivity of ~80%. (Murray 2022) 
  • Pleural fluid cultures are usually positive.
• Disseminated infection:
  • Urine culture is often positive among patients with cryptococcal meningitis.
  • Blood cultures may be positive in ~20% of patients overall. (Murray 2022)

serum cryptococcal antigen (CrAg)

• Pulmonary disease:
  • Serum cryptococcal antigen is very sensitive (~90%) among patients with AIDS. (Fishman 2023)
  • Sensitivity is reduced (~65%) among patients who are immunocompetent with disease limited to the lungs. Sensitivity is higher among patients with a higher disease burden.
• CNS disease:
  • Serum cryptococcal antigen may be useful if lumbar puncture is contraindicated, with a sensitivity of ~90% and specificity of ~95% among patients with cryptococcal meningitis. (30921084; 31378872) 
  • Serum cryptococcal antigen may be positive in a small subset of patients with cryptococcal meningitis with a negative CSF cryptococcal antigen. (34016288)
• Specificity is excellent. However:
  • False-positive results can occur due to rheumatoid factor, infection with Trichosporon beigelii, or certain bacterial infections (Klebsiella pneumoniae, Stomatococcus mucilaginosus, or Capnocytophaga canimorsus). (Murray 2022)
  • Serum CrAg may persist for months after resolution of an infection, so a positive result doesn't necessarily indicate active infection. (30329097)
• Understanding cryptococcal antigen titer:
  • The median serum CrAg titer is 1:16 among immunocompetent patients, or 1:32 among immunocompromised patients. (36354923)
  • Implications of a high serum cryptococcal antigen titer (≧1:64):
    • Suggests disseminated disease with CNS involvement. (Murray 2022)
    • May increase the risk of failing antifungal therapy. (26540422)

beta-D-glucan

• Cryptococcus produces relatively little beta-D-glucan, so this will generally be negative.
• However, in disseminated disease, beta-D-glucan may be detectable. (Fishman 2023)

lumbar puncture

• See the section above on cryptococcal meningitis: ⚡️

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biopsy

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pulmonary nodules

• Tissue diagnosis may be required depending on the context and results of other tests.
• Transbronchial biopsy or percutaneous biopsy via interventional radiology may be utilized. Large nodules are often located peripherally and may be amenable to transthoracic needle biopsy. (36354923)

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management

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general principles

• Treatment is generally recommended, even for immunocompetent patients with mild disease (due to the risk of dissemination). (36354923)
• All patients with pulmonary cryptococcosis should have a lumbar puncture and brain imaging to exclude cryptococcal meningitis. (36354923) Fundoscopic examination to evaluate for ophthalmologic lesions may also be considered. 
• Most patients require an induction regimen (with amphotericin), as outlined below. However, patients with mild-moderate, localized (single-organ), nonmeningeal disease may be treated simply with fluconazole (400 mg/day, duration depending on clinical context).
• Fluconazole is the azole of choice. Experience with other azoles is limited. For patients intolerant of fluconazole, itraconazole is the recommended alternative. (32000285)
• ⚠️ Adjunctive steroids are not routinely recommended for patients with CNS cryptococcosis, as a recent trial showed an increase in adverse effects. (31378870)

ICP management for patients with cryptococcal meningitis

• Elevated intracranial pressure due to communicating hydrocephalus often requires management either with a lumbar drain or serial lumbar punctures.
• Therapeutic lumbar puncture should be performed daily in patients with persistent opening pressures of >25 cm. (33896533) Lumbar punctures may target a closing pressure of <20 cm water or a 50% decrease in pressure among patients with extremely high opening pressures. (34016288)
• Some patients may require a long-term CSF shunt.

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antimicrobial therapy for CNS, disseminated, and/or severe disease 

[1/3] induction therapy (often 2 weeks)

• Traditional: Liposomal Amphotericin B 3-4 mg/kg/d plus flucytosine 100 mg/kg/day. (34016288)
• Newer option: Liposomal Amphotericin B 10 mg/kg one dose, followed by 14 days of combined therapy with fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day).  The AMBITION study in 2022 demonstrated this regimen to be equivalent to traditional induction therapy with fewer side effects for therapy of cryptococcal meningitis among patients with HIV. (35320642) 
• Alternative: Fluconazole 1200 mg/day plus flucytosine 100 mg/kg/day. (34016288)
  • The ACTA trial (Advancing Cryptococcal Meningitis Treatment for Africa) showed equivalent efficacy for 7 days of amphotericin deoxycholate plus flucytosine, 14 days of amphotericin deoxycholate plus flucytosine, or 14 days of fluconazole plus flucytosine. (29539274)
• Severe pulmonary disease: No RCTs have been performed to evaluate newer regimens in pulmonary disease (e.g., liposomal amphotericin B versus high-dose fluconazole).

[2/3] consolidation therapy (~8 weeks)

• Fluconazole 400-800 mg/day.
• For cryptococcal meningitis, may consider fluconazole 800 mg/day.

[3/3] maintenance therapy (>1 year)

• Fluconazole 200 mg/day

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questions & discussion

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