History and exam
Key diagnostic factors
common
presence of risk factors
Risk factors for cryptococcal infection include HIV infection, immunosuppression, and other comorbidities (e.g., diabetes, chronic lung disease).
constitutional symptoms
Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnoea, chest pain, weight loss, and fatigue.
Central nervous system involvement also causes lethargy and pyrexia.
dyspnoea
Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnoea, chest pain, weight loss, and fatigue.
productive cough
Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnoea, chest pain, weight loss, and fatigue.
dullness to percussion
Dullness to percussion, diminished breath sounds, and crackles on the affected side represent pleural effusion, diffuse alveolar and interstitial infiltrates, or endobronchial lesions.
diminished breath sounds
Dullness to percussion, diminished breath sounds, and crackles on the affected side represent pleural effusion, diffuse alveolar and interstitial infiltrates, or endobronchial lesions.
crackles
Dullness to percussion, diminished breath sounds, and crackles on the affected side represent pleural effusion, diffuse alveolar and interstitial infiltrates, or endobronchial lesions.
headache
Headache, pyrexia, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent central nervous system 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 non-specific presentation of meningoencephalitis in these patients.
alteration of consciousness
Headache, pyrexia, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent central nervous system involvement and can present over several days or over months.
meningeal irritation
Headache, pyrexia, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent central nervous system involvement and can present over several days or over months.
Neck stiffness, photophobia, and vomiting are seen in one quarter to one third of HIV-positive patients with meningoencephalitis.[1][2][4][35]
papilloedema
Papilloedema is a sign of increased intracranial pressure, which may result from meningeal inflammation, cryptococcoma, or hydrocephalus. It occurs in almost 50% of HIV-negative and HIV-positive patients with cryptococcal meningitis and it complicates management, leading to visual or hearing loss.[35]
skin lesions
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]
uncommon
coma
Headache, pyrexia, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent central nervous system involvement and can present over several days or over months.
Other diagnostic factors
uncommon
chest pain
Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnoea, chest pain, weight loss, and fatigue.
cranial neuropathy
Headache, pyrexia, cranial neuropathies, alteration of consciousness, lethargy, meningeal irritation, and coma represent central nervous system involvement and can present over several days or over months.
ocular manifestations
Cryptococcal meningoencephalitis may present with ocular signs and symptoms, including papilloedema.
The most common ocular manifestations include retinal and peripapillary haemorrhages and other retinal lesions, all of which can result in visual loss.[1]
Risk factors
strong
HIV infection
Patients with compromised cell-mediated immunity are at higher risk of acquiring cryptococcosis, particularly those with CD4 cell counts <100 cells/mm³.[20] HIV infection is associated with >80% of cryptococcosis cases worldwide.[1][9][11][21][22] The use of antiretroviral treatment (ART) has been associated with a lower incidence of cryptococcosis.[20] However, in countries with uncontrolled HIV infection, limited access to ART, or poor retention in care, such as in Africa and Asia, the incidence of and mortality from cryptococcosis are extremely high.[11]
HIV-associated cryptococcosis is characterised by more central nervous system 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] Mortality remains high in people with HIV infection and cryptococcal meningitis, at approximately 70% mortality in low-income countries.[10][23]
immunosuppression
Although exposure to Cryptococcus species is common, the development of symptomatic disease usually requires immunosuppression. Organ transplantation, the use of corticosteroids or other immunosuppressive agents and monoclonal antibodies (e.g., alemtuzumab and infliximab), idiopathic CD4 lymphocytopenia, liver disease, systemic lupus erythematosus, diabetes mellitus, and haematological malignancies can result in immunosuppression and allow reactivation of a cryptococcal infection.[1]
In immunosuppressed patients, haematogenous dissemination can occur to multiple organs, including the central nervous system (CNS), skin, prostate, eyes, bone, urinary tract, and blood.[1] A total of 53% to 72% of cryptococcal disease cases among organ transplant recipients have disseminated or CNS involvement. Aggressive treatment of early cryptococcal disease may prevent loss of the transplanted organ.[14][24][25]
In one Cryptococcus var. gattii epidemic, although a small number of patients were overtly immunosuppressed, a significant proportion had had previous corticosteroid exposure.[4][13][16]
weak
exposure to Cryptococcus species
Outdoor activities and exposure to bird droppings and eucalypt reservoirs may play a role in the transmission of the fungus.[1][5][13]
Serotypes A and D of Cryptococcus neoformans are associated with bird droppings, especially those of pigeons.[1][2] Pigeons may carry the fungus on their beaks, feathers, and legs, thus contributing to the worldwide distribution of these strains. Cryptococcus neoformans has also been isolated from the heartwood of several species of trees.[4]
Evidence for it being a significant risk factor for human infection is low.
male sex
pregnancy and postnatal period
Cryptococcal meningitis, central nervous system lesions, pulmonary nodules and/or infiltrates, soft-tissue infections, and osteoarticular infections have been described during pregnancy and the postnatal period.[26] This has been attributed to helper T-cell (Th2 and Th1) reversal during the postnatal period.[1][27][28][29]
Case reports of mother-to-child transmission of cryptococcosis have also been reported. Immune reconstitution inflammatory syndrome can occur in women in the postnatal phase.[27]
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