History and exam

Key diagnostic factors

common

constitutional symptoms

Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnea, chest pain, weight loss, and fatigue.

Central nervous system involvement also causes lethargy and pyrexia.

dyspnea

Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnea, chest pain, weight loss, and fatigue.

productive cough

Acute pulmonary cryptococcosis presents with pyrexia, a productive cough, dyspnea, 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 patients with HIV and immunocompromised patients, even with headache alone, due to the subacute onset and nonspecific 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 people with HIV and meningoencephalitis.[1][2][4][37]

papilledema

Papilledema is a sign of increased intracranial pressure, which may result from meningeal inflammation, cryptococcoma, or hydrocephalus. It occurs in almost 50% of people with cryptococcal meningitis, and it complicates management, leading to visual or hearing loss.[37]

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 people with HIV 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, dyspnea, 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 papilledema.

The most common ocular manifestations include retinal and peripapillary hemorrhages, 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/microliter.[20] HIV infection is associated with >80% of cryptococcosis cases worldwide.[1][9][11][21][22]​ The use of antiretroviral therapy (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 and mortality from cryptococcosis are extremely high.[11]

HIV-associated cryptococcosis is characterized 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 hematologic malignancies can result in immunosuppression and allow reactivation of a cryptococcal infection.[1]

In immunosuppressed patients, hematogenous 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. C 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

A male predominance has been shown among patients with cryptococcosis.[11][12]

pregnancy and postpartum 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 postpartum period.[26] This has been attributed to helper T-cell (Th2 and Th1) reversal during the postpartum 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 postpartum phase.[27]

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