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Cryptococcosis

Chapter 221 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Fungal

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points

  1. Cryptococcus neoformans and C. gattii are WHO critical priority pathogens; C. neoformans found in soils with avian excreta, C. gattii in arboreal species like eucalyptus trees
  2. Cryptococcosis is rare in immunocompetent hosts; high risk in HIV with CD4+ <200/μL, hematologic malignancies, solid organ transplants, advanced liver disease, diabetes, glucocorticoid therapy
  3. CNS cryptococcosis presents as chronic meningitis (weeks duration) with headache, fever, lethargy, cranial nerve deficits; meningismus often absent unlike bacterial meningitis
  4. Diagnosis requires demonstration of cryptococcal cells or antigen in sterile tissues; CSF examination with India ink, Gram stain, cultures, and cryptococcal antigen (CRAg) assay
  5. Induction therapy for severe/CNS disease: lipid AmB 3-5 mg/kg daily + flucytosine 25 mg/kg qid for 2-6 weeks, followed by fluconazole 400-800 mg daily for consolidation/maintenance
  6. Nonsevere pulmonary cryptococcosis in immunocompetent hosts: fluconazole 400 mg daily for 6-12 months; pulmonary disease may resolve spontaneously but prophylaxis recommended due to dissemination risk
  7. CRAg detection in CSF and blood is highly sensitive/specific; positive test provides strong presumptive evidence; point-of-care tests available in resource-limited regions
  8. Pregnant women: lipid AmB 3-5 mg/kg daily for 6-8 weeks preferred; avoid azole antifungals due to teratogenicity (fluconazole causes craniofacial/skeletal/cardiac defects)

📑 Table of Contents

📋 Figures in This Chapter

# Type Description
1 🖼 Figure and FIGURE 221-1 Cryptococcal antigen in human brain tissue, as revealed by...
2 🖼 Figure Disseminated fungal infection

1. DEFINITION & ETIOLOGY

Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of cryptococcosis. In 2022, the World Health Organization (WHO) declared Cryptococcus neoformans as a critical priority pathogen. Until recently, cryptococcal strains were separated into two species. However, genome sequencing studies have now revealed tremendous diversity among isolates previously assigned to each species, leading to the proposal that each of the prior species classifications includes numerous new species complexes. For clinical purposes, these species complexes cause indistinguishable disease referred to as cryptococcosis. Consequently, this chapter continues to use the nomenclature C. neoformans and C. gattii with the understanding that these terms refer to species complexes.

1.1 Species Classification

  • C. neoformans and C. gattii are now considered as species complexes
  • C. neoformans var. grubii (serotype A) strains are far more common than var. neoformans (serotype D) strains among both clinical and environmental isolates
  • C. gattii was thought to be largely limited to tropical regions until an outbreak of cryptococcosis caused by a new serotype B strain began in Vancouver in 1999
  • This outbreak has extended into the United States, and C. gattii infections are being encountered increasingly in several states in the Pacific Northwest
  • C. gattii is not found in bird feces; instead, it inhabits a variety of arboreal species, including eucalyptus trees

1.2 Pathogenesis Overview

  • Cryptococcal infection is almost always acquired by inhalation of aerosolized particles
  • The exact nature of the infectious particles is not known; the two leading candidate forms are small desiccated yeast cells and basidiospores
  • Occasionally, infection is acquired via direct inoculation of the skin
  • Little is known about the pathogenesis of initial infection
  • Serologic studies have shown that cryptococcal infection is acquired in childhood, but it is not known whether the initial infection is symptomatic
  • Given that cryptococcal infection is common while disease is rare, the consensus is that pulmonary defense mechanisms in immunologically intact individuals are highly effective at containing this fungus
  • It is not clear whether initial infection leads to a state of immunity or whether most individuals are subject throughout life to frequent and recurrent infections that resolve without clinical disease
  • Some human cryptococcal infections lead to a state of latency in which viable organisms are harbored for prolonged periods, possibly in granulomas
  • Thus, the inhalation of cryptococcal cells and/or spores can be followed by either clearance or establishment of the latent state
  • The consequences of prolonged harboring of cryptococcal cells in the lung are not known, but evidence from animal studies indicates that the organisms' prolonged presence could alter the immunologic milieu in the lung and predispose to allergic airway disease

2. EPIDEMIOLOGY

Cryptococcosis was first described in the 1890s but remained rare until the mid-twentieth century, when advances in diagnosis and increases in the number of immunosuppressed individuals markedly raised its reported prevalence. Although serologic evidence of cryptococcal infection is common among immunocompetent individuals, cryptococcal disease (cryptococcosis) is rare in the absence of impaired immunity.

2.1 Risk Factors

  • Conditions associated with high risk for C. neoformans infection include:
  • Hematologic malignancies
  • Receipt of solid-organ transplants
  • Advanced liver disease
  • Diabetes mellitus
  • Illnesses necessitating glucocorticoid therapy
  • Advanced HIV infection with CD4+ T lymphocyte counts of <200/μL
  • In contrast, C. gattii-related disease is not generally associated with specific immune deficits and often occurs in immunocompetent individuals but is associated with autoantibodies to granulocyte-macrophage colony-stimulating factor
  • Among HIV-infected persons, those with a decreased percentage of memory B cells expressing IgM may be at greater risk for cryptococcosis
  • In wealthier countries, most cryptococcosis cases are in people without HIV

2.2 Global Burden

  • The global burden of cryptococcosis was estimated in 2012 at ~1 million cases, with >600,000 deaths annually
  • Although the prevalence of this disease has declined since then with the greater availability of antiretroviral therapy (ART) for HIV
  • Since the onset of the HIV pandemic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS
  • In the early 1990s there were >1000 cases of cryptococcal meningitis each year in New York City—a figure far exceeding that for all cases of bacterial meningitis
  • With the advent of effective ART, the incidence of AIDS-related cryptococcosis has been sharply reduced among treated individuals
  • Therefore, most cases of cryptococcosis now occur in resource-limited regions of the world
  • The disease remains distressingly common in regions where ART is not readily available (e.g., parts of Africa and Asia)
  • In these regions, up to one-third of patients with AIDS have cryptococcosis

3. PATHOGENESIS

Cryptococcosis usually presents clinically as pulmonary disease and/or chronic meningoencephalitis. The mechanisms by which the fungus undergoes extrapulmonary dissemination and enters the central nervous system (CNS) remain poorly understood. Current evidence suggests that both direct fungal-cell migration across the endothelium and fungal-cell carriage inside macrophages as 'Trojan horse' invaders can occur.

3.1 Virulence Factors

  • Cryptococcus species have well-defined virulence factors that include:
  • Expression of the polysaccharide capsule
  • The ability to make melanin
  • The elaboration of enzymes (e.g., phospholipase and urease) that enhance the survival of fungal cells in tissue
  • Among these virulence factors, the capsule and melanin production have been most extensively studied
  • The cryptococcal capsule is antiphagocytic
  • The capsular polysaccharide has been associated with numerous deleterious effects on host immune function
  • Cryptococcal infections can elicit little or no tissue inflammatory response
  • The immune dysfunction seen in cryptococcosis has been attributed to the release of copious amounts of capsular polysaccharide into tissues, where it probably interferes with local immune responses

3.2 Environmental Niches

  • C. neoformans and C. gattii species complexes inhabit different ecological niches
  • C. neoformans is frequently found in soils contaminated with avian excreta and can be recovered from shaded and humid soils contaminated with pigeon droppings
  • C. gattii is not found in bird feces
  • C. neoformans strains are found throughout the world
  • C. gattii inhabits a variety of arboreal species, including eucalyptus trees

4. CLINICAL MANIFESTATIONS

The clinical manifestations reflect the site of infection. The spectrum of cryptococcal disease consists predominantly of meningoencephalitis and pneumonia, but skin and soft tissue infections also occur and cryptococcosis can affect any tissue or organ. Symptoms may arise from fungal tissue invasion and from an overactive immune response.

4.1 CNS Disease

  • CNS involvement usually presents as signs and symptoms of chronic meningitis, such as:
  • Headache
  • Fever
  • Lethargy
  • Sensory deficits
  • Memory deficits
  • Cranial nerve paresis
  • Vision deficits
  • Meningismus
  • Cryptococcal meningitis differs from bacterial meningitis in that many patients present with symptoms of several weeks in duration
  • In addition, classic characteristics of meningeal irritation, such as meningismus, may be absent
  • Indolent cases can present as subacute dementia or depression
  • Meningeal cryptococcosis can lead to sudden catastrophic vision loss
  • Symptoms may reflect elevated intracranial pressure (ICP)

4.2 Pulmonary Disease

  • Pulmonary cryptococcosis usually presents as:
  • Cough
  • Increased sputum production
  • Chest pain
  • Radiographic findings include:
  • Nodules
  • Infiltrates
  • Masses
  • C. gattii pneumonia can present with granulomatous masses known as cryptococcomas
  • Fever develops in a minority of cases
  • Pulmonary cryptococcosis can follow an indolent course, and many cases probably do not come to clinical attention
  • In fact, many cases are discovered incidentally during the workup of an abnormal chest radiograph obtained for other purposes
  • Pulmonary cryptococcosis can be associated with antecedent diseases such as:
  • Malignancy
  • Diabetes
  • Tuberculosis

4.3 Skin and Soft Tissue Infections

  • Skin lesions are common in patients with disseminated cryptococcosis and can be highly variable, including:
  • Papules
  • Plaques
  • Purpura
  • Vesicles
  • Tumor-like lesions
  • Rashes
  • The spectrum of cryptococcosis in HIV-infected patients is so varied and has changed so much since the advent of ART that a distinction between HIV-related and HIV-unrelated cryptococcosis is no longer pertinent
  • In highly immunosuppressed patients, the lesions of cutaneous cryptococcosis often resemble those of molluscum contagiosum
  • Important features of the lesion include a benign-appearing fleshy papule with central umbilication resembling molluscum contagiosum

5. DIAGNOSIS

A diagnosis of cryptococcosis requires the demonstration of cryptococcal cells or antigen in normally sterile tissues. Visualization of encapsulated fungal cells in CSF mixed with India ink remains a useful rapid diagnostic technique. Cryptococcal cells can also be visualized on Gram stain. However, these staining techniques may yield negative results in patients with a low fungal burden or be misread as positive by inexperienced operators. Cultures of CSF and blood that are positive for cryptococcal cells are diagnostic for cryptococcosis.

5.1 CSF Examination

  • CSF examination usually reveals evidence of chronic meningitis with:
  • Mononuclear cell pleocytosis
  • Increased protein levels
  • A particularly useful test is cryptococcal antigen (CRAg) detection in CSF and blood
  • The assay is based on serologic detection of cryptococcal polysaccharide and is both sensitive and specific
  • A positive CRAg test provides strong presumptive evidence for cryptococcosis
  • However, because the result is often negative in pulmonary cryptococcosis, the test is less useful for diagnosing pulmonary disease and is of only limited usefulness in monitoring the response to therapy
  • Polymerase chain reaction is available and effective for the diagnosis of cryptococcosis, but physicians should seek confirmation of positive or negative tests with independent methods such as CRAg and culture
  • Cryptococcal cells with negative cultures may be seen on CSF staining, and elevated cryptococcal antigen may be present in CSF and blood, long after clearance of cultures
  • These do not indicate treatment failure

5.2 Diagnostic Approach

  • Cryptococcosis should be included in the differential diagnosis when any patient presents with findings suggestive of chronic pulmonary or CNS infection
  • Concern about cryptococcosis is heightened by a history of headache and neurologic symptoms in a patient with an underlying immunosuppressive disorder such as:
  • Advanced HIV infection
  • Malignancy
  • Immunosuppressive use
  • Solid-organ transplantation
  • Evaluation of cerebrospinal fluid (CSF) is critical for diagnosis of CNS disease and should include:
  • Measurements of CSF pressure
  • Protein
  • Glucose
  • Cell count
  • Gram stain
  • Cultures
  • A cryptococcal antigen assay
  • In areas of Africa where there is a high prevalence of HIV infection, routine screening of blood for CRAg in HIV-infected patients with low CD4+ T lymphocyte counts may identify individuals at high risk of cryptococcal disease who are candidates for antifungal therapy
  • CRAg screening has shown that a significant proportion of HIV-infected patients hospitalized with pneumonia in Thailand harbor cryptoccal infection
  • Inexpensive point-of-care CRAg tests in the form of lateral flow assays provide rapid and accurate information and are of great diagnostic benefit in resource-limited regions

6. TREATMENT

When the infection is nonsevere and limited to the lungs or other non-CNS sites, treatment is typically with fluconazole. While pulmonary cryptococcosis in an immunocompetent host sometimes resolves without therapy, given the propensity of Cryptococcus species to disseminate from the lung, the inability to gauge the host's immune status precisely, and the availability of low-toxicity therapy in the form of fluconazole, the current recommendation for nonsevere pulmonary cryptococcosis in an immunocompetent individual is fluconazole 400 mg daily for 6–12 months. Fluconazole can cause drug interactions, QT interval prolongation, and liver dysfunction (especially at higher doses), and the dose should be adjusted for renal function. In general, extrapulmonary cryptococcosis without CNS involvement requires less intensive therapy, with the caveat that morbidity and death are associated with meningeal involvement. Thus, the decision to categorize cryptococcosis as 'extrapulmonary without CNS involvement' should be made only after evaluation of the CSF reveals no evidence of cryptococcal infection. When cryptococcosis is severe or involves the CNS, treatment involves induction, consolidation, and maintenance phases.

6.1 Induction Phase

  • The induction phase ideally includes a combination of:
  • Intravenous amphotericin B (AmB)
  • Oral flucytosine (5-FC)
  • If feasible, lipid formulations of AmB should be used because those have less toxicity than deoxycholate AmB
  • The recommended daily doses are:
  • Liposomal AmB 3–5 mg/kg
  • AmB lipid complex 5 mg/kg
  • Deoxycholate AmB 0.7–1 mg/kg
  • The dose of 5-FC is 25 mg/kg four times daily
  • 5-FC can cause bone marrow suppression, and the dose should be adjusted for renal function
  • The duration of induction therapy is a minimum of 2 weeks but may require extension to 4–6 weeks when there is:
  • Poor initial response to therapy
  • Neurologic complications
  • Brain cryptococcomas
  • In people without HIV
  • For people with HIV, WHO recommends several alternative approaches to induction:
  • A single dose of liposomal AmB 10 mg/kg given along with 14 days of 5-FC at 25 mg/kg four times daily and fluconazole 1200 mg daily
  • If liposomal AmB is not available, a 7-day course of AmB deoxycholate 1 mg/kg per day can be used in its place
  • If AmB is not available, an all-oral 14-day induction regimen of fluconazole 1200 mg daily and 5-FC 25 mg/kg four times daily can be used

6.2 Consolidation and Maintenance Phases

  • The consolidation phase is typically with fluconazole 400–800 mg daily for 8 weeks
  • This is followed by fluconazole maintenance at 200–400 mg daily for a year or longer
  • For nonsevere pulmonary cryptococcosis in an immunocompetent individual: fluconazole 400 mg daily for 6–12 months
  • Fluconazole can cause drug interactions, QT interval prolongation, and liver dysfunction (especially at higher doses), and the dose should be adjusted for renal function

6.3 Treatment Considerations

  • Cryptococcal cells with negative cultures may be seen on CSF staining, and elevated cryptococcal antigen may be present in CSF and blood, long after clearance of cultures
  • These do not indicate treatment failure
  • For people with HIV, WHO recommends several alternative approaches to induction
  • These include a single dose of liposomal AmB 10 mg/kg given along with 14 days of 5-FC at 25 mg/kg four times daily and fluconazole 1200 mg daily
  • If liposomal AmB is not available, a 7-day course of AmB deoxycholate 1 mg/kg per day can be used in its place
  • If AmB is not available, an all-oral 14-day induction regimen of fluconazole 1200 mg daily and 5-FC 25 mg/kg four times daily can be used

7. SPECIAL CONSIDERATIONS

All women of childbearing age should undergo pregnancy testing before initiation of therapy. For pregnant women, lipid AmB treatment for 6–8 weeks is recommended because, unlike the triazole antifungals, lipid AmB is not teratogenic. Fluconazole can cause craniofacial, skeletal, and cardiac defects in the developing fetus (Antley-Bixler-like syndrome); voriconazole and posaconazole also can result in skeletal abnormalities. Itraconazole increases the risk of spontaneous abortion. Before starting antifungal therapy, women of childbearing age with blastomycosis should have a pregnancy test.

7.1 Pregnancy Considerations

  • For pregnant women, lipid AmB treatment for 6–8 weeks is recommended
  • Unlike the triazole antifungals, lipid AmB is not teratogenic
  • Fluconazole can cause craniofacial, skeletal, and cardiac defects in the developing fetus (Antley-Bixler-like syndrome)
  • Voriconazole and posaconazole also can result in skeletal abnormalities
  • Itraconazole increases the risk of spontaneous abortion
  • Before starting antifungal therapy, women of childbearing age with blastomycosis should have a pregnancy test
  • All women of childbearing age should undergo pregnancy testing before initiation of therapy
  • The majority of solid organ transplant recipients do not require lifelong suppression because rates of relapse are low when treatment guidelines are followed
  • For patients requiring irreversible immunosuppression, indefinite suppressive azole therapy may be needed
  • However, in light of the heterogeneity of this patient population, a decision about suppressive therapy should be made on a case-by-case basis
  • Consider lifelong suppression with itraconazole (200 mg daily) if immunosuppression cannot be reversed
  • This decision should be made on a case-by-case basis; not all immunosuppressed patients require lifelong suppressive therapy
  • In addition, lifelong antifungal suppression can be considered in patients who experience relapse after appropriate therapy

8. PROGNOSIS

Mortality rates for blastomycosis range from 5 to 13%; most deaths are associated with respiratory failure due to ARDS. Analysis of 11,776 hospital admissions for blastomycosis from 2010 through 2020 (HCUP data) demonstrated a 7.9% mortality rate, with increased mortality in patients who were older or who had underlying chronic obstructive pulmonary disease or concomitant malignancy (solid or hematologic). The vast majority of patients who recover from pulmonary blastomycosis do not experience long-term loss of pulmonary function. Cutaneous blastomycosis typically results in scarring.

8.1 Mortality and Outcomes

  • Mortality rates for blastomycosis range from 5 to 13%
  • Most deaths are associated with respiratory failure due to ARDS
  • Analysis of 11,776 hospital admissions for blastomycosis from 2010 through 2020 (HCUP data) demonstrated a 7.9% mortality rate
  • Increased mortality in patients who were:
  • Older
  • Had underlying chronic obstructive pulmonary disease
  • Had concomitant malignancy (solid or hematologic)
  • The vast majority of patients who recover from pulmonary blastomycosis do not experience long-term loss of pulmonary function
  • Cutaneous blastomycosis typically results in scarring

Figures & Illustrations

Reproduced from Harrison's 22nd Edition.

Figure 1

and FIGURE 221-1 Cryptococcal antigen in human brain tissue, as...

Caption: and FIGURE 221-1 Cryptococcal antigen in human brain tissue, as revealed by with immunohistochemical staining. Brown areas show polysaccharide deposits factor. in the midbrain of a patient who died of cryptococcal meningitis. (Reproduced with permission from SC Lee et al: Immunohistochemical localization of capsular polysaccharide antigen in the central nervous system cells in cryptococcal eco- meningoencephalitis. Am J Pathol 148:1267, 1996.) soils not found includ- However, some human cryptococcal infections lead to a state of latency — Figure 221-1: Immunohistochemical staining of cryptococcal antigen in human brain tissue. Brown areas show polysaccharide deposits in the midbrain of a patient who died of cryptococcal meningitis, demonstrating capsular polysaccharide antigen localization in central nervous system cells.

Figure 2

Disseminated fungal infection

Caption: FIGURE 221-2 Disseminated fungal infection. A liver transplant recipient developed six cutaneous lesions similar to the one shown. Biopsy and serum antigen testing demonstrated Cryptococcus. Important features of the lesion include a benign-appearing fleshy papule with central umbilication resembling molluscum contagiosum. (Photo courtesy of Dr. Lindsey Baden; with permission.) — Figure 221-2: Disseminated fungal infection in liver transplant recipient. Six cutaneous lesions resembling molluscum contagiosum with benign-appearing fleshy papules and central umbilication. Biopsy and serum antigen testing confirmed Cryptococcus.

Generated from Harrison's Principles of Internal Medicine, 22nd Edition.