114 - 221 Cryptococcosis

221 Cryptococcosis

TABLE 220-1  Treatment of Blastomycosis SEVERITY OF INFECTION SITE OF INFECTION THERAPY PATIENT POPULATION Immunocompetent Mild to moderatea Lung Itraconazole for 6–12 monthsb     Disseminated Itraconazole for 6–12 monthsb (≥12 months for osteomyelitis)   Severec CNS Lipid AmB (5 mg/kg dailyd,e for 4–6 weeks) followed by voriconazole (200–400 mg bid), itraconazoleb or fluconazole (800 mg daily) for at least 12 months of treatment     Lung Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb for 6–12 months     Disseminated Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb for 12 months of treatment

(≥12 months for osteomyelitis) Immunocompromised Any severity CNS Lipid AmB (5 mg/kg dailyd,e for 4–6 weeks) followed by voriconazole (200–400 mg bid), itraconazoleb or fluconazole (800 mg daily) for at least 1 year of treatmentg     Lung or disseminated Lipid AmB (3–5 mg/kg dailye,f for 7–14 days) followed by itraconazoleb for 12 monthsg Pregnanth Any severity Any site Lipid AmB (3–5 mg/kg dailye,f for 6–8 weeks), with avoidance of azole antifungals aMild to moderate infections can typically be managed in the outpatient setting. bA loading dose of 200 mg PO tid for 3 days followed by 200 mg PO daily or bid, with dosing based on serum itraconazole levels. The goal for levels of total itraconazole (i.e., itraconazole plus hydroxyitraconazole) is 1–5 μg/mL. Liquid itraconazole has greater bioavailability than the capsule formulation. Liquid itraconazole and oral capsules are administered differently (see text for details). Serum itraconazole levels should be measured after steady state has been reached (2 weeks). Because of the drug’s long half-life, blood for serum itraconazole determinations can be drawn regardless of the time of administration. In contrast, serum drug levels for voriconazole, posaconazole, and isavuconazole should be measured before a dose is administered when steady state has been reached (~1 week). cSevere blastomycosis requires hospitalization on a medical ward, an intermediate care unit, or an intensive care unit. dLipid amphotericin B (AmB) is the preferred formulation because it has the best central nervous system (CNS) penetration among AmB formulations. For patients with CNS blastomycosis that results in neurologic dysfunction, surgical intervention should be considered. eFor patients with CNS blastomycosis, severe pulmonary blastomycosis, or severe disseminated blastomycosis, combination therapy with lipid AmB plus a triazole antifungal can be considered; however, this combination has not been formally studied. For patients with acute respiratory distress syndrome, adjunctive steroid therapy with prednisone (40–60 mg daily for 1–2 weeks) can be considered; however, the benefit of steroid administration is not well defined. fIf lipid AmB is not available, then AmB deoxycholate (0.7–1. 0 mg/kg daily) can be substituted; however, this formulation is associated with higher rates of nephrotoxicity and infusion reactions than lipid AmB. gConsider 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. hAll women of childbearing age should undergo pregnancy testing before initiation of therapy. requiring irreversible immunosuppression, indefinite suppressive azole therapy may be needed; however, in light of the heterogene­ ity of this patient population, a decision about suppressive therapy should be made on a case-by-case basis. The majority of solid organ transplant recipients do not require lifelong suppression because rates of relapse are low when treatment guidelines are followed. 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 syn­ drome); voriconazole and posaconazole also can result in skeletal abnormalities. Itraconazole increases the risk of spontaneous abor­ tion. Before starting antifungal therapy, women of childbearing age with blastomycosis should have a pregnancy test. Voriconazole, posaconazole, and isavuconazonium sulfate have potent activity against B. dermatitidis and B. gilchristii and can be considered as alternatives for persons who cannot tolerate itra­ conazole. These agents, along with itraconazole and AmB, also exhibit good activity against newly identified species of Blastomy­ ces, such as B. helicus, B. percursus, and B. emzantsi. Fluconazole MICs against B. percursus and B. emzantsi are higher than those of other triazoles. Moreover, fluconazole appears to have poor activity against B. helicus, B. parvus, and B. silverae. ■ ■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 blastomy­ cosis do not experience long-term loss of pulmonary function. Cutane­ ous blastomycosis typically results in scarring. ■ ■PREVENTION Prevention of blastomycosis is challenging because most infections are sporadic and unpredictably acquired from the environment. How­ ever, substantial progress has been made in understanding vaccinemediated immunity conferred by a live, attenuated vaccine strain that

CHAPTER 221 is deficient in BAD1. When injected subcutaneously into mice, the

B. dermatitidis BAD1-null vaccine strain induces sterilizing immunity by activating TH17 lymphocytes to protect against lethal pulmonary challenge. Major antigenic components of the vaccine identified to date include calnexin and Blastomyces endoglucanase-2, which is con­ served in other pathogenic fungi, including Histoplasma capsulatum, Coccidioides species, Aspergillus species, Fonsecaea pedrosoi, and Pseu­ dogymnoascus destructans. Neither the BAD1-null attenuated vaccine nor recombinant antigen-based vaccines are commercially available. Cryptococcosis ■ ■FURTHER READING Benedict K et al: Blastomycosis-associated hospitalizations, United States 2010-2020. J Fungi 9:867, 2023. Limper AH et al: An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 183:96, 2011. Smith D et al: Clinical testing guidance for coccidioidomycosis, histo­ plasmosis, and blastomycosis in patients with community-acquired pneumonia for primary and urgent care providers. Clin Infect Dis 78:1559, 2024. Arturo Casadevall, Shmuel Shoham

Cryptococcosis ■ ■DEFINITION AND ETIOLOGY Cryptococcus, a genus of yeast-like fungi, is the etiologic agent of cryp­ tococcosis. 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. Hence, C. neoformans and C. gattii are now considered as

species complexes. However, for clinical purposes, these species com­ plexes cause indistinguishable disease referred to as cryptococcosis. Consequently, this chapter will continue to use the nomenclature C. neoformans and C. gattii with the understanding that these terms refer to species complexes.

■ ■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, cryp­ tococcal disease (cryptococcosis) is rare in the absence of impaired immunity. Conditions associated with high risk for C. neoformans infection include hematologic malignancies, receipt of solid-organ transplants, advanced liver disease, diabetes mellitus, illnesses neces­ sitating glucocorticoid therapy, and 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. Cryptococcal infection is acquired from the environment.

C. neoformans and C. gattii species complexes inhabit different eco­ logic 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. In contrast, C. gattii is not found in bird feces. Instead, it inhabits a variety of arboreal species, includ­ ing eucalyptus trees. C. neoformans strains are found throughout the world; however, 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. PART 5 Infectious Diseases 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 pan­ demic in the early 1980s, the overwhelming majority of cryptococcosis cases have occurred in patients with AIDS (Chap. 208). To compre­ hend the impact of HIV infection on the epidemiology of cryptococ­ cosis, it is instructive to note that 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. Among HIVinfected 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. ■ ■PATHOGENESIS 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.

FIGURE 221-1  Cryptococcal antigen in human brain tissue, as revealed by immunohistochemical staining. Brown areas show polysaccharide deposits 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 meningoencephalitis. Am J Pathol 148:1267, 1996.) However, 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. 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. Cryptococcus species have well-defined virulence factors that include the expression of the polysaccharide cap­ sule, the ability to make melanin, and 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 produc­ tion have been most extensively studied. The cryptococcal capsule is antiphagocytic, and the capsular polysaccharide has been associated with numerous deleterious effects on host immune function. Crypto­ coccal 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 (Fig. 221-1). In clinical practice, the capsular polysaccharide is the antigen that is measured as a diagnostic marker of cryptococcal infection. APPROACH TO THE PATIENT Cryptococcosis Cryptococcosis should be included in the differential diagnosis when any patient presents with findings suggestive of chronic pul­ monary or CNS infection. Concern about cryptococcosis is height­ ened by a history of headache and neurologic symptoms in a patient with an underlying immunosuppressive disorder such as advanced HIV infection, malignancy, immunosuppressive use, or 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, and a cryptococcal antigen assay.

■ ■CLINICAL MANIFESTATIONS The clinical manifestations reflect the site of infection. The spectrum of 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 inva­ sion and from an overactive immune response. In CNS disease, symp­ toms may reflect elevated intracranial pressure (ICP). 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, and meningismus. Cryptococcal meningi­ tis differs from bacterial meningitis in that many patients present with symptoms of several weeks in duration. In addition, classic characteris­ tics of meningeal irritation, such as meningismus, may be absent. Indo­ lent cases can present as subacute dementia or depression. Meningeal cryptococcosis can lead to sudden catastrophic vision loss. Pulmonary cryptococcosis usually presents as cough, increased sputum production, and chest pain. Radiographic findings include nodules, infiltrates, and 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, and tuberculosis. Skin lesions are common in patients with disseminated cryptococ­ cosis and can be highly variable, including papules, plaques, purpura, vesicles, tumor-like lesions, and rashes. The spectrum of cryptococ­ cosis 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 immu­ nosuppressed patients, the lesions of cutaneous cryptococcosis often resemble those of molluscum contagiosum (Fig. 221-2; Chap. 201). ■ ■DIAGNOSIS A diagnosis of cryptococcosis requires the demonstration of cryp­ tococcal 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. CSF examina­ tion usually reveals evidence of chronic meningitis with mononuclear 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.)

cell pleocytosis and 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 major advance in recent years was the intro­ duction of rapid point-of-care CRAgs that provide results in minutes. A positive CRAg test provides strong presumptive evidence for cryp­ tococcosis; 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.

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 cryptococcal 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. TREATMENT Cryptococcosis When the infection is nonsevere and limited to the lungs or other non-CNS sites, treatment is typically with fluconazole. While pul­ monary cryptococcosis in an immunocompetent host sometimes resolves without therapy, given the propensity of Cryptococcus spe­ cies 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 nonse­ vere 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 involve­ ment. Thus, the decision to categorize cryptococcosis as “extra­ pulmonary without CNS involvement” should be made only after evaluation of the CSF reveals no evidence of cryptococcal infection. CHAPTER 221 Cryptococcosis When cryptococcosis is severe or involves the CNS, treatment involves induction, consolidation, and maintenance phases. The induction phase ideally includes a combination of intravenous amphotericin B (AmB) and 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 liposo­ mal AmB 3–5 mg/kg, AmB lipid complex 5 mg/kg, and 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, or brain cryptococcomas and in people without HIV. 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. 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.