Cryptococcus infection


Cryptococcus neoformans infection outside the central nervous system

Humans likely become infected with C. neoformans by inhaling the basidiospore form of the fungus or small, poorly encapsulated yeasts. Basidiospores are smaller than the yeast forms obtained from clinical samples and have much smaller polysaccharide capsules, facilitating deposition in the alveoli and terminal bronchioles after inhalation [1]. Following inhalation, C. neoformans likely cause a focal pneumonitis that may or may not be symptomatic. The immune status is the most important determinant of the subsequent course of the infection (eg, whether the pneumonitis resolves or progresses to symptomatic dissemination) [2,3].

A large segment of the population has been exposed to C. neoformans [4]. Subclinical primary infections are common and most are asymptomatic. Postmortem studies on immunocompetent persons without antecedent respiratory complaints have demonstrated small areas of granulomatous inflammation in the lung parenchyma and/or hilar lymph nodes due to C. neoformans [5,6]. The foci are generally smaller than those seen in tuberculosis and do not appear to calcify as frequently as seen with histoplasmosis. Infection can persist in a latent state; if the host immune system becomes compromised, organisms may be liberated from the granulomatous complexes and cause active infection.

There are also descriptions of pulmonary cryptococcosis in apparently immunocompetent patients [7,8]. In a review of approximately 90 immunocompetent hosts with pulmonary cryptococcosis, 32 percent of the patients were asymptomatic, and pulmonary infection was discovered as an incidental finding [7]. Asymptomatic patients with chest radiograph findings suspicious for malignancy who undergo biopsy are occasionally found to have cryptococcosis.

The factors that determine whether an exposed person develops symptomatic infection are uncertain but may include the inoculum of fungi (eg, burden of exposure) and/or virulence factors of the infecting strain. Common symptoms include cough, sputum production, hemoptysis, dyspnea, chest pain, fever, malaise, night sweats, and weight loss [7,9-11]. Less common symptoms include rash and gastrointestinal complaints. Rare manifestations include obstruction of the superior vena cava, Pancoast syndrome due to granulomatous inflammation from the host response to C. neoformans, eosinophilic pneumonia, and extension from the lung to the chest wall [12-15].

SUMMARY AND RECOMMENDATIONS

●A large segment of the population has been exposed to Cryptococcus neoformans. Subclinical primary infections are common, and most are asymptomatic. Infection can persist in a latent state; if the host immune system becomes compromised, organisms may be liberated from the granulomatous complexes and cause active infection. Symptomatic pulmonary cryptococcosis can also occur in apparently immunocompetent patients. (See ‘Pulmonary infection in immunocompetent adults’ above and ‘Pulmonary infection in immunocompromised adults’ above.)

●Clinical manifestations due to cryptococcal pneumonia range from asymptomatic pneumonia to acute respiratory failure. The presentation of pulmonary cryptococcosis in patients with HIV is more acute and severe than in other hosts. Most symptomatic cases occur in patients with CD4 counts less than 100 cells/microL. (See ‘HIV-positive patients’ above.)

●The diagnosis of cryptococcal pneumonia in immunocompetent hosts is established by culturing the organism from sputum or another specimen. Visualization of encapsulated yeast forms in sputum, bronchoalveolar lavage, or tissue specimens is suggestive of cryptococcal pulmonary infection. The most common radiographic findings are solitary or few well-defined, noncalcified nodules. Lumbar puncture is warranted for patients with neurologic symptoms and for patients with serum cryptococcal antigen titer >1:512. (See ‘Diagnosis’ above.)

●The serum cryptococcal antigen titer is often positive in immunocompromised patients with cryptococcal pneumonia. Culture of respiratory specimens is also a useful tool. A lumbar puncture to rule out central nervous system disease should be performed in those with pulmonary cryptococcosis who are considered to be immunosuppressed even in the absence of neurologic signs or symptoms.(See ‘Diagnosis’ above.)

●We suggest that patients with mild to moderate pulmonary cryptococcosis in the absence of diffuse pulmonary infiltrates or disseminated infection be treated with fluconazole (Grade 2B). Dosing is fluconazole 400 mg (6 mg/kg) orally once daily for 6 to 12 months (table 1). (See ‘Antifungal therapy’ above.)

●Patients with severe pulmonary disease (eg, diffuse pulmonary infiltrates) or disseminated disease (eg, at least two noncontiguous sites or cryptococcal antigen titer ≥1:512) should be managed as outlined separately. (See “Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in HIV seronegative patients”.)


Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis

Cryptococcus gattii is a fungal pathogen that is endemic in the tropics and subtropics and that has also caused an outbreak that is ongoing in British Columbia, Canada, and the United States Pacific Northwest; C. gattii is genetically and biochemically distinct from Cryptococcus neoformans [1-3]. Together, C. gattii and C. neoformans account for most cases of cryptococcal infections in humans, although C. neoformans is more common. Like C. neoformans, infection with C. gattii manifests most often as meningoencephalitis and/or pneumonia.

Historically, C. gattii infection has been associated with exposure to certain trees. In particular, an environmental link with two species of Australian eucalypts (or red gum), Eucalyptus camaldulensis and Eucalyptus tereticornis, was first reported in the 1990s [46,47]. The concentration of E. camaldulensis along water courses and the association of rural-dwelling Aborigines with these trees are thought to explain the high prevalence of infection in this population, although host genetic factors in Aborigines and the non-Aboriginal population have not been studied. This link was subsequently confirmed by clinical and molecular epidemiologic studies [25,48] and the association of C. gattii infection with residence or work in a rural or semi-rural domicile has been maintained [49].

Unlike C. neoformans, which typically causes disease in patients with compromised cell-mediated immunity, most cases of C. gattii have been detected in persons with apparently normal immune systems

SUMMARY

●Cryptococcus gattii is an important fungal pathogen that is endemic in the tropics and subtropics and that has also caused an outbreak that is ongoing in British Columbia, Canada, and the United States Pacific Northwest. C. gattii is genetically and biochemically distinct from Cryptococcus neoformans. (See ‘Introduction’ above.)

●Information about the epidemiology and clinical syndromes caused by C. gattii in nonendemic regions is relatively limited due to the failure of many microbiology laboratories to distinguish between C. neoformans and C. gattii. (See ‘Epidemiology’ above.)

●There are at least four molecular types or genotypes of C. gattii, VGI to VGIV, each containing subtypes. Data from studies of molecular types of clinical and environmental strains indicate that genotype distribution and frequency vary in different geographic regions (table 1). The reasons for this are unknown but may relate to preferred ecologic niches for different genotypes. (See ‘Molecular types’ above.)

●Australia and Papua New Guinea have long been known to be sites of C. gattii endemic disease. Although C. gattii was formerly thought to be geographically restricted to tropical and subtropical regions, an outbreak that began in Vancouver Island, Canada, in 1999 and that has spread to the United States Pacific Northwest, and emergence of cases in Europe, has changed our understanding of the epidemiology of C. gattii infection. (See ‘Geographic distribution’ above.)

●The primary difference in host distribution between C. gattii and C. neoformans is that, at least in regions endemic for C. gattii, this species to a large extent causes infection in people with no apparent immunocompromise, although it has been hypothesized that some patients may have subclinical defects in immunity. C. gattii has also been detected in patients with human immunodeficiency virus (HIV) infection, solid organ transplantation, and other causes of immunodeficiency. (See ‘Hosts’ above.)

●The outcome of infection is determined by a complex set of interacting pathogen and host factors, including inoculum size, the cryptococcal strain, and the innate susceptibility or resistance of the host. (See ‘Pathogenesis’ above.)


Microbiology and epidemiology of Cryptococcus neoformans infection

SUMMARY

●Cryptococcosis is an invasive fungal infection due to Cryptococcus neoformans or Cryptococcus gattii. C. neoformans is the principal pathogenic member of the genus and has a worldwide distribution. (See ‘Introduction’ above.)

●C. neoformans is a basidiomycetous, encapsulated yeast that can be subclassified in two varieties, var grubii and var neoformans. These organisms are found in soil samples from around the world, in areas frequented by birds, especially pigeons and chickens. (See ‘Taxonomy’ above and ‘Epidemiology’ above.)

●The life cycle of C. neoformans involves asexual and sexual forms. The asexual forms exist as yeasts and reproduce by budding. These haploid, unicellular yeasts are the only forms of C. neoformans that have been recovered from human infections. (See ‘Life cycle’ above.)

●The vast majority of patients with cryptococcosis are immunocompromised. The serotypes or genotypes of C. neoformans in cases of cryptococcosis vary according to geographic location. (See ‘Epidemiology’ above.)


Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis

SUMMARY AND RECOMMENDATIONS

●Cryptococcus neoformans meningoencephalitis is the most frequently encountered disseminated manifestation of cryptococcosis. The term “meningoencephalitis” is more appropriate than “meningitis” since histopathological examination has demonstrated that the brain parenchyma is almost always involved. (See ‘Introduction’ above.)

●C. neoformans causes infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the central nervous system. The inflammatory response in the brain is generally milder than that seen in bacterial meningoencephalitis. The inflammatory cell infiltrate is predominantly comprised of mononuclear cells with occasional polymorphonuclear leukocytes. In general, involvement of the brain is diffuse, but localized infection (ie, cryptococcoma) can also occur. (See ‘Pathogenesis’ above.)

●Most patients with cryptococcal meningitis are immunocompromised. The most common forms of immunosuppression other than HIV include glucocorticoid therapy, solid organ transplantation, cancer (particularly hematologic malignancy), and other conditions such as sarcoidosis and hepatic failure. (See ‘Epidemiology’ above.)

●Clinical presentation is variable. Some patients have symptoms for up to several months prior to diagnosis, whereas others present with an acute illness of only a few days. Fever is observed in approximately 50 percent of cases. Typically, headache, lethargy, personality changes, and memory loss develop over two to four weeks. Patients may also present with disseminated disease (eg, >1 noncontiguous site). (See ‘Clinical manifestations’ above.)

●A lumbar puncture is necessary for diagnosis of cryptococcal meningoencephalitis. The opening pressure should be measured, along with India ink evaluation, cryptococcal antigen testing, fungal culture, and routine spinal fluid studies. The diagnosis is established definitively by culturing the organism from the spinal fluid. (See ‘Cerebrospinal fluid’ above.)

●Serum cryptococcal antigen testing is useful for evaluation of patients without HIV infection, although a negative result cannot be used to rule out cryptococcal meningoencephalitis. The height of the antigen titer generally correlates with the burden of organisms, although serial measurement of antigen titers is not a reliable indicator of response to therapy. (See ‘Cryptococcal antigen’ above.)

●Radiographic imaging of the brain with computed tomography or magnetic resonance imaging prior to lumbar puncture is important in the setting of focal neurologic signs, papilledema, or impaired mentation. Radiographic images frequently show no abnormality or cerebral atrophy without obstruction or other pathology. Less commonly, hydrocephalus may be seen. Mass lesions are seen in about 10 percent of patients with central nervous system cryptococcal infections. (See ‘Radiography’ above.)


Clinical management and monitoring during antifungal therapy

SUMMARY AND RECOMMENDATIONS

●Cryptococcal meningoencephalitis is a serious opportunistic infection that is seen among patients with untreated advanced AIDS. The management of cryptococcal meningoencephalitis is discussed in detail separately. (See ‘Introduction’ above and “Cryptococcus neoformans meningoencephalitis in patients with HIV infection: Treatment and prevention”.)

●The antifungal drugs used in the treatment of cryptococcal meningoencephalitis can be associated with significant toxicity, particularly amphotericin B and flucytosine. Close laboratory monitoring is needed for renal insufficiency, hematologic abnormalities, and electrolyte disturbances during induction therapy. (See ‘Monitoring for drug toxicity’ above.)

●For most patients, a lumbar puncture (LP) should be performed after two weeks of induction therapy to confirm sterilization of the cerebrospinal fluid (CSF) and to reassess intracranial pressure (ICP). We do not monitor serum cryptococcal antigen during treatment, since changes in this laboratory parameter do not correlate with clinical improvement. (See ‘Laboratory monitoring for fungal infection’ above and ‘Monitoring of intracranial pressure’ above.)

●For patients with persistent symptoms, or new symptoms after initial clinical improvement, an LP should be performed to rule out the possibility of increased ICP. Increased ICP may be related to the immune reconstitution inflammatory syndrome (IRIS) among patients who have initiated antiretroviral therapy (ART), or have persistent or relapsing infection, as suggested by a positive culture. (See ‘Evaluation for treatment failure’ above.)

●For patients with persistent or relapsing cryptococcal infection, the clinical management depends upon the suspected cause (eg, poor adherence, drug resistance, refractory disease). (See ‘Management of persistent or relapsing infection’ above.)

●For patients with IRIS, most minor signs resolve spontaneously after days to a few weeks. However, symptomatic patients with CSF pleocytosis and increased ICP are at risk for herniation. For such patients, serial LPs should be performed until stabilization of symptoms and normalization of ICP occurs. In addition, we suggest glucocorticoids (Grade 2C). Although the dose and duration are unclear, we typically initiate 0.5 to 1 mg/kg of prednisone (or equivalent) daily and then taper the dose over two to six weeks. (See ‘Management of IRIS’ above.)
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SUMMARY AND RECOMMENDATIONS

●Patients with HIV and advanced immunosuppression (CD4 cell count <50 cells/microL) are at risk for severe cryptococcal meningoencephalitis, which is uniformly fatal within approximately two weeks if untreated. (See ‘Overview’ above.)

●Treatment of cryptococcal meningoencephalitis includes antifungal therapy, control of intracranial pressure (ICP), and immune recovery with potent antiretroviral medications. (See ‘Overview’ above.)

●The optimal approach to antifungal therapy involves three phases: induction therapy for approximately two weeks, followed by consolidation therapy for approximately eight weeks, and then maintenance (ie, suppressive) therapy for at least one year to decrease the risk of relapse. (See ‘Antifungal therapy’ above.)

●For most patients with cryptococcal meningoencephalitis, we recommend intravenous (IV) amphotericin B with oral flucytosine during the induction phase of therapy (Grade 1B). (See ‘Induction therapy’ above.)

•For patients with reduced kidney function and risk factors for renal failure, we recommend liposomal amphotericin B (3 to 4 mg/kg IV daily) rather than amphotericin B deoxycholate (Grade 1B). We also suggest liposomal amphotericin for patients with normal renal function (Grade 2B). Liposomal amphotericin is associated with fewer toxicities compared with amphotericin B deoxycholate, and therefore, therapy is less likely to be interrupted. However, for patients with normal kidney function, amphotericin B deoxycholate (0.7 mg/kg IV daily) is a suitable alternative if liposomal amphotericin is not available. (See ‘Regimen’ above.)

•The dose of flucytosine is 100 mg/kg per day in four divided doses, adjusted for renal function. If flucytosine is not available or if it is not tolerated, we administer fluconazole (800 mg daily orally) in addition to amphotericin B during the induction phase of therapy. (See ‘Regimen’ above.)

•For patients in resource-rich settings, we suggest that induction therapy with amphotericin B and flucytosine be administered for at least two weeks (Grade 2C). It should be extended if clinical improvement is not observed and/or if cerebrospinal fluid (CSF) sterilization has not yet been achieved. (See ‘Duration’ above.)

•For patients in resource-limited settings, we recommend induction therapy with one week of amphotericin B deoxycholate plus flucytosine followed by one week of high-dose oral fluconazole (Grade 1B). If IV therapy is not possible, then a two-week course of fluconazole plus flucytosine may have similar efficacy to some amphotericin-containing regimens. (See ‘Considerations in resource-limited settings’ above.)

●After completing induction therapy, patients should receive consolidation therapy for a minimum of eight weeks. We suggest fluconazole rather than itraconazole (Grade 2C). Fluconazole is generally preferred over itraconazole due to better bioavailability and a reduced risk of drug interactions and gastrointestinal symptoms. The dose of fluconazole depends upon the induction regimen:

•For patients who received at least two weeks of amphotericin B plus flucytosine during the induction phase of therapy, we administer fluconazole at 400 mg per day orally. (See ‘Consolidation therapy’ above.)

•For patients who received an induction regimen that included less than two weeks of amphotericin B plus flucytosine (eg, the preferred regimen in resource-limited settings) or an alternative regimen (eg, fluconazole in combination with amphotericin B or flucytosine), we administer fluconazole at a dose of 800 mg per day orally. (See ‘Consolidation therapy’ above and ‘Considerations in resource-limited settings’ above.)

●For patients who complete the induction and consolidation phases of therapy, we recommend fluconazole (200 mg daily) for maintenance treatment compared with no therapy or itraconazole (Grade 1B). In early studies, patients who received maintenance therapy had a much lower incidence of relapse. The minimum duration of maintenance therapy should be at least one year. After that, maintenance therapy can be discontinued in individuals receiving antiretroviral therapy (ART) who have a CD4 cell count greater than 100 cells/microL and have achieved an undetectable viral load on ART for more than three months. (See ‘Maintenance therapy’ above.)

●Patients with increased ICP should be managed aggressively to reduce the risk of mortality associated with cryptococcal meningoencephalitis. In general, a lumbar puncture (LP) should be performed to reduce the opening pressure to <20 cm CSF; however, in symptomatic patients with extremely high CSF pressures, the goal is to reduce the ICP by 50 percent of the initial value. We perform daily LPs until the patient is asymptomatic and the CSF pressure has been documented to be normal and/or stable. Lumbar or ventricular drains may be preferred in patients who require frequent LPs. (See ‘Management of increased intracranial pressure’ above.)

●For patients with cryptococcal meningoencephalitis who are not receiving ART, we suggest initiation of ART be delayed at least two weeks after antifungal induction therapy has been started (Grade 2B). For patients with access to close medical follow-up and preventative therapy, we often start ART 10 weeks after the initiation of antifungal therapy to minimize the risk of drug interactions and development of an immune reconstitution inflammatory syndrome (IRIS). However, for individuals without these resources, we would consider starting ART four to six weeks after induction therapy has been initiated. (See ‘When to initiate antiretroviral therapy’ above.)

●The best way to prevent cryptococcal disease in HIV-infected individuals is through early initiation of ART. However, in patients with a low CD4 count, a strategy involving serum cryptococcal antigen (CrAg) screening and antifungal therapy in addition to ART may further reduce the risk of developing cryptococcal meningitis.

•For asymptomatic patients with a CD4 count <100 cells/microL who are not receiving ART, we suggest serum cryptococcal antigen screening prior to initiation of ART (Grade 2C). For people in resource-limited settings where the prevalence of cryptococcal antigenemia is >3 percent, there may also be a benefit to screening at a higher CD4 count threshold (<200 cells/microL), and some countries have adopted screening at this threshold, although evidence continues to be gathered. The management of patients who screen positive for cryptococcal antigen is discussed above. (See ‘Preventing symptomatic disease’ above.)

•If screening is not available, we suggest not routinely administering antifungal prophylaxis for prevention of cryptococcal disease in resource-rich countries where the incidence of cryptococcal infection is low (Grade 2B). However, in less-resourced areas with a high prevalence of disease, it is reasonable to initiate primary prophylaxis with fluconazole in asymptomatic adults with CD4 counts <100 cells/microL. (See ‘If screening is not available’ above.)

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