The epidemiology of cryptococcosis and the characterization of Cryptococcus neoformans isolated in a Brazilian University Hospital

Aguiar, Paula Augusta Dias Fogaça de; Pedroso, Reginaldo dos Santos; Borges, Aércio Sebastião; Moreira, Tomaz de Aquino; Araújo, Lúcio Borges de; Röder, Denise Von Dolingër de Brito

doi:10.1590/s1678-9946201759013

Cited by 42 publications

(48 citation statements)

References 47 publications

(66 reference statements)

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“…Between the two, C. neoformans is the more common pathogen with a worldwide distribution and a tendency to infect immunocompromised hosts [1,2]. Historically, infection rates were highest amongst human immunodeficiency virus (HIV)-positive patients and C. neoformans was the leading cause of fungal-related death in these patients due to cryptococcal meningitis and sepsis [3,4]. However, improvements such as highly active antiretroviral therapy (HAART) have reduced HIV-related cryptococcal mortality in nations where the highest standard of care is widely available compared to developing countries [5].…”

Section: Introductionmentioning

confidence: 99%

Shift in Epidemiology of Cryptococcal Infections in Ottawa with High Mortality in Non-HIV Immunocompromised Patients

Patel

Desjardins

Cowan

2019

JoF

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Cryptococcus neoformans is a fungus that can cause life-threatening infections. While human immunodeficiency virus (HIV)-positive status historically had the highest risk for cryptococcal infection and was associated with high mortality rates, there have been changes in HIV treatment and the epidemiology of other acquired immunodeficiencies, such as hematological malignancies. We conducted a retrospective case series analysis of patients who had cryptococcal infections documented at the Ottawa Hospital from 2005 to 2017. The Ottawa Hospital is a tertiary care hospital and provides complex care such as chemotherapy and transplantations. There were 28 confirmed cryptococcal infections. The most common underlying condition associated with cryptococcal infection was hematological malignancy (n = 8, 29%), followed by HIV (n = 5, 18%) and solid organ transplantation (n = 4, 14%). Furthermore, while there was a decrease in the number of cryptococcal infections in HIV patients after 2010 (four to one case), the number of cases in non-HIV immunocompromised patients increased from four in the years 2005–2010 to fourteen in 2011–2017. There were nine cryptococcal-attributable deaths. The case fatality rate was highest among patients with underlying hematological malignancies (63%), followed by solid organ transplant (50%) and HIV patients (20%). In conclusion, this study showed that there may be an epidemiological shift of cryptococcal infection in Ottawa. Additionally, infections may be associated with a worse prognosis in patients with a hematological malignancy and solid organ transplant than in patients with HIV infection in the modern era. Better prevention and/or treatment is warranted for high-risk populations.

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Section: Introductionmentioning

confidence: 99%

Shift in Epidemiology of Cryptococcal Infections in Ottawa with High Mortality in Non-HIV Immunocompromised Patients

Patel

Desjardins

Cowan

2019

JoF

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“…70% of all infected patients in low-income countries to 20% of all infected patients in high-income countries (2). Although differences in mortality rates between high-and low-income countries can be linked to suboptimal antifungal treatments in low-income countries (3), variations in mortality rates between patient groups receiving similar treatments and residing in the same region of the world are observed (1,(4)(5)(6). Mortality is a measure influenced by many intrinsic host and pathogen factors (as well as host-pathogen interaction factors).…”

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confidence: 99%

“…Previous studies showed that pathogen-specific characteristics, such as the genotype or the degree of antigen shedding, influence immune responses to C. neoformans and the clinical outcome of patients (5,(7)(8)(9). Multilocus sequence typing (MLST) of 7 genetic loci has previously been used to identify genetically similar strains (5)(6)(7)(8)(9)(10). For example, studies of clinical isolates in both Uganda and Brazil showed higher patient mortality associated with sequence type 93 (ST93) strains (5,10).…”

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The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence

et al. 2019

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Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet the Cryptococcus factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the strain genotype and degree of antigen shedding, are associated with the clinical outcome, but the underlying biology remains elusive. In this study, we examined factors determining disease outcome in HIVinfected cryptococcal meningitis patients infected with Cryptococcus neoformans strains with the same multilocus sequence type (MLST). Both patient mortality and survival were observed during infections with the same sequence type. Disease outcome was not associated with the patient CD4 count. Patient mortality was associated with higher cryptococcal antigen levels, the cerebrospinal fluid (CSF) fungal burden by quantitative culture, and low CSF fungal clearance. The virulence of a subset of clinical strains with the same sequence type was analyzed using a mouse inhalation model of cryptococcosis. We showed a strong association between human and mouse mortality rates, demonstrating that the mouse inhalation model recapitulates human infection. Similar to human infection, the ability to multiply in vivo, demonstrated by a high fungal burden in lung and brain tissues, was associated with mouse mortality. Mouse survival time was not associated with single C. neoformans virulence factors in vitro or in vivo; rather, a trend in survival time correlated with a suite of traits. These observations show that MLST-derived genotype similarities between C. neoformans strains do not necessarily translate into similar virulence either in the mouse model or in human patients. In addition, our results show that in vitro assays do not fully reproduce in vivo conditions that influence C. neoformans virulence.

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“…Mortality rates due to Cryptococcus infection varies by region from 70% in low-income countries to 20-40% of all infected patients in high-income countries (2). Although differences in mortality rates between high- and low-income countries can be linked to sub-optimal antifungal treatments in low-income countries (3), variations in mortality rates between patient groups receiving similar treatments and residing in the same region of the world are observed (1, 4–6). Mortality is a measure influenced by many intrinsic host and pathogen factors (as well as host-pathogen interaction factors).…”

Section: Introductionmentioning

confidence: 99%

Closely related Cryptococcus neoformans strains possess differential virulence both in humans and the mouse inhalation model

Mukaremera

McDonald

Nielsen

et al. 2019

Preprint

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24Cryptococcal meningitis (CM) causes high rates of HIV-related mortality, yet Cryptococcus 25 factors influencing patient outcome are not well understood. Pathogen-specific traits, such as the 26 strain genotype and degree of antigen shedding, are associated with clinical outcome but the 27 underlying biology remains elusive. In this study, we examined factors determining disease 28 outcome in HIV-infected cryptococcal meningitis patients infected with C. neoformans strains 29 with the same multi-locus sequence type. Both patient mortality and survival were observed 30 during infections with the same sequence type. Disease outcome did not correlate with 31 underlying patient immune deficiencies. Patient mortality was associated with higher antigen 32 levels, fungal burden in the CSF, and low CSF fungal clearance. Virulence of a subset of clinical 33 strains with the same sequence type were analyzed using the mouse inhalation model of 34 cryptococcosis. We showed a strong correlation between human and mouse mortality rates, 35 demonstrating the mouse inhalation model recapitulates human infection. Similar to human 36 infection, the ability to multiply in vivo, demonstrated by high fungal burden in the lung and 37 brain tissues, was associated with mouse mortality. Mortality rate was not associated with single 38 C. neoformans virulence factors in vitro or in vivo; rather, a trend in mortality rate correlated 39 with a suite of traits. These observations show that genotype similarities between C. neoformans 40 strains do not necessarily translate into similar virulence either in the mouse model or in human 41 patients. In addition, our results show that in vitro assays do not fully reproduce in vivo 42 conditions that influence C. neoformans virulence. 44Cryptococcus neoformans is a fungal pathogen that causes disease mainly in 45 immunocompromised patients such as individuals living with HIV/AIDS or receiving organ 46 transplants. The availability of antiretroviral therapy has reduced AIDS-related mortality, 47 however deaths due to cryptococcal meningitis (CM) have plateaued with C. neoformans still 48 causing 15 % of all AIDS-related deaths globally (1, 2). Mortality rates due to Cryptococcus 49 infection varies by region from 70% in low-income countries to 20-40% of all infected patients 50 in high-income countries (2). Although differences in mortality rates between high-and low-51 income countries can be linked to sub-optimal antifungal treatments in low-income countries (3), 52 variations in mortality rates between patient groups receiving similar treatments and residing in 53 the same region of the world are observed (1,(4)(5)(6). Mortality is a measure influenced by many 54 intrinsic host and pathogen factors (as well as host-pathogen interaction factors). Thus, we need 55 better proxies to understand C. neoformans pathogenesis in patients and identify factors 56 determining clinical outcome. 57Although C. neoformans pathogenesis in the mouse model of cryptococcosis has been 58 extensively studied, the...

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The epidemiology of cryptococcosis and the characterization of Cryptococcus neoformans isolated in a Brazilian University Hospital

Cited by 42 publications

References 47 publications

Shift in Epidemiology of Cryptococcal Infections in Ottawa with High Mortality in Non-HIV Immunocompromised Patients

Shift in Epidemiology of Cryptococcal Infections in Ottawa with High Mortality in Non-HIV Immunocompromised Patients

The Mouse Inhalation Model of Cryptococcus neoformans Infection Recapitulates Strain Virulence in Humans and Shows that Closely Related Strains Can Possess Differential Virulence

Closely related Cryptococcus neoformans strains possess differential virulence both in humans and the mouse inhalation model

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