Cryptococcosis in renal transplant recipients

Introdução: A criptococose e a terceira causa de infeccao fungica invasiva nos pacientes submetidos a transplante renal, apresentando alta mortalidade. Objetivo: Descrever as caracteristicas epidemiologicas, clinicas e diagnostica, assim como os fatores prognosticos e o impacto da anfotericina B sobre a funcao do enxerto da criptococose em pacientes submetidos a transplante renal. Metodos: Foi utilizada ficha clinica padrao, com mais de 250 variaveis, para avaliar todos os casos de criptococose acompanhados nos hospitais do complexo UNIFESP/EPM durante o periodo de janeiro de 1995 a janeiro de 2007. Resultados: Um total de 40 casos de criptococose foi identificado entre 4.727 transplantes renais, sendo 67,5 por cento do genero masculino. Desses, 37,5 por cento apresentaram rejeicao do enxerto previa a micose e 30 por cento dos casos eram portadores de hepatite C. A criptococose ocorreu com media de 4,5 anos apos o transplante renal, sendo que em 77,5 por cento dos casos ocorreu apos um ano do transplante. O antigeno criptococico teve alta sensibilidade, mas, correlacao limitada com a evolucao clinica frente ao tratamento. Os comprometimentos mais frequentes foram: do sistema nervoso central (75 por cento), pulmonar (30 por cento), cutaneo (30 por cento) e doenca disseminada (40 por cento). Dos 40 pacientes, 97,5 por cento foram tratados, sendo a anfotericina B utilizada em 89,7 por cento dos casos. A diminuicao da imunossupressao durante o tratamento foi realizado em 57,9 por cento dos casos. Apenas 41,4 por cento apresentaram resposta terapeutica favoravel em duas semanas. A mortalidade de 90 dias ocorreu em 29,4 por cento dos individuos, sendo maior no comprometimento disseminado. Os fatores prognosticos encontrados foram: sonolencia na admissao; hipoglicorraquia e tinta da China positiva no liquor inicial e resposta desfavoravel ao tratamento com duas semanas. A anfotericina B desoxicolato causou nefrotoxicidade em 97,1 por cento dos casos, sendo grave em 45,5 por cento. Observou-se a perda do enxerto em 12,1 por cento dos pacientes que utilizaram essa medicacao. A perda do enxerto em 30 dias foi significantemente mais frequente nos pacientes com idade superior a 50 anos; nos com creatinina basal ou do diagnostico elevada e nos pacientes que apresentavam causas adicionais para a nefrotoxicidade. Conclusoes: A criptococose se mantem como uma complicacao importante nos pacientes submetidos a transplante renal, com uma apresentacao tardia no periodo pos-transplante e alta mortalidade. A anfotericina B desoxicolato mostrou alta nefrotoxicidade nessa populacao, associada a significante taxa de perda do enxertoIntroduction: Cryptococcosis, which is the third cause of invasive fungal infections in renal transplant recipients, is an important life-threatening opportunistic infection. Objective: Describe the epidemiological, clinical and diagnostic features of cryptococcosis in renal transplant recipients, as well as the outcome, predictors of mortality and the amphotericin B impact on renal graft function. Methods: Cases of cryptococcosis among renal transplant recipients were identified in UNIFESP/EPM hospitals from January 1995 through January 2007. Results: Forty renal transplant recipients were diagnosed with cryptococcosis among 4,727 consecutive transplant recipients, being 67.5% male. 37.5% out of 40 patients had graft rejection preceding the infection and 30% had hepatitis C. Cryptococcosis occurred a mean of 4.5 years after transplantation; 77,5% of the infections developed more than 1 year after transplantation. The cryptococcal antigen had a high sensibility, although a limited clinical correlation during treatment. Cryptococcus neoformans was isolated in 22 patients and in 1 patient, Cryptococcus gattii infection was documented. Central nervous system involvement occurred in 75% of the cases, pulmonary and cutaneous involvement in 30% each and disseminated infection was observed in 40% of the patients. Regarding treatment, 97.5% of cases received antifungal therapy, whose primary therapy comprised amphotericin B in 89.7%. Primary Immunosuppression was reduced in 57.9% of cases during the infection and the outcome was favorable in 41.4% within 2 weeks. Mortality rate at 90 days was 29.4% and it was higher in disseminated cryptococcosis. Drowsiness on admission; low glucose and positive India ink in the initial cerebrospinal fluid and unfavorable outcome within 2 weeks were a significant predictor of death in these patients. In 45.5% of cases, the baseline serum creatinine level increased more than 50% during amphotericin B therapy and 12.1% had graft loss. The graft loss within 30 days was significantly more likely to occur in patient older than 50; in those with higher baseline and diagnostic serum creatinine levels and in patients who had an additional factor for nephrotoxicity. Conclusion: Cryptococcosis remains a relevant late-onset complication in renal transplant recipients, which describes high mortality rate. Amphotericin B deoxycholate had a negative influence on graft function, with a significant high graft loss rate.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).BV UNIFESP: Teses e dissertaçõe

Caracterização clínica e genotípica da Criptococose em pacientes submetidos a transplante renal

Cryptococcosis is the second most common invasive fungal infections in renal transplant recipients and Brazil has substantial genotypic diversity in C. neoformans/C. gattii species complexes. Clinical outcome of cryptococcosis, graft outcome after treatment and the impact of the molecular type of the yeasts in renal transplant recipients have been scarcely studied, especially in less resource-available countries. Article 1: The purpose of this study was to assess renal allograft dysfunction and its impact on renal transplant recipients with cryptococcosis receiving antifungal therapy. Data from 47 renal transplant recipients were retrospectively collected at a single institution during a period of 13 years. Graft dysfunction, graft loss and mortality rates were evaluated. Predictors of mortality and graft loss were estimated. A total of 38 (97.4%) patients treated with amphotericin B deoxycholate showed graft dysfunction and eight (18.2%) had kidney graft loss. Graft loss within 30 days after cryptococcosis onset was significantly associated with disseminated infection, greater baseline creatinine levels and graft dysfunction concomitant to amphotericin B deoxycholate therapy and an additional renal injury condition. The 30-day mortality rate was 19.2% and it was significantly associated with disseminated and pulmonary infections, somnolence at admission, high cerebrospinal fluid opening pressure, positive cerebrospinal fluid India ink, creatinine levels greater than 2.0 mg/dL at admission, graft dysfunction in patients treated with amphotericin B deoxycholate and an additional renal injury condition and graft loss within 30 days. The rate of graft loss rate was high, most frequently in patients with concomitant renal injury conditions. Therefore, the clinical focus should be on the use of less nephrotoxic lipid formulations of amphotericin B in this specific population. Article 2:The purpose of this study was to characterize the molecular types of C. neoformans/C. gattii species complexes and assess the factors associated with clinical outcome of cryptococcosis in renal transplant recipients in Brazil. We examined the genotypic diversity and fluconazole susceptibility pattern of 82 C. neoformans and C. gattii isolates from 60 renal transplant recipients. Clinical characteristics of the patients and prognostic factors were analyzed. A total of 72 (87.8%) isolates were C. neoformans and 10 (12.2%) were C. gattii. VNI was the most common molecular type (40 cases; 66.7%), followed by VNII (9 cases; 15%), VGII (6 cases; 10%), VNB (4 cases; 6.7%) and VNI/II (1 case; 1.7%). The isolates showed a high genetic diversity in the haplotype network and six new sequence types were described, most of them for VNB. There was a bias towards skin involvement in the non-VNI population (P = 0.012). VGII isolates exhibited higher fluconazole minimum inhibitory concentrations compared to C. neoformans isolates (P = 0.008). The 30-day mortality rate was 38.3% and it was significantly associated with fungemia and absence of headache. Furthermore, patients infected with VGII had a particularly high mortality rate at 90 days (66.7%). A variety of molecular types produces disease in renal transplant recipients in Brazil and highlighted by VGII and VNB. Cryptococcosis in renal transplant recipients is associated with high mortality in less-available resource health care settings. We report the clinical appearance and impact of the molecular type, fluconazole susceptibility of the isolates, and certain clinical characteristics on the patient outcome in this high risk population.Criptococose é a segunda doença fúngica invasiva mais prevalente em pacientes submetidos a transplante de órgãos. O Brasil apresenta uma substancial diversidade genotípica dos complexos de espécies Cryptococcus neoformans e Cryptococcus gattii. O desfecho clínico da criptococose, a evolução do enxerto após o tratamento e o impacto clínico dos diferentes genótipos dessa levedura nos pacientes submetidos a transplante renal foram pobremente estudados, especialmente nos países emergentes. Artigo 1: O objetivo desse estudo foi avaliar a disfunção do enxerto e seu impacto nos pacientes submetidos a transplante renal com criptococose que receberam terapia antifúngica. Foram coletados os dados de 47 pacientes transplantados de uma única instituição, durante o período de 13 anos. A disfunção do enxerto e mortalidade foram analisados, assim como foram estimados os fatores de risco para mortalidade e perda do enxerto. Trinta e oito (97,4%) pacientes tratados com anfotericina B desoxicolato evoluíram com disfunção do enxerto e oito (18,2%) apresentaram perda do enxerto renal. A perda o enxerto com 30 dias após a criptococose foi significantemente associado à doença disseminada, creatinina basal alta e disfunção do enxerto em pacientes tratados com anfotericina B desoxicolato e que apresentavam uma condição adicional de injúria renal. A taxa de mortalidade em 30 dias foi de 19,2% e significantemente associada à doença disseminada, comprometimento pulmonar, sonolência na admissão, pressão de abertura liquórica alta, tinta da China positiva no líquor, creatinina admissional maior que 2,0 mg/dL, disfunção do enxerto em pacientes tratados com anfotericina B desoxicolato associada a uma condição adicional de injúria renal e perda do enxerto em 30 dias. A taxa de perda do enxerto foi alta, principalmente nos pacientes com condições adicionais de injúria renal. Portanto, nossos dados colaboram na recomendação de evitar anfotericina B desoxicolato nessa população, particularmente nos pacientes com disfunção renal na admissão ou expostos a outra condição de injúria renal. Artigo 2: O objetivo desse estudo foi caracterizar os genótipos dos complexos de espécies C. neoformans/C. gattii e analisar os fatores associados ao desfecho clínico da criptococose em pacientes submetidos a transplante renal no Brasil. Foi analisada a diversidade genética e o padrão de susceptibilidade para o fluconazol de 82 isolados de C. neoformans e C. gattii de 60 transplantados renais. As características clínicas dos pacientes e os fatores prognósticos foram determinados. Setenta e dois isolados (87,8%) foram identificados como C. neoformans e 10 (12,2%) como C. gattii. O VNI foi o genótipo mais frequente (40 casos; 66,7%), seguido do VNII (9 casos; 15%), VGII (6 casos; 10%), VNB (4 casos; 6,7%) e VNI/II (1 caso; 1,7%). Os isolados apresentaram uma alta diversidade genética na rede haplotípica e seis novos “sequence types” foram encontrados. Pacientes infectados por isolados não identificados como tipo molecular VNI apresentaram significantemente mais comprometimento cutâneo que os infectados por VNI (P = 0,012). Isolados do genótipo VGII exibiram alta concentração inibitória mínima para fluconazol quando comparado com os isolados de C. neoformans (P = 0,008). A taxa de mortalidade em 30 dias foi de 28,3% e foi significantemente associada à fungemia e ausência de cefaleia. Além disso, pacientes infectados pelo genótipo VGII apresentaram uma alta taxa de mortalidade em 90 dias (66,7%). Uma grande variedade de genótipos infecta pacientes transplantados no Brasil, ressaltando os genótipos VGII e VNB. A criptococose em pacientes submetidos a transplante renal foi associada à alta mortalidade no Brasil. Nós reportamos o impacto das particularidades clínicas, dos diferentes genótipos e do perfil de susceptibilidade para o fluconazol dos isolados sobre o desfecho de pacientes com alto risco de criptococose.Dados abertos - Sucupira - Teses e dissertações (2019

Risk factors for bloodstream infection in patients at a Brazilian hemodialysis center: a case-control study

Background: Infection is the leading cause of morbidity and the second leading cause of mortality in patients on renal replacement therapy. the rates of bloodstream infection in hemodialysis patients vary according to the type of venous access used. Gram- positive bacteria are most frequently isolated in blood cultures of hemodialysis patients. This study evaluated risk factors for the development of bloodstream infections in patients undergoing hemodialysis. Methods: Risk factors associated with bloodstream infections in patients on hemodialysis were investigated using a case- control study conducted between January 2010 and June 2013. Chronic renal disease patients on hemodialysis who presented with positive blood cultures during the study were considered as cases. Controls were hemodialysis patients from the same institution who did not present with positive blood cultures during the study period. Data were collected from medical records. Logistic regression was used for statistical analysis. Results: There were 162 patients included in the study (81 cases and 81 controls). Gram- positive bacteria were isolated with the highest frequency (72%). in initial logistic regression analysis, variables were hypertension, peritoneal dialysis with previous treatment, type and time of current venous access, type of previous venous access, previous use of antimicrobials, and previous hospitalization related to bloodstream infections. Multiple regression analysis showed that the patients who had a central venous catheter had an 11.2- fold (CI 95%: 5.17- 24.29) increased chance of developing bloodstream infections compared with patients who had an arteriovenous fistula for vascular access. Previous hospitalization increased the chance of developing bloodstream infections 6.6- fold (CI 95%: 1.9- 23.09). Conclusions: Infection prevention measures for bloodstream infections related to central venous catheter use should be intensified, as well as judicious use of this route for vascular access for hemodialysis. Reducing exposure to the hospital environment through admission could contribute to a reduction in bloodstream infections in this population.Universidade Federal de São Paulo, Paulista Sch Nursing, Sch Nursing, EPE UNIFESP, BR-04024002 São Paulo, BrazilUniv São Paulo ITACI FMUSP, Sch Med, Childrens Inst, Infect Control Unit, BR-05403000 São Paulo, BrazilUniv São Paulo ITACI FMUSP, Sch Med, Inst Treatment Childhood Canc, BR-05403000 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Nursing, EPM UNIFESP, Div Infect Dis,Escola Paulista Med, BR-04024002 São Paulo, BrazilFdn Oswaldo Ramos, HRIM FOR, Kidney & Hypertens Hosp, Div Dialysis, BR-04039030 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Nursing, Div Nephrol, EPM UNIFESP, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Nursing, Sch Nursing, EPE UNIFESP, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Nursing, EPM UNIFESP, Div Infect Dis,Escola Paulista Med, BR-04024002 São Paulo, BrazilUniversidade Federal de São Paulo, Paulista Sch Nursing, Div Nephrol, EPM UNIFESP, BR-04023900 São Paulo, BrazilWeb of Scienc

Consenso em criptococose - 2008

Univ Sao Paulo, Fac Med, Div Clin Mol Infecciosas, Hosp Clin, Sao Paulo, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Med, Sao Paulo, BrazilUniv Estadual Campinas, Hosp Clin, Inst Infectol Emilio Ribas, Campinas, SP, BrazilFundacao Oswaldo Cruz, Dept Microbiol Immunol & Parasitol, Inst Pesquisa Clin Evandro Chagas, Rio De Janeiro, BrazilUniv Fed Parana, Fac Med, Dept Saude Comunitaria, BR-80060000 Curitiba, Parana, BrazilUniv Fed Rio Grande do Sul, Fac Med, Dept Clin Med, Porto Alegre, RS, BrazilUniv Estadual Campinas, Fac Ciencias Med, Dept Clin Med, Sao Paulo, BrazilInst Doencas Trop Natan Portela, Teresina, PI, BrazilUniv Sao Paulo, Fac Med, Dept Mol Infecciosas & Parasitarias, Sao Paulo, BrazilUniv Estadual Campinas, Fac Ciencias Med, Dept Clin Med, Campinas, SP, BrazilUniv Fed Uberlandia, Fac Med, BR-38400 Uberlandia, MG, BrazilFac Med Triangulo Mineiro, Dept Clin Med, Uberaba, MG, BrazilInst Infectol Emilio Ribas, Sao Paulo, BrazilUniv Estadual Sao Paulo, Fac Med Botucatu, Dept Doencas Trop & Diagnost Imagem, Sao Paulo, BrazilUniv Sao Paulo, Fac Med Ribeirao Preto, Dept Clin Med, Ribeirao Preto, SP, BrazilUniv Fed Sao Paulo, Escola Paulista Med, Dept Med, Sao Paulo, BrazilWeb of Scienc

Tracing Genetic Exchange and Biogeography of Cryptococcus neoformans var. grubii at the Global Population Level

Cryptococcus neoformans var. grubii is the causative agent of cryptococcal meningitis, a significant source of mortality in immunocompromised individuals, typically human immunodeficiency virus/AIDS patients from developing countries. Despite the worldwide emergence of this ubiquitous infection, little is known about the global molecular epidemiology of this fungal pathogen. Here we sequence the genomes of 188 diverse isolates and characterize the major subdivisions, their relative diversity, and the level of genetic exchange between them. While most isolates of C. neoformans var. grubii belong to one of three major lineages (VNI, VNII, and VNB), some haploid isolates show hybrid ancestry including some that appear to have recently interbred, based on the detection of large blocks of each ancestry across each chromosome. Many isolates display evidence of aneuploidy, which was detected for all chromosomes. In diploid isolates of C. neoformans var. grubii (serotype AA) and of hybrids with C. neoformans var. neoformans (serotype AD) such aneuploidies have resulted in loss of heterozygosity, where a chromosomal region is represented by the genotype of only one parental isolate. Phylogenetic and population genomic analyses of isolates from Brazil reveal that the previously “African” VNB lineage occurs naturally in the South American environment. This suggests migration of the VNB lineage between Africa and South America prior to its diversification, supported by finding ancestral recombination events between isolates from different lineages and regions. The results provide evidence of substantial population structure, with all lineages showing multi-continental distributions; demonstrating the highly dispersive nature of this pathogen

Univariate sensitivity analysis—Parameters and results.

Univariate sensitivity analysis—Parameters and results.</p

Cost-utility results.

ObjectivesThis study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS).MethodsIn this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022.ResultsThe economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year.ConclusionCompared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.</div

Costs of laboratory tests.

ObjectivesThis study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS).MethodsIn this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022.ResultsThe economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year.ConclusionCompared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.</div

Model design.

First level decision nodes represent the treatment comparison, second level decision nodes represent the IA/mucormycosis pathogen split, third level decision nodes are associated with second-line treatment options, areas in grey represent the parts of the tree branch where pathogen information has/may have an effect on treatment decisions. IMI: invasive mold infection; IA: invasive aspergillosis; IM: invasive mucormycosis; L-anfB: liposomal amphotericin B.</p

Lower and upper limits used in sensitivity analysis.

Lower and upper limits used in sensitivity analysis.</p