Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
1.
N Engl J Med ; 378(11): 1004-1017, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29539274

RESUMO

BACKGROUND: Cryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODS: We randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTS: A total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P=0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen. CONCLUSIONS: One week of amphotericin B plus flucytosine and 2 weeks of fluconazole plus flucytosine were effective as induction therapy for cryptococcal meningitis in resource-limited settings. (ACTA Current Controlled Trials number, ISRCTN45035509 .).


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Anfotericina B/administração & dosagem , Antifúngicos/uso terapêutico , Fluconazol/administração & dosagem , Flucitosina/administração & dosagem , Meningite Criptocócica/tratamento farmacológico , Administração Oral , Adulto , África/epidemiologia , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Esquema de Medicação , Quimioterapia Combinada , Feminino , Fluconazol/efeitos adversos , Flucitosina/efeitos adversos , Soropositividade para HIV/complicações , Humanos , Estimativa de Kaplan-Meier , Masculino , Meningite Criptocócica/mortalidade , Modelos de Riscos Proporcionais
2.
BMC Med ; 19(1): 303, 2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34794434

RESUMO

BACKGROUND: By August 2021, the COVID-19 pandemic has been less severe in sub-Saharan Africa than elsewhere. In Malawi, there have been three subsequent epidemic waves. We therefore aimed to describe the dynamics of SARS-CoV-2 exposure in Malawi. METHODS: We measured the seroprevalence of anti-SARS-CoV-2 antibodies amongst randomly selected blood transfusion donor sera in Malawi from January 2020 to July 2021 using a cross-sectional study design. In a subset, we also assessed in vitro neutralisation against the original variant (D614G WT) and the Beta variant. RESULTS: A total of 5085 samples were selected from the blood donor database, of which 4075 (80.1%) were aged 20-49 years. Of the total, 1401 were seropositive. After adjustment for assay characteristics and applying population weights, seropositivity reached peaks in October 2020 (18.5%) and May 2021 (64.9%) reflecting the first two epidemic waves. Unlike the first wave, both urban and rural areas had high seropositivity in the second wave, Balaka (rural, 66.2%, April 2021), Blantyre (urban, 75.6%, May 2021), Lilongwe (urban, 78.0%, May 2021), and Mzuzu (urban, 74.6%, April 2021). Blantyre and Mzuzu also show indications of the start of a third pandemic wave with seroprevalence picking up again in July 2021 (Blantyre, 81.7%; Mzuzu, 71.0%). More first wave sera showed in vitro neutralisation activity against the original variant (78% [7/9]) than the beta variant (22% [2/9]), while more second wave sera showed neutralisation activity against the beta variant (75% [12/16]) than the original variant (63% [10/16]). CONCLUSION: The findings confirm extensive SARS-CoV-2 exposure in Malawi over two epidemic waves with likely poor cross-protection to reinfection from the first on the second wave. The dynamics of SARS-CoV-2 exposure will therefore need to be taken into account in the formulation of the COVID-19 vaccination policy in Malawi and across the region. Future studies should use an adequate sample size for the assessment of neutralisation activity across a panel of SARS-CoV-2 variants of concern/interest to estimate community immunity.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Doadores de Sangue , Vacinas contra COVID-19 , Estudos Transversais , Humanos , Pandemias , Estudos Soroepidemiológicos
3.
BMC Infect Dis ; 21(1): 724, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-34332543

RESUMO

BACKGROUND: Managing HIV-associated cryptococcal meningitis (CM) can become challenging in the presence of concurrent unusual central nervous system infections. CASE PRESENTATION: A 58-year old HIV infected woman new ART starter, who was being treated effectively for cryptococcal meningitis, represented with worsening of neurological symptoms. Brain MRI revealed a multicystic lesion in the left temporal lobe. Anti-fungal treatment was escalated for a suspected cryptococcoma, but post-mortem CSF serological test confirmed racemose neurocysticercosis. CONCLUSION: Patients with HIV-associated CM are highly immunocompromised and may have multiple pathologies simultaneously. In endemic countries, neurocysticercosis should be considered in the differential diagnosis where there is central nervous system deterioration despite effective therapy for CM.


Assuntos
Infecções por HIV , Meningite Criptocócica , Neurocisticercose , Antifúngicos/uso terapêutico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Imageamento por Ressonância Magnética , Meningite Criptocócica/complicações , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/tratamento farmacológico , Pessoa de Meia-Idade , Neurocisticercose/complicações , Neurocisticercose/tratamento farmacológico
4.
BMC Infect Dis ; 18(1): 520, 2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30326861

RESUMO

BACKGROUND: Cryptococcal meningitis remains the leading cause of adult meningitis in Sub-Saharan Africa. Immune Reconstitution Inflammatory Syndrome (IRIS) following anti-retroviral therapy (ART) initiation is an important complication. Here we report the first documented case of a IRIS reaction presenting as an ischemic stroke. CASE PRESENTATION: A 38 year old newly diagnosed HIV-infected, ART naive Malawian male presented to a tertiary referral hospital in Blantyre, Malawi with a 2 week history of headache. A diagnosis of cryptococcal meningitis was made and the patient was started on 1200 mg fluconazole once daily and flucytosine 25 mg/kg four times daily as part of the Advancing Cryptococcal Treatment for Africa (ACTA) clinical trial. There was an initial clinical and microbiological response to anti-fungal treatment and anti-retroviral therapy was started at week 4. The patient re-presented 16 days later with recurrence of headache, fever, and a sudden onset of left sided weakness in the context of rapid immune reconstitution; peripheral CD4 count had increased from a baseline of 29 cells/µl to 198 cells/µl. Recurrence of cryptococcal meningitis was excluded through CSF examination and fungal culture. Magnetic Resonance Imaging (MRI) of the brain demonstrated multi-focal DWI (diffusion weighted imaging) positive lesions consistent with an ischemic stroke. Given the temporal relationship to ART initiation, these MRI findings in the context of sterile CSF with raised CSF protein and a rapid immune reconstitution, following an earlier favorable response to treatment is most consistent with a paradoxical Immune Reconstitution Inflammatory Syndrome. CONCLUSIONS: Stroke is an increasing cause of morbidity and mortality amongst HIV infected persons. Ischemic stroke is a recognized complication of cryptococcal meningitis in the acute phase and is thought to be mediated by an infectious vasculitis. This is the first time an ischemic stroke has been described as part of a paradoxical IRIS reaction. This report adds to the spectrum of clinical IRIS presentations recognized and highlights to clinicians the potential complications encountered at ART initiation in severely immunocompromised patients.


Assuntos
Isquemia Encefálica/etiologia , Síndrome Inflamatória da Reconstituição Imune/complicações , Meningite Criptocócica/complicações , Acidente Vascular Cerebral/etiologia , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/patologia , Adulto , Antifúngicos/uso terapêutico , Isquemia Encefálica/patologia , Cryptococcus neoformans/imunologia , Cryptococcus neoformans/isolamento & purificação , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Síndrome Inflamatória da Reconstituição Imune/diagnóstico , Síndrome Inflamatória da Reconstituição Imune/patologia , Hospedeiro Imunocomprometido , Malaui , Masculino , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/patologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologia
5.
mBio ; 13(6): e0262622, 2022 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-36354332

RESUMO

Cryptococcus neoformans is the causative agent of cryptococcosis, a disease with poor patient outcomes that accounts for approximately 180,000 deaths each year. Patient outcomes may be impacted by the underlying genetics of the infecting isolate; however, our current understanding of how genetic diversity contributes to clinical outcomes is limited. Here, we leverage clinical, in vitro growth and genomic data for 284 C. neoformans isolates to identify clinically relevant pathogen variants within a population of clinical isolates from patients with human immunodeficiency virus (HIV)-associated cryptococcosis in Malawi. Through a genome-wide association study (GWAS) approach, we identify variants associated with the fungal burden and the growth rate. We also find both small and large-scale variation, including aneuploidy, associated with alternate growth phenotypes, which may impact the course of infection. Genes impacted by these variants are involved in transcriptional regulation, signal transduction, glycosylation, sugar transport, and glycolysis. We show that growth within the central nervous system (CNS) is reliant upon glycolysis in an animal model and likely impacts patient mortality, as the CNS yeast burden likely modulates patient outcome. Additionally, we find that genes with roles in sugar transport are enriched in regions under selection in specific lineages of this clinical population. Further, we demonstrate that genomic variants in two genes identified by GWAS impact virulence in animal models. Our approach identifies links between the genetic variation in C. neoformans and clinically relevant phenotypes and animal model pathogenesis, thereby shedding light on specific survival mechanisms within the CNS and identifying the pathways involved in yeast persistence. IMPORTANCE Infection outcomes for cryptococcosis, most commonly caused by C. neoformans, are influenced by host immune responses as well as by host and pathogen genetics. Infecting yeast isolates are genetically diverse; however, we lack a deep understanding of how this diversity impacts patient outcomes. To better understand both clinical isolate diversity and how diversity contributes to infection outcomes, we utilize a large collection of clinical C. neoformans samples that were isolated from patients enrolled in a clinical trial across 3 hospitals in Malawi. By combining whole-genome sequence data, clinical data, and in vitro growth data, we utilize genome-wide association approaches to examine the genetic basis of virulence. Genes with significant associations display virulence attributes in both murine and rabbit models, demonstrating that our approach can identify potential links between genetic variants and patho-biologically significant phenotypes.


Assuntos
Criptococose , Cryptococcus neoformans , Humanos , Animais , Camundongos , Coelhos , Fatores de Virulência/genética , Saccharomyces cerevisiae/genética , Estudo de Associação Genômica Ampla , Modelos Animais de Doenças , Cryptococcus neoformans/genética , Criptococose/microbiologia , Genômica , Açúcares/metabolismo
6.
Open Forum Infect Dis ; 8(4): ofab066, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33937434

RESUMO

Among 472 patients with human immunodeficiency virus-associated cryptococcal meningitis, 16% had severe visual loss at presentation, and 46% of these were 4-week survivors and remained severely impaired. Baseline cerebrospinal fluid opening pressure ≥40 cmH2O (adjusted odds ratio [aOR], 2.56; 95% confidence interval [CI], 1.36-4.83; P = .02) and fungal burden >6.0 log10 colonies/mL (aOR, 3.01; 95% CI, 1.58-5.7; P = .003) were independently associated with severe visual loss.

7.
Open Forum Infect Dis ; 8(10): ofab397, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34646905

RESUMO

BACKGROUND: An increasing proportion of patients with HIV-associated cryptococcal meningitis have received antiretroviral therapy (ART) before presentation. There is some evidence suggesting an increased 2-week mortality in those receiving ART for <14 days compared with those on ART for >14 days. However, presentation and outcomes for cryptococcal meningitis patients who have recently initiated ART, and those with virologic failure and/or nonadherence, are not well described. METHODS: Six hundred seventy-eight adults with a first episode of cryptococcal meningitis recruited into a randomized, noninferiority, multicenter phase 3 trial in 4 Sub-Saharan countries were analyzed to compare clinical presentation and 2- and 10-week mortality outcomes between ART-naïve and -experienced patients and between patients receiving ART for varying durations before presentation. RESULTS: Over half (56%; 381/678) the study participants diagnosed with a first episode of cryptococcal meningitis were ART-experienced. All-cause mortality was similar at 2 weeks (17% vs 20%; hazard ratio [HR], 0.85; 95% CI, 0.6-1.2; P = .35) and 10 weeks (38% vs 36%; HR, 1.03; 95% CI, 0.8-1.32; P = .82) for ART-experienced and ART-naïve patients. Among ART-experienced patients, using different cutoff points for ART duration, there were no significant differences in 2- and 10-week mortality based on duration of ART. CONCLUSIONS: In this study, there were no significant differences in mortality at 2 and 10 weeks between ART-naïve and -experienced patients and between ART-experienced patients according to duration on ART.

8.
BMJ Open ; 9(11): e030981, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31727654

RESUMO

INTRODUCTION: Africa harbours a high burden of pneumococcal disease, with associated high mortality rates. Despite 34 countries introducing the pneumococcal conjugate vaccine, which reduces the risk of pneumococcal carriage (a prerequisite for disease) of some of the most pathogenic pneumococcal serotypes, it remains uncertain whether they will achieve the sustained direct or indirect protection necessary to reduce pneumococcal carriage to levels sufficient to interrupt transmission and disease. We will therefore summarise the available data on the impact of the pneumococcal conjugate vaccine in reducing vaccine serotype carriage and pneumococcal pneumonia in Africa between 2000 and 2019. METHODS AND ANALYSIS: Using a predetermined search strategy, we will conduct a comprehensive search of PubMed, MEDLINE database, the Excerpta Medica Database, the ISI Web of Science (Science Citation Index), Scopus and the African Index Medicus to identify published studies reporting the prevalence of Streptococcus pneumoniae carriage (vaccine type and non-vaccine type), incidence rates of pneumococcal pneumonia and mortality among children, adults and HIV-infected (all-ages) pre-pneumococcal conjugate vaccine (PCV) and post-PCV introduction (published between 1st January 2000 and 31st December 2019) in African countries that have introduced PCVs (PCV7/PCV10/PCV13) in their routine national immunisation programme. The studies retained and data extracted will be assessed for bias using prevalidated tools and checklists. Heterogeneity across studies will be assessed using the χ2 test on Cochrane Q statistic. A random effect meta-analysis will be used to estimate the overall prevalence of pneumococcal carriage and incidence of pneumococcal pneumonia across studies with similar characteristics. Results will be reported in compliance with the Meta-Analysis Of Observational Studies in Epidemiology guidelines. The protocol has been prepared in accordance to the 2015 guidelines on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. ETHICS AND DISSEMINATION: This systematic review will not require ethical approval as we will be using already published data. The final manuscript will be submitted for publication in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42019130976.


Assuntos
Portador Sadio/epidemiologia , Vacina Pneumocócica Conjugada Heptavalente/imunologia , Vacinas Pneumocócicas/imunologia , Pneumonia Pneumocócica/epidemiologia , África/epidemiologia , Portador Sadio/imunologia , Humanos , Pneumonia Pneumocócica/imunologia , Pneumonia Pneumocócica/prevenção & controle , Pneumonia Pneumocócica/transmissão , Prevalência , Streptococcus pneumoniae/isolamento & purificação , Revisões Sistemáticas como Assunto
9.
Lancet Infect Dis ; 19(4): e143-e147, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30344084

RESUMO

In 2018, WHO issued guidelines for the diagnosis, prevention, and management of HIV-related cryptococcal disease. Two strategies are recommended to reduce the high mortality associated with HIV-related cryptococcal meningitis in low-income and middle-income countries (LMICs): optimised combination therapies for confirmed meningitis cases and cryptococcal antigen screening programmes for ambulatory people living with HIV who access care. WHO's preferred therapy for the treatment of HIV-related cryptococcal meningitis in LMICs is 1 week of amphotericin B plus flucytosine, and the alternative therapy is 2 weeks of fluconazole plus flucytosine. In the ACTA trial, 1-week (short course) amphotericin B plus flucytosine resulted in a 10-week mortality of 24% (95% CI -16 to 32) and 2 weeks of fluconazole and flucytosine resulted in a 10-week mortality of 35% (95% CI -29 to 41). However, with widely used fluconazole monotherapy, mortality because of HIV-related cryptococcal meningitis is approximately 70% in many African LMIC settings. Therefore, the potential to transform the management of HIV-related cryptococcal meningitis in resource-limited settings is substantial. Sustainable access to essential medicines, including flucytosine and amphotericin B, in LMICs is paramount and the focus of this Personal View.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Quimioterapia Combinada/métodos , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Infecções por HIV/mortalidade , Meningite Criptocócica/tratamento farmacológico , África/epidemiologia , Anfotericina B/agonistas , Anfotericina B/provisão & distribuição , Antifúngicos/economia , Antifúngicos/provisão & distribuição , Coinfecção , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/patogenicidade , Países em Desenvolvimento , Gerenciamento Clínico , Esquema de Medicação , Quimioterapia Combinada/economia , Fluconazol/economia , Fluconazol/provisão & distribuição , Flucitosina/economia , Flucitosina/provisão & distribuição , Guias como Assunto , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Renda , Meningite Criptocócica/microbiologia , Meningite Criptocócica/mortalidade , Meningite Criptocócica/patologia , Análise de Sobrevida
10.
Wellcome Open Res ; 2: 103, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29387802

RESUMO

Background: Four million people die each year from diseases caused by exposure to household air pollution. There is an association between exposure to household air pollution and pneumonia in children (half a million attributable deaths a year); however, whether this is true in adults is unknown. We conducted a case-control study in urban Malawi to examine the association between exposure to household air pollution and pneumonia in adults. Methods: Hospitalized patients with radiologically confirmed pneumonia (cases) and healthy community controls underwent 48 hours of ambulatory and household particulate matter (µg/m 3) and carbon monoxide (ppm) exposure monitoring. Multivariate logistic regression, stratified by HIV status, explored associations between these and other potential risk factors with pneumonia. Results: 145 (117 HIV-positive; 28 HIV-negative) cases and 253 (169 HIV-positive; 84 HIV-negative) controls completed follow up. We found no evidence of association between household air pollution exposure and pneumonia in HIV-positive (e.g. ambulatory particulate matter adjusted odds ratio [aOR] 1.00 [95% CI 1.00-1.01, p=0.141]) or HIV-negative (e.g. ambulatory particulate matter aOR 1.00 [95% CI 0.99-1.01, p=0.872]) participants. Chronic respiratory disease was associated with pneumonia in both HIV-positive (aOR 28.07 [95% CI 9.29-84.83, p<0.001]) and HIV-negative (aOR 104.27 [95% CI 12.86-852.35, p<0.001]) participants. Conclusions: We found no evidence that exposure to household air pollution is associated with pneumonia in Malawian adults. In contrast, chronic respiratory disease was strongly associated with pneumonia.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA