RESUMO
Streptococcus pneumoniae, a common colonizer of the upper respiratory tract, invades nasopharyngeal epithelial cells without causing disease in healthy participants of controlled human infection studies. We hypothesized that surface expression of pneumococcal lipoproteins, recognized by the innate immune receptor TLR2, mediates epithelial microinvasion. Mutation of lgt in serotype 4 (TIGR4) and serotype 6B (BHN418) pneumococcal strains abolishes the ability of the mutants to activate TLR2 signaling. Loss of lgt also led to the concomitant decrease in interferon signaling triggered by the bacterium. However, only BHN418 lgt::cm but not TIGR4 lgt::cm was significantly attenuated in epithelial adherence and microinvasion compared to their respective wild-type strains. To test the hypothesis that differential lipoprotein repertoires in TIGR4 and BHN418 lead to the intraspecies variation in epithelial microinvasion, we employed a motif-based genome analysis and identified an additional 525 a.a. lipoprotein (pneumococcal accessory lipoprotein A; palA) encoded by BHN418 that is absent in TIGR4. The gene encoding palA sits within a putative genetic island present in ~10% of global pneumococcal isolates. While palA was enriched in the carriage and otitis media pneumococcal strains, neither mutation nor overexpression of the gene encoding this lipoprotein significantly changed microinvasion patterns. In conclusion, mutation of lgt attenuates epithelial inflammatory responses during pneumococcal-epithelial interactions, with intraspecies variation in the effect on microinvasion. Differential lipoprotein repertoires encoded by the different strains do not explain these differences in microinvasion. Rather, we postulate that post-translational modifications of lipoproteins may account for the differences in microinvasion.IMPORTANCEStreptococcus pneumoniae (pneumococcus) is an important mucosal pathogen, estimated to cause over 500,000 deaths annually. Nasopharyngeal colonization is considered a necessary prerequisite for disease, yet many people are transiently and asymptomatically colonized by pneumococci without becoming unwell. It is therefore important to better understand how the colonization process is controlled at the epithelial surface. Controlled human infection studies revealed the presence of pneumococci within the epithelium of healthy volunteers (microinvasion). In this study, we focused on the regulation of epithelial microinvasion by pneumococcal lipoproteins. We found that pneumococcal lipoproteins induce epithelial inflammation but that differing lipoprotein repertoires do not significantly impact the magnitude of microinvasion. Targeting mucosal innate immunity and epithelial microinvasion alongside the induction of an adaptive immune response may be effective in preventing pneumococcal colonization and disease.
Assuntos
Células Epiteliais , Lipoproteínas , Infecções Pneumocócicas , Streptococcus pneumoniae , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Lipoproteínas/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/imunologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Nasofaringe/microbiologia , Mutação , Aderência BacterianaRESUMO
Hematological malignancies place individuals at risk of CNS involvement from their hematological disease and opportunistic intracranial infection secondary to disease-/treatment-associated immunosuppression. Differentiating CNS infection from hematological disease infiltration in these patients is valuable but often challenging. We sought to determine if statistical models might aid discrimination between these processes. Neuroradiology, clinical and laboratory data for patients with hematological malignancy at our institution between 2007 and 2017 were retrieved. MRI were deep-phenotyped across anatomical distribution, presence of pathological enhancement, diffusion restriction and hemorrhage and statistically modelled with Bayesian-directed probability networks and multivariate logistic regression. 109 patients were studied. Irrespective of a diagnosis of CNS infection or hematological disease, the commonest anatomical distributions of abnormality were multifocal-parenchymal (34.9%), focal-parenchymal (29.4%) and leptomeningeal (11.9%). Pathological enhancement was the most frequently observed abnormality (46.8%), followed by hemorrhage (22.9%) and restricted diffusion (19.3%). Logistic regression could differentiate CNS infection from hematological disease infiltration with an AUC of 0.85 where, with OR > 1 favoring CNS infection and < 1 favoring CNS hematological disease, significantly predictive imaging features were hemorrhage (OR 24.61, p = 0.02), pathological enhancement (OR 0.17, p = 0.04) and an extra-axial location (OR 0.06, p = 0.05). In conclusion, CNS infection and hematological disease are heterogeneous entities with overlapping radiological appearances but a multivariate interaction of MR imaging features may assist in distinguishing them.
Assuntos
Doenças do Sistema Nervoso Central , Infecções do Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central , Neoplasias Hematológicas , Teorema de Bayes , Neoplasias Hematológicas/complicações , Humanos , Imageamento por Ressonância Magnética/métodos , Estudos RetrospectivosRESUMO
BACKGROUND: Human immunodeficiency virus-exposed uninfected (HEU) infants are a rapidly expanding population in sub-Saharan Africa and are highly susceptible to encapsulated bacterial disease in the first year of life. The mechanism of this increased risk is still poorly understood. We investigated whether human immunodeficiency virus (HIV)-exposure dysregulates HEU immunity, vaccine-antibody production, and human herpes virus amplify this effect. METHODS: Thirty-four HIV-infected and 44 HIV-uninfected pregnant women were recruited into the birth cohort and observed up to 6 weeks of age; and then a subsequent 43 HIV-infected and 61 HIV-uninfected mother-infant pairs were recruited into a longitudinal infant cohort at either: 5-7 to 14-15; or 14-15 to 18-23 weeks of age. We compared monocyte function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HIV-unexposed uninfected (HU) infants. RESULTS: We demonstrate (1) altered monocyte phagosomal function and B-cell subset homeostasis and (2) lower vaccine-induced anti-Haemophilus influenzae type b (Hib) and anti-tetanus toxoid immunoglobulin G titers in HEU compared with HU infants. Human herpes virus infection was similar between HEU and HU infants. CONCLUSIONS: In the era of antiretroviral therapy-mediated viral suppression, HIV exposure may dysregulate monocyte and B-cell function, during the vulnerable period of immune maturation. This may contribute to the high rates of invasive bacterial disease and pneumonia in HEU infants.
Assuntos
Infecções por HIV , Monócitos , Feminino , HIV , Humanos , Imunoglobulina G , Lactente , Fenótipo , Gravidez , Toxoide TetânicoRESUMO
BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi. METHODS: We conducted a household study in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%-6.1%) among adults and 0.3% (95% CI, .1%-.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%-99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy.
Assuntos
Infecções por HIV , Hepatite B , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Hepatite B/tratamento farmacológico , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B , Vacinas contra Hepatite B/uso terapêutico , Vírus da Hepatite B , Humanos , Lactente , Malaui/epidemiologia , Masculino , Estudos Soroepidemiológicos , VacinaçãoAssuntos
COVID-19/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Subpopulações de Linfócitos/imunologia , Vacinação/métodos , Adulto , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Vacina BNT162/administração & dosagem , COVID-19/diagnóstico , COVID-19/prevenção & controle , COVID-19/virologia , Estudos de Casos e Controles , ChAdOx1 nCoV-19/administração & dosagem , Humanos , Imunidade/imunologia , Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/virologia , Modelos Logísticos , Subpopulações de Linfócitos/metabolismo , Pessoa de Meia-Idade , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
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 farmacológicoRESUMO
OBJECTIVES: To assess baseline prevalence of cryptococcal antigen (CrAg) positivity; and its contribution to reductions in all-cause mortality, deaths from cryptococcus and unknown causes, and new cryptococcal disease in the REALITY trial. DESIGN: Retrospective CrAg testing of baseline and week-4 plasma samples in all 1805 African adults/children with CD4+ cell count less than 100 cells/µl starting antiretroviral therapy who were randomized to receive 12-week enhanced-prophylaxis (fluconazole 100âmg/day, azithromycin, isoniazid, cotrimoxazole) vs. standard-prophylaxis (cotrimoxazole). METHODS: Proportional hazards models were used to estimate the relative impact of enhanced-prophylaxis vs. standard-cotrimoxazole on all, cryptococcal and unknown deaths, and new cryptococcal disease, through 24 weeks, by baseline CrAg positivity. RESULTS: Excluding 24 (1.4%) participants with active/prior cryptococcal disease at enrolment (all treated for cryptococcal disease), 133/1781 (7.5%) participants were CrAg-positive. By 24 weeks, 105 standard-cotrimoxazole vs. 78 enhanced-prophylaxis participants died. Of nine standard-cotrimoxazole and three enhanced-prophylaxis cryptococcal deaths, seven and two, respectively, were CrAg-positive at baseline. Among deaths of unknown cause, only 1/46 standard-cotrimoxazole and 1/28 enhanced-prophylaxis were CrAg-positive at baseline. There was no evidence that relative reductions in new cryptococcal disease associated with enhanced-prophylaxis varied between baseline CrAg-positives [hazard-ratioâ=â0.36 (95% confidence interval 0.13-0.98), incidence 19.5 vs. 56.5/100 person-years] and CrAg-negatives [hazard-ratioâ=â0.33 (0.03-3.14), incidence 0.3 vs. 0.9/100 person-years; Pheterogeneityâ=â0.95]; nor for all deaths, cryptococcal deaths or unknown deaths (Pheterogeneityâ>â0.3). CONCLUSION: Relative reductions in cryptococcal disease/death did not depend on CrAg status. Deaths of unknown cause were unlikely to be cryptococcus-related; plausibly azithromycin contributed to their reduction. Findings support including 100âmg fluconazole in an enhanced-prophylaxis package at antiretroviral therapy initiation where CrAg screening is unavailable/impractical.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS , Infecções por HIV , Meningite Criptocócica , Infecções Oportunistas Relacionadas com a AIDS/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/prevenção & controle , Adulto , Antifúngicos/uso terapêutico , Antígenos de Fungos , Contagem de Linfócito CD4 , Criança , Infecções por HIV/tratamento farmacológico , Humanos , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/prevenção & controle , Estudos RetrospectivosRESUMO
Streptococcus pneumoniae is a natural colonizer of the human respiratory tract and an opportunistic pathogen. Although epithelial cells are among the first to encounter pneumococci, the cellular processes and contribution of epithelial cells to the host response are poorly understood. Here, we show that a S. pneumoniae serotype 6B ST90 strain, which does not cause disease in a murine infection model, induces a unique NF-κB signature response distinct from an invasive-disease-causing isolate of serotype 4 (TIGR4). This signature is characterized by activation of p65 and requires a histone demethylase KDM6B. We show, molecularly, that the interaction of the 6B strain with epithelial cells leads to chromatin remodelling within the IL-11 promoter in a KDM6B-dependent manner, where KDM6B specifically demethylates histone H3 lysine 27 dimethyl. Remodelling of the IL-11 locus facilitates p65 access to three NF-κB sites that are otherwise inaccessible when stimulated by IL-1ß or TIGR4. Finally, we demonstrate through chemical inhibition of KDM6B with GSK-J4 inhibitor and through exogenous addition of IL-11 that the host responses to the 6B ST90 and TIGR4 strains can be interchanged both in vitro and in a murine model of infection in vivo. Our studies therefore reveal how a chromatin modifier governs cellular responses during infection.
Assuntos
Montagem e Desmontagem da Cromatina , Interações Hospedeiro-Patógeno/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/patogenicidade , Células A549 , Células Epiteliais Alveolares , Animais , Benzazepinas/farmacologia , Modelos Animais de Doenças , Inibidores Enzimáticos , Células Epiteliais/microbiologia , Regulação da Expressão Gênica , Humanos , Interleucina-11/genética , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , NF-kappa B/farmacologia , Infecções Pneumocócicas/enzimologia , Infecções Pneumocócicas/genética , Regiões Promotoras Genéticas , Pirimidinas/farmacologiaRESUMO
BACKGROUND: Typhoid fever remains a major source of morbidity and mortality in low-income settings. Its most feared complication is intestinal perforation. However, due to the paucity of diagnostic facilities in typhoid-endemic settings, including microbiology, histopathology, and radiology, the etiology of intestinal perforation is frequently assumed but rarely confirmed. This poses a challenge for accurately estimating burden of disease. METHODS: We recruited a prospective cohort of patients with confirmed intestinal perforation in 2016 and performed enhanced microbiological investigations (blood and tissue culture, plus tissue polymerase chain reaction [PCR] for Salmonella Typhi). In addition, we used a Poisson generalized linear model to estimate excess perforations attributed to the typhoid epidemic, using temporal trends in S. Typhi bloodstream infection and perforated abdominal viscus at Queen Elizabeth Central Hospital from 2008-2017. RESULTS: We recruited 23 patients with intraoperative findings consistent with intestinal perforation. 50% (11/22) of patients recruited were culture or PCR positive for S. Typhi. Case fatality rate from typhoid-associated intestinal perforation was substantial at 18% (2/11). Our statistical model estimates that culture-confirmed cases of typhoid fever lead to an excess of 0.046 perforations per clinical typhoid fever case (95% CI, .03-.06). We therefore estimate that typhoid fever accounts for 43% of all bowel perforation during the period of enhanced surveillance. CONCLUSIONS: The morbidity and mortality associated with typhoid abdominal perforations are high. By placing clinical outcome data from a cohort in the context of longitudinal surgical registers and bacteremia data, we describe a valuable approach to adjusting estimates of the burden of typhoid fever.
Assuntos
Epidemias , Perfuração Intestinal , Febre Tifoide , Humanos , Perfuração Intestinal/epidemiologia , Malaui , Estudos Prospectivos , Salmonella typhi , Febre Tifoide/complicações , Febre Tifoide/epidemiologiaRESUMO
BACKGROUND: Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. METHODS: The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. RESULTS: The mean costs per patient were US $847 (95% confidence interval [CI] $776-927) for FLU+5FC, and US $628 (95% CI $557-709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9-41.7%) with FLU+5FC and 53.8% (95% CI 43.1-64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28-208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. CONCLUSIONS: The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus-infected persons in Africa.
Assuntos
Flucitosina , Meningite Criptocócica , África , Antifúngicos/uso terapêutico , Análise Custo-Benefício , Fluconazol/uso terapêutico , Flucitosina/uso terapêutico , Humanos , Meningite Criptocócica/tratamento farmacológicoRESUMO
In Malawi, 236 participants from the Advancing Cryptococcal Meningitis Treatment for Africa trial were followed for 12 months. The trial outcomes reported at 10 weeks were sustained to 1 year. One-week amphotericin B plus flucytosine was associated with the lowest 1 year mortality (27.5% [95% confidence interval, 16.3 to 44.1]).
Assuntos
Meningite Criptocócica , Antifúngicos/uso terapêutico , Fluconazol , Flucitosina , Humanos , Malaui/epidemiologia , Meningite Criptocócica/tratamento farmacológico , Meningite Criptocócica/epidemiologiaRESUMO
Immune senescence is a significant contributor to health problems in the developed world and may be accelerated by chronic viral infections. To date, there have been few studies of immune function in healthy older people in sub-Saharan Africa. We assessed T cell and B cell phenotypes and immune responses to CMV, EBV, and influenza virus in Malawians aged 20-69 y. Notably, the proportion of naive (CCR7+CD45RA+) CD4 and CD8 T cells was only 14% of the lymphoid repertoire even in donors aged under 30 y but did not decrease further with age. A small increase in the late differentiated (CD27-CD28-) CD8 T cell subpopulation was observed in older donors but the CD4/CD8 T cell ratio remained stable in all age groups. Interestingly, the regulatory (CD25hiFOXP3hi) T cell subpopulation was small in all age groups, and we observed no age-associated accumulation of cells expressing the senescence- and exhaustion-associated markers CD57 and PD-1. We assessed functional T cell responses to mitogenic and viral antigenic stimulation by the expression of CD154, IFN-γ, TNF-α, IL-2, and IL-17 and proliferation. All responses were robust across the life course, although we observed an age-associated shift from IFN-γ to TNF-α in the response to EBV. In summary, we found the naive T cell subpopulation of young adult Malawians was smaller than in their contemporaries in high-income settings but remains stable thereafter and that lymphocyte function is retained across the life course. These observations indicate that studies of the genetic and environmental factors influencing immune function in different environments may provide insights into minimizing immune ageing.
Assuntos
Subpopulações de Linfócitos T/imunologia , Adulto , Fatores Etários , Idoso , Diferenciação Celular , Citomegalovirus/imunologia , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Memória Imunológica , Influenza Humana/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/citologiaRESUMO
Streptococcus pneumoniae (Spn) is a common cause of respiratory infection, but also frequently colonizes the nasopharynx in the absence of disease. We used mass cytometry to study immune cells from nasal biopsy samples collected following experimental human pneumococcal challenge in order to identify immunological mechanisms of control of Spn colonization. Using 37 markers, we characterized 293 nasal immune cell clusters, of which 7 were associated with Spn colonization. B cell and CD8+CD161+ T cell clusters were significantly lower in colonized than in non-colonized subjects. By following a second cohort before and after pneumococcal challenge we observed that B cells were depleted from the nasal mucosa upon Spn colonization. This associated with an expansion of Spn polysaccharide-specific and total plasmablasts in blood. Moreover, increased responses of blood mucosal associated invariant T (MAIT) cells against in vitro stimulation with pneumococcus prior to challenge associated with protection against establishment of Spn colonization and with increased mucosal MAIT cell populations. These results implicate MAIT cells in the protection against pneumococcal colonization and demonstrate that colonization affects mucosal and circulating B cell populations.
Assuntos
Imunidade Adaptativa , Imunidade Inata , Imunidade nas Mucosas , Mucosa Nasal , Infecções Pneumocócicas , Streptococcus pneumoniae/imunologia , Adulto , Linfócitos B/imunologia , Linfócitos B/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Humanos , Masculino , Mucosa Nasal/imunologia , Mucosa Nasal/microbiologia , Mucosa Nasal/patologia , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/patologiaRESUMO
Control of Streptococcus pneumoniae colonisation at human mucosal surfaces is critical to reducing the burden of pneumonia and invasive pneumococcal disease, interrupting transmission, and achieving herd protection. Here, we use an experimental human pneumococcal carriage model (EHPC) to show that S. pneumoniae colonisation is associated with epithelial surface adherence, micro-colony formation and invasion, without overt disease. Interactions between different strains and the epithelium shaped the host transcriptomic response in vitro. Using epithelial modules from a human epithelial cell model that recapitulates our in vivo findings, comprising of innate signalling and regulatory pathways, inflammatory mediators, cellular metabolism and stress response genes, we find that inflammation in the EHPC model is most prominent around the time of bacterial clearance. Our results indicate that, rather than being confined to the epithelial surface and the overlying mucus layer, the pneumococcus undergoes micro-invasion of the epithelium that enhances inflammatory and innate immune responses associated with clearance.
Assuntos
Portador Sadio/imunologia , Nasofaringe/imunologia , Infecções Pneumocócicas/imunologia , Mucosa Respiratória/imunologia , Streptococcus pneumoniae/imunologia , Adulto , Portador Sadio/microbiologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Feminino , Voluntários Saudáveis , Humanos , Imunidade Inata , Masculino , Pessoa de Meia-Idade , Nasofaringe/microbiologia , Infecções Pneumocócicas/microbiologia , Mucosa Respiratória/microbiologia , Streptococcus pneumoniae/patogenicidade , Adulto JovemRESUMO
BACKGROUND: Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. METHODS: Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. RESULTS: Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91-1210) per life-year saved. CLINICAL TRIALS REGISTRATION: ISRCTN45035509. CONCLUSIONS: Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.
Assuntos
Antifúngicos , Meningite Criptocócica , África Subsaariana , Antifúngicos/economia , Antifúngicos/uso terapêutico , Flucitosina/economia , Flucitosina/uso terapêutico , Custos de Cuidados de Saúde/estatística & dados numéricos , Humanos , Meningite Criptocócica/diagnóstico , Meningite Criptocócica/economia , Meningite Criptocócica/epidemiologia , Meningite Criptocócica/terapiaRESUMO
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/patologiaRESUMO
: We assessed the effect of fluconazole 1200âmg/day on the QT interval in cryptococcal meningitis patients. Mean corrected QT (QTc) change from baseline to day 7 was 10.1âms (IQR: -28 to 46âms) in the fluconazole treatment group and -12.6âms (IQR: -39 to 13.5âms) in those not taking fluconazole (Pâ=â0.04). No significant increase in QTc measurements over 500âms was observed with fluconazole. Nevertheless, it remains important to correct any electrolyte imbalance and avoid concomitant drugs that may increase QTc.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Fluconazol/administração & dosagem , Fluconazol/efeitos adversos , Infecções por HIV/complicações , Sistema de Condução Cardíaco/efeitos dos fármacos , Meningite Criptocócica/tratamento farmacológico , Adulto , África , HumanosRESUMO
BACKGROUND: Intestinal protozoa are common opportunistic infections in HIV patients. Longitudinal studies on either the clinical relevance or the effect of immune reconstitution by antiretroviral therapy on intestinal protozoan infections in children are lacking however. This study investigates prevalence and clinical relevance of intestinal protozoa in HIV-infected Malawian children before and during their first year of antiretroviral treatment (ART). METHODS: Stool samples collected at enrolment and during follow-up were tested for nonopportunistic (Giardia lamblia, Dientamoeba fragilis, Entamoeba histolytica) and opportunistic protozoa (Enterocytozoon bieneusi, Encephalitozoon spp., Cryptosporidium spp. and Cystoisospora belli) using multiplex real-time polymerase chain reaction. Associations between infections and clinical symptoms were evaluated using univariate methods. RESULTS: Nonopportunistic and opportunistic protozoa were detected in 40% (14/35) and 46% (16/35) of children at baseline, respectively. E. bieneusi was the most prevalent protozoa (37%, 13/35) and associated with gastrointestinal complaints (43% in positive (10/13) versus 18% (4/22) in E. bieneusi-negative children, P = 0.001. Body mass index recovery during 12 months of ART was more commonly delayed in E. bieneusi-positive children (+0.29 +standard deviation 0.83) than E. bieneusi-negative children (+1.03 +standard deviation 1.25; P = 0.05). E. bieneusi was not detected after 12 months of ART. CONCLUSIONS: E. bieneusi was the most prevalent opportunistic intestinal protozoa, present in over a third of study participants before initiation of ART. Although all children cleared E. bieneusi after 12 months of ART, E. bieneusi was associated with gastrointestinal complaints and may delay body mass index recovery. Trials to assess effect of treatment of E. bieneusi on nutritional status should be considered in HIV-infected African children.
Assuntos
Índice de Massa Corporal , Enterocytozoon/isolamento & purificação , Infecções por HIV/parasitologia , Intestinos/parasitologia , Estado Nutricional , Infecções Oportunistas Relacionadas com a AIDS/parasitologia , Antirretrovirais/uso terapêutico , Criança , Fezes/parasitologia , Feminino , HIV , Infecções por HIV/complicações , Humanos , Malaui , Masculino , Reação em Cadeia da Polimerase Multiplex , Prevalência , Estudos ProspectivosRESUMO
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 .).