BACKGROUND: Chronic granulomatous disease (CGD) is a primary immunode ciency with increased susceptibility to several bacteria, fungi, and mycobacteria, caused by defective or null superoxide production by the NADPH oxidase enzymatic complex. Accepted treatment consists mainly of antimicrobial prophylaxis. The role of human recombinant subcutaneous interferon gamma (IFNγ) is less clear, as available clinical evidence on its safety and e cacy is scarce and con icting. OBJECTIVE: We aimed to assess the e cacy and safety of IFNγ as an added treatment for CGD when compared to antimicrobial prophylaxis alone. METHODS: A literature search was conducted using MeSH terms "Chronic granulomatous disease" AND ("interferon gamma" OR "interferon-gamma"), as well as antibiotics, placebo, no therapy, clinical trial, trial; on MEDLINE, EMBASE, LILACS, WHOs, CENTRAL, KOREAMED, The Cochrane Library, clinicaltrials.gov, and abstracts from meetings, from 1976 to July 2022. We included clinical trials (CT) and prospective follow-up studies and registered the number of serious infections (requiring hospitalization and IV antibiotics) and deaths; adverse events, and autoimmune complications, in patients treated for CGD with antimicrobial prophylaxis plus IFN-γ, versus antimicrobial prophylaxis alone. We assessed the quality of the studies using Risk of Bias and STROBE. We performed a meta-analysis by calculating both Peto odds ratio (OR), and Risk Reduction (RR) through the Mantel-Haenzsel method with a xed effect model, using Review Manager 5.4, and we reported the number needed to treat (NNT). RESULTS: We identi ed 54 matches from databases, and 4 from other sources. We excluded 12 duplicates, 7 titles, and 9 abstracts for relevance, after which we had 30 eligible studies. Twenty-four were then excluded after reading the full text. Six papers were included: one randomized CT, and 5 follow-up studies. In total, 324 patients with Chronic granulomatous disease were followed for 319 months under treatment with antibiotic prophylaxis plus interferon-gamma or placebo (or antibiotic prophylaxis alone), reported between the years 1991 and 2016. Three of the studies included a control group, allowing for the aggregate analysis of e cacy (prevention of serious infections). The aggregate OR was 0.49, with a 95% con dence interval of 0.19 to 1.23. The Risk Ratio for serious infection was 0.56 (95%CI 0.35-0.90) under IFNG. The meta-analysis thus favors interferon-gamma for a risk reduction of serious infection. DISCUSSION: The results from this meta-analysis support the use of IFNg in the treatment of patients with CGD. However, we found insu cient clinical evidence and believe more clinical trials are needed to better assess the e cacy and long-term safety of IFNγ.
ANTECEDENTES: Un estudio de cohorte es un diseño epidemiológico que pretende estimar la relación de causalidad entre una o más variables y un desenlace de interés. Existen distintos tipos y sus aportaciones a la bibliografía científica han sido decisivos para identificar factores de riesgo para múltiples condiciones clínicas.OBJETIVO: Analizar las principales características de este diseño para facilitar la interpretación de sus resultados y apoyar su correcta conducción.DESCRIPCIÓN: Los estudios de cohorte se caracterizan por ser observacionales y longitudinales, sus observaciones permiten identificar claramente la relación causal entre variables (factores de riesgo) y desenlaces de interés (enfermedades, mortalidad, etc.). De acuerdo con la relación temporal de las variables estudiadas pueden clasificarse en cohortes prospectivas, retrospectivas o ambispectivas. La forma de reclutar a los sujetos también puede clasificarlas como incipientes, estáticas, dinámicas, etc. Las comparaciones pueden ser de carácter regional-local (cohortes internas) o, bien, permitir comparaciones con distintas poblaciones (cohortes externas). Los resultados de estos estudios han permitido conocer tasas de incidencia, riesgos relativos, riesgos atribuibles, factores de protección, etc. Aunque se consideran estudios ideales para establecer causalidad, casi siempre son costosos, largos y complicados de realizar.CONCLUSIONES: Este diseño se conidera el patrón de referencia para estimar causalidad entre variables y su aplicación práctica más común es la identificación de factores de riesgo. Conocer las características principales de los estudios de cohorte habilita para analizar críticamente sus contribuciones al campo de la Medicina.PALABRAS CLAVE: Factores de riesgo; estudio longitudinal; prospectivo; retrospectivo; incidencia.
ANTECEDENTES: los estudios de casos y controles son de utilidad cuando se buscan factores de riesgo para enfermedades poco comunes o que tienen un periodo de latencia prologado.OBJETIVO: identificar las principales características del estudio de casos y controles (Ca-Co) para favorecer la disminución de sesgos durante su evaluación o conducción.DESCRIPCIÓN: este diseño se caracteriza por la selección de sujetos con o sin el evento de interés. Éstos se comparan para identificar los factores de riesgo que favorecieron la presencia de este evento. La finalidad de este tipo de estudios es la de inferir una relación causal expresada mediante razón de momios y los intervalos de confianza al 95%.CONCLUSIONES: el diseño de Ca-CO es relativamente fácil y rápido de realizar. Sin embargo, es susceptible a múltiples fuentes de sesgo, las cuales deben de ser minimizadas para obtener mayor confiabilidad de las inferencias obtenidas.
BackgroundX-linked agammaglobulinemia (XLA) is characterized by impaired B-cell differentiation caused by mutations in Bruton's tyrosine kinase (Btk) gen. Btk is expressed in myeloid cells and recent evidence support that it participates in Toll like receptor signaling, but results regarding its rol in XLA patients are contradictories.ObjectiveTo evaluate lipopolysaccharide (LPS)-induced pro-inflammatory cytokine response in peripheral blood mononuclear cells (PBMC) from XLA patients.MethodsThirteen patients with XLA were included in the study. PBMC LPS-induced TNF-α, IL-1β, IL-6, and IL-10 production was determined by ELISA and compared with that obtained from matched healthy controls. Cytokine production was correlated with the severity of the mutation, affected domain and clinical characteristics.ResultsIn response to LPS, PBMC from XLA patients produced significantly higher amounts of pro-inflammatory cytokines and IL-10 compared with controls and this production is not influenced by the neither severity of mutation or the affected domain. PBMC from patients with a history of more hospital admissions before diagnosis and patients with lower expression of Btk in monocytes produced higher levels of TNF-α and IL-1β, respectively. PBMC from patients with lower IgA levels showed a higher production of TNF-α and IL-1β. Less severe (punctual) mutations in Btk gene were associated with higher IgG levels at diagnosis.ConclusionsOur results demonstrated a predominantly inflammatory response in XLA patients after LPS stimuli and suggest a TLR signaling dysregulation in absence of Btk. This response may be influenced by environmental factors.
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