THE B LYMPHOCYTE DIFFERENTIATION FACTOR (BAFF) IS EXPRESSED IN THE AIRWAYS OF CHILDREN WITH CF AND IN LUNGS OF MICE INFECTED WITH PSEUDOMONAS AERUGINOSA

Background Chronic lung infection with Pseudomonas aeruginosa remains a major cause of mortality and morbidity among individuals with CF. Expression of mediators promoting recruitment and differentiation of B cells, or supporting antibody production is poorly understood yet could be key to controlling infection. Methods BAFF was measured in BAL from children with CF, both with and without P. aeruginosa, and controls. Mice were intra-nasally infected with P. aeruginosa strain LESB65 for up to 7 days. Cellular infiltration and expression of B cell chemoattractants and B cell differentiation factor, BAFF were measured in lung tissue. Results BAFF expression was elevated in both P. aeruginosa negative and positive CF patients and in P. aeruginosa infected mice post infection. Expression of the B cell chemoattractants CXCL13, CCL19 and CCL21 increased progressively post infection. Conclusions In a mouse model, infection with P. aeruginosa was associated with elevated expression of BAFF and other B cell chemoattractants suggesting a role for airway B cell recruitment and differentiation in the local adaptive immune response to P. aeruginosa. The paediatric CF airway, irrespective of pseudomonal infection, was found to be associated with an elevated level of BAFF implying that BAFF expression is not specific to pseudomonas infection and may be a feature of the CF airway. Despite the observed presence of a potent B cell activator, chronic colonisation is common suggesting that this response is ineffective

Treating nontuberculous mycobacteria in children with cystic fibrosis: a multicentre retrospective study

BackgroundRespiratory infection with nontuberculous mycobacteria (NTM) in children with cystic fibrosis (CF) has increased in prevalence. The condition is difficult to diagnose and treatments are complex with limited evidence to guide practice. This study describes the approaches to diagnosis, management and consequences of treatment in a multicentre cohort of children with CF in the UK.MethodsRetrospective data were collected from 11 CF specialist centres from patients less than 17 years old, treated for NTM infection between 2006 and 2017. Descriptive statistics were used to describe the clinical characteristics of children treated. Treatment regimens, adverse events and success of treatment, with respect to lung function and culture conversion, were evaluated.ResultsData from 70 patients treated for NTM pulmonary disease were collated (60 Mycobacterium abscessus complex (MABSC); 10 M. avium complex (MAC)). Older age and previous diagnosis of allergic bronchopulmonary aspergillosis were all significantly associated with NTM. There was a wide variance in drug choice and side effects were reported with all agents. NTM eradication occurred in 80% of patients with MAC and 48% with MABSC, with variable outcomes on lung function.ConclusionsDiagnosis and treatment of NTM infection in children with CF is challenging. Treatment success is not guaranteed, particularly for MABSC. Large clinical trials are urgently required to evaluate treatment regimes and their suitability and efficacy in children.</jats:sec

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Airway leukocyte number following LESB65 infection.

<p>Average B lymphocyte, CD4+ve T cell, CD8+ve T cell and neutrophil count shown as mean and standard deviation per mg of tissue at 24, 48, and 72 hours post infection [N = 5 each time point]. * = p<0.05, ** = p<0.01.</p

BAFF expression in BAL fluid.

<p>Expression was measured by ELISA in BAL fluid from <i>P. aeruginosa</i> positive [n = 6] and negative [n = 14] CF patients and healthy controls [n = 7]. BAFF expression was significantly elevated [p<0.01] in both the PA infected group and non PA infected group in comparison to the control group.</p

Expression of BAFF, CXCL13, CCL19 and CCL21 in mouse lung tissue.

<p>Each cytokine was measured at days 1, 2, 3 and 7 days after infection with 10⁶ CFU of <i>P. aeruginosa</i> LESB65 by ELISA. [n = 5]. BAFF was significantly expressed at days 1 [p<0.001], 2 [p<0.01], 3 [p<0.001], and 7 [p<0.05] in comparison to day 0 control. CXCL13 at days 1, 2, 3, [all p<0.001] and 7 [p<0.01]. CCL19 at days 1 [p<0.01], 2 [p<0.001], and 7 [p<0.001]. CCL21 at days 2 [p<0.001], 3 [p<0.01] and 7 [p<0.001]. * = p<0.05, ** = p<0.01, *** = p<0.001.</p

Kinetics of airway infection by <i>P. aeruginosa</i> LESB65.

<p>Mice were challenged [intranasal] with 10⁶ CFU. Values shown as an average Log CFU/mg of lung tissue homogenised, n = 5 mice at each time point. Time zero samples were taken at 15 minutes post infection to confirm entry into the lung and determine levels immediately post infection.</p