Expression of interleukin-4, interleukin-9 and interleukin-13 in peripheral blood mononuclear cells of cystic fibrosis patients with and without allergy

Bronchial hyperresponsiveness (BHR) and mucus overproduction are common in CF pulmonary disease and allergic reactions can be frequently observed in cystic fibrosis (CF) lung disease. However, the underlying pathophysiological mechanisms are far from being completely understood. Therefore the expression of the Th2 type cytokines interleukin (IL)-4, IL-9 and IL-13 in CF patients with allergy was compared to patients without allergy. Peripheral blood mononuclear cells (PBMC) samples from 9 allergic CF patients and 8 non-allergic CF patients were obtained. In situ hybridization and immunocytochemistry were performed to determine mRNA and protein expression of IL-4, IL-9, and IL-13 in PBMC. PBMC from allergic CF patients expressed significantly more IL-13 mRNA and protein compared to non-allergic patients (p < 0.05). There was no significant difference for IL-4 and IL-9 between the two groups. In both groups IL-9 mRNA and protein expression were significantly higher compared to IL-4 and IL-13 expression (p < 0.05). These results suggest that IL-13 plays an important role in allergic disease in CF. Moreover, IL-9 may be important in CF disease whether allergy is present or not as it may contribute to BHR and mucus overproduction

Predictors of Perioperative Stroke in Patients With Ischemic-Type Moyamoya Disease Treated With Surgical Revascularization: A Retrospective Multicenter Study

INTRODUCTION: Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive stenosis or occlusion of the internal carotid arteries and the development of collateral moyamoya vessels. Surgical revascularization is commonly used to prevent future ischemic events in ischemic-type MMD, but there remains a high rate of stroke perioperatively. This study aims to analyze the predictive factors for perioperative stroke in patients with ischemic-type MMD undergoing surgical revascularization using a large multicenter database. METHODS: We conducted a multicenter retrospective study in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. This study included patients with ischemic-type MMD who underwent surgical revascularization across 13 academic institutions in North America. Data were collected and analyzed on a per-hemisphere basis, covering patient demographics, disease characteristics, procedural details, and outcomes. Statistical analyses were performed using Stata (V.17.0), comparing baseline characteristics, and using univariable and multivariable logistic regression to identify predictors of perioperative stroke. RESULTS: A total of 301 patients with ischemic-type MMD underwent surgical revascularization, with 34 patients (11.3 %) experiencing perioperative stroke. Patients who experienced perioperative stroke had a mean age of 43.6 years (SD 14.0) compared to 40.0 years (SD 13.9) in those without perioperative stroke (P = 0.16). Hypertension was significantly more prevalent in the perioperative stroke group (73.5 % vs. 47.9 %, P = 0.005). Current smoking was also more common in the perioperative stroke group (55.8 % vs. 38.2 %, P = 0.04). Multivariate logistic regression identified hypertension (OR 2.32, 95 % CI 1.01 to 5.37, P = 0.04) and current smoking (OR 2.28, 95 % CI 1.04 to 4.97, P = 0.03) as significant independent predictors of perioperative stroke. CONCLUSION: Hypertension and smoking were significant predictors of perioperative stroke in patients with ischemic-type MMD undergoing surgical revascularization. These findings emphasize the importance of managing risk factors in ischemic-type MMD. Further prospective studies are needed to validate these findings

PHARMACOKINETICS AND CLINICAL OUTCOMES OF TOBRAMYCIN IN ADULT CYSTIC FIBROSIS PATIENTS WITH ACUTE PULMONARY EXACERBATION

Background Acute pulmonary exacerbation (APE) in cystic fibrosis patients is frequent and associated with a decline in pulmonary function, quality of life and survival. Tobramycin is often used in regimens requiring activity against Pseudomonas aeruginosa, however, an important number of centers do not use official dosing recommendation. The current dosing strategy may be suboptimal. Methods This retrospective cohort analysis was performed on all adult cystic fibrosis patients that were admitted at a tertiary care facility for treatment of APE and with tobramycin between January 2015 and December 2019. The primary objective was to evaluate the predictive performance of previously published pharmacokinetic (PK) models and, secondly, to evaluate potential factors that impact clinical outcomes. Clinical outcomes were only evaluated in a sub-group of patients with cultures positive for P. aeruginosa. Results A total of 202 APEs from 51 patients were included in the PK analysis. Two population PK models were assessed and failed to fit our data. In all, 109 APEs from 32 patients were included in the clinical analysis. Factors that significantly impacted clinical outcome were the number of prior APE and concomitant antibiotics. Clinical success rate for regimens containing at least one active agent against P. aeruginosa according to its susceptibility was 67%. Conclusion Population PK models evaluated in this study cannot be used to perform simulations. A new model must be developed for our population. In patients positive for P. aeruginosa, Ceftazidime in combination to tobramycin may be a superior regimen. APE history remains predictive for outcomes in adult CF patients treated for an APE.</jats:p

Corticosteroid-resistant inflammatory signalling in Pseudomonas-infected bronchial cells

Decreasing the inflammatory response that leads to tissue damage during cystic fibrosis (CF) lung disease has been a long-standing goal of CF therapy. While corticosteroids are widely used anti-inflammatory drugs, their efficacy in CF lung disease remains debated. The complex interaction between the colonising bacteria and the host environment may impact corticosteroid responsiveness. In this study, sputum samples from adult CF patients were collected at baseline and during pulmonary exacerbation episodes. Lung function measurements and sputum microbiological analyses were performed. In parallel, the inflammatory response and corticosteroid sensitivity of airway epithelial cells to Pseudomonas-derived exoproducts was investigated. We report that adult CF patients colonised with mucoid Pseudomonas aeruginosa have higher levels of baseline inflammation, more frequent exacerbations and worse lung function compared with patients colonised with nonmucoid P. aeruginosa. Moreover, mucoid P. aeruginosa activates NF-κB via Toll-like receptor (TLR) 2, which acts in an additive manner to TLR5 to drive inflammation in airway epithelial cells. Furthermore, TLR2-mediated intracellular signalling is more resistant to the anti-inflammatory effects of corticosteroid when compared with other TLR signalling pathways. Overall, these results suggest that airway inflammation triggered by mucoid P. aeruginosa is less responsive to the anti-inflammatory action of corticosteroids. Whether this translates into a diminished response of CF patients to corticosteroid therapy should be examined in future clinical studies

A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.</jats:p

Clinical outcomes associated with Staphylococcus aureus and Pseudomonas aeruginosa airway infections in adult cystic fibrosis patients

Staphylococcus aureus (SA) is the most prevalent organism infecting the respiratory tract of CF children, and remains the second most prevalent organism in CF adults. During early childhood, SA infections are associated with pulmonary inflammation and decline in FEV 1 , but their clinical significance in adult CF patients is poorly characterized