A randomised trial of oral prednisone for cystic fibrosis pulmonary exacerbation treatment.

BACKGROUND: Elevated markers of systemic and pulmonary inflammation are associated with failure to recover lung function following pulmonary exacerbations in people with cystic fibrosis (pwCF). Our aim was to determine whether adjuvant oral prednisone treatment would improve recovery of forced expiratory volume in 1 s (FEV1) % pred in CF pulmonary exacerbations not responding to antibiotic therapy. METHODS: This was a randomised, double-blind, placebo-controlled trial in pwCF treated with intravenous antibiotics for a pulmonary exacerbation. At day 7, those who had not returned to >90% baseline FEV1 % pred were randomised to adjuvant prednisone 1 mg·kg-1 twice daily (maximum 60 mg·day-1) or placebo for 7 days. The primary outcome was the difference in proportion of subjects who recovered >90% baseline FEV1 % pred at day 14 of i.v. antibiotic therapy. RESULTS: 173 subjects were enrolled, with 76 randomised. 50% of subjects in the prednisone group recovered baseline FEV1 on day 14 compared with 39% of subjects in the placebo group (difference of 11%, 95% CI -11-34%; p=0.34). The mean±sd change in FEV1 % pred from day 7 to day 14 was 6.8±8.8% predicted in the prednisone group and 4.6±6.9% predicted in the placebo group (mean difference 2.2% predicted, 95% CI -1.5-5.9%; p=0.24). Time to subsequent exacerbation was not prolonged in prednisone-treated subjects (hazard ratio 0.83, 95% CI 0.45-1.53; p=0.54). CONCLUSIONS: This study failed to detect a difference in FEV1 % pred recovery between adjuvant oral prednisone and placebo treatment in pwCF not responding at day 7 of i.v. antibiotic therapy for pulmonary exacerbations.

Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): protocol for a multicentre randomised placebo-controlled triple-blind trial.

INTRODUCTION: Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D3 supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations. METHODS AND ANALYSIS: This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D3 (3.5 months apart) with 400 IU vitamin D3 daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety. ETHICS AND DISSEMINATION: This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines. TRIAL REGISTRATION NUMBER: NCT03365687.

A review of congenital lung malformations with a simplified classification system for clinical and research use.

PURPOSE: Congenital lung abnormalities are rare malformations increasingly detected early by prenatal ultrasound. Whether management of these frequently asymptomatic lesions should be surgical or conservative is an unresolved issue. The necessary prospective studies are limited by the absence of a widely accepted practical classification system. Our aim was to develop a simple, clinically relevant system for classifying and studying congenital lung abnormalities. MATERIALS AND METHODS: We based our proposed grouping on a detailed analysis of clinical, radiological, and histological data from well-documented cases, plus an extensive review of the literature. RESULTS: The existence of hybrid lesions and common histological findings suggested a unified embryological mechanism-possibly obstruction of developing airways with distal dysplasia. Malformations could be classified by their anatomical and pathological findings; however, a system based on the prenatal ultrasound plus initial chest X-ray findings had greater clinical relevance: Group 1-Congenital solid/cystic lung malformation, Group 2-Congenital hyperlucent lobe, Group 3-Congenital small lung. CONCLUSIONS: Pathological classification is academically important but is unnecessarily complex for clinical and research use. Our simple radiological-based system allows unambiguous comparison between the results of different studies and also guides the choice of necessary investigations specific to each group.

Safety of live-attenuated influenza vaccination in cystic fibrosis.

OBJECTIVES: Given the improved efficacy of the nasal live-attenuated influenza virus vaccine (LAIV) compared with the injectable vaccine in children, we aimed to determine its safety in individuals with cystic fibrosis (CF). METHODS: A cohort of 168 study participants, aged 2 to 18 years with CF, vaccinated with LAIV between October 1, 2012, and January 30, 2013, was followed prospectively for 56 days after initial vaccination in 3 pediatric CF clinics across the province of Quebec. Days 0 to 28 post-LAIV were considered the at-risk period for all outcomes of interest, and days 29 to 56 post-LAIV were considered the non-at-risk period. Incident respiratory deteriorations were defined as an unscheduled medical visit, hospitalization, or a new course of oral antibiotics for respiratory complaints. Using a self-controlled design, incidence rate ratios (IRR) were used to compare at-risk and non-at-risk periods. RESULTS: Comparing at-risk to non-at-risk periods, there was no significant increase in the rate of incident respiratory deteriorations (IRR, 0.72; 95% confidence interval, 0.11-4.27) or all-cause hospitalizations (IRR, 1.16; 95% confidence interval, 0.30-4.81). A greater proportion of participants reported experiencing at least 1 minor respiratory and/or systemic adverse event after immunization during the at-risk period compared with the non-at-risk period (77% vs 54%, respectively). During the first week after LAIV, 13 of 168 (8%) children reported some wheezing, with the vast majority, 9 of 13 (69%), on the day of vaccination. CONCLUSIONS: There was no increased risk of respiratory deterioration or all-cause hospitalization associated with LAIV in our study population. LAIV seems well tolerated in children and adolescents with CF.

Toll-like receptors 4 and 2 expression in the bronchial mucosa of patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is a lung disease characterized by chronic infection with Gram-negative bacteria Pseudomonas aeruginosa and Gram-positive bacteria Staphylococcus aureus. Recently, toll-like receptor (TLR) 4 has been shown to be responsible for the lipopolysaccharide (LPS)-mediated immune response. While TLR2 mediates responses driven by bacterial lipoproteins and peptidoglycans from Gram-positive bacteria, LPS derived from P aeruginosa may stimulate the immune response in the airways of patients with CF via activation of TLR4. OBJECTIVES: To investigate TLR4 and TLR2 expression in the bronchial mucosa of patients with CF and normal control subjects. PATIENTS AND METHODS: Endoscopic bronchial biopsies from seven patients with CF and six healthy control subjects were obtained. TLR4 and TLR2 expression was assessed using immmunocytochemistry. Real-time polymerase chain reaction was used to detect TLR4 messenger RNA in blood cells from patients with CF and to compare TLR4 expression in CF bronchial epithelial cells with non-CF bronchial epithelial cells. RESULTS: In patients with CF, the number of TLR4-positive cells was significantly increased in their submucosa (P<0.05) but significantly reduced in their epithelium compared with control subjects (P<0.05). The majority of TLR4-positive cells were neutrophils. Patients with CF (n=4) and control subjects (n=4) had a similar percentage of TLR4-expressing neutrophils and monocytes/lymphocytes in peripheral blood. CF cells (IB-3) had significantly decreased basal TLR4 messenger RNA expression compared with non-CF cells (Calu-3) (P<0.05). Although there was a trend toward reduced TLR2 expression in the airway epithelium of patients with CF (P=0.07), there was no significant difference in TLR2 expression in the submucosa of patients with CF compared with that of control subjects. CONCLUSIONS: Both TLR4 and TLR2 expression in the bronchial epithelium of patients with CF were significantly reduced compared with healthy control subjects. In contrast, the number of TLR4-positive neutrophils in the submucosa of patients with CF was higher than in control subjects. This may suggest that the loss of epithelial TLR expression may contribute to the impaired defense against LPS.

Niflumic acid and MSI-2216 reduce TNF-alpha-induced mucin expression in human airway mucosa.

BACKGROUND: Human chloride channel, calcium-activated 1 (hCLCA1) has been shown to induce mucin (MUC) gene expression and mucus production in bronchial epithelial cells. Objective To investigate whether blocking hCLCA1 decreases mucus production. METHODS: Expression of hCLCA1 and mucus was stimulated with TNF-alpha in human upper airway mucosal explant tissue. MUC5AC mRNA and mucus protein expression was blocked by inhibiting hCLCA1 by using channel blockers (niflumic acid [NFA] and MSI-2216) without and with TNF-alpha stimulation. Expression of MUC5AC, hCLCA1, and COX-2 mRNA was quantified by using real-time PCR. Mucus protein was assessed by periodic acid Schiff staining. Laser capture microdissection was performed to quantify hCLCA1 and MUC5AC mRNA expression in epithelial cells derived from mucosal explant tissue. RESULTS: TNF-alpha significantly increased MUC5AC and hCLCA1 mRNA as well as mucus and hCLCA1 protein expression in the mucosal explant tissue ( P < .05). Inhibition of hCLCA1 with NFA or MSI-2216 showed a significant dose-dependent reduction of mucus production for both blockers in the mucosal explant tissue ( P < .05). MUC5AC mRNA was also decreased by both blockers in the whole mucosal tissue and in laser-captured mucosa epithelial cells. CONCLUSIONS: Unstimulated and TNF-alpha-induced mucin expression could be decreased by NFA and MSI-2216. Inhibiting hCLCA1 may be a potential new approach to reduce mucus overproduction.

Spontaneous pneumomediastinum: are we overinvestigating?

BACKGROUND: Spontaneous pneumomediastinum (SPM) is uncommon in pediatrics. Because of the growing concern about the risks of radiation in children, the authors analyzed whether an extensive radiologic workup influences management and outcome. METHODS: In a retrospective study from 1991 to 2003, 53 patients were diagnosed with SPM. Charts were reviewed for demographics, predisposing factors, presentation, investigation, and evolution. Pneumomediastinum occurring in the neonatal period or related to either pneumothorax, barotrauma, or trauma were excluded. RESULTS: Of 53 cases, 26 (49%) were bronchospasm related, 11 (21%) had respiratory tract infections, and 8 (15%) were idiopathic. Four (7.5%) were caused by inhaled foreign bodies while other causes accounted for the remaining 7.5%. No esophageal perforations were identified. Presentations included dyspnea (64%), subcutaneous emphysema (60%), cough (45%), cervical or chest pain (42%), and Hamman's sign (19%). Postero-anterior chest x-rays (CXR) were diagnostic in all cases except one. Mean number of CXR per hospitalization was 3. Only 3 patients subsequently had pneumothorax, and none required pleural drainage. Of the 8 patients with idiopathic SPM, 5 underwent a barium swallow, and 2 had a chest CT scan; results of all were normal. CONCLUSIONS: More than 70% of SPMs were related to bronchospasm or respiratory tract infections. Idiopathic SPMs deserve more attention because of the concern about esophageal perforation, although most investigations will be negative. SPM usually is a self-limited condition, and prognosis is related to the underlying disorder. Consequently, with clinical improvement, aggressive investigation and follow-up x-ray rarely is warranted.