Among children with uncontrolled moderate-to-severe asthma, those who received add-on dupilumab had fewer asthma exacerbations and better lung function and asthma control than those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; Liberty Asthma VOYAGE ClinicalTrials.gov number, NCT02948959.

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Alterations in nuclear factor kappa B (NF-κB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-κB inhibitor IκBα, one of two phosphorylation sites that are essential for targeting IκBα for proteasomal degradation and hence for activation of NF-κB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-κB signaling by functioning as a dominant negative on NF-κB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-κB in the human immune response.

Until recently, no point-of-care tool was available for assessing the underlying airway inflammation associated with asthma. Fractional exhaled nitric oxide (FeNO) emerged in the last decade as an important biomarker for asthma assessment and management. Evidence also indicates that FeNO is most accurately classified as a marker of T-helper cell type 2 (Th2)-mediated airway inflammation with a high positive and negative predictive value for identifying corticosteroid-responsive airway inflammation. This manuscript evaluates the evidence for FeNO as a predictor of Th2-mediated corticosteroid-responsive airway inflammation and presents the results of a meta-analysis of three adult studies comparing asthma exacerbation rates with FeNO-based versus clinically-based asthma management algorithms, one of which was not included in a 2012 Cochrane meta-analysis. The primary purpose of the updated meta-analysis was to evaluate asthma exacerbation rates. The results demonstrate that the rate of exacerbations was significantly reduced in favor of FeNO-based asthma management (mean treatment difference = -0.27; 95% CI [-0.42, -0.12] as was the relative rate of asthma exacerbations (relative rate = 0.57; 95% CI [0.41, 0.80]). In summary, FeNO has value for identifying patients with airway inflammation who will and will not respond to corticosteroids. Importantly, the use of FeNO in conjunction with clinical parameters is associated with significantly lower asthma exacerbation rates compared with asthma managed using clinical parameters alone. Together these data indicate that FeNO testing has an important role in the assessment and management of adult asthma. Further studies will continue to define the exact role of FeNO testing in adult asthma.

Although National Heart Lung Institute (NHLBI) guidelines categorize asthma severity based on spirometry, few studies have evaluated the utility of these spirometric values in grading asthma severity in children. Asthma is thought to be progressive, but little is known about the loss of lung function in childhood. This study sought to determine the spirometric indices in children from 4-18 years of age. Retrospective cross-sectional analysis was performed on all spirometries done in children at the National Jewish Medical and Research Center from 1999-2002. In total, 2,728 children performed 24,388 measures. The mean +/- SD values for forced vital capacity (FVC), forced expired volume in 1 sec (FEV(1)), FEV(1)/FVC ratio, and forced expiratory flow (FEF)(25-75) were 92.7 +/- 16.2, 92.2 +/- 18.0, 85.3 +/- 9.3, and 78.0 +/- 36.5 percent predicted, respectively. Seventy-seven percent of FEV(1) values were >/= 80%, 18.6% were between 60-80%, and 3.1% were <60% of predicted. FEV(1) was highest in 5-year-old children; it declined thereafter, reaching a nadir at 11 years, followed by a partial recovery from 12-18 years. Expressed in liters, FEV(1) values were lower than expected at every age, with the greatest difference at 18 years. FEV(1)/FVC ratios declined through childhood, suggesting impaired airway but not lung growth in children with asthma. In conclusion, the majority of asthmatic children attending a tertiary care facility had FEV(1) values within normal range. With increasing age, the increase in FEV(1) lags behind that of nonasthmatics, so that by 18 years, maximum FEV(1) is impaired. The NHLBI FEV(1) cutoff values do not appear to accurately stratify pediatric asthma, and no useful FEV(1) cutoff could be generated.

The aim of this study was to compare air-trapping as quantified by high-resolution computed tomography (HRCT) of the chest with measures of lung function and airway inflammation in children with mild to moderate asthma. Plethysmography indices, respiratory resistance, and reactance before and after bronchodilator with impulse oscillation (IOS), exhaled nitric oxide (eNO), total eosinophil count (TEC), and serum eosinophil cationic protein (ECP) levels were measured in 21 subjects. A single-cut HRCT image at end-expiration was obtained. Air-trapping was quantified and expressed in terms of the pixel index (PI) by determining the percentage of pixels in lung fields below -856 and -910 Hounsfeld units (HU). Pairwise linear correlations between PI and other parameters were evaluated. Subjects had only mild airflow limitation based on prebronchodilator forced expiratory volume in 1 sec (FEV(1)), but were hyperinflated and had air-trapping based on elevated total lung capacity (TLC) and residual volume (RV)/TLC ratio, respectively. The PI at -856 HU was positively correlated with % predicted TLC, total gas volume (TGV), and ECP level, and was inversely correlated with FEV(1)/forced vital capacity (FVC) and % predicted forced expiratory flow between 25-75% FVC (FEF(25-75)). The PI at -910 HU correlated similarly with these variables, and also correlated positively with IOS bronchodilator reversibility. This data suggest that quantitative HRCT may be a useful tool in the evaluation of peripheral airflow obstruction in children with asthma.

Background Few studies have examined how developing obesity in early adulthood affects the course of asthma. Objective We analyzed lung function and asthma impairment and risk among non-obese children with asthma, comparing those who were obese in young adulthood to those who remained non-obese. Methods Post-hoc analysis of 771 subjects with mild-moderate asthma who were not obese (pediatric definition, body mass index (BMI) <95th percentile) when enrolled in the Childhood Asthma Management Program at ages 5–12 years. Subjects were then followed to age ≥ 20 years. For visits at ages ≥ 20 years, spirometry values as percent predicted and recent asthma symptom scores and prednisone exposure were compared between 579 subjects who were non-obese at all visits and 151 who obese (adult definition of BMI ≥ 30 kg/m2) on at least one visit (median number of visits when obese = 4, IQR 2–7). Results Compared to participants who were non-obese (BMI 23.4 ± 2.6 kg/m2), those who became obese (BMI 31.5 ± 3.8 kg/m2) had significant decreases in FEV1/FVC (p<0.0003) and FEV1 (p = 0.001), without differences in FVC (p=0.15) during visits at ages ≥ 20 years. For each unit increase of BMI, FEV1 percent predicted decreased by 0.29 (p=0.0009). The relationship between BMI and lung function was not confounded by sex or BMI at baseline. Asthma impairment (symptom scores) and risk (prednisone use) did not differ between the two groups. Conclusion Becoming obese in early adulthood was associated with increased airway obstruction, without impact on asthma impairment or risk.

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