Bronchiolitis hospital admission in infancy is associated with later preschool ventilation inhomogeneity.

BACKGROUND: Rhinovirus (RV) positive bronchiolitis episodes in infancy confer a higher risk to develop asthma in later childhood with associated lung function impairments. We aimed to investigate the association between the type of virus causing a bronchiolitis hospitalization episode and lung ventilation inhomogeneities at preschool age. METHODS: Infants hospitalized with a clinical diagnosis of moderate (ward admission) or severe (pediatric intensive care ward admission) bronchiolitis were prospectively followed-up at preschool age to assess nitrogen (N2 ) multiple breath washout (MBW). Lung clearance index (LCI), functional residual capacity (FRC), and concentration normalized phase III slope analysis (SnIII ) indices were reported from ≥2 technically acceptable trials. Differences between groups were calculated using logistic and linear regression and adjusted for confounders (sex, age at bronchiolitis admission, height at visit, maternal asthma, and doctor-diagnosed asthma, including interaction terms between the latter three). An interaction term was included in a regression model to test for an interaction between RV bronchiolitis severity and MBW parameters at preschool age. RESULTS: One hundred and thirty-nine subjects attended preschool follow-up, of which 84 out of 103 (82%) performing MBW had technically acceptable data. Children with a history of RV positive bronchiolitis (n = 39) had increased LCI (adjusted ß-coefficient [aß] = 0.33, 95% confidence interval [CI] 0.02-0.65, p = 0.040) and conductive airways ventilation inhomogeneity [Scond ] (aß = 0.016, CI 0.004-0.028, p = 0.011) when compared with those with a RV negative bronchiolitis history (n = 45). In addition, we found a statistical interaction between RV bronchiolitis and bronchiolitis severity strengthening the association with LCI (aß = 0.93, CI 0.20-1.58, p = 0.006). CONCLUSION: Children with a history of hospital admission for RV positive bronchiolitis in infancy might be at a higher risk of lung ventilation inhomogeneities at preschool age, arising from the peripheral conducting airways.

The effects of increasing fruit and vegetable intake in children with asthma: A randomized controlled trial.

BACKGROUND: A high fruit and vegetable (F&V) diet reduces asthma exacerbations in adults; this has not been examined in children to date. OBJECTIVE: To investigate the effect of a 6-month, high F&V diet on the time to first asthma exacerbation in children with asthma, in a parallel-group, randomized, controlled trial. METHODS: Children (aged 3-11 years) with asthma, history of exacerbations and usual low F&V intake (≤3 serves/day) were randomized to the intervention (high F&V diet) or control group (usual diet) for 6 months. The primary outcome was time to first exacerbation requiring medical intervention. Secondary outcomes included exacerbation rate, lung function, plasma TNF-α, CRP, and IL-6, faecal microbiota and peripheral blood mononuclear cell (PBMC) histone deacetylase (HDAC) activity and G-protein coupled receptor (GPR) 41/43 and HDAC (1-11) expression. RESULTS: 67 children were randomized between September 2015 and July 2018. F&V intake (difference in change (∆): 3.5 serves/day, 95% CI: [2.6, 4.4] p < 0.001) and plasma total carotenoids (∆: 0.44 µg/ml [0.19, 0.70] p = 0.001) increased after 6 months (intervention vs control). Time to first exacerbation (HR: 0.81, 95% CI: [0.38, 1.69], p = 0.569; control vs. intervention) and exacerbation rate (IRR: 0.84, [0.47, 1.49], p = 0.553; control vs. intervention) were similar between groups. In per-protocol analysis, airway reactance z-scores increased in the intervention versus control group (X5 ∆: 0.76 [0.04, 1.48] p = 0.038, X20 ∆: 0.93 [0.23, 1.64] p = 0.009) and changes in faecal microbiota were observed though there was no difference between groups in systemic inflammation or molecular mechanisms. In the control group, CRP and HDAC enzyme activity increased, while GPR41 expression decreased. No adverse events attributable to the interventions were observed. CONCLUSION & CLINICAL RELEVANCE: A high F&V diet did not affect asthma exacerbations over the 6-month intervention, though warrants further investigation as a strategy for improving lung function and protecting against systemic inflammation in children with asthma.

miR-122 promotes virus-induced lung disease by targeting SOCS1.

Virus-induced respiratory tract infections are a major health burden in childhood, and available treatments are supportive rather than disease modifying. Rhinoviruses (RVs), the cause of approximately 80% of common colds, are detected in nearly half of all infants with bronchiolitis and the majority of children with an asthma exacerbation. Bronchiolitis in early life is a strong risk factor for the development of asthma. Here, we found that RV infection induced the expression of miRNA 122 (miR-122) in mouse lungs and in human airway epithelial cells. In vivo inhibition specifically in the lung reduced neutrophilic inflammation and CXCL2 expression, boosted innate IFN responses, and ameliorated airway hyperreactivity in the absence and in the presence of allergic lung inflammation. Inhibition of miR-122 in the lung increased the levels of suppressor of cytokine signaling 1 (SOCS1), which is an in vitro-validated target of miR-122. Importantly, gene silencing of SOCS1 in vivo completely reversed the protective effects of miR-122 inhibition on RV-induced lung disease. Higher miR-122 expression in nasopharyngeal aspirates was associated with a longer time on oxygen therapy and a higher rate of treatment failure in 87 infants hospitalized with moderately severe bronchiolitis. These results suggest that miR-122 promotes RV-induced lung disease via suppression of its target SOCS1 in vivo. Higher miR-122 expression was associated with worse clinical outcomes, highlighting the potential use of anti-miR-122 oligonucleotides, successfully trialed for treatment of hepatitis C, as potential therapeutics for RV-induced bronchiolitis and asthma exacerbations.

Rhinovirus bronchiolitis, maternal asthma, and the development of asthma and lung function impairments.

BACKGROUND: Children with a history of rhinovirus (RV) positive bronchiolitis have a high risk of developing subsequent asthma. Maternal asthma might also increase this risk. The aim of this study was to investigate the combined effects of hospitalization for RV positive bronchiolitis in infancy and a history of maternal asthma on the development of asthma at preschool age. METHODS: This is a prospective cohort study of 139 preschool-aged children, with a history of hospital admission for bronchiolitis in infancy, followed-up to ascertain asthma and asthma-like symptoms, skin prick allergy test positivity, and lung function measured pre- and post-bronchodilator using impulse oscillometry. RESULTS: Children with a past hospitalization for RV positive bronchiolitis (42.4% of all) and a history of maternal asthma (36.7% of all) had the greatest prevalence and risk ratio (RR) for doctor-diagnosed asthma (prevalence 81.8% and RR 2.10, 95% confidence interval [CI] 1.37-3.19, p = .001), use of inhaled corticosteroids (68.2% and RR 2.17, 95% CI 1.19-3.99, p = .001) and short-acting ß-agonists in the last 12 months (95.2% and RR 1.49, 95% CI 1.17-1.89, p = .001), as compared to those with RV negative bronchiolitis and no maternal asthma history. More children in this group had an abnormal airway resistance (33.3% and adjusted risk ratio [aRR] 3.11, 95% CI 1.03-9.47, p = .045) and reactance (27.8% and aRR 2.11, 95% CI 1.06-4.26, p = .035) at 5 Hz, as compared to those with RV negative bronchiolitis and no maternal asthma history. CONCLUSION: Hospitalization for RV positive bronchiolitis in early life combined with a history of maternal asthma identifies a subgroup of children with a high asthma burden while participants with only one of the two risk factors had intermediate risk for asthma.

The Role of Pathological Aging in Cardiac and Pulmonary Fibrosis.

Aging promotes a range of degenerative pathologies characterized by progressive losses of tissue and/or cellular function. Fibrosis is the hardening, overgrowth and scarring of various tissues characterized by the accumulation of extracellular matrix components. Aging is an important predisposing factor common for fibrotic heart and respiratory disease. Age-related processes such as senescence, inflammaging, autophagy and mitochondrial dysfunction are interconnected biological processes that diminish the regenerative capacity of the aged heart and lung and have been shown to play a crucial role in cardiac fibrosis and idiopathic pulmonary fibrosis. This review focuses on these four processes of aging in relation to their role in fibrosis. It has long been established that the heart and lung are linked both functionally and anatomically when it comes to health and disease, with an ever-expanding aging population, the incidence of fibrotic disease and therefore the number of fibrosis-related deaths will continue to rise. There are currently no feasible therapies to treat the effects of chronic fibrosis therefore highlighting the importance of exploring the processes of aging and its role in inducing and exacerbating fibrosis of each organ. The focus of this review may help to highlight potential avenues of therapeutic exploration.

Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma.

BACKGROUND: The single-center double-blind, randomized controlled Managing Asthma in Pregnancy (MAP) trial in Newcastle, Australia, compared a treatment algorithm using the fraction of exhaled nitric oxide (FENO) in combination with asthma symptoms (FENO group) against a treatment algorithm using clinical symptoms only (clinical group) in pregnant asthmatic women (Australian New Zealand Clinical Trials Registry, no. 12607000561482). The primary outcome was a 50% reduction in asthma exacerbations during pregnancy in the FENO group. However, the effect of FENO-guided management on the development of asthma in the offspring is unknown. OBJECTIVE: We sought to investigate the effect of FENO-guided asthma management during pregnancy on asthma incidence in childhood. METHODS: A total of 179 mothers consented to participate in the Growing into Asthma (GIA) double-blind follow-up study with the primary aim to determine the effect of FENO-guided asthma management on childhood asthma incidence. RESULTS: A total of 140 children (78%) were followed up at 4 to 6 years of age. FENO-guided as compared to symptoms-only approach significantly reduced doctor-diagnosed asthma (25.9% vs 43.2%; odds ratio [OR], 0.46, 95% CI, 0.22-0.96; P = .04). Furthermore, frequent wheeze (OR, 0.27; 95% CI, 0.09-0.87; P = .03), use of short-acting ß-agonists (OR, 0.49; 95% CI, 0.25-0.97; P = .04), and emergency department visits for asthma (OR, 0.17; 95% CI, 0.04-0.76; P = .02) in the past 12 months were less common in children born to mothers from the FENO group. Doctor-diagnosed asthma was associated with common risk alleles for early onset asthma at gene locus 17q21 (P = .01 for rs8069176; P = .03 for rs8076131), and higher airways resistance (P = .02) and FENO levels (P = .03). A causal mediation analysis suggested natural indirect effects of FENO-guided asthma management on childhood asthma through "any use" and "time to first change in dose" of inhaled corticosteroids during the MAP trial (OR: 0.83; 95% CI: 0.59-0.99, and OR: 0.90; 95% CI: 0.70-1.03, respectively). CONCLUSIONS: FENO-guided asthma management during pregnancy prevented doctor-diagnosed asthma in the offspring at preschool age, in part mediated through changes in use and dosing of inhaled corticosteroids during the MAP trial.

Exercise capacity is not decreased in children who have undergone lung resection early in life for congenital thoracic malformations compared to healthy age-matched children.

PURPOSE: The purpose of this study was to compare (i) the exercise capacity and (ii) lung function prior to and immediately post cardiopulmonary exercise tests (CPET) of children who underwent early life lung resection for Congenital Pulmonary Airway Malformations (CPAM) to healthy control children. METHOD: Eight children with CPAM (four males, age 9.6 ± 1.8 years) and eight control children without respiratory disease (three males, age 9.4 ± 1.4 years) performed a CPET on a cycle ergometer, during which maximal oxygen consumption (V̇O2max ) and heart rate were measured. Prior to and immediately post CPET, lung function measures including Nitrogen Multiple Breath Washout (MBW) and spirometry were performed. RESULTS: There were no significant between group differences in pre CPET lung function (P > 0.05) or maximal exercise capacity (V̇O2max CPAM: 39.4 mL. kg-1. min-1 , Control: 40.5 mL. kg-1. min-1 ). Post CPET, FEV1 was significantly lower in the CPAM group, with two participants diagnosed subsequently with exercise induced bronchospasm based on post-CPET spirometry and follow-up clinical investigations. CONCLUSION: Early life lung resection for CPAM does not appear to have negative implications for exercise capacity later in childhood. Clinicians should be aware that dyspnoea following exercise may be due to asthma rather than residual effects of CPAM in these children.

Ventilation inhomogeneities in children with congenital thoracic malformations.

BACKGROUND: Congenital thoracic malformations (CTM) are rare lung lesions that are managed with surgical resection or active surveillance. The objective of this study was to comprehensively assess large and small airway function in children with CTM who underwent lobectomy in early life. We hypothesise that sensitive measures of lung function will demonstrate residual impairments in CTM compared to healthy children. METHODS: Nitrogen lung clearance index (LCI), reactance and resistance (X5Hz and R5Hz), forced expiratory volume in 1 s and forced vital capacity (FEV1 and FVC) were prospectively measured in 10 children with CTM (mean age/SD: 7.6/1.3) who had undergone surgical resection in early life and in 17 healthy children (mean age/SD: 4.8/0.4). Total lung capacity (TLC) was also conducted in children older than 7 years of age with CTM (n = 8). RESULTS: Mean LCI was 8.0 (95% CI 7.5 to 8.5) in the CTM group and 7.3 (95% CI 7.0 to 7.6) in healthy children (p = 0.016). Mean X5Hz was -0.44kPa/l/s (95% CI -0.58 to -0.31) in the CTM group and -0.31kPa/l/s (95% CI -0.35 to -0.27) in healthy children (p = 0.02). Mean Z score for X5Hz was -2.11 (95% CI -3.59 to -0.63) in the CTM group and -0.11 (95% CI -0.55 to 0.33) in healthy children (p = 0.0008). Mean FEV1 was 1.21 L (95% CI 0.97 to 1.45) in the CTM group and 1.02 L (95% CI 0.90 to 1.15) in healthy children (p = 0.22). Mean % predicted FEV1 was 83% (95% CI 74 to 92) in the CTM group and 97% (95% CI 87 to 107) in healthy children (p < 0.05). Mean % predicted TLC in CTM children was 121.3% (95% CI 88.45 to 154.1). Mean LCI was inversely correlated with height z-scores in the CTM group (rs = -0.88, p = 0.002) but not in healthy children (rs = 0.22, p = 0.4). CONCLUSIONS: Children with CTM have impaired lung function as demonstrated by the significant differences in LCI, reactance and FEV1 but not FVC, resistance and TLC. These findings may be of clinical relevance as ventilation inhomogeneities are closely correlated with somatic growth in this study.

Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A.

BACKGROUND: ß-Agonists are used for relief and control of asthma symptoms by reversing bronchoconstriction. They might also have anti-inflammatory properties, but the underpinning mechanisms remain poorly understood. Recently, a direct interaction between formoterol and protein phosphatase 2A (PP2A) has been described in vitro. OBJECTIVE: We sought to elucidate the molecular mechanisms by which ß-agonists exert anti-inflammatory effects in allergen-driven and rhinovirus 1B-exacerbated allergic airways disease (AAD). METHODS: Mice were sensitized and then challenged with house dust mite to induce AAD while receiving treatment with salmeterol, formoterol, or salbutamol. Mice were also infected with rhinovirus 1B to exacerbate lung inflammation and therapeutically administered salmeterol, dexamethasone, or the PP2A-activating drug (S)-2-amino-4-(4-[heptyloxy]phenyl)-2-methylbutan-1-ol (AAL[S]). RESULTS: Systemic or intranasal administration of salmeterol protected against the development of allergen- and rhinovirus-induced airway hyperreactivity and decreased eosinophil recruitment to the lungs as effectively as dexamethasone. Formoterol and salbutamol also showed anti-inflammatory properties. Salmeterol, but not dexamethasone, increased PP2A activity, which reduced CCL11, CCL20, and CXCL2 expression and reduced levels of phosphorylated extracellular signal-regulated kinase 1 and active nuclear factor κB subunits in the lungs. The anti-inflammatory effect of salmeterol was blocked by targeting the catalytic subunit of PP2A with small RNA interference. Conversely, increasing PP2A activity with AAL(S) abolished rhinovirus-induced airway hyperreactivity, eosinophil influx, and CCL11, CCL20, and CXCL2 expression. Salmeterol also directly activated immunoprecipitated PP2A in vitro isolated from human airway epithelial cells. CONCLUSIONS: Salmeterol exerts anti-inflammatory effects by increasing PP2A activity in AAD and rhinovirus-induced lung inflammation, which might potentially account for some of its clinical benefits.

Inhibiting AKT phosphorylation employing non-cytotoxic anthraquinones ameliorates TH2 mediated allergic airways disease and rhinovirus exacerbation.

BACKGROUND: Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro. OBJECTIVE: To determine the anti-inflammatory potential of anthraquinones in-vivo. METHODS: BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation. RESULTS: Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung. CONCLUSION: Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.