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Pediatric Asthma

Machine learning to identify pairwise interactions between specific IgE antibodies and their association with asthma: A cross-sectional analysis within a population-based birth cohort.

Fontanella S, Frainay C, Murray CS, Simpson A, Custovic A. PLoS Med. 2018 Nov 13;15(11):e1002691.

Reasons for recommending the article:

  • It suggests an approach and helps disentangle the association between atopy and asthma

Reviewer’s comments:

I think that this exhaustive study fathoms into the relationships between allergy and asthma (assuming that, in opposite to the general thinking, allergic sensitization is not a single entity but a collection of several different classes of sensitization), and shows how sIgE responses to multiple allergens are functionally connected and coordinated to induce clinical phenotypes, and a higher risk to develop asthma. The study identifies 4 different clusters of allergic sensitization and suggests an important change of paradigm: We need to rethink the way we interpret data obtained using CRD and move away from the focus on individual component-specific IgEs to a more holistic approach that takes into account the patterns of connectivity between IgEs.

Complementary, and taking into account the growing interest in the cluster analysis and latent class analysis methodology for identification of asthma phenotypes, the following study can be very useful to understand the causes behind the great variability shown by different studies analysis that question

Abstract

Background:The relationship between allergic sensitisation and asthma is complex; the data about the strength of this association are conflicting. We propose that the discrepancies arise in part because allergic sensitisation may not be a single entity (as considered conventionally) but a collection of several different classes of sensitisation. We hypothesise that pairings between immunoglobulin E (IgE) antibodies to individual allergenic molecules (components), rather than IgE responses to ‘informative’ molecules, are associated with increased risk of asthma.

Methods and findings: In a cross-sectional analysis among 461 children aged 11 years participating in a population-based birth cohort, we measured serum-specific IgE responses to 112 allergen components using a multiplex array (ImmunoCAP Immuno‑Solid phase Allergy Chip [ISAC]). We characterised sensitivity to 44 active components (specific immunoglobulin E [sIgE] > 0.30 units in at least 5% of children) among the 213 (46.2%) participants sensitised to at least one of these 44 components. We adopted several machine learning methodologies that offer a powerful framework to investigate the highly complex sIgE–asthma relationship. Firstly, we applied network analysis and hierarchical clustering (HC) to explore the connectivity structure of component-specific IgEs and identify clusters of component-specific sensitisation (‘component clusters’). Of the 44 components included in the model, 33 grouped in seven clusters (C.sIgE-1–7), and the remaining 11 formed singleton clusters. Cluster membership mapped closely to the structural homology of proteins and/or their biological source. Components in the pathogenesis-related (PR)-10 proteins cluster (C.sIgE-5) were central to the network and mediated connections between components from grass (C.sIgE-4), trees (C.sIgE-6), and profilin clusters (C.sIgE-7) with those in mite (C.sIgE-1), lipocalins (C.sIgE-3), and peanut clusters (C.sIgE-2). We then used HC to identify four common ‘sensitisation clusters’ among study participants: (1) multiple sensitisation (sIgE to multiple components across all seven component clusters and singleton components), (2) predominantly dust mite sensitisation (IgE responses mainly to components from C.sIgE-1), (3) predominantly grass and tree sensitisation (sIgE to multiple components across C.sIgE-4–7), and (4) lower-grade sensitisation. We used a bipartite network to explore the relationship between component clusters, sensitisation clusters, and asthma, and the joint density-based nonparametric differential interaction network analysis and classification (JDINAC) to test whether pairwise interactions of component-specific IgEs are associated with asthma. JDINAC with pairwise interactions provided a good balance between sensitivity (0.84) and specificity (0.87), and outperformed penalised logistic regression with individual sIgE components in predicting asthma, with an area under the curve (AUC) of 0.94, compared with 0.73. We then inferred the differential network of pairwise component-specific IgE interactions, which demonstrated that 18 pairs of components predicted asthma. These findings were confirmed in an independent sample of children aged 8 years who participated in the same birth cohort but did not have component-resolved diagnostics (CRD) data at age 11 years. The main limitation of our study was the exclusion of potentially important allergens caused by both the ISAC chip resolution as well as the filtering step. Clustering and the network analyses might have provided different solutions if additional components had been available. 

Conclusions Interactions between pairs of sIgE components are associated with increased risk of asthma and may provide the basis for designing diagnostic tools for asthma.

Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma.

O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Jorup C, Lamarca R, Ivanov S, Reddel HK. N Engl J Med. 2018 May 17;378(20):1865-1876. doi: 10.1056/NEJMoa1715274.

Reasons for recommending the article:

  • This study explores an interesting and mechanistically sound approach to managing mild asthma

Abstract

Background: In patients with mild asthma, as-needed use of an inhaled glucocorticoid plus a fast-acting β2-agonist may be an alternative to conventional treatment strategies.

Methods: We conducted a 52-week, double-blind trial involving patients 12 years of age or older with mild asthma. Patients were randomly assigned to one of three regimens: twice-daily placebo plus terbutaline (0.5 mg) used as needed (terbutaline group), twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed (budesonide-formoterol group), or twice-daily budesonide (200 μg) plus terbutaline used as needed (budesonide maintenance group). The primary objective was to investigate the superiority of as-needed budesonide-formoterol to as-needed terbutaline with regard to electronically recorded weeks with well-controlled asthma.

Results: A total of 3849 patients underwent randomization, and 3836 (1277 in the terbutaline group, 1277 in the budesonide-formoterol group, and 1282 in the budesonide maintenance group) were included in the full analysis and safety data sets. With respect to the mean percentage of weeks with well-controlled asthma per patient, budesonide-formoterol was superior to terbutaline (34.4% vs. 31.1% of weeks; odds ratio, 1.14; 95% confidence interval [CI], 1.00 to 1.30; P=0.046) but inferior to budesonide maintenance therapy (34.4% and 44.4%, respectively; odds ratio, 0.64; 95% CI, 0.57 to 0.73). The annual rate of severe exacerbations was 0.20 with terbutaline, 0.07 with budesonide-formoterol, and 0.09 with budesonide maintenance therapy; the rate ratio was 0.36 (95% CI, 0.27 to 0.49) for budesonide-formoterol versus terbutaline and 0.83 (95% CI, 0.59 to 1.16) for budesonide-formoterol versus budesonide maintenance therapy. The rate of adherence in the budesonide maintenance group was 78.9%. The median metered daily dose of inhaled glucocorticoid in the budesonide-formoterol group (57 μg) was 17% of the dose in the budesonide maintenance group (340 μg).

Conclusions: In patients with mild asthma, as-needed budesonide-formoterol provided superior asthma-symptom control to as-needed terbutaline, assessed according to electronically recorded weeks with well-controlled asthma, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide-formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy.

As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma.

Bateman ED, Reddel HK, O'Byrne PM, Barnes PJ, Zhong N, Keen C, Jorup C, Lamarca R, Siwek-Posluszna A, FitzGerald JM. N Engl J Med. 2018 May 17;378(20):1877-1887. doi: 10.1056/NEJMoa1715275.

Reasons for recommending the article:

In mild asthma:

  • Prn ICS/LABA better than SABA but was inferior to ICS daily. and both ICS preparations better than SABA. The ICS/LABA gives lower corticosteroid exposure.
  • Prn ICS/LABA same as BID ICS maintenance but inferior in controlling symptoms. As in Sygmi1 ICS/LABA had 1/4 exposure of ICS as maintenance ICS group.

Reviewer’s comments:

These papers highlight that maybe we shouldn't be giving SABA alone ever for exacerbations and PRN ICS/LABA may be a strategy in kids by reducing corticosteroid exposure but still may not be as good as daily maintenance dosing in maintaining control. The lower corticosteroid exposure is really of interest in kids so needs further study in younger children

Abstract

Background: Patients with mild asthma often rely on inhaled short-acting β2-agonists for symptom relief and have poor adherence to maintenance therapy. Another approach might be for patients to receive a fast-acting reliever plus an inhaled glucocorticoid component on an as-needed basis to address symptoms and exacerbation risk.

Methods:We conducted a 52-week, double-blind, multicenter trial involving patients 12 years of age or older who had mild asthma and were eligible for treatment with regular inhaled glucocorticoids. Patients were randomly assigned to receive twice-daily placebo plus budesonide-formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed or budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed. The primary analysis compared budesonide-formoterol used as needed with budesonide maintenance therapy with regard to the annualized rate of severe exacerbations, with a prespecified noninferiority limit of 1.2. Symptoms were assessed according to scores on the Asthma Control Questionnaire-5 (ACQ-5) on a scale from 0 (no impairment) to 6 (maximum impairment).

Results: A total of 4215 patients underwent randomization, and 4176 (2089 in the budesonide-formoterol group and 2087 in the budesonide maintenance group) were included in the full analysis set. Budesonide-formoterol used as needed was noninferior to budesonide maintenance therapy for severe exacerbations; the annualized rate of severe exacerbations was 0.11 (95% confidence interval [CI], 0.10 to 0.13) and 0.12 (95% CI, 0.10 to 0.14), respectively (rate ratio, 0.97; upper one-sided 95% confidence limit, 1.16). The median daily metered dose of inhaled glucocorticoid was lower in the budesonide-formoterol group (66 μg) than in the budesonide maintenance group (267 μg). The time to the first exacerbation was similar in the two groups (hazard ratio, 0.96; 95% CI, 0.78 to 1.17). The change in ACQ-5 score showed a difference of 0.11 units (95% CI, 0.07 to 0.15) in favor of budesonide maintenance therapy.

Conclusions: In patients with mild asthma, budesonide-formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide-formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group

Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy

Valovirta, E. Petersen TH, Piotrowska T, Laursen MK, Andersen JS, Sørensen HF, Klink R. J Allergy Clin Immunol. 2018 Feb;141(2):529-538.e13. doi: 10.1016/j.jaci.2017.06.014. Epub 2017 Jul 6.

Reasons for recommending the article:

-A major effort to evaluate the long term effects of immunotherapy in children

Reviewer’s comments:

This study shows that secondary prevention of asthma in children with rhinitis is possible through immunotherapy. The effects of treatment persist for at least 2 years after the 3-year treatment.

Abstract

Background:Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease.

Objective: The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma.

Methods: A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up.

Results: There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P < .036), during the 2-year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P < .005 for all 5 years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen-specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo.

Conclusions: Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma

Pediatric asthma: An unmet need for more effective, focused treatments.

Papadopoulos NG, Čustović A, Cabana MD, Dell SD, Deschildre A, Hedlin G, Hossny E, Le Souëf P, Matricardi PM, Nieto A, Phipatanakul W, Pitrez PM, Pohunek P, Gavornikova M, Jaumont X, Price DB. Pediatr Allergy Immunol. 2019 Feb;30(1):7-16. doi: 10.1111/pai.12990. Epub 2018 Nov 15. Review.

Reasons for recommending the article:

-Highlights key unmet needs that require attention in pediatric asthma

Reviewer’s comments:

Pediatric asthma requires much more attention. Key unmet needs are highlighted and direactions are suggested in this rostrum article

Abstract

Background:Despite remarkable advances in our understanding of asthma, there are still several unmet needs associated with the management of pediatric asthma.

Methods:A two-day, face-to-face meeting was held in London, United Kingdom, on October 28 and 29, 2017, involving a group of international expert clinicians and scientists in asthma management to discuss the challenges and unmet needs that remain to be addressed in pediatric asthma.

Results:These unmet needs include a lack of clinical efficacy and safety evidence, and limited availability of non-steroid-based alternative therapies in patients <6 years of age. An increased focus on children is needed in the context of clinical practice guidelines for asthma; current pediatric practice relies mostly on extrapolations from adult recommendations. Furthermore, no uniform definition of pediatric asthma exists, which hampers timely and robust diagnosis of the condition in affected patients.

Conclusions: There is a need for a uniform definition of pediatric asthma, clearly distinguishable from adult asthma. Furthermore, guidelines which provide specific treatment recommendations for the management of pediatric asthma are also needed. Clinical trials and real-world evidence studies assessing anti-immunoglobulin E (IgE) therapies and other monoclonal antibodies in children <6 years of age with asthma may provide further information regarding the most appropriate treatment options in these vulnerable patients. Early intervention with anti-IgE and non-steroid-based alternative therapies may delay disease progression, leading to improved clinical outcomes.

Wheeze trajectories are modifiable through early-life intervention and predict asthma in adolescence.

Owora AH, Becker AB, Chan-Yeung M, Chan ES, Chooniedass R, Ramsey C, Watson WTA, Azad MB. Pediatr Allergy Immunol. 2018 Sep;29(6):612-621. doi: 10.1111/pai.12922. Epub 2018 Jun 19.

Reviewer’s comments:

The hope for pediatric asthma prevention gets some backing from this study that describes wheeze trajectories and identifies modifiable in addition to non-modifiable risk factors

Abstract

Background: The objectives of this study were to identify developmental trajectories of wheezing using data-driven methodology, and to examine whether trajectory membership differentially impacts the effectiveness of primary preventive efforts that target modifiable asthma risk factors.

Methods: Secondary analysis of the Canadian Asthma Primary Prevention Study (CAPPS), a multifaceted prenatal intervention among children at high risk of asthma, followed from birth to 15 years. Wheezing trajectories were identified by latent class growth analysis. Predictors, intervention effects, and asthma diagnoses were examined between and within trajectory groups.

Results: Among 525 children, 3 wheeze trajectory groups were identified: Low-Progressive (365, 69%), Early-Transient (52, 10%), and Early-Persistent (108, 21%). The study intervention was associated with lower odds of Early-Transient and Early-Persistent wheezing (P < .01). Other predictors of wheeze trajectories included, maternal asthma, maternal education, city of residence, breastfeeding, household pets, infant sex and atopy at 12 months. The odds of an asthma diagnosis were three-fold to six-fold higher in the Early-Persistent vs Low-Progressive group at all follow-up assessments (P = .03), whereas Early-Transient wheezing (limited to the first year) was not associated with asthma. In the Early-Persistent group, the odds of wheezing were lower among intervention than control children (adjusted odds ratio: 0.67; 95% CI: 0.48; 0.93) at 7 years.

Conclusions: Using data-driven methodology, children can be classified into clinically meaningful wheeze trajectory groups that appear to be programmed by modifiable and non-modifiable factors, and are useful for predicting asthma risk. Early-life interventions can alter some wheeze trajectories (ie, Early-Persistent) in infancy and reduce wheezing prevalence in mid-childhood.

Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial.

VrijlandtEJLE, El Azzi G, Vandewalker M, Rupp N, Harper T, Graham L, Szefler S, Moroni-Zentgraf P, Sharma A, Vulcu SD, Sigmund R, Chawes B, Engel M, Bisgaard H. Lancet Respir Med. 2018 Feb;6(2):127-137. doi: 10.1016/S2213-2600(18)30012-2. Epub 2018 Jan 18.

Reviewer’s comments:

This is the first small clinical trial of tiotropium in preschoolers with persistent asthmatic symptoms, showing tolerability and a potential to reduce asthma exacerbation risk in this population.

Abstract

Background: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.

Methods: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.

Findings: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.

Interpretation: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.

 Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.

Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, Ford L, Sher L, FitzGerald JM, Katelaris C, Tohda Y, Zhang B, Staudinger H, Pirozzi G, Amin N, Ruddy M, Akinlade B, Khan A, Chao J, Martincova R, Graham NMH, Hamilton JD, Swanson BN, Stahl N, Yancopoulos GD, Teper A. N Engl J Med. 2018 Jun 28;378(26):2486-2496. doi: 10.1056/NEJMoa1804092. Epub 2018

Reviewer’s comments:

This study including adults and children>12 years of age, showed significantly lower rates of severe asthma exacerbations compared to placebo in patients with marked blood eosinophilia. Based on these results a positive opinion from EMA for the use of Dupilumab in asthma was released in early 2019.

Abstract

Background: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma.

Methods: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV1) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV1 in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.

Results: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV1 had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. Matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.

Conclusions: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients

Asthma is associated with carotid arterial injury in children: The Childhood Origins of Asthma (COAST) Cohort. 

Tattersal MC, Evans MD, Korcarz CE, Mitchell C, Anderson E, DaSilva DF, Salazar LP, Gern JE, Jackson DJ, Lemanske RF Jr,Stein JH. PLoS One. 2018 Sep 27;13(9):e0204708. doi: 10.1371/journal.pone.0204708. eCollection 2018.

Reviewer’s comments:

In this contemporary birth cohort, asthmatic children with or without other atopic disease had increased markers of arterial wall thickening (thicker RCB and RCCA walls) compared to non-asthmatic/non-atopic children, indicating evidence of arterial injury, that is antecedent to the development of Cardio Vascular Disease. The underlying mechanism possibly involves a common inflammatory pathophysiology. This is the first study exploring such a relationship in children. 

Abstract

Background: Asthma is associated with an increased cardiovascular disease (CVD) risk in adults, but the impact of asthma and atopic conditions on CVD risk in children is less well established. We hypothesized that children in the Childhood Origins of Asthma (COAST) Cohort with asthma and atopic conditions would have early carotid arterial injury.

Methods: The COAST study is a longitudinal birth cohort of children at increased risk of developing asthma. Children underwent ultrasonography measuring far wall right carotid bifurcation (RCB) and common carotid artery (RCCA) intima-media thickness (IMT; a measure of arterial injury). Multivariable linear regression models adjusted for age, gender, race, blood pressure, and body-mass index were used to assess associations of asthma and markers of arterial injury.

Results: The 89 participants were a mean (standard deviation) 15.3 (0.6) years old and 42% were female; 28 asthmatics had atopic disease, 34 asthmatics were without other atopic disease, and 15 non-asthmatics had atopic disease. This study population was compared to 12 controls (participants free of asthma or atopic disease). Compared to controls (589 μm), those with atopic disease (653 μm, p = 0.07), asthma (649 μm, p = 0.05), or both (677 μm, p = 0.005) had progressively higher RCB IMT values (ptrend = 0.011). In adjusted models, asthmatic and/or atopic participants had significantly higher RCB IMT than those without asthma or atopic disease (all p≤0.03). Similar relationships were found for RCCA IMT.

Conclusion: Adolescents with asthma and other atopic diseases have an increased risk of subclinical arterial injury compared to children without asthma or other atopic disease.

PreDicta chip-based high resolution diagnosis of rhinovirus-induced wheeze.

Katarzyna Niespodziana, Katarina Stenberg-Hammar, Spyridon Megremis, Clarissa R. Cabauatan, Kamila Napora-Wijata, Phyllis C. Vacal, Daniela Gallerano, Christian Lupinek, Daniel Ebner, Thomas Schlederer, Christian Harwanegg, Cilla Söderhäll, Marianne van Hage, Gunilla Hedlin, Nikolaos G. Papadopoulos & Rudolf Valenta. Nature Communications volume 9, Article number: 2382 (2018) doi: 10.1038/s41467-018-04591-0

Reviewer’s comments:

The study describes the generation of a novel chip for the serological identification of RV-induced respiratory illness which should be useful for the rational development of preventive and therapeutic strategies targeting the most important RV types.

Abstract:

Rhinovirus (RV) infections are major triggers of acute exacerbations of severe respiratory diseases such as pre-school wheeze, asthma and chronic obstructive pulmonary disease (COPD). The occurrence of numerous RV types is a major challenge for the identification of the culprit virus types and for the improvement of virus type-specific treatment strategies. Here, we develop a chip containing 130 different micro-arrayed RV proteins and peptides and demonstrate in a cohort of 120 pre-school children, most of whom had been hospitalized due to acute wheeze, that it is possible to determine the culprit RV species with a minute blood sample by serology. Importantly, we identify RV-A and RV-C species as giving rise to most severe respiratory symptoms. Thus, we have generated a chip for the serological identification of RV-induced respiratory illness which should be useful for the rational development of preventive and therapeutic strategies targeting the most important RV types.

CDHR3 extracellular domains EC1-3 mediate rhinovirus C interaction with cells and as recombinant derivatives, are inhibitory to virus infection

Watters K, Palmenberg AC. PLoS pathogens. 2018;14(12):e1007477.

Reviewer’s comments:

This paper describes variants within the CDHR3 rhinovirus C receptor that confer protection against rhinovirus C infection - the most common cause of severe wheeze/asthma exacerbations in preschool children. As such, this paper provides new and important insight into susceptibility to asthma exacerbations in young children and the CDHR3 variants offer a potential pathway to prevention of asthma exacerbations

Abstract: Viruses in the rhinovirus C species (RV-C) are more likely to cause severe wheezing illnesses and asthma exacerbations in children than related isolates of the RV-A or RV-B. The RV-C capsid is structurally distinct from other rhinoviruses and does not bind ICAM-1 or LDL receptors. The RV-C receptor is instead, human cadherin-related family member 3 (CDHR3), a protein unique to the airway epithelium. A single nucleotide polymorphism (rs6967330, encoding C529Y) in CDHR3 regulates the display density of CDHR3 on cell surfaces and is among the strongest known genetic correlates for childhood virus-induced asthma susceptibility. CDHR3 immunoprecipitations from transfected or transduced cell lysates were used to characterize the RV-C interaction requirements. The C529 and Y529 variations in extracellular repeat domain 5 (EC5), bound equivalently to virus. Glycosylase treatment followed by mass spectrometry mapped 3 extracellular N-linked modification sites, and further detected surface-dependent, α2–6 sialyation unique to the Y529 format. None of these modifications were required for RV-C recognition, but removal or even dilution of structurally stabilizing calcium ions from the EC junctions irreversibly abrogated virus binding. CDHR3 deletions expressed in HeLa cells or as bacterial recombinant proteins, mapped the amino-terminal EC1 unit as the required virus contact. Derivatives containing the EC1 domain, could not only recapitulate virus: receptor interactions in vitro, but also directly inhibit RV-C infection of susceptible cells for several virus genotypes (C02, C15, C41, and C45). We propose that all RV-C use the same EC1 landing pad, interacting with putative EC3-mediated multimerization formats of CDHR3.

Cytokine Responses to Rhinovirus and Development of Asthma, Allergic Sensitization and Respiratory Infections during Childhood.

 Custovic A, Belgrave D, Lin L, Bakhsoliani E, Telcian AG, Solari R, et al. Am J Respir Crit Care Med. 2018.

Reviewer’s comments:

This paper examines immune responses to rhinovirus infection and relates this to clinical phenotypes.  Those with the highest risk of asthma exacerbations had a pattern of low interferon and Th2 responses, and high levels of inflammatory responses.

Abstract

Rationale: Immunophenotypes of antiviral responses, and their relationship with asthma, allergy, and lower respiratory tract infections, are poorly understood.

Objectives: We characterized multiple cytokine responses of peripheral blood mononuclear cells to rhinovirus stimulation, and their relationship with clinical outcomes.

Methods: In a population-based birth cohort, we measured 28 cytokines after stimulation with rhinovirus-16 in 307 children aged 11 years. We used machine learning to identify patterns of cytokine responses, and related these patterns to clinical outcomes, using longitudinal models. We also ascertained phytohemagglutinin-induced T-helper cell type 2 (Th2)-cytokine responses (PHA-Th2).

Measurements and main results: We identified six clusters of children based on their rhinovirus-16 responses, which were differentiated by the expression of four cytokine/chemokine groups: interferon-related (IFN), proinflammatory (Inflam), Th2-chemokine (Th2-chem), and regulatory (Reg). Clusters differed in their clinical characteristics. Children with an IFNmodInflamhighestTh2-chemhighestReghighestrhinovirus-16-induced pattern had a PHA-Th2low response, and a very low asthma risk (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.01-0.81; P = 0.03). Two clusters had a high risk of asthma and allergic sensitization, but with different trajectories from infancy to adolescence. The IFNlowestInflamhighTh2-chemlowRegmod cluster exhibited a PHA-Th2lowest response and was associated with early-onset asthma and sensitization, and the highest risk of asthma exacerbations (OR, 1.37; 95% CI, 1.07-1.76; P = 0.014) and lower respiratory tract infection hospitalizations (OR, 2.40; 95% CI, 1.26-4.58; P = 0.008) throughout childhood. In contrast, the IFNhighestInflammodTh2-chemmodReghigh cluster with a rhinovirus-16-cytokine pattern was characterized by a PHA-Th2highest response, and a low prevalence of asthma/sensitization in infancy that increased sharply to become the highest among all clusters by adolescence (but with a low risk of asthma exacerbations).

Conclusions: Early-onset troublesome asthma with early-life sensitization, later-onset milder allergic asthma, and disease protection are each associated with different patterns of rhinovirus-induced immune responses.

Epigenome-wide meta-analysis of DNA methylation and childhood asthma.

Reese SE et al. J Allergy Clin Immunol. 2018 Dec 21. pii: S0091-6749(18)32788-X. doi: 10.1016/j.jaci.2018.11.043.

DNA methylation in nasal epithelium, atopy, and atopic asthma in children: a genome-wide study. 

Forno E et al.  Lancet Respir Med. 2018 Dec 21. pii: S2213-2600(18)30466-1. doi: 10.1016/S2213-2600(18)30466-1.

Reviewer’s comments:

These articles show a potential tool to detect the epigenetic influence on the methylation of CpGs on epithelial barrier and immune cells and their function, with multiple markers on the presence and association to development of asthma in children. These findings should be replicated in different and larger populations

(1) Abstract

Background: Epigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.

Objective: We sought to identify differential DNA methylation in newborns and children related to childhood asthma.

Methods: Within the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.

Results: In newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.

Conclusion: Novel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.

(2) Abstract

Background: Epigenetic mechanisms could alter the airway epithelial barrier and ultimately lead to atopic diseases such as asthma. We aimed to identify DNA methylation profiles that are associated with-and could accurately classify-atopy and atopic asthma in school-aged children.

Methods: We did a genome-wide study of DNA methylation in nasal epithelium and atopy or atopic asthma in 483 Puerto Rican children aged 9-20 years, recruited using multistage probability sampling. Atopy was defined as at least one positive ige (≥0·35 IU/ml) to common aeroallergens, and asthma was defined as a physician's diagnosis plus wheeze in the previous year. Significant (false discovery rate p<0·01) methylation signals were correlated with gene expression, and top cpgs were validated by pyrosequencing. We then replicated our top methylation findings in a cohort of 72 predominantly African American children, and in 432 children from a European birth cohort. Next, we tested classification models based on nasal methylation for atopy or atopic asthma in all cohorts.

Findings: DNA methylation profiles were markedly different between children with (n=312) and without (n=171) atopy in the Puerto Rico discovery cohort, recruited from Feb 12, 2014, until May 8, 2017. After adjustment for covariates and multiple testing, we found 8664 differentially methylated cpgs by atopy, with false discovery rate-adjusted p values ranging from 9·58 × 10-17 to 2·18 × 10-22 for the top 30 cpgs. These cpgs were in or near genes relevant to epithelial barrier function, including CDHR3 and CDH26, and in other genes related to airway epithelial integrity and immune regulation, such as FBXL7, NTRK1, and SLC9A3. Moreover, 28 of the top 30 cpgs replicated in the same direction in both independent cohorts. Classification models of atopy based on nasal methylation performed well in the Puerto Rico cohort (area under the curve [AUC] 0·93-0·94 and accuracy 85-88%) and in both replication cohorts (AUC 0·74-0·92, accuracy 68-82%). The models also performed well for atopic asthma in the Puerto Rico cohort (AUC 0·95-1·00, accuracy 88%) and the replication cohorts (AUC 0·82-0·88, accuracy 86%).

Interpretation: We identified specific methylation profiles in airway epithelium that are associated with atopy and atopic asthma in children, and a nasal methylation panel that could classify children by atopy or atopic asthma. Our findings support the feasibility of using the nasal methylome for future clinical applications, such as predicting the development of asthma among wheezing infants.