Subsequent Development Of Asthma Research Articles

Rhinovirus protease cleavage of nucleoporins: perspective on implications for airway remodeling.

Human Rhinoviruses (RV) are a major cause of common colds and infections in early childhood and can lead to subsequent development of asthma via an as yet unknown mechanism. Asthma is a chronic inflammatory pulmonary disease characterized by significant airway remodeling. A key component of airway remodeling is the transdifferentiation of airway epithelial and fibroblast cells into cells with a more contractile phenotype. Interestingly, transforming growth factor-beta (TGF-β), a well characterized inducer of transdifferentiation, is significantly higher in airways of asthmatics compared to non-asthmatics. RV infection induces TGF-β signaling, at the same time nucleoporins (Nups), including Nup153, are cleaved by RV proteases disrupting nucleocytoplasmic transport. As Nup153 regulates nuclear export of SMAD2, a key intermediate in the TGF-β transdifferentiation pathway, its loss of function would result in nuclear retention of SMAD2 and dysregulated TGF-β signaling. We hypothesize that RV infection leads to increased nuclear SMAD2, resulting in sustained TGF-β induced gene expression, priming the airway for subsequent development of asthma. Our hypothesis brings together disparate studies on RV, asthma and Nup153 with the aim to prompt new research into the role of RV infection in development of asthma.

From preschool wheezing to asthma: Environmental determinants.

Wheezing is common among preschool children, representing a group of highly heterogeneous conditions with varying natural history. Several phenotypes of wheezing have been proposed to facilitate the identification of young children who are at risk of subsequent development of asthma. Epidemiological and immunological studies across different populations have revealed the key role of environmental factors in influencing the progression from preschool wheezing to childhood asthma. Significant risk factors include severe respiratory infections, allergic sensitization, and exposure to tobacco smoke. In contrast, a farming/rural environment has been linked to asthma protection in both human and animal studies. Early and intense exposures to microorganisms and microbial metabolites have been demonstrated to alter host immune responses to allergens and viruses, thereby driving the trajectory away from wheezing illness and asthma. Ongoing clinical trials of candidate microbes and microbial products have shown promise in shaping the immune function to reduce episodes of viral-induced wheezing. Moreover, restoring immune training may be especially important for young children who had reduced microbial exposure due to pandemic restrictions. A comprehensive understanding of the role of modifiable environmental factors will pave the way for developing targeted prevention strategies for preschool wheezing and asthma.

From preschool wheezing to asthma: Immunological determinants.

Asthma represents a chronic respiratory disease affecting millions of children worldwide. The transition from preschool wheezing to school-age asthma involves a multifaceted interplay of various factors, including immunological aspects in early childhood. These factors include complex cellular interactions among different immune cell subsets, induction of pro-inflammatory mediators and the molecular impact of environmental factors like allergens or viral infections on the developing immune system. Furthermore, the activation of specific genes and signalling pathways during this early phase plays a pivotal role in the manifestation of symptoms and subsequent development of asthma. Early identification of the propensity or risk for asthma development, for example by allergen sensitisation and viral infections during this critical period, is crucial for understanding the transition from wheeze to asthma. Favourable immune regulation during a critical 'window of opportunity' in early childhood can induce persistent changes in immune cell behaviour. In this context, trained immunity, including memory function of innate immune cells, has significant implications for understanding immune responses, potentially shaping long-term immunological outcomes based on early-life environmental exposures. Exploration of these underlying immune mechanisms that drive disease progression will provide valuable insights to understand childhood asthma development. This will be instrumental to develop preventive strategies at different stages of disease development for (i) inhibiting progression from wheeze to asthma or (ii) reducing disease severity and (iii) uncovering novel therapeutic strategies and contributing to more tailored and effective treatments for childhood asthma. In the long term, this shall empower healthcare professionals to develop evidence-based interventions that reduce the burden of asthma for children, families and society overall.

Skin surface biomarkers are associated with future development of atopic dermatitis in children with family history of allergic disease.

Atopic dermatitis (AD) is a common childhood chronic inflammatory skin disorder that can significantly impact quality of life and has been linked to the subsequent development of food allergy, asthma, and allergic rhinitis, an association known as the "atopic march." The aim of this study was to identify biomarkers collected non-invasively from the skin surface in order to predict AD before diagnosis across a broad age range of children. Non-invasive skin surface measures and biomarkers were collected from 160 children (3-48 months of age) of three groups: (A) healthy with no family history of allergic disease, (B) healthy with family history of allergic disease, and (C) diagnosed AD. Eleven of 101 children in group B reported AD diagnosis in the subsequent 12 months following the measurements. The children who developed AD had increased skin immune markers before disease onset, compared to those who did not develop AD in the same group and to the control group. In those enrolled with AD, lesional skin was characterized by increased concentrations of certain immune markers and transepidermal water loss, and decreased skin surface hydration. Defining risk susceptibility before onset of AD through non-invasive methods may help identify children who may benefit from early preventative interventions.

Emerging role for interferons in respiratory viral infections and childhood asthma.

Respiratory syncytial virus (RSV) and Rhinovirus (RV) infections are major triggers of severe lower respiratory illnesses (sLRI) in infants and children and are strongly associated with the subsequent development of asthma. Decades of research has focused on the role of type I interferons in antiviral immunity and ensuing airway diseases, however, recent findings have highlighted several novel aspects of the interferon response that merit further investigation. In this perspective, we discuss emerging roles of type I interferons in the pathogenesis of sLRI in children. We propose that variations in interferon response patterns exist as discrete endotypes, which operate locally in the airways and systemically through a lung-blood-bone marrow axis. We discuss new insights into the role of interferons in immune training, bacterial lysate immunotherapy, and allergen-specific immunotherapy. Interferons play complex and diverse roles in the pathogenesis of sLRI and later asthma, providing new directions for mechanistic studies and drug development.

Environmental influences on childhood asthma: Allergens

Allergen exposure is associated with the development of allergen-specific sensitization, but their relationship is influenced by other contemporaneous exposures (such as microbial exposure) and the genetic predisposition of the host. Clinical outcomes of the primary prevention studies that tested the effectiveness of allergen avoidance in pregnancy and early life on the subsequent development of sensitization and asthma published to date are inconsistent. Therefore, we cannot provide any evidence-based advice on the use of allergen avoidance for the primary prevention of these conditions. The evidence about the impact of allergen exposure among and among sensitized children with asthma is more consistent, and the combination of sensitization and high exposure to sensitizing allergen increases airway inflammation, triggers symptoms, adversely impacts upon disease control, and is associated with poorer lung function in preschool age. However, there are differing opinions about the role of inhalant allergen avoidance in asthma management, and recommendations differ in different guidelines. Evidence from more recent high-quality trials suggests that mite allergen-impermeable bed encasings reduce hospital attendance with asthma attacks and that multifaceted targeted environmental control improves asthma control in children. We therefore suggest a pragmatic approach to allergen avoidance in the management of childhood asthma for clinical practice, including the recommendations to: (1) tailor the intervention to the patient's sensitization and exposure status by using titer of allergen-specific IgE antibodies and/or the size of the skin test as indicators of potential response; (2) use a multifaceted allergen control regime to reduce exposure as much as possible; and (3) start intervention as early as possible upon diagnosis.

Microbial dysbiosis and childhood asthma development: Integrated role of the airway and gut microbiome, environmental exposures, and host metabolic and immune response.

Asthma is a chronic and heterogeneous respiratory disease with many risk factors that typically originate during early childhood. A complex interplay between environmental factors and genetic predisposition is considered to shape the lung and gut microbiome in early life. The growing literature has identified that changes in the relative abundance of microbes (microbial dysbiosis) and reduced microbial diversity, as triggers of the airway-gut axis crosstalk dysregulation, are associated with asthma development. There are several mechanisms underlying microbial dysbiosis to childhood asthma development pathways. For example, a bacterial infection in the airway of infants can lead to the activation and/or dysregulation of inflammatory pathways that contribute to bronchoconstriction and bronchial hyperresponsiveness. In addition, gut microbial dysbiosis in infancy can affect immune development and differentiation, resulting in a suboptimal balance between innate and adaptive immunity. This evolving dysregulation of secretion of pro-inflammatory mediators has been associated with persistent airway inflammation and subsequent asthma development. In this review, we examine current evidence around associations between the airway and gut microbial dysbiosis with childhood asthma development. More specifically, this review focuses on discussing the integrated roles of environmental exposures, host metabolic and immune responses, airway and gut microbial dysbiosis in driving childhood asthma development.

Association between early viral lower respiratory tract infections and subsequent asthma development.

BACKGROUNDThe association between hospitalization for human respiratory syncytial virus (HRSV) bronchiolitis in early childhood and subsequent asthma is well established. The long-term prognosis for non-bronchiolitis lower respiratory tract infections (LRTI) caused by viruses different from HRSV and rhinovirus, on the other hand, has received less interest.AIMTo investigate the relationship between infant LRTI and later asthma and examine the influence of confounding factors.METHODSThe PubMed and Global Index Medicus bibliographic databases were used to search for articles published up to October 2021 for this systematic review. We included cohort studies comparing the incidence of asthma between patients with and without LRTI at ≤ 2 years regardless of the virus responsible. The meta-analysis was performed using the random effects model. Sources of heterogeneity were assessed by stratified analyses.RESULTSThis review included 15 articles (18 unique studies) that met the inclusion criteria. LRTIs at ≤ 2 years were associated with an increased risk of subsequent asthma up to 20 years [odds ratio (OR) = 5.0, 95%CI: 3.3-7.5], with doctor-diagnosed asthma (OR = 5.3, 95%CI: 3.3-8.6), current asthma (OR = 5.4, 95%CI: 2.7-10.6), and current medication for asthma (OR = 1.2, 95%CI: 0.7-3.9). Our overall estimates were not affected by publication bias (P = 0.671), but there was significant heterogeneity [I2 = 58.8% (30.6-75.5)]. Compared to studies with hospitalized controls without LRTI, those with ambulatory controls had a significantly higher strength of association between LRTIs and subsequent asthma. The strength of the association between LRTIs and later asthma varied significantly by country and age at the time of the interview. The sensitivity analyses including only studies with similar proportions of confounding factors (gender, age at LRTI development, age at interview, gestational age, birth weight, weight, height, smoking exposure, crowding, family history of atopy, and family history of asthma) between cases and controls did not alter the overall estimates.CONCLUSIONRegardless of the causative virus and confounding factors, viral LRTIs in children < 2 years are associated with an increased risk of developing a subsequent asthma. Parents and pediatricians should be informed of this risk.

Microbiome–Immune Interactions in Allergy and Asthma

The human microbiota has been established as a key regulator of host health, in large part owing to its constant interaction with and impact on host immunity. A range of environmental exposures spanning from the prenatal period through adulthood are known to affect the composition and molecular productivity of microbiomes across mucosal and dermal tissues with short- and long-term consequences for host immune function. Here we review recent findings in the field that provide insights into how microbial-immune interactions promote and sustain immune dysfunction associated with allergy and asthma. We consider both early life microbiome perturbation and the molecular underpinnings of immune dysfunction associated with subsequent allergy and asthma development in childhood, as well as microbiome features that relate to phenotypic attributes of allergy and asthma in older patients with established disease.

Role and Diagnostic Performance of Host Epigenome in Respiratory Morbidity after RSV Infection: The EPIRESVi Study.

BackgroundRespiratory syncytial virus (RSV) infection has been associated with the subsequent development of recurrent wheezing and asthma, although the mechanisms involved are still unknown. We investigate the role of epigenetics in the respiratory morbidity after infection by comparing methylation patterns from children who develop recurrent wheezing (RW-RSV), subsequent asthma (AS-RVS), and those experiencing complete recovery (CR-RSV).MethodsProspective, observational study of infants aged < 2 years with RSV respiratory infection admitted to hospital and followed-up after discharge for at least three years. According to their clinical course, patients were categorized into subgroups: RW-RSV (n = 36), AS-RSV (n = 9), and CR-RSV (n = 32). The DNA genome-wide methylation pattern was analyzed in whole blood samples, collected during the acute phase of the infection, using the Illumina Infinium Methylation EPIC BeadChip (850K CpG sites). Differences in methylation were determined through a linear regression model adjusted for age, gender and cell composition.ResultsPatients who developed respiratory sequelae showed a statistically significant higher proportion of NK and CD8T cells (inferred through a deconvolution approach) than those with complete recovery. We identified 5,097 significant differentially methylated positions (DMPs) when comparing RW-RSV and AS-RVS together against CR-RSV. Methylation profiles affect several genes involved in airway inflammation processes. The most significant DMPs were found to be hypomethylated in cases and therefore generally leading to overexpression of affected genes. The lead CpG position (cg24509398) falls at the gene body of EYA3 (P-value = 2.77×10-10), a tyrosine phosphatase connected with pulmonary vascular remodeling, a key process in the asthma pathology. Logistic regression analysis resulted in a diagnostic epigenetic signature of 3-DMPs (involving genes ZNF2698, LOC102723354 and RPL15/NKIRAS1) that allows to efficiently differentiate sequelae cases from CR-RSV patients (AUC = 1.00). Enrichment pathway analysis reveals the role of the cell cycle checkpoint (FDR P-value = 4.71×10-2), DNA damage (FDP-value = 2.53×10-2), and DNA integrity checkpoint (FDR P-value = 2.56×10-2) in differentiating sequelae from CR-RSV patients.ConclusionsEpigenetic mechanisms might play a fundamental role in the long-term sequelae after RSV infection, contributing to explain the different phenotypes observed.

Susceptibility to Rhinovirus-induced Early Wheezing as a Risk Factor for Subsequent Asthma Development

Abstract: Rhinovirus is one of the two most common viral agents that cause bronchiolitis in young children. During the first 12 months, it is second to the respiratory syncytial virus, but after 12 months, it begins dominating the statistics. Wheezing and dry cough are typical clinical symptoms indicative of rhinovirus-induced bronchiolitis, although overlap of symptoms with other virus infections is common. Several studies have shown that atopic predisposition and reduced interferon responses increase susceptibility to rhinovirus-induced wheezing. More recent studies have found that certain genetic variations at strong asthma loci also increase susceptibility. Rhinovirus-induced wheezing in the early years of life is known to increase the risk of subsequent asthma development and may be associated with airway remodeling. This risk is increased by aeroallergen sensitization. Currently, there are no clinically approved preventive treatments for asthma. However, studies show promising results indicating that children with rhinovirus-affected first-time wheezing respond to bronchodilators in terms of less short-term symptoms and that controlling airway inflammatory responses with anti-inflammatory medication may markedly decrease asthma development. Also, enhancing resistance to respiratory viruses has been a topic of discussion. Primary and secondary prevention strategies are being developed with the aim of decreasing the incidence of asthma. Here, we review the current knowledge on rhinovirus-induced early wheezing as a risk factor for subsequent asthma development and related asthma-prevention strategies.

Early-Life Lung and Gut Microbiota Development and Respiratory Syncytial Virus Infection.

Several environmental factors can influence the development and establishment of the early-life microbiota. For example, exposure to different environmental factors from birth to childhood will shape the lung and gut microbiota and the development of the immune system, which will impact respiratory tract infection and widespread disease occurrence during infancy and later in life. Respiratory syncytial virus (RSV) infects most infants by the age of two and is the primary cause of bronchiolitis in children worldwide. Approximately a third of infants hospitalized with bronchiolitis develop asthma later in life. However, it is unclear what factors increase susceptibility to severe RSV-bronchiolitis and the subsequent asthma development. In recent years, the role of the gut and lung microbiota in airway diseases has received increased interest, and more studies have focused on this field. Different epidemiological studies and experimental animal models have associated early-life gut microbiota dysbiosis with an increased risk of lung disease later in life. This work will review published evidence that correlated environmental factors that affect the early-life microbiota composition and their role in developing severe RSV infection.

Modulations Of Natural Delivery On Yogurt-induced Reduction Of Non-specific Skin Reactivity In Healthy Infants

Both immune dysregulation and skin barrier dysfunction/hypersensitivity are known to be involved in the development of atopic dermatitis (AD). Perinatal probiotics administration, especially to infants, suppresses AD development in infancy; however, the mechanism remains unknown. Because such probiotics administration showed no effects on the IgE levels or subsequent asthma development in infants, we hypothesized that perinatal probiotics consumption influences on the skin barrier function/reactivity, but not on immune systems, in infants.

Internalizing behavior problems in early life are associated with the risk of childhood asthma: The COCOA study

Previous clinical studies suggest the relationship between children’s behavior problems and asthma. This study aimed to investigate children’s behavior problems in early life and subsequent development of childhood asthma through longitudinal birth cohort study in Korea.

Serum periostin among infants with severe bronchiolitis and risk of developing asthma: A prospective multicenter cohort study.

Infants hospitalized for bronchiolitis (severe bronchiolitis) are at high risk for developing childhood asthma. However, the pathobiological link between these conditions remains unclear. We examined the longitudinal relationship of periostin (an extracellular matrix protein upregulated in response to type 2 inflammation) during bronchiolitis with the subsequent development of asthma. In a 17-center prospective cohort study of infants (aged <1year) with severe bronchiolitis, we measured the serum periostin level at hospitalization and grouped infants into 3groups: low, intermediate, and high levels. We examined their association with asthma development by age 6years and investigated effect modification by allergic predisposition (eg, infant's IgE sensitization). The analytic cohort consists of 847 infants with severe bronchiolitis (median age, 3months). Overall, 28% developed asthma by age 6years. In the multivariable model adjusting for nine patient-level factors, compared to the low periostin group, the asthma risk was significantly higher among infants in the intermediate group (23% vs. 32%, OR 1.68, 95%CI 1.12-2.51, p = .01) and non-significantly higher in the high-level group (28%, OR 1.29, 95%CI 0.86-1.95, p = .22). In the stratified analysis, infants with IgE sensitization had a significantly higher risk for developing asthma (intermediate group, OR 4.76, 95%CI 1.70-13.3, p = .002; high group, OR 3.19, 95%CI 1.08-9.36, p = .04). By contrast, infants without IgE sensitization did not have a significantly higher risk (p > .15). In infants with severe bronchiolitis, serum periostin level at bronchiolitis hospitalization was associated with asthma risk by age 6years, particularly among infants with an allergic predisposition.

Nasopharyngeal metatranscriptome profiles of infants with bronchiolitis and risk of childhood asthma: a multicentre prospective study.

Bronchiolitis is not only the leading cause of hospitalisation in US infants but also a major risk factor for asthma development. Growing evidence supports clinical heterogeneity within bronchiolitis. Our objectives were to identify metatranscriptome profiles of infant bronchiolitis, and to examine their relationship with the host transcriptome and subsequent asthma development. As part of a multicentre prospective cohort study of infants (age <1 year) hospitalised for bronchiolitis, we integrated virus and nasopharyngeal metatranscriptome (species-level taxonomy and function) data measured at hospitalisation. We applied network-based clustering approaches to identify metatranscriptome profiles. We then examined their association with the host transcriptome at hospitalisation and risk for developing asthma. We identified five metatranscriptome profiles of bronchiolitis (n=244): profile A: virusRSVmicrobiomecommensals; profile B: virusRSV/RV-Amicrobiome H.influenzae ; profile C: virusRSVmicrobiome S.pneumoniae ; profile D: virusRSVmicrobiome M.nonliquefaciens ; and profile E: virusRSV/RV-Cmicrobiome M.catarrhalis . Compared with profile A, profile B infants were characterised by a high proportion of eczema, Haemophilus influenzae abundance and enriched virulence related to antibiotic resistance. These profile B infants also had upregulated T-helper 17 and downregulated type I interferon pathways (false discovery rate (FDR) <0.005), and significantly higher risk for developing asthma (17.9% versus 38.9%; adjusted OR 2.81, 95% CI 1.11-7.26). Likewise, profile C infants were characterised by a high proportion of parental asthma, Streptococcus pneumoniae dominance, and enriched glycerolipid and glycerophospholipid metabolism of the microbiome. These profile C infants had an upregulated RAGE signalling pathway (FDR <0.005) and higher risk of asthma (17.9% versus 35.6%; adjusted OR 2.49, 95% CI 1.10-5.87). Metatranscriptome and clustering analysis identified biologically distinct metatranscriptome profiles that have differential risks of asthma.

Association Between Neonatal Gut Microbiome and Infant Wheeze

Background: Asthma is a chronic respiratory disease that affects 10% of children. Infant wheeze at 1 year and the subsequent development of asthma in early childhood has been associated with infant gut dysbiosis. However, little is known about the relationship between neonatal gut microbiome and the development of wheeze during the first 18 months of life. We hypothesize that the gut microbiome at birth and throughout the first 18 months of life is associated with infant wheeze. &#x0D; Project Methods: Stool samples were collected from infants at birth, 1, 3, and 12 months of age. The Illumina Miseq system was used to sequence the bacterial V4 region of 16S-rRNA gene. Mothur software was used for analysis. Statistical analysis was used to measure stool shannon diversity and evenness as they relate to timepoint and wheeze vs no wheeze groups. &#x0D; Results: The study population consisted of 28 infants (18 males and 10 females). 11% of participants reported they had been diagnosed with wheeze by a physician (n=3). Statistical analysis of shannon diversity showed no differences in the stool between participants who wheeze vs those who do not wheeze (p=0.78). No difference in stool evenness was detected between participants who reported wheeze vs no wheeze (p=0.71). However, this analysis includes multiple timepoints. Analysis of stool shannon diversity across timepoints did show a significant difference in stool microbiome (p=0.01). &#x0D; Conclusion: No differences in stool microbiome were found between infants who do not wheeze and those who do. Further studies can investigate a greater number of samples at each timepoint and relate these to objective measures such as pulmonary function tests. Understanding the association between infant gut dysbiosis and wheeze could have implications for predicting development of asthma in early childhood and potentially lead to targeted interventions.

Maternal Smoking During Pregnancy Affects Adult Onset of Asthma in Offspring: A Follow Up From Birth to Age 46 Years

Previous evidence has revealed an effect of environmental tobacco smoke (ETS) exposure on the development of childhood asthma. However, few studies have investigated the link between prenatal ETS exposure and adult-onset asthma. Therefore, in this study, we aim to determine if an association exists between adult-onset asthma and prenatal ETS exposure. Genetic predisposition to the development of asthma was also examined in conjunction with prenatal ETS exposure.This study was comprised of mothers and their offspring who were included in the Northern Finland Birth Cohort in 1966, a total of 12053 births. Data were collected from 7148 subjects, and 5491 met the inclusion criteria. The final study population consisted of 5200 subjects.Analysis was conducted on maternal smoking status in the last 3 months of pregnancy, and asthma status was conducted at 31 and 46 years of age (n = 5200). Questionnaire data were collected from subjects at 31 and 46 years of age regarding history of asthma or wheeze to determine incident asthma between 31 and 46 years. Information regarding maternal smoking status was gathered at clinical visits via questionnaire at 6- and 7-months’ gestation. Association between the development of asthma and maternal smoking (1 or more cigarette/pipe per day) was analyzed via Pearson’s χ2 test. Maternal smoking and associated changes in forced expiratory volume in 1 second (FEV1) and the FEV1 to forced vital capacity ratio were examined by using linear regression. Binary logistic regression was used to evaluate the relationship between maternal smoking status, adult-onset asthma, and single-nucleotide polymorphisms (SNPs). Linear regression controlled for covariates including maternal education and parental asthma as well as offspring smoking status, education, ponderal index, parity, and Apgar score at first minute.Maternal smoking during the last 3 months of pregnancy was associated with an increased risk for the development of asthma in offspring between 31 and 46 years of age, and reduced offspring FEV1 to forced vital capacity ratio at 31 years of age. This association was more prominent in individuals with haplotype rs11702779-AA and with the subgroup that reported previous wheeze. No association was found between maternal smoking during the last 3 months of pregnancy and offspring FEV1 at 31 years.Gestational smoke exposure is associated with increased incidence of adult-onset asthma and reduced pulmonary function in adult offspring.The results of this study are consistent with previous research revealing an association between gestational maternal smoke exposure and the subsequent development of asthma in offspring. This reveals susceptibility of the developing airway to maternal ETS exposure and the importance of smoking cessation during pregnancy. A limitation of this study is the inability to distinguish the role of prenatal maternal smoke exposure from maternal smoking in the home during the postnatal period.

Association of Treated and Untreated Gastroesophageal Reflux Disease in the First Year of Life with the Subsequent Development of Asthma.

Introduction: Gastroesophageal reflux disease (GERD) as well as its treatment with acid-suppressive medications have been considered possible risk factors for the development of asthma, but few studies have disentangled the role of GERD with that of its treatment. The present study aimed at estimating the association of treated and untreated GERD in the first year of life with the risk of asthma. Methods: Retrospective cohort study including all children born between 2004 and 2015 registered in Pedianet, an Italian primary care database. We analyzed the association of children exposed to GERD (both treated and untreated) in the first year of life with the risk of developing clinically assessed asthma (clinical asthma) after 3 years. Secondary outcomes included asthma identified by anti-asthmatic medications (treated asthma) and wheezing after 3 years. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated comparing children with and without GERD, stratifying by treatment with acid-suppressive medications. Results: Out of 86,381 children, 1652 (1.9%) were affected by GERD in the first year of life, of which 871 (53%) were treated with acid-suppressive medications. Compared with controls, children with GERD were at increased risk of clinical asthma (HR: 1.40, 95% CI 1.15–1.70). Risks were similar between treated and untreated GERD (p = 0.41). Comparable results were found for treated asthma, but no risk increase was seen for wheezing. Discussion: Early-life GERD was associated with subsequent childhood asthma. Similar risks among children with treated and untreated GERD suggest that acid-suppressive medications are unlikely to play a major role in the development asthma.

Phenotypes of atopic dermatitis and the risk for subsequent asthma: A systematic review and meta-analysis

Various atopic dermatitis (AD) phenotypes showed an enormously heterogenic risk for subsequent asthma development. We aimed to investigate the association between AD phenotypes and the risk for progression to asthma. We searched PubMed, Embase, and Web of Science databases for relevant publications. Pooled relative risks (RR) with 95% CI were calculated using the CMA-3.0 software. This study has been registered with PROSPERO (CRD42019129273). We analyzed 39 publications with 458,810 participants. The RR for asthma in AD was 2.16 (95% CI, 1.88-2.48). The risk in persistent AD (RR, 3.36; 95% CI, 2.83-3.99) was higher than in transient AD (RR, 1.52; 95% CI, 1.34-1.73), and the risk in severe AD (RR, 2.40; 95% CI, 1.96-2.94) was higher than in mild AD (RR, 1.82; 95% CI, 1.03-3.23) or moderate AD (RR, 1.51; 95% CI, 1.30-1.75). The risk for asthma in early-onset AD was slightly higher than in late-onset AD and higher in boys than in girls. The AD and asthma definitions differed across the included studies. Patients with persistent or severe AD were at a higher risk for developing asthma. These findings further elucidate the atopic march and identify target populations for asthma prevention.