Editorial Comment on: „Short-acting β 2 -agonist use and asthma exacerbations in Swedish children: A SABINA Junior study.”Boccabella C. 1, Kalayci O. 2, Eigenmann P. 3Affiliations1Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario “A Gemelli” - IRCCS, University of the Sacred Heart, Rome, Italy2Pediatric Allergy and Asthma Unit, Hacettepe University School of Medicine, Ankara, Turkey3Pediatric Allergy Unit, Department of Women-Children-Teenagers, University Hospitals of Geneva, Geneva, SwitzerlandAsthma is one of the most common chronic lung diseases with major public health consequences for both children and adults, including high morbidity and even mortality (1). For years, standard asthma treatment for mild asthma has been as needed short acting beta agonist (SABA). Global Initiative for Asthma (GINA) guidelines have questioned this approach suggesting that the use of SABAs should always be accompanied by inhaled corticosteroids (ICSs) (2). Recently, Papi et al. have shown that in adolescents and adults with uncontrolled moderate-to-severe asthma receiving inhaled glucocorticoid-containing maintenance therapies, the risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of albuterol and budesonide than with as-needed use of albuterol alone (3). In children, on the other hand, even though many years ago Martinez et al. have shown that inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children aged 5-18 years with well controlled mild asthma , SABA has remained to be the only reliever option recommended for those under 6 years of age (4).The SABA use IN Asthma (SABINA) program in adults and adolescents with asthma reported that SABA overuse (≥3 canisters/year) is prevalent in Sweden and is associated with poor asthma-related outcomes (5). Melen et al and the SABINA Junior investigators have attempted to investigate the same question in the paediatric population (6). This retrospective cohort study conducted in Sweden, has included patients with physician-diagnosed asthma (aged 0-17 years) in secondary care. Patients have been categorized by the number of SABA canisters collected (dichotomized as 0-2 vs ≥3, based on evidence from studies in adults and adolescents) from pharmacies at baseline and followed up over 12 months (5,7). During the baseline year, SABA overuse (≥3 canisters) has been registered for the majority of the study population, particularly for those aged 0-5 years. A strong correlation between SABA overuse and increased risk of exacerbation episodes has been observed. This result confirms what has been already seen among adult patients, that is strongly connected to the inflammatory nature of asthma disease. SABAs can resolve the immediate bronchospasm but have no anti-inflammatory actions and no effect on the late phase of inflammation. Furthermore, chronic and long-term use of SABAs seems also to contribute to a decreased response to SABA therapy as a reliever (8,9). SABINA investigators have also conducted a post-hoc analysis, stratifying study population based on the presence of atopic comorbidity. Interestingly, increased SABA use has been associated with a higher exacerbation risk also in nonatopic patients with asthma. This may be due to the lack of response to ICSs that is a distinctive aspect of non-atopic population who may in turn resort to the use SABA reliever treatment.There are still several questions that remain unanswered in children mainly due to the difficulties in obtaining data in this specific population. First, recruitment of paediatric patients especially those <6 years old into randomized controlled trials (RCTs) can be a challenge due to ethical issues. In addition, diagnosis of asthma in this age group is often problematic. Despite all the limits of a retrospective study, SABINA study provides extremely useful data in a population where there are hardly any solid data. These results emphasize the need for a better understanding of childhood asthma endotypes and the response to different drugs and disease behaviour over time. Avoiding asthma exacerbations and consequent disease progression should be the principal aim of clinical management in children. This may only be possible by linking the underlying pathophysiology with the clinical response to anti-asthma treatment.References1. Asher MI, Rutter CE, Bissell K, Chiang CY, El Sony A, Ellwood E, et al. Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study. Lancet. 2021;398(10311):1569–80.2. GINA committee. Global Strategy for Asthma Management and Prevention 2022 Update [Internet]. Global Initiative for Asthma. 2022. p. 225. Available from: http://www.ginasthma.org3. Alberto Papi, M.D., Bradley E. Chipps, M.D., Richard Beasley, D.Sc., Reynold A. Panettieri, Jr., M.D., Elliot Israel, M.D., Mark Cooper, M.Sc., Lynn Dunsire, M.Sc., Allison Jeynes-Ellis, M.D., Eva Johnsson, M.D., Robert Rees, Ph.D., Christy Cappelletti, P MD. Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med [Internet]. 2022 Aug 17;387(7):662–3. Available from: https://doi.org/10.1056/NEJMc22091894. Martinez L, Handel A, Shen Y, Chakraburty S, Quinn FD, Stein CM, et al. detect tuberculosis in child contacts are urgently needed in Sub-Saharan Africa to improve case detection. n. 2018;197(9):2016–9.5. Nwaru BI, Ekström M, Hasvold P, Wiklund F, Telg G, Janson C. Overuse of short-acting β2-agonists in asthma is associated with increased risk of exacerbation and mortality: A nationwide cohort study of the global SABINA programme. Eur Respir J [Internet]. 2020;55(4). Available from: http://dx.doi.org/10.1183/13993003.01872-20196. Melen E., Nwaaru B., Wiklund F., Licht S., Telg G., Maslova E., Valk R., Tran TN, Ekstrom M. JC. Short-acting β 2 -agonist use and asthma exacerbations in Swedish children: A SABINA Junior study. Pediatr Allergy Immunol Manuscr.7. Bloom CI, Cabrera C, Arnetorp S, Coulton K, Nan C, van der Valk RJP, et al. Asthma-Related Health Outcomes Associated with Short-Acting β2-Agonist Inhaler Use: An Observational UK Study as Part of the SABINA Global Program. Adv Ther [Internet]. 2020;37(10):4190–208. Available from: https://doi.org/10.1007/s12325-020-01444-58. Lohse MJ, Benovic JL, Caron MG, Lefkowitz RJ. Multiple pathways of rapid β2-adrenergic receptor desensitization. Delineation with specific inhibitors. J Biol Chem. 1990;265(6):3202–11.9. Gauvreau GM, Jordana M, Watson RM, Cockcroft DW, O’Byrne PM. Effect of regular inhaled albuterol on allergen-induced late responses and sputum eosinophils in asthmatic subjects. Am J Respir Crit Care Med. 1997;156(6):1738–45.

Editorial to the special issue “Environmental influences on childhood asthma”Back in 1892, Sir William Osler gave an accurate description of asthma as a disease that is associated with “spasm of the bronchial muscles, inflammation of the smaller bronchioles, bizarre and extraordinary variety of circumstances and cold infections, often running in families (1,2). This is basically a true reflection of our modern understanding of asthma which states that asthma is a complex genetic disorder that involves interactions between genetic and environmental factors.Since the human genetic makeup has not changed significantly in the last couple of decades, there is reason to believe that the overall increase in asthma prevalence (3) can be attributed to the changing environmental conditions of modern life. The role of environment in asthma is not limited to its role in the pathogenesis of the disease. Since it is currently not possible to change the genetic make-up of an individual underlying a complex genetic disorder such as asthma, modification of environmental conditions emerges as a significant tool for its treatment. Therefore, understanding the environmental factors that play an important role in asthma is crucial in understanding the disease pathogenesis as well as modification of factors that modulate the inception and progress of the disease as well as its treatment.Various studies published in the last years in the journal and included in this virtual issue have addressed these questions. Garcia-Serna et al. have found out that gestational exposure to traffic-related air pollutants (TRAP) may increase the pro-inflammatory and Th2-related cytokines in newborns which might influence immune system responses later in life (4). Similarly, Pesce et al. (5) have investigated the association between prenatal exposures to heavy metals and atopic diseases. The serum concentrations of lead, cadmium and manganese were assessed in maternal blood samples collected during pregnancy and in cord blood of 651 mother-children pairs. The authors have concluded that the levels of cadmium in cord blood were associated with greater risk of asthma at the age of 8. Baek et al. have documented that exposure to phthalates are associated with airway dysfunction in childhood and this effect was partially attributable to increased serum periostin levels (6). Regarding the association between the genes and environment, Theodorou et al. (7) have investigated the role of mitogen-activated protein kinase (MAPK) pathway in 232 children who were selected from two cross-sectional cohorts and one birth cohort study. They have isolated peripheral blood mononuclear cells (PBMC) from children with asthma along with healthy controls and stimulated them with farm-dust extracts or lipopolysaccharide. The results have shown that the children with asthma have expressed significantly less dual-specificity phosphatase-1 (DUSP1) which is the negative regulator of MAPK pathway. They have conclusively indicated the possible role of DUSP1 for future therapeutical interventions regarding the anti-inflammatory features of farming environments.In an effort to further elucidate the environmental factors that are central to our understanding of asthma, the journal has started a review series to provide a comprehensive picture on the role of environment on various aspect of asthma. Major subheadings includedBiodiversityUrban exposuresGene-environment interactionsFarm effectAir pollutionClimate changeAllergensDiet microbiome and obesityIn the virtual issue of the journal Tari Haahtela (8) has focused on the effect of biodiversity. Evidence supports that the immunomodulating roles of different micro-organisms may be protective for asthma and allergic diseases. The studies from the neighboring Finnish and Russian Karelia regions, which the author named as “the living laboratory”, have shown strong evidence for the central role of environment and lifestyle which modify the human microbiome, immune balance, and thus allergy and asthma risk. Diversity of the human microbiome as well as the diversity of the natural environment that we live in and more contact with the nature are important determinants of physical health.Grant et al. (9) have focused on the influence of urban exposures on childhood asthma. The authors have meticulously summarized and analyzed the results of previous studies which aimed to investigate the interaction between indoor allergens, microbes, indoor and outdoor pollutants, social determinants and childhood asthma along with the opportunities for intervention. Multiple environmental exposures and influences contribute to the increased incidence of asthma and excess asthma morbidity among children with asthma living in urban communities. Indoor pest allergen and mold exposures have been repeatedly linked to increased asthma diagnosis, symptoms, and exacerbations in urban children. However, studies in high-risk urban populations also found that early life pest allergen exposure, along with microbial and endotoxin exposure may be associated with a decreased risk of wheezing and asthma suggesting that the association is more complex than previously thought.Since asthma prevalence varies widely depending on the socio-economical level, changes to help reduce inequities and inequalities in social determinants of health such as poverty, housing disrepair, higher rates of obesity, and chronic stress may produce positive effects at the population-level.Hernandez-Pacheco et al (10) have reviewed the latest gene-environment interaction (GxE) studies in childhood asthma. They have summarized the role of various environmental exposures and the current state of knowledge on asthma genetics. The field of GxE in asthma has drastically evolved together with technological advances over the last years. However, despite reports on the effect of numerous environmental factors on childhood asthma, the availability of detailed and diverse exposure data is limited. Tobacco smoke remains to be the most accessible and extensively explored factor followed by traffic-related air pollution in GxE studies.Airway epithelium seems to be central in gene-environment interactions. The effect of the exposure to certain environmental factors early in life on the modification of the risk and severity of asthma later in childhood is partially dependent on the functionality and integrity of the airway epithelium. It is known that the environmental exposures can trigger an inflammatory response and the disruption of the barrier and mucociliary function.Although there are several methodological and conceptual challenges with GxE interaction studies, recent data have led to new insights into childhood asthma pathophysiology which is best exemplified by the 17q12-21 asthma locus. Some of the SNPs at this locus seem to be associated with the onset of childhood asthma, thereby highlighting the importance of age related factors in gene environment interactions.The need for longitudinal and functional studies which provide insights into the biological mechanisms underlying the observed associations between environmental exposures and epigenetic changes that modify the asthma risk is highlighted.Another extensively studied environmental factor that is associated with childhood as is the so called “farm effect”. Frei et al. (11) have summarized the current knowledge on how “farm effect” influences the immune homeostasis during the intrauterine period and in childhood with a focus on immune mechanisms induced by environmental microbial diversity and microbial components. Farming lifestyle factors including nutrition influence the immune homeostasis either by regulating the innate immune system or by induction of regulatory T cells or TH1. We see diversity as a significant factor also in the farm effect. Diversity of environmental microbes, the diversity of the gut microbiome, or the diversity of the nutrition emerge as significant factors.Paciencia et al. (12) investigated the association and mechanisms between air pollution and asthma in children along with the precautions that should be taken to reduce the burden of air pollution on asthma. Environmental conditions are not shared equally across the populations, regions, and settings where people live, work, and spend their time. Urban conditions and air quality are not only important features for national and local authorities to shape healthy cities and protect their citizens from environmental and health risks, but they also provide opportunities to mitigate inequalities in the most deprived areas where the environmental burden is highest. Actions to avoid exposure to indoor and outdoor air pollutants should be complementary at different levels –individual, local, and national levels – to take strong measures to protect children.Taken together, these reviews provide a very comprehensive coverage on the role of environmental factors on childhood asthma and suggest that efforts to modify these factors may have beneficial effects not only on the individual level but also at the population level.S. Tolga Yavuz1Ömer Kalayci2Philippe A. Eigenmann3

Background: Childhood allergic rhinitis (AR) is clinically highly heterogeneous. We aimed to identify distinct subgroups amongst children with AR, and to ascertain their association with patterns of symptoms, allergic sensitization and concomitant physician-diagnosed asthma. Methods: We recruited 510 children with physician-diagnosed AR, of whom 205 (40%) had asthma. Latent class analysis (LCA) was performed to identify latent structure within the data set using 17 variables (allergic conjunctivitis, eczema, asthma, family history of asthma, family history of allergic rhinitis, skin sensitization to 8 common allergens, tonsillectomy, adenoidectomy). Results: A four−class solution was selected as the optimal model based on statistical fit. We labeled AR latent classes as: (1) AR with grass mono-sensitization and conjunctivitis (n=361, 70.8%); (2) AR with house dust mite sensitization and asthma (n=75, 14.7%); (3) AR with pet and grass polysensitization and conjunctivitis (n=35, 6.9%) and (4) AR among children with tonsils and adenoids removed (n=39, 7.6%). Perennial AR was significantly more common among children in Class 2 (OR 5.83, 95%CI 3.42−9.94, p<0.001) and Class 3 (OR 2.88, 95%CI 1.36−6.13, p=0.006). Mild and intermittent AR symptoms were significantly more common in children in Class 3 compared to those in Class 1. AR was more severe in Class 1, compared to other 3 classes, indicating that upper respiratory symptoms are more severe among children with isolated seasonal rhinitis, than in those with rhinitis and coexisting asthma. Conclusion: We have identified 4 phenotypes in school-age children with AR, which were associated with different patterns of clinical symptoms and comorbidities.

Montelukast therapy in asthmatic children with and without food allergyUmit Murat Sahiner1*, Ebru Arik Yilmaz1*, Sara Fontanella2, Sadia Haider2, Ozge Soyer1, Adnan Custovic2, Omer Kalayci1, Cansin Sackesen1,3*Equal contribution1 Hacettepe University School of Medicine, Division of Pediatric Allergy, Ankara, Turkey2 National Heart and Lung Institute, Imperial College London, UK3 Koc University School of Medicine, Division of Pediatric Allergy, Istanbul TukeyRunning Title: Montelukast in asthma and food allergyFunding Source: The study drugs, placebos and laboratory kits were provided by Merck Sharpe and Dohme Company. The protocol was developed by the corresponding author Prof Cansin Sackesen and reviewed by Merck Sharpe and Dohme Company. However, there is no contribution of Merck Sharpe and Dohme Company to the results and discussion of the article.Conflicts of Interest: The authors declare no conflicts of interest in relation to this study.