Pediatric asthma comorbidities: Global impact and unmet needs.

Real-world data on the range and impact of comorbid health conditions that affect pediatric asthma are scant, especially from developing countries. Lack of data hinders effective diagnosis, treatment, and overall management of these complex cases. We, hereby, describe the common pediatric asthma comorbid conditions in terms of evidence for association, potential mechanisms of impact on asthma control, and treatment benefit. Obesity, upper airway allergies, dysfunctional breathing, multiple sensitizations, depressive disorders, food allergy, and gastro-esophageal reflux are common associations with difficult-to-treat asthma. On the other hand, asthma symptoms and/or management may negatively impact the well-being of children through drug adverse effects, worsening of anaphylaxis symptoms, and disturbing mental health. Awareness of these ailments may be crucial for designing the optimum care for each asthmatic child individually and may ultimately improve the quality of life of patients and their families. A multidisciplinary team of physicians is required to identify and manage such comorbidities aiming to mitigate the over-use of asthma pharmacotherapy. Asthma research should target relevant real-world difficulties encountered at clinical practice and focus on interventions that would mitigate the impact of such comorbidities. Finally, policymakers and global healthcare organizations are urged to recognize pediatric asthma control as a healthcare priority and allocate resources for research and clinical interventions. In other words, global asthma control needs support by compassionate scientific partnership.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Telemedicine with special focus on allergic diseases and asthma-Status 2022: An EAACI position paper.

Efficacious, effective and efficient communication between healthcare professionals (HCP) and patients is essential to achieve a successful therapeutic alliance. Telemedicine (TM) has been used for decades but during the COVID-19 pandemic its use has become widespread. This position paper aims to describe the terminology and most important forms of TM among HCP and patients and review the existing studies on the uses of TM for asthma and allergy. Besides, the advantages and risks of TM are discussed, concluding that TM application reduces costs and time for both, HCP and patients, but cannot completely replace face-to-face visits for physical examinations and certain tests that are critical in asthma and allergy. From an ethical point of view, it is important to identify those involved in the TM process, ensure confidentiality and use communication channels that fully guarantee the security of the information. Unmet needs and directions for the future regarding implementation, data protection, privacy regulations, methodology and efficacy are described.

Unanswered questions on the use of biologics in pediatric asthma.

The emergence of biologic therapies for the management of asthma has been a revolutionary change in our capacity to manage this disease. Since the launch of omalizumab, several other biologics have been marketed or are close to being marketed, suggesting that a plethora of monoclonal antibodies can be expected in the coming years. This will facilitate the transition to the paradigm of personalized medicine, but on the other hand will decisively further complicate the choice of the most appropriate treatment, in the absence of reliable enough biological markers. For these reasons, along with the relatively short time of use with these treatments, there are recurrently arising questions for which there are not even moderately documented answers, and for which the only solution must be based, with all reservations, on the combination of indirect evidence and expertise. In this paper, we attempt to address such questions, providing relevant commentaries and considering the whole width of the evidence base.

Oxidative stress stimulation leads to cell-specific oxidant and antioxidant responses in airway resident and inflammatory cells.

AIMS: The imbalance between reactive oxygen species (ROS) and the antioxidant response has been linked to various airway diseases, including asthma. However, knowledge on cell-specific responses of the airway resident and inflammatory cells against increased oxidant stress is very limited. We aim to better understand the cell-specific antioxidant response that contributes to the pathophysiology of lung disease in response to oxidative stress. MATERIALS AND METHODS: The human cell lines of epithelial, fibroblast, endothelial, monocyte, eosinophil and neutrophil were incubated with tert-butyl hydroperoxide (tBHP) or cigarette smoke condensate (CSC). Following stimulation, cell viability, total oxidant and antioxidant activity were assessed in both residential and inflammatory cells. Human Oxidative Stress Plus RT2 Profiler PCR array was used to determine 84 gene expression differences in oxidant and antioxidant pathways following oxidant stimulus in all cells. KEY FINDINGS: We showed that various cell types respond differently to oxidative stress inducers, with distinct gene expression and oxidant-antioxidant generation. Most importantly, eosinophils increased the activity of all main antioxidant enzymes in response to both oxidants. Monocytes, on the other hand, showed no change in response to each stimulation, whereas neutrophils only increased their CAT activity in response to both stimuli. The increase in NRF2-regulated genes HSPA1A, HMOX1 and DUSP1 after both tBHP and CSC in epithelial cells and fibroblasts indicates Nfr2 pathway activation. SIGNIFICANCE: This study advances our knowledge of the molecular and cellular mechanisms of cell-specific antioxidant response upon exposure to oxidative stress. Additionally, our observations imply that the eosinophils' distinct biological response may be utilized for endotype-based cell-targeted antioxidant therapy.

Allergic diseases and immunodeficiencies in children, lessons learnt from COVID-19 pandemic by 2022: A statement from the EAACI-section on pediatrics.

By the April 12, 2022, the COVID-19 pandemic had resulted in over half a billion people being infected worldwide. There have been 6.1 million deaths directly due to the infection, but the pandemic has had many more short- and long-term pervasive effects on the physical and mental health of the population. Allergic diseases are among the most prevalent noncommunicable chronic diseases in the pediatric population, and health-care professionals and researchers were seeking answers since the beginning of pandemic. Children are at lower risk of developing severe COVID-19 or dying from infection. Allergic diseases are not associated with a higher COVID-19 severity and mortality, apart from severe/poorly controlled asthma. The pandemic disrupted routine health care, but many mitigation strategies, including but not limited to telemedicine, were successfully implemented to continue delivery of high-standard care. Although children faced a multitude of pandemic-related issues, allergic conditions were effectively treated remotely while reduction in air pollution and lack of contact with outdoor allergens resulted in improvement, particularly respiratory allergies. There is no evidence to recommend substantial changes to usual management modalities of allergic conditions in children, including allergen immunotherapy and use of biologicals. Allergic children are not at greater risk of multisystem inflammatory syndrome development, but some associations with Long COVID were reported, although the data are limited, and further research is needed. This statement of the EAACI Section on Pediatrics provides recommendations based on the lessons learnt from the pandemic, as available evidence.

The role of environmental allergen control in the management of asthma.

Allergen exposure may exacerbate asthma symptoms in sensitized patients. Allergen reduction or avoidance measures have been widely utilized; however, there is ongoing controversy on the effectiveness of specific allergen control measures in the management of children with asthma. Often, allergen avoidance strategies are not recommended by guidelines because they can be complex or burdensome, although individual patients may benefit. Here we explore the potential for intervention against exposure to the major allergens implicated in asthma (ie, house dust mites, indoor molds, rodents, cockroaches, furry pets, and outdoor molds and pollens), and subsequent effects on asthma symptoms. We critically assess the available evidence regarding the clinical benefits of specific environmental control measures for each allergen. Finally, we underscore the need for standardized and multifaceted approaches in research and real-life settings, which would result in the identification of more personalized and beneficial prevention strategies.

The Expression Profile of Protease Inhibitors in the Airway Epithelial Cells after Allergen (Der p 1) Stimulation.

BACKGROUND: Airway epithelial cells are constantly exposed to intracellular and extracellular proteases that play a pivotal role in several airway diseases. Dermatophagoides pteronyssinus (Der p) 1 derived from house dust mite has protease activity that causes epithelial barrier defect and inflammatory response. Protease inhibitors released against proteases are involved in the maintenance of homeostasis. A disruption of the balance between proteases and protease inhibitors can lead to distortion of the cellular structures and cellular activities and thus culminate in disease processes. Although the effects of Der p 1 allergen on epithelial barrier integrity and inflammatory response are well-established, its contribution to protease inhibitor production is highly limited. OBJECTIVE: This study aimed to determine the profile of the protease inhibitor response to Der p 1 allergen in human airway epithelial cells, A549 and BEAS-2B. METHODS: Differentiated cells by the air-liquid interface were exposed to Der p 1 with or without Th2 type cytokines (IL-4 and IL-13). Gene expression of protease inhibitors was determined by qPCR at 2 different time points. RESULTS: We found that the effect of allergen exposure on the protease inhibitor profile can vary depending on the antigen concentration, treatment duration, and the presence or absence of type 2 cytokines. Gene expressions of serine protease inhibitor (SERPIN)B3 and SERPINB4 were increased following Th2 cytokine stimulation in both cell types at both time points, whereas SERPINB2 and TFPI-2 expressions were induced by 24-h Der p 1 stimulation in both cells. CONCLUSIONS: Our study suggests that Der p 1 exposure of the airway epithelium may have consequences related to its protease activity in the presence as well as in the absence of Th2 cytokines in the microenvironment.

House dust mite-derived allergens effect on matrix metalloproteases in airway epithelial cells.

Aim of the Study: Many allergens have protease activities. Although the immunomodulatory effects of these antigens are well known, the effects attributed to their protease activities are not thoroughly investigated. We set out to determine the effects of house dust mite (HDM) allergens with varying protease activities on bronchial epithelial cell functions. Materials and methods: BEAS-2B cells were maintained in ALI-culture and stimulated with Der p1 (cysteine protease), Der p6 (serine protease), and Der p2 (non-protease) with and without specific protease inhibitors or heat denaturation. Cell viability and epithelial permeability were measured with MTT and paracellular flux assay, respectively. The effect of heat denaturation on allergen structure was examined using in silico models. Matrix metalloproteinases (MMPs) were investigated at the transcription (qPCR), protein (ELISA), and functional (zymography) levels. Results: Epithelial permeability increased only after Der p6 but not after Der p1 or Der p2 stimulation. Der p2 increased both MMP-2 and MMP-9 expression, while Der p1 increased only MMP-9 expression. The heat-denatured form of Der p1 unexpectedly increased MMP-9 gene expression, which, through the use of in silico models, was attributed to its ability to change receptor connections by the formation of new electrostatic and hydrogen bonds. IL-8 and GM-CSF production were increased after Der p1 and Der p2 but decreased after Der p6 stimulation. IL-6 decreased after Der p1 but increased following stimulation with Der p6 and heat-denatured Der p2. Conclusion: Allergens in house dust mites are capable of inducing various changes in the epithelial cell functions by virtue of their protease activities.