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Background Objective measures are required that may be used as a proxy for exacerbations in asthma. The aim was to determine the sensitivity and specificity of electronic diary data to detect severe exacerbations (SEs) of asthma. A secondary aim was to identify phenotypic variables associated with a higher risk of exacerbation. Methods In the BIOAIR study, 169 patients with asthma (93 severe (SA); 76 mild to moderate (MA)) recorded lung function, symptoms and medication use in electronic diaries for 1 year. Data were analysed using receiver-operator characteristics curves and related to physician-diagnosed exacerbations. Medical history and baseline clinical data were used to assess risk of exacerbation. Results Of 122 physician-diagnosed exacerbations, 104 occurred in the SA group (1.1 per patient/year), 18 in the MA group (0.2 per patient/year) and 63 were severe using American Thoracic Society/European Respiratory Society criteria. During exacerbations, peak expiratory flow (PEF) and forced expiratory volume in 1 s significantly decreased, whereas day and night symptoms significantly increased. An algorithm combining a 20% decrease in PEF or a 20% increase in day symptoms on 2 consecutive days was able to detect SEs with 65% sensitivity and 95% specificity. The strongest risk factors for SEs were low Asthma Control Questionnaire score, sputum eosinophils =3%, body mass index >25 and low quality of life (St George's Respiratory Questionnaire), with ORs between 3.61 and 2.22 ( p<0.05). Conclusions Regular electronic monitoring of PEF and asthma symptoms provides an acceptable sensitivity and specificity for the detection of SEs and may be suitable for personal internet-based monitoring of asthma control. [ABSTRACT FROM AUTHOR]

Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods We performed a randomised double-blind placebo-controlled trial in subjects with exacerbationprone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting ß2 agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with noneosinophilic severe asthma (blood eosinophilia =200/µl): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study. [ABSTRACT FROM AUTHOR]

Background: Accurate interpretation of lung function testing requires appropriate reference values. Unfortunately, few African countries have produced spirometric reference values for their populations. Objectives: The present study was carried out in order to establish normal lung function values for subjects living in Rwanda, East Africa. Methods: The study was conducted in Kigali, capital of Rwanda, and in the rural district of Huye in southern Rwanda. The variables studied were forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow. Multiple regression analysis was performed using age, height, weight and BMI as independent variables to obtain predicted equations for both sexes. Results: Predicted equations for normal lung functions were obtained from 740 healthy nonsmoking subjects; 394 were females and 346 were males. Minor differences in FEV1 and FVC were observed in comparison with other studies of Africans, African-Americans (difference in FEV1 and FVC of less than 5%), Chinese and Indians. When compared with selected studies from Caucasians and white Americans, our results for FEV1 and FVC were 9-12% and 16-18% lower in men and 12-23% and 17-28% lower in women, respectively. Conclusions: This study provides reference values for pulmonary function in a healthy, nonsmoking Rwandan population and enables comparisons to be made with other prediction equations from other populations. Spirometric reference values in our study were similar to those obtained in a study of black Americans by Hankinson et al. [ABSTRACT FROM AUTHOR]

Background: The inhalation of diesel exhaust particles (DEPs) is associated with increased sensitization toward inhaled allergens. Dendritic cells (DCs) are important mediators in immune regulation. We previously showed that the inhalation of DEPs increased the accumulation of DCs in the lung and enhanced the TH2 response in the mediastinal lymph node. Objective: We hypothesized that CC chemokine receptors CCR2, CCR5, and CCR6 critically mediate the DC recruitment upon exposure to DEPs and that these CC chemokine receptors are important in the DEP-induced TH2 response. Methods: We exposed CCR2 knockout, CCR5 knockout, CCR6 knockout, and wild-type mice to DEPs and examined the pulmonary monocyte and DC accumulation. By an adoptive transfer experiment, we assessed the direct involvement of CCR2 and CCR6 in the recruitment of blood monocytes toward the lung upon exposure to DEPs. We also examined the TH2 cytokine production in the mediastinal lymph nodes of DEP-exposed CCR2 knockout and CCR6 knockout mice. Results: We observed that the DEP-induced monocyte and monocyte-derived DC recruitment was completely abolished in CCR2 knockout mice. CCR6 knockout mice also showed impaired monocyte recruitment upon exposure to DEPs. In contrast, monocyte and DC recruitment was comparable between DEP-exposed wild-type and CCR5 knockout mice. The impaired monocyte-derived DC recruitment in DEP-exposed CCR2 knockout, not CCR6 knockout, mice resulted in an abolished TH2 response in the mediastinal lymph node. Conclusion: These data suggest that monocyte-derived DCs, recruited in a CCR2-dependent manner, are critical in inducing TH2 responses upon inhalation of DEPs. [ABSTRACT FROM AUTHOR]

The article presents a study which evaluates the feasibility and effectiveness of pulmonary rehabilitation in restrictive lung diseases (RLD) patients. It states that patients participated in a 24-week outpatient rehabilitation program and various factors including pulmonary function, muscle force, and dyspnea were measured at inclusion after the program. It is found that the rehabilitation leads to relevant improvements on the said factors and patients respond well to it.

Background: Cigarette smoke (CS) is known to initiate a cascade of mediator release and accumulation of immune and inflammatory cells in the lower airways. We investigated and compared the effects of CS on upper and lower airways, in a mouse model of subacute and chronic CS exposure. Methods: C57BL/6 mice were whole-body exposed to mainstream CS or air, for 2, 4 and 24 weeks. Bronchoalveolar lavage fluid (BAL) was obtained and tissue cryosections from nasal turbinates were stained for neutrophils and T cells. Furthermore, we evaluated GCP-2, KC, MCP-1, MIP-3α, RORc, IL-17, FoxP3, and TGF-β1 in nasal turbinates and lungs by RT-PCR. Results: In both upper and lower airways, subacute CS-exposure induced the expression of GCP-2, MCP-1, MIP-3α and resulted in a neutrophilic influx. However, after chronic CS-exposure, there was a significant downregulation of inflammation in the upper airways, while on the contrary, lower airway inflammation remained present. Whereas nasal FoxP3 mRNA levels already increased after 2 weeks, lung FoxP3 mRNA increased only after 4 weeks, suggesting that mechanisms to suppress inflammation occur earlier and are more efficient in nose than in lungs. Conclusions: Altogether, these data demonstrate that CS induced inflammation may be differently regulated in the upper versus lower airways in mice. Furthermore, these data may help to identify new therapeutic targets in this disease model. [ABSTRACT FROM AUTHOR]

Background: The tachykinins, substance P and neurokinin A, present in sensory nerves and inflammatory cells such as macrophages and dendritic cells, are considered as pro-inflammatory agents. Inflammation of the airways and lung parenchyma plays a major role in the pathogenesis of chronic obstructive pulmonary disease (COPD) and increased tachykinin levels are recovered from the airways of COPD patients. The aim of our study was to clarify the involvement of the tachykinin NK1 receptor, the preferential receptor for substance P, in cigarette smoke (CS)-induced pulmonary inflammation and emphysema in a mouse model of COPD. Methods: Tachykinin NK1 receptor knockout (NK1-R-/-) mice and their wild type controls (all in a mixed 129/sv-C57BL/6 background) were subjected to sub acute (4 weeks) or chronic (24 weeks) exposure to air or CS. 24 hours after the last exposure, pulmonary inflammation and development of emphysema were valuated. Results: Sub acute and chronic exposure to CS resulted in a substantial accumulation of inflammatory cells in the airways of both WT and NK1-R-/- mice. However, the CS-induced increase in macrophages and dendritic cells was significantly impaired in NK1-R-/- mice, compared to WT controls, and correlated with an attenuated release of MIP-3α/CCL20 and TGF-β1. Chronic exposure to CS resulted in development of pulmonary emphysema in WT mice. NK1-R-/- mice showed already enlarged airspaces upon air-exposure. Upon CS-exposure, the NK1-R-/- mice did not develop additional destruction of the lung parenchyma. Moreover, an impaired production of MMP-12 by alveolar macrophages upon CS-exposure was observed in these KO mice. In a pharmacological validation experiment using the NK1 receptor antagonist RP 67580, we confirmed the protective effect of absence of the NK1 receptor on CS-induced pulmonary inflammation. Conclusion: These data suggest that the tachykinin NK1 receptor is involved in the accumulation of macrophages and dendritic cells in the airways upon CS-exposure and in the development of smoking-induced emphysema. As both inflammation of the airways and parenchymal destruction are important characteristics of COPD, these findings may have implications in the future treatment of this devastating disease. [ABSTRACT FROM AUTHOR]

Measures of bronchial responsiveness are widely used for the diagnosis and monitoring of asthma. A vast array of non-specific bronchoconstrictor stimuli is available. Methacholine and histamine cause airflow limitation predominantly through a direct effect on airway smooth muscle. Indirect challenges (adenosine, exercise and hypertonic saline) induce airflow limitation by an action on cells other than smooth muscle cells, with a variety of cells, mediators and receptors being involved in this process. Bronchial responsiveness to a direct stimulus is only weakly related to airway inflammation, whereas indirect airway challenges might better reflect active airway inflammation. Both direct and indirect airway challenges are useful outcome parameters in clinical studies of asthma. For example, an indirect challenge responds to treatment with inhaled steroids within hours to days, whereas improvement in direct responsiveness might take months to years. Bronchial challenges are also an essential step in the development of new anti-asthma treatments, such as adenosine or tachykinin receptor antagonists. [Copyright &y& Elsevier]

Since novel treatments to target eosinophilic inflammation in Type 2 asthma are emerging, we aimed to evaluate and meta-analyze the efficacy of monoclonal antibodies to reduce exacerbation rate. PubMed and Web of Science were searched for phase II and phase III randomized clinical trials with monoclonal antibodies targeting key mediators of type 2-associated asthma. Thirty trials were selected involving biologics that target the IL-5 pathway, IL-13, the common IL-4 and IL-13 receptor, IL-9, IL-2 and TSLP. As no head-to-head trials were retrieved from literature, we performed an arm-based network meta-analysis to compare effects on exacerbation rate between the different treatments.Mepolizumab, reslizumab and benralizumab significantly reduced the risk of exacerbations compared to placebo (by 47-52%, 50-60%, and 28-51% respectively). Reslizumab and benralizumab also improved lung function. Dupilumab and tezepelumab improved lung function in frequent exacerbators. Lebrikizumab had no significant effect on the number of exacerbations, symptom control or health-related quality of life. Tralokinumab improved lung function compared to placebo. Network meta-analysis of all treatment and placebo arms, showed no superiority of one biologic over the others. Large reductions in exacerbation rates were observed compared to placebo, though only benralizumab was sufficiently powered (n = 2051) to demonstrate significantly decreased exacerbation rates in the subgroup analysis of IL-5 acting agents compared to placebo.Monoclonal antibodies such as mepolizumab, reslizumab and benralizumab have proven their benefit to reduce exacerbation rates in severe persistent eosinophilic asthma in the published trials. However, no statistically significant superiority was observed of one biologic over the other in the network meta-analysis. More studies with direct head to head comparisons and better defined endotypes are required. [ABSTRACT FROM AUTHOR]

Background Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. Objective We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Methods Wild-type, Gata-3 +/nlslacZ (Gata-3–haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 −/− mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Results Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 −/− mice. Conclusion These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. [ABSTRACT FROM AUTHOR]

Since microRNA (miR)-223-3p modulates inflammatory responses and chronic obstructive pulmonary disease (COPD) is associated with amplified pulmonary inflammation, we hypothesized that miR-223-3p plays a role in COPD pathogenesis. Expression of miR-223-3p was measured in lung tissue of two independent cohorts with patients with GOLD stage II-IV COPD, never smokers, and smokers without COPD. The functional role of miR-223-3p was studied in deficient mice and on overexpression in airway epithelial cells from COPD and controls. We observed higher miR-223-3p levels in patients with COPD stage II-IV compared with (non)-smoking controls, and levels were associated with higher neutrophil numbers in bronchial biopsies of patients with COPD. MiR-223-3p expression was also increased in lungs and bronchoalveolar lavage of cigarette smoke (CS)-exposed mice. CS-induced neutrophil and monocyte lung infiltration was stronger in miR-223-deficient mice on acute (5 days) exposure, but attenuated on subchronic (4 wk) exposure. Additionally, miR-223 deficiency attenuated acute and subchronic CS-induced lung infiltration of dendritic cells and T lymphocytes. Finally, in vitro overexpression of miR-223-3p in non-COPD airway epithelial cells suppressed C-X-C motif chemokine ligand 8 (CXCL8) and granulocyte monocyte-colony stimulation factor (GM-CSF) secretion and gene expression of the proinflammatory transcription factor TRAF6. Importantly, this suppressive effect of miR-223-3p was compromised in COPD-derived cultures. In conclusion, we demonstrate that miR-223-3p is increased in lungs of patients with COPD and CS-exposed mice and is associated with neutrophilic inflammation. In vivo data indicate that miR-223 acts as negative regulator of acute CS-induced neutrophilic and monocytic inflammation. In vitro data suggest that miR-223-3p does so by suppressing proinflammatory airway epithelial responses, which is less effective in COPD epithelium. [ABSTRACT FROM AUTHOR]

Objectives: Innate lymphoid cells (ILCs) secrete cytokines, such as IFN‐γ, IL‐13 and IL‐17, which are linked to chronic obstructive pulmonary disease (COPD). Here, we investigated the role of pulmonary ILCs in COPD pathogenesis. Methods: Lung ILC subsets in COPD and control subjects were quantified using flow cytometry and associated with clinical parameters. Tissue localisation of ILC and T‐cell subsets was determined by immunohistochemistry. Mice were exposed to air or cigarette smoke (CS) for 1, 4 or 24 weeks to investigate whether pulmonary ILC numbers and activation are altered and whether they contribute to CS‐induced innate inflammatory responses. Results: Quantification of lung ILC subsets demonstrated that ILC1 frequency in the total ILC population was elevated in COPD and was associated with smoking and severity of respiratory symptoms (COPD Assessment Test [CAT] score). All three ILC subsets localised near lymphoid aggregates in COPD. In the COPD mouse model, CS exposure in C57BL/6J mice increased ILC numbers at all time points, with relative increases in ILC1 in bronchoalveolar lavage (BAL) fluid. Importantly, CS exposure induced increases in neutrophils, monocytes and dendritic cells that remained elevated in Rag2/Il2rg‐deficient mice that lack adaptive immune cells and ILCs. However, CS‐induced CXCL1, IL‐6, TNF‐α and IFN‐γ levels were reduced by ILC deficiency. Conclusion: The ILC1 subset is increased in COPD patients and correlates with smoking and severity of respiratory symptoms. ILCs also increase upon CS exposure in C57BL/6J mice. In the absence of adaptive immunity, ILCs contribute to CS‐induced pro‐inflammatory mediator release, but are redundant in CS‐induced innate inflammation. [ABSTRACT FROM AUTHOR]

Suppression of airway inflammation with inhaled corticosteroids has been the key therapeutic approach for asthma for many years. Identification of inflammatory phenotypes in asthma has moreover led to important breakthroughs, e.g. with specific targeting of the IL-5 pathway as add-on treatment in difficult-to-treat eosinophilic asthma. However, the impact of interfering with the neutrophilic component in asthma is less documented and understood. This review provides an overview of established and recent insights with regard to the role of neutrophils in asthma, focusing on research in humans. We will describe the main drivers of neutrophilic responses in asthma, the heterogeneity in neutrophils and how they could contribute to asthma pathogenesis. Moreover we will describe findings from clinical trials, in which neutrophilic inflammation was targeted. It is clear that neutrophils are important actors in asthma development and play a role in exacerbations. However, more research is required to fully understand how modulation of neutrophil activity could lead to a significant benefit in asthma patients with airway neutrophilia. [ABSTRACT FROM AUTHOR]

Increased expression of pulmonary ACE2, the SARS-CoV-2 receptor, could contribute to increased infectivity of COVID-19 in patients with diabetes, but ACE2 expression has not been studied in lung tissue of subjects with diabetes. We therefore studied ACE2 mRNA and protein expression in lung tissue samples of subjects with and without diabetes that were collected between 2002 and 2020 from patients undergoing lobectomy for lung tumors. For RT-PCR analyses, samples from 15 subjects with diabetes were compared with 91 randomly chosen control samples. For immunohistochemical staining, samples from 26 subjects with diabetes were compared with 66 randomly chosen control samples. mRNA expression of ACE2 was measured by quantitative RT-PCR. Protein levels of ACE2 were visualized by immunohistochemistry on paraffin-embedded lung tissue samples and quantified in alveolar and bronchial epithelium. Pulmonary ACE2 mRNA expression was not different between subjects with or without diabetes. In contrast, protein levels of ACE2 were significantly increased in both alveolar tissue and bronchial epithelium of patients with diabetes compared with control subjects, independent of smoking, chronic obstructive pulmonary disease, BMI, renin-angiotensin-aldosterone system inhibitor use, and other potential confounders. To conclude, we show increased bronchial and alveolar ACE2 protein expression in patients with diabetes. Further research is needed to elucidate whether upregulation of ACE2 expression in airways and lungs has consequences on infectivity and clinical outcomes of COVID-19. [ABSTRACT FROM AUTHOR]

Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2‐targeting biologics such as anti‐IgE, anti‐IL4Rα, anti‐IL5, and anti‐IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma. [ABSTRACT FROM AUTHOR]

Background. Middle East respiratory syndrome coronavirus (MERS-CoV) causes pneumonia with a relatively high case fatality rate in humans. Smokers and chronic obstructive pulmonary disease (COPD) patients have been reported to be more susceptible to MERS-CoV infection. Here, we determined the expression of MERS-CoV receptor, dipeptidyl peptidase IV (DPP4), in lung tissues of smokers without airflow limitation and COPD patients in comparison to nonsmoking individuals (never-smokers). Methods. DPP4 expression was measured in lung tissue of lung resection specimens of never-smokers, smokers without airflow limitation, COPD GOLD stage II patients and in lung explants of end-stage COPD patients. Both control subjects and COPD patients were well phenotyped and age-matched. The mRNA expression was determined using qRT-PCR and protein expression was quantified using immunohistochemistry. Results. In smokers and subjects with COPD, both DPP4 mRNA and protein expression were significantly higher compared to never-smokers. Additionally, we found that both DPP4 mRNA and protein expression were inversely correlated with lung function and diffusing capacity parameters. Conclusions. We provide evidence that DPP4 is upregulated in the lungs of smokers and COPD patients, which could partially explain why these individuals are more susceptible to MERS-CoV infection. These data also highlight a possible role of DPP4 in COPD pathogenesis. [ABSTRACT FROM AUTHOR]

Background An important percentage of subjects diagnosed with chronic upper airway disease report alcohol-induced worsening of their symptoms. The prevalence and characteristics of respiratory reactions provoked by alcohol-containing drinks have not been fully investigated yet. Objective The aim of this study was to estimate the prevalence and characteristics of alcohol hyper-responsiveness in patients with chronic airway disease and healthy controls. Furthermore, nasal inflammation was evaluated in nasal polyp patients with and without hyper-responsiveness. Methods We evaluated the prevalence and characteristics of alcohol-induced respiratory complaints in 1281 subjects. Chronic rhinosinusitis with nasal polyps (CRSwNP) patients with and without NSAID exacerbated respiratory disease (NERD), chronic rhinosinusitis patients without nasal polyps (CRSsNP), allergic rhinitis (AR) patients and healthy controls were approached by means of a questionnaire. Inflammatory markers (eosinophilic cationic protein (ECP), IL-5, IgE, SAE-specific IgE, IL-17, TNFα and IFNγ) in tissue were then compared between alcohol hyper-responsive and non-hyper-responsive CRSwNP patients. Results The highest prevalence of nasal and bronchial alcohol hyper-responsiveness was observed in patients with NERD, followed by CRSwNP, and less frequent in CRSsNP, AR and healthy controls. Alcohol hyper-responsiveness is significantly more prevalent in CRSwNP patients suffering from recurrent disease and in patients with severe symptomatology. In nasal tissue of the hyper-responsive CRSwNP group, we observed significantly higher nasal levels of the eosinophilic biomarker ECP. Conclusion and Clinical Relevance Nasal hyper-responsiveness to alcohol is significantly more prevalent in severe eosinophilic upper airway disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: Chronic obstructive pulmonary disease (COPD) arises from an interaction between genetic host factors and environmental exposures (mainly cigarette smoke (CS)). Genome Wide Association studies have demonstrated that genetic variations in the gene encoding 5-hydroxytryptamine 4 receptors (5-HT4R), HTR4, were associated with measures of airway obstruction and with COPD. We hypothesised that 5-HT4 receptors, in addition to 5-HT2AR and muscarinic receptors, contribute to the pathogenesis of COPD by facilitating cholinergic bronchoconstriction. Methods: The levels of pulmonary 5-HT4R mRNA were measured in CS-exposed mice by qRT-PCR. We investigated the effect of CS exposure on bronchial hyperresponsiveness (BHR) to 5-HT and evaluated the contribution of 5-HT2AR, muscarinic receptors and 5-HT4R in the response to 5-HT by using the corresponding antagonists and 5-HT4R knockout (KO) mice. Results: The 5-HT4R mRNA levels were significantly elevated upon acute (3 days), subacute (4 weeks) and chronic (24 weeks) CS exposure. Both acute and subacute CS exposure significantly increased BHR to 5-HT. Antagonism of 5-HT2AR abolished the CS-induced BHR to 5-HT, and antagonism of muscarinic receptors significantly reduced the response to 5-HT. However, pre-treatment with GR113808, a specific 5-HT4R antagonist, did not alter the response to 5-HT in CS-exposed mice. Accordingly, the CS-induced BHR to 5-HT was not different between wild-type and 5-HT4R KO mice. Conclusion: CS increased the levels of 5-HT4R mRNA in the lungs, concomitantly with bronchial responsiveness to 5-HT. Our in vivo data using pharmacologic and genetic approaches suggest that 5-HT4 receptors are not involved in the BHR to 5-HT in CS-exposed mice. [Copyright &y& Elsevier]

Abstract: Neuroimmune interactions are important in airway diseases such as asthma. We evaluated the role of the tachykinin NK1 receptor in the contractile response of isolated trachea from tachykinin NK1 receptor wild type (WT) and knockout (KO) mice, to the antigen ovalbumin and the contractile agonist serotonin (5-hydroxytryptamine). One percent ovalbumin induced contractions of tracheas obtained from ovalbumin-immunized and exposed mice. The tracheas from WT animals showed larger contractions compared to the KO mice. Tracheas from sensitized and ovalbumin-exposed animals released 5-hydroxytyptamine upon addition of ovalbumin. No higher levels of 5-hydroxytryptamine were released from tracheas of WT animals. Tracheas of non-sensitized animals did not release 5-hydroxytryptamine upon ovalbumin challenge. Responses to ovalbumin were abrogated by methysergide, a broad 5-hydroxytryptamine receptor antagonist. Exogenous 5-hydroxytryptamine contracted tracheas but WT tracheas responded significantly more. Atropine and tetrodotoxin (TTX) reduced 5-hydroxytryptamine-induced contractions of the WT tracheas, while they did not affect 5-hydroxytryptamine-induced contractions of KO tracheas. 5-Hydroxytryptamine-induced contractions from atropine- or TTX-treated WT tracheas did not differ significantly from the contractions of the KO tracheas. Single tachykinin NK1 receptor antagonists SR140333 and RP67580 had no effect on 5-hydroxytryptamine-induced contractions. In conclusion, the 5-hydroxytryptamine-induced tracheal contraction includes a cholinergic mechanism that requires the presence of the tachykinin NK1 receptor. [Copyright &y& Elsevier]

Context: Although early integrated palliative home care (PHC) is believed to be beneficial for patients with chronic obstructive pulmonary disease (COPD), trials testing this hypothesis are rare and show inconclusive results.Objectives: To test feasibility, acceptability, and preliminary effectiveness of early integrated PHC for end-stage COPD.Methods: Testing a six-month early integrated PHC pilot randomized controlled trial given by palliative home care nurses (PHCNs) for end-stage COPD with five components: 1) preinclusion COPD support training for PHCNs; 2) monthly PHC visits; 3) leaflets on coping mechanisms; 4) a protocol on symptom management and support, a care plan and an action plan; and 5) integration of PHC and usual care through reporting and communication mechanisms. Patient-reported outcomes were assessed six times weekly. Participants and health care professionals involved were interviewed.Results: Of 70 eligible patients, 39 (56%) participated (20:19 intervention vs control group) and 64% completed the trial. A patient received on average 3.4 PHC visits, mainly for disease insight, symptom management, and care planning. Nurses distributed all reports but hardly connected with health professionals except general practitioners (GPs); eight of 10 interviewed patients referred to the psychosocial support, breathing exercises, and care decisions as helpful. Some GPs criticized PHC being given too early, but pulmonologists and PHCNs did not. Effectiveness analysis showed no overall intervention effect for the outcomes, but between baseline and week 24, fewer hospitalizations in the control group (P = 0.03) and a trend of higher perceived quality of care in the intervention group (P = 0.06) were found. A clinically relevant difference was observed at week 24 for health-related quality of life in favor of the control group.Conclusion: Our intervention on early integrated PHC for end-stage COPD is feasible and accepted but did not yield the anticipated preliminary effectiveness. Before moving to a Phase III trial, enhanced coordination of care, more GP involvement, more intensive training for PHCNs in COPD support, and revision of the trial design, for example, of targeted outcomes in line with individual patient goals and care preferences should be done. [ABSTRACT FROM AUTHOR]

Experimental studies suggest that neutrophils could contribute to allergic asthma pathogenesis, that is mainly driven by type 2 immunity. Inhalation of diesel exhaust particles (DEP) is implicated in both exacerbation and development of asthma. Since exposure to DEP is associated with a neutrophilic component, we aimed to investigate how exposure to the combination of allergens and DEP modulates neutrophilic responses. Human bronchial epithelial cells (HBEC) were exposed to house dust mite (HDM), DEP or HDM + DEP in vitro to determine the expression of neutrophil-recruiting chemokines. Female (C57BL/6 J) mice were intranasally instilled with saline, DEP, HDM or combined HDM + DEP for 3 weeks (subacute) or 6 weeks (chronic). The neutrophilic responses were determined in lung tissue and bronchoalveolar lavage fluid (BALF). Simultaneous exposure to HDM + DEP resulted in increased CXCL1 and CXCL8 mRNA expression by HBEC in vitro. In mice, subacute exposure to HDM + DEP induced a strong mixed eosinophilic/neutrophilic inflammation in BALF and lung and was associated with higher expression of neutrophil-attracting chemokines and NET formation compared to the sole exposures. After chronic HDM + DEP exposure, a similar neutrophilic response was observed, however the NET formation was less pronounced. Interestingly, the increase of BALF eosinophils was also significantly attenuated after chronic HDM + DEP exposure compared to the subacute exposure. Subacute and chronic HDM + DEP exposure induced goblet cell hyperplasia and airway hyperresponsiveness. Our data suggest a role for neutrophils and NETs in pollutant-aggravated eosinophilic allergic asthma. Moreover, subacute exposure to HDM + DEP induces a mixed eosinophilic/neutrophilic response whereas upon chronic HDM + DEP exposure there is a shift in inflammatory response with a more prominent neutrophilic component., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Department of Respiratory Medicine (Ghent University) was funded by Scientific Research in Flanders (FWO Vlaanderen, FWO041819N and FWO-EOS projects G0G2318N, G0H1222N) and a Ghent University Grant (BOF/GOA 01G00819). TM holds a Chiesi Chair on the Role of Environmental factors in Asthma development and a GSK chair on eosinophilic airway disease., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of-life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Objectives: The International Respiratory Coalition's Lung Facts web resource provides the latest data on a range of lung conditions covering the World Health Organization's European Region, informed by the Global Burden of Disease studies: https://international-respiratory-coalition.org/lung-facts/ . Within Lung Facts, disability-adjusted life-years (DALYs) are monetised based on gross domestic product (GDP) per capita. We describe the conceptual and empirical basis for using monetised DALYs to inform negotiations with policymakers to invest in lung care across the World Health Organization European region., Methods: We reflect on the existing debate and research evidence regarding the X value in an X*GDP per capita framework to monetise DALYs, with a focus on if 1*GDP per capita is conceptually and practically appropriate. Using an asthma case study, Global Burden of Disease study 2019 DALY estimates per country are presented. Gross domestic product per capita are converted to international dollars using purchasing power parity (Int$2019)., Results: Using 1*GDP per capita, the estimated monetised asthma DALY burden, for example, in Kyrgyzstan or Germany is: across the whole population, $44,860,483 or $9,264,767,882, respectively; per 100,000 people, $731,600 or $10,208,317, respectively., Conclusions: Our indicative monetised DALY estimates can enable informed discussions with policy and decision makers, to guide financial investment in alleviating the burden of lung conditions. We suggest 1*GDP per capita as a benchmarked value forms a starting point for negotiation with policymakers for investing in lung care, by scaling the estimated lung condition DALY burden to the resource available in each country to tackle the burden., (© 2023. The Author(s).)

Background: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of COPD pathogenesis. We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD., Methods: We assessed RIPK1 expression in single-cell RNA sequencing (RNA-seq) data from human and mouse lungs, and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1 S25D/S25D kinase-deficient mice and the RIPK1 kinase inhibitor GSK'547., Results: RIPK1 expression increased in alveolar type 1 (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients compared with never-smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T-cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS exposure, as well as airway remodelling, emphysema, and apoptotic and necroptotic cell death upon chronic CS exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-seq on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition., Conclusions: RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach., Competing Interests: Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The RIPK1 kinase inhibitor GSK′547 was a kind gift from A.M. Beal (GlaxoSmithKline) who approved the manuscript but was not involved in funding or designing the study. T. Maes reports grants from FWO Flanders, Chiesi and GlaxoSmithKline, and is a shareholder of Oryzon Genomics and Mendelion Lifesciences SL, outside the submitted work. G.F. Joos reports consulting fees from GlaxoSmithKline and AstraZeneca, lecture honoraria from GlaxoSmithKline, AstraZeneca, Novartis, Lapharcon and EURECA VZW, travel support from GlaxoSmithKline, and acts as chair of the operational Committee IRC (International Respiratory Coalition) for the European Respiratory Society, outside the submitted work. G.G. Brusselle reports advisory board participation and lecture honoraria from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merch Sharp & Dohme, Novartis and Sanofi, outside the submitted work. P.M. Hansbro reports grants from the National Health and Medical Research Council (APP1138004, Defining the roles and targeting interferon-epsilon as a new therapy for influenza in asthma and COPD; and APP1179092, Development of a novel effective therapy for asthma and COPD), outside the submitted work., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Validated questionnaires are used to assess asthma control over the past 1-4 weeks from reporting. However, they do not adequately capture asthma control in patients with fluctuating symptoms. Using the Mobile Airways Sentinel Network for airway diseases (MASK-air) app, we developed and validated an electronic daily asthma control score (e-DASTHMA)., Methods: We used MASK-air data (freely available to users in 27 countries) to develop and assess different daily control scores for asthma. Data-driven control scores were developed based on asthma symptoms reported by a visual analogue scale (VAS) and self-reported asthma medication use. We included the daily monitoring data from all MASK-air users aged 16-90 years (or older than 13 years to 90 years in countries with a lower age of digital consent) who had used the app in at least 3 different calendar months and had reported at least 1 day of asthma medication use. For each score, we assessed construct validity, test-retest reliability, responsiveness, and accuracy. We used VASs on dyspnoea and work disturbance, EQ-5D-VAS, Control of Allergic Rhinitis and Asthma Test (CARAT), CARAT asthma, and Work Productivity and Activity Impairment: Allergy Specific (WPAI:AS) questionnaires as comparators. We performed an internal validation using MASK-air data from Jan 1 to Oct 12, 2022, and an external validation using a cohort of patients with physician-diagnosed asthma (the INSPIRERS cohort) who had had their diagnosis and control (Global Initiative for Asthma [GINA] classification) of asthma ascertained by a physician., Findings: We studied 135 635 days of MASK-air data from 1662 users from May 21, 2015, to Dec 31, 2021. The scores were strongly correlated with VAS dyspnoea (Spearman correlation coefficient range 0·68-0·82) and moderately correlated with work comparators and quality-of-life-related comparators (for WPAI:AS work, we observed Spearman correlation coefficients of 0·59-0·68). They also displayed high test-retest reliability (intraclass correlation coefficients range 0·79-0·95) and moderate-to-high responsiveness (correlation coefficient range 0·69-0·79; effect size measures range 0·57-0·99 in the comparison with VAS dyspnoea). The best-performing score displayed a strong correlation with the effect of asthma on work and school activities in the INSPIRERS cohort (Spearman correlation coefficients 0·70; 95% CI 0·61-0·78) and good accuracy for the identification of patients with uncontrolled or partly controlled asthma according to GINA (area under the receiver operating curve 0·73; 95% CI 0·68-0·78)., Interpretation: e-DASTHMA is a good tool for the daily assessment of asthma control. This tool can be used as an endpoint in clinical trials as well as in clinical practice to assess fluctuations in asthma control and guide treatment optimisation., Funding: None., Competing Interests: Declaration of interests IA is an associate editor for Allergy and Clinical and Translational Allergy journals. RAl reports personal fees from operation POCI-01–0145–36 FEDER-029130 (titled “mINSPIRE-mHealth to measure and improve adherence to medication in chronic respiratory diseases—generalisation and evaluation of gamification, peer support and advanced image processing technologies”), co-funded by European Regional Development Fund, Programa Operacional Competitividade e Internacionalização, Portugal 2020, and by Portuguese Funds through Fundação para a Ciência e a Tecnologia, outside the submitted work. SB-A reports grants from TEVA, and personal fees from Teva, AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Mylan, outside the submitted work. L-PB reports grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, and Sanofi-Regeneron; personal fees from AstraZeneca, Novartis, GlaxoSmithKline, Merck, Sanofi-Regeneron, Covis, and Sanofi, outside the submitted work; and is a member of the Chair of Global Initiative for Asthma (GINA) Board of Directors, President of the Global Asthma Organisation (Interasma), and is a member of the Canadian Thoracic Society Respiratory Guidelines Committee and Laval University Chair on Knowledge Transfer, and Prevention and Education in Respiratory and Cardiovascular Health. JB reports personal fees from Chiesi, Cipla, Hikma, Menarini, Mundipharma, Mylan, Novartis, Purina, Sanofi-Aventis, Takeda, Teva, and Uriach; and other from Kyomed-Innov, outside the submitted work. GB reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, and Sanofi, outside the submitted work. RB reports grants to Mainz University Hospital from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche; and personal fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Roche, Sanofi, and Teva, all outside the submitted work. LC reports personal fees from Thermofisher, Sanofi, Novartis, and AstraZeneca, outside the submitted work. AAC reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Eurofarma, GSK, Novartis, and Sanofi, outside the submitted work. FdB reports other grants from Novartis, ALK, Stallergenes, Regeneron, DBV, Sanofi, Boehringer, and AstraZeneca, outside the submitted work. PD reports non-financial support from AstraZeneca, Boehringer Ingelheim, Stallergenes, and ALK Abelló; and personal fees from AstraZeneca, Chiesi, Boehringer Ingelheim, GlaxoSmithKline, Menarini, Stallergenes, ALK Abelló, and IQVIA, outside the submitted work. JAF reports grants from Astrazeneca and Mundipharma; and personal fees from AstraZeneca, Mundipharma, Sanofi, GSK, and Teva, outside the submitted work; and is co-founder of a company that develops mobile health technologies and has the copyright of the Control of Allergic Rhinitis and Asthma Test Patient-Reported Outcome Measurement. BG reports grants from AstraZeneca, Sanofi, Deva, Abdi Ibrahim, and Sandoz, outside the submitted work. TH reports personal fees from Orion Pharma, outside the submitted work. GJ reports personal fees from AstraZeneca, GSK, Chiesi, Novartis, and Laparcon; support from GSK, outside the submitted work; and is a member of European Respiratory Society Chair of Operational Committee International Respiratory Coalition. MJ reports personal fees from ALK-Abello, Allergopharma, Stallergenes, Anergis, Allergy Therapeutics, Leti, and HAL, during the conduct of the study; and personal fees from GSK, Novartis, Teva, Takeda, and Chiesi, outside the submitted work. LK reports grants from Allergopharma, MEDA/Mylan, ALK Abelló, LETI Pharma, Stallergenes, Sanofi, ASIT biotech, Lofarma Quintiles, AstraZeneca, GSK, and Inmunotk; and personal fees from Allergopharma, MEDA/Mylan, HAL Allergie, LETI Pharma, Sanofi, Allergy Therapeut, and Cassella Med, outside the submitted work; and is a member of Ärzteverband Deutscher Allergologen, Deutsche Gesellschaft für Hals-Nasen-Ohren, Deutsche Akademie für Allergologie und klinische Immunologie, Berufsverband der Hals-Nasen-Ohrenärzte, Gesellschaft für Pädiatrische Allergologie, andEuropean Academy of Allergy and Clinical Immunology. PK reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva, outside the submitted work. MKup reports personal fees from AstraZeneca, Chiesi, GlaxoSmithKline, Novartis, Lekam, Alvogen, Emma, Nexter, Teva, Sanofi Aventis, and Berlin Chemie, outside the submitted work. VK reports non-financial support from Norameda and Berlin Chemie Menarini, outside the submitted work. DL-L reports personal fees from ALK, Allakos, Amstrong, Astrazeneca national and global, Chiesi, DBV Technologies, Grunenthal, GSK national and global, Mylan/Viatris, Menarini, MSD, Novartis, Pfizer, Sanofi, Siegfried, UCB, Alakos, Gossamer, and Carnot; and grants from Sanofi, Astrazeneca, Lilly, Pfizer, Novartis, Circassia, UCB, GSK, and Purina institute, outside the submitted work. RL reports personal fees from GSK and AZ; and grants from GSK, AZ, and Chiesi, outside the submitted work. NGP reports personal fees from Novartis, Nutricia, HAL, MENARINI/FAES FARMA, SANOFI, MYLAN/MEDA, BIOMAY, AstraZeneca, GSK, MSD, ASIT BIOTECH, and Boehringer Ingelheim; and grants from Gerolymatos International SA and Capricare, outside the submitted work. AP reports grants from Chiesi, Astrazeneca, GSK, BI, Pfizer, Teva, and Sanofi; personal fees from CHIESI, Astrazeneca, GSK, Novartis, Sanofi, Iqvia, Avillion, Elpen Pharmaceuticals, BI, Menarini, Zambon, Mundipharma, Teva, Edmon Pharma, and MSD, outside the submitted work. OP reports grants from ALK Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding BV/HAL Allergie, Bencard Allergie/Allergy Therapeutics, Lofarma, Biomay, Circassia, ASIT Biotech Tools SA, Laboratorios LETI/LETI Pharma, Anergis SA, GlaxoSmithKline, Pohl-Boskamp, Inmunotek SL, and AstraZeneca; and personal fees from ALK-Abelló, Allergopharma, Stallergenes Greer, HAL Allergy Holding BV/HAL Allergie, Bencard Allergie/Allergy Therapeutics, Lofarma, ASIT Biotech Tools SA, Laboratorios LETI/LETI Pharma, MEDA Pharma/MYLAN, Anergis SA, AstraZeneca, Mobile Chamber Experts (a GA2LEN Partner), Indoor Biotechnologies, GlaxoSmithKline, Astellas Pharma Global, EUFOREA, ROXALL Medizin, Novartis, Sanofi-Aventis and Sanofi-Genzyme, Med Update Europe, streamedup!, John Wiley and Sons, AS, Paul-Martini-Stiftung, Regeneron Pharmaceuticals, RG Aerztefortbildung, Institut für Disease Management, Springer, IQVIA Commercial, Ingress Health, Wort & Bild Verlag, Verlag ME, and Procter & Gamble, outside the submitted work; and is a member of EAACI Excom, member of external board of directors Deutsche Gesellschaft für Allergologie und klinische Immunologie; and is a coordinator, main author, or coauthor of different position papers and guidelines in rhinology, allergology, and allergen immunotherapy. FSR reports speaker and advisory fees from AstraZeneca, Novartis, Sanofi, GSK, Teva, Kedrion, Takeda, LEO Pharma, and Lusomedicamenta, all outside the submitted work. NR reports grants from Boehringer Ingelheim, Novartis, GSK, and Pfizer; and personal fees from Boehringer Ingelheim, Novartis, GSK, AstraZeneca, Chiesi, Pfizer, Sanofi, Zambon, and MSD, outside the submitted work. JS reports grants from Sanofi; and personal fees from Sanofi, GSK, Novartis, AstraZeneca, MundiPharma, and Faes Farma, outside the submitted work. CSU reports personal fees from GSK, AZ, TEVA, Novartis, BI, Chiesi, Sanofi, Orion Pharma, and Covis Pharma; and grants from AZ, Novartis, BI, Sanofi, Orion Pharma, and Covis Pharma, outside the submitted work. OV reports grants from Astrazeneca and Chiesi, outside the submitted work. TZ reports grants from Novartis and Henkel; personal fees from Bayer Health Care, FAES, Novartis, Henkel, AstraZeneca, AbbVie, ALK, Almirall, Astellas, Bencard, Berlin Chemie, HAL, Leti, Meda, Menarini, Merck, MSD, Pfizer, Sanofi, Stallergenes, Takeda, Teva, UCB, Kryolan, and L'Oréal, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)