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Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP. [ABSTRACT FROM AUTHOR]

Background: In the 52‐week Phase III SYNAPSE study, mepolizumab given every 4 weeks (100 mg subcutaneously) reduced nasal polyp (NP) size, improved symptoms and quality of life (QoL), and reduced corticosteroid use and number of sinus surgeries in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP), versus placebo. Because the durability of mepolizumab's efficacy after discontinuation is poorly understood in CRSwNP, the efficacy of mepolizumab after discontinuation was analyzed in severe CRSwNP, over a 24‐week follow‐up. Methods: Changes from SYNAPSE baseline to end of treatment (week 52) and end of follow‐up (week 76) were assessed for total endoscopic NP score, nasal obstruction and overall symptoms visual analog scale scores, and 22‐item Sino‐Nasal Outcome Test score. Time to first sinus surgery, time to first corticosteroid use, and geometric mean blood eosinophil counts (BECs) were also assessed. Results: Among 134 follow‐up patients, clinical improvements observed with mepolizumab versus placebo were partially evident 24 weeks after discontinuation despite BEC returning to baseline. The mean (95% confidence interval [CI]) change from baseline in NP score (week 52: −1.3 [1.8 to −0.9] vs. −0.3 [−0.6 to 0.1]; week 76: −1.2 [−1.6 to −0.7] vs. −0.1 [−0.5 to 0.3]) and the proportion of patients having sinus surgery (week 52: 4% vs. 25%; week 76: 9% vs. 31%) remained substantially improved with mepolizumab versus placebo. Mepolizumab‐associated improvements in overall symptoms, quality of life, and corticosteroid use versus placebo were partially sustained at week 76. Conclusion: Fifty‐two weeks of mepolizumab treatment is associated with sustained clinical benefits up to 24 weeks after discontinuation in patients with severe CRSwNP, which should be considered by physicians when making treatment decisions. [ABSTRACT FROM AUTHOR]

Over the past years, eosinophils have become a focus of scientific interest, especially in the context of their recently uncovered functions (e.g. antiviral, anti‐inflammatory, regulatory). These versatile cells display both beneficial and detrimental activities under various physiological and pathological conditions. Eosinophils are involved in the pathogenesis of many diseases which can be classified into primary (clonal) and secondary (reactive) disorders and idiopathic (hyper)eosinophilic syndromes. Depending on the biological specimen, the eosinophil count in different body compartments may serve as a biomarker reflecting the underlying pathophysiology and/or activity of distinct diseases and as a therapy‐driving (predictive) and monitoring tool. Personalized selection of an appropriate therapeutic strategy directly or indirectly targeting the increased number and/or activity of eosinophils should be based on the understanding of eosinophil homeostasis including their interactions with other immune and non‐immune cells within different body compartments. Hence, restoring as well as maintaining homeostasis within an individual's eosinophil pool is a goal of both specific and non‐specific eosinophil‐targeting therapies. Despite the overall favourable safety profile of the currently available anti‐eosinophil biologics, the effect of eosinophil depletion should be monitored from the perspective of possible unwanted consequences. [ABSTRACT FROM AUTHOR]

Introduction: In allergic asthma patients, one of the more common phenotypes might benefit from allergen immunotherapy (AIT) as add‐on intervention to pharmacological treatment. AIT is a treatment with disease‐modifying modalities, the evidence for efficacy is based on controlled clinical trials following standardized endpoint measures. However, so far there is a lack of a consensus for asthma endpoints in AIT trials. The aim of a task force (TF) of the European Academy of Allergy and Clinical Immunology (EAACI) is evaluating several outcome measures for AIT in allergic asthma. Methods: The following domains of outcome measures in asthmatic patients have been evaluated for this position paper (PP): (i) exacerbation rate, (ii) lung function, (iii) ICS withdrawal, (iv) symptoms and rescue medication use, (v) questionnaires (PROMS), (vi) bronchial/nasal provocation, (vii) allergen exposure chambers (AEC) and (viii) biomarkers. Results: Exacerbation rate can be used as a reliable objective primary outcome; however, there is limited evidence due to different definitions of exacerbation. The time after ICS withdrawal to first exacerbation is considered a primary outcome measure. Besides, the advantages and disadvantages and clinical implications of further domains of asthma endpoints in AIT trials are elaborated in this PP. Conclusion: This EAACI‐PP aims to highlight important aspects of current asthma measures by critically evaluating their applicability for controlled trials of AIT. [ABSTRACT FROM AUTHOR]

"Epidemiology of comorbidities and their association with asthma control" (Tomisa, G., Horváth, A., Sánta, B. et al. Epidemiology of comorbidities and their association with asthma control. Allergy Asthma Clin Immunol 17, 95 (2021). https://doi.org/10.1186/s13223-021-00598-3) is an interesting paper reflecting data collection from more than 12,000 asthmatic patients in Hungary regarding their condition and associated comorbidities. We found it valuable that the paper provides an overview of asthma comorbidities not usually considered in similar reports. Nevertheless, we believe that chronic rhinosinusitis (CRS) with or without nasal polyps (CRSwNP or CRSsNP) should have been listed due to its high incidence and prevalence, its association with asthma which is also endorsed in both GINA and EPOS, as well as in several peer-reviewed scientific papers, and to reflect the role of this comorbidity in poor control and a most severe presentation of asthma for the patient. Consequently, several targeted therapies (especially monoclonal antibodies) used for several years in severe forms of asthma are now indicated also for the effective treatment of nasal polyps. [ABSTRACT FROM AUTHOR]

Asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) or without (CRSsNP) are chronic respiratory diseases. These two disorders often co-exist based on common anatomical, immunological, histopathological, and pathophysiological basis. Usually, asthma with comorbid CRSwNP is driven by type 2 (T2) inflammation which predisposes to more severe, often intractable, disease. In the past two decades, innovative technologies and detection techniques in combination with newly introduced targeted therapies helped shape our understanding of the immunological pathways underlying inflammatory airway diseases and to further identify several distinct clinical and inflammatory subsets to enhance the development of more effective personalized treatments. Presently, a number of targeted biologics has shown clinical efficacy in patients with refractory T2 airway inflammation, including anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab)/anti-IL5R (benralizumab), anti-IL-4R-a (anti-IL-4/IL-13, dupilumab), and anti-TSLP (tezepelumab). In non-type-2 endotypes, no targeted biologics have consistently shown clinical efficacy so far. Presently, multiple therapeutical targets are being explored including cytokines, membrane molecules and intracellular signalling pathways to further expand current treatment options for severe asthma with and without comorbid CRSwNP. In this review, we discuss existing biologics, those under development and share some views on new horizons. [ABSTRACT FROM AUTHOR]

To the Editor, Asthma is a heterogeneous disease, as reflected by differences in age of onset, severity, treatment response and inflammatory profile. In all, FP-025 in a dose-dependent manner significantly attenuated AHR, BAL inflammatory cell numbers and lung pathohistology in a mouse model of persistent HDM-allergic asthma. FP-025 markedly reduced MMP-12 expression in airway epithelial cells and levels of MMP-12 in lung parenchyma and airways, indicating that the enhanced expression in allergic asthma depends on an autocrine process. [Extracted from the article]

Introduction: Allergic asthmatics with both an early (EAR) and a late allergic reaction (LAR) following allergen exposure are termed 'dual responders' (DR), while 'single responders' (SR) only have an EAR. Mechanisms that differentiate DR from SR are largely unknown, particularly regarding the role and phenotypes of neutrophils. Therefore, we aimed to study neutrophils in DR and SR asthmatics. Methods: Thirty‐four allergic asthmatics underwent an inhaled allergen challenge, samples were collected before and up to 24 h post‐challenge. Cell differentials were counted from bronchial lavage, alveolar lavage and blood; and tissue neutrophils were quantified in immune‐stained bronchial biopsies. Lavage neutrophil nuclei lobe segmentation was used to classify active (1–4 lobes) from suppressive neutrophils (≥5 lobes). Levels of transmigration markers: soluble (s)CD62L and interleukin‐1Ra, and activity markers: neutrophil elastase (NE), DNA‐histone complex and dsDNA were measured in lavage fluid and plasma. Results: Compared with SR at baseline, DR had more neutrophils in their bronchial airways at baseline, both in the lavage (p =.0031) and biopsies (p =.026) and elevated bronchial neutrophils correlated with less antitransmigratory IL‐1Ra levels (r = −0.64). DR airways had less suppressive neutrophils and more 3‐lobed (active) neutrophils (p =.029) that correlated with more bronchial lavage histone (p =.020) and more plasma NE (p =.0016). Post‐challenge, DR released neutrophil extracellular trap factors in the blood earlier and had less pro‐transmigratory sCD62L during the late phase (p =.0076) than in SR. Conclusion: DR have a more active airway neutrophil phenotype at baseline and a distinct neutrophil response to allergen challenge that may contribute to the development of an LAR. Therefore, neutrophil activity should be considered during targeted diagnosis and bio‐therapeutic development for DR. [ABSTRACT FROM AUTHOR]

This review presents state‐of‐the‐art knowledge and identifies knowledge gaps for future research in the area of exercise‐associated modifications of infection susceptibility. Regular moderate‐intensity exercise is believed to have beneficial effects on immune health through lowering inflammation intensity and reducing susceptibility to respiratory infections. However, strenuous exercise, as performed by professional athletes, may promote infection: in about half of athletes presenting respiratory symptoms, no causative pathogen can be identified. Acute bouts of exercise enhance the release of pro‐inflammatory mediators, which may induce infection‐like respiratory symptoms. Relatively few studies have assessed the influence of regularly repeated exercise on the immune response and systemic inflammation compared to the effects of acute exercise. Additionally, ambient and environmental conditions may modify the systemic inflammatory response and infection susceptibility, particularly in outdoor athletes. Both acute and chronic regular exercise influence humoral and cellular immune response mechanisms, resulting in decreased specific and non‐specific response in competitive athletes. The most promising areas of further research in exercise immunology include detailed immunological characterization of infection‐prone and infection‐resistant athletes, examining the efficacy of nutritional and pharmaceutical interventions as countermeasures to infection symptoms, and determining the influence of various exercise loads on susceptibility to infections with respiratory viruses, including SARS‐CoV‐2. By establishing a uniform definition of an "elite athlete," it will be possible to make a comparable and straightforward interpretation of data from different studies and settings. [ABSTRACT FROM AUTHOR]

Non‐steroidal anti‐inflammatory drugs (NSAIDs) and other eicosanoid pathway modifiers are among the most ubiquitously used medications in the general population. Their broad anti‐inflammatory, antipyretic, and analgesic effects are applied against symptoms of respiratory infections, including SARS‐CoV‐2, as well as in other acute and chronic inflammatory diseases that often coexist with allergy and asthma. However, the current pandemic of COVID‐19 also revealed the gaps in our understanding of their mechanism of action, selectivity, and interactions not only during viral infections and inflammation, but also in asthma exacerbations, uncontrolled allergic inflammation, and NSAIDs‐exacerbated respiratory disease (NERD). In this context, the consensus report summarizes currently available knowledge, novel discoveries, and controversies regarding the use of NSAIDs in COVID‐19, and the role of NSAIDs in asthma and viral asthma exacerbations. We also describe here novel mechanisms of action of leukotriene receptor antagonists (LTRAs), outline how to predict responses to LTRA therapy and discuss a potential role of LTRA therapy in COVID‐19 treatment. Moreover, we discuss interactions of novel T2 biologicals and other eicosanoid pathway modifiers on the horizon, such as prostaglandin D2 antagonists and cannabinoids, with eicosanoid pathways, in context of viral infections and exacerbations of asthma and allergic diseases. Finally, we identify and summarize the major knowledge gaps and unmet needs in current eicosanoid research. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that spread around the world during the past 2 years, has infected more than 260 million people worldwide and has imposed an important burden on the healthcare system. Several risk factors associated with unfavorable outcome were identified, including elderly age, selected comorbidities, immune suppression as well as laboratory markers. The role of immune system in the pathophysiology of SARS-CoV-2 infection is indisputable: while an appropriate function of the immune system is important for a rapid clearance of the virus, progression to the severe and critical phases of the disease is related to an exaggerated immune response associated with a cytokine storm. We analyzed differences and longitudinal changes in selected immune parameters in 823 adult COVID-19 patients hospitalized in the Martin University Hospital, Martin, Slovakia. Examined parameters included the differential blood cell counts, various parameters of cellular and humoral immunity (serum concentration of immunoglobulins, C4 and C3), lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, NK cells, CD4+CD45RO+), expression of activation (HLA-DR, CD38) and inhibition markers (CD159/NKG2A). Besides already known changes in the differential blood cell counts and basic lymphocyte subsets, we found significantly higher proportion of CD8+CD38+ cells and significantly lower proportion of CD8+NKG2A+ and NK NKG2A+ cells on admission in non-survivors, compared to survivors; recovery in survivors was associated with a significant increase in the expression of HLA-DR and with a significant decrease of the proportion of CD8+CD38+cells. Furthermore, patients with fatal outcome had significantly lower concentrations of C3 and IgM on admission. However, none of the examined parameters had sufficient sensitivity or specificity to be considered a biomarker of fatal outcome. Understanding the dynamic changes in immune profile of COVID-19 patients may help us to better understand the pathophysiology of the disease, potentially improve management of hospitalized patients and enable proper timing and selection of immunomodulator drugs. [ABSTRACT FROM AUTHOR]

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence. [ABSTRACT FROM AUTHOR]

Bronchial lavage, cysteinyl-leukotriene pathway, allergen bronchoprovocation test, asthma, prostaglandin pathway Keywords: Bronchial lavage; cysteinyl-leukotriene pathway; prostaglandin pathway; allergen bronchoprovocation test; asthma EN Bronchial lavage cysteinyl-leukotriene pathway prostaglandin pathway allergen bronchoprovocation test asthma 2549 2551 3 08/09/22 20220801 NES 220801 ACKNOWLEDGMENTS This work was supported by independent grants from the Swedish Asthma and Allergy Association's Research Foundation, Crafoord Foundation, Swedish Heart and Lung Foundation and Alfred Österlund Foundation. The levels of cysteinyl-leukotriene metabolites, Cys-LT, and prostaglandin metabolites, prostaglandin E metabolites (PGEM), were measured in the lavage fluids by the respective ELISA from Cayman Chemical (Ann Arbor, MI). [Extracted from the article]

Vaccines are essential public health tools with a favorable safety profile and prophylactic effectiveness that have historically played significant roles in reducing infectious disease burden in populations, when the majority of individuals are vaccinated. The COVID‐19 vaccines are expected to have similar positive impacts on health across the globe. While serious allergic reactions to vaccines are rare, their underlying mechanisms and implications for clinical management should be considered to provide individuals with the safest care possible. In this review, we provide an overview of different types of allergic adverse reactions that can potentially occur after vaccination and individual vaccine components capable of causing the allergic adverse reactions. We present the incidence of allergic adverse reactions during clinical studies and through post‐authorization and post‐marketing surveillance and provide plausible causes of these reactions based on potential allergenic components present in several common vaccines. Additionally, we review implications for individual diagnosis and management and vaccine manufacturing overall. Finally, we suggest areas for future research. [ABSTRACT FROM AUTHOR]

The velocity of the COVID-19 pandemic spread and the variable severity of the disease course has forced scientists to search for potential predictors of the disease outcome. We examined various immune parameters including the markers of immune cells exhaustion and activation in 21 patients with COVID-19 disease hospitalised in our hospital during the first wave of the COVID-19 pandemic in Slovakia. The results showed significant progressive lymphopenia and depletion of lymphocyte subsets (CD3+, CD4+, CD8+ and CD19+) in correlation to the disease severity. Clinical recovery was associated with significant increase in CD3+ and CD3+CD4+ T-cells. Most of our patients had eosinopenia on admission, although no significant differences were seen among groups with different disease severity. Non-survivors, when compared to survivors, had significantly increased expression of PD-1 on CD4+ and CD8+ cells, but no significant difference in Tim-3 expression was observed, what suggests possible reversibility of immune paralysis in the most severe group of patients. During recovery, the expression of Tim-3 on both CD3+CD4+ and CD3+CD8+ cells significantly decreased. Moreover, patients with fatal outcome had significantly higher proportion of CD38+CD8+ cells and lower proportion of CD38+HLA-DR+CD8+ cells on admission. Clinical recovery was associated with significant decrease of proportion of CD38+CD8+ cells. The highest AUC values within univariate and multivariate logistic regression were achieved for expression of CD38 on CD8+ cells and expression of PD1 on CD4+ cells alone or combined, what suggests, that these parameters could be used as potential biomarkers of poor outcome. The assessment of immune markers could help in predicting outcome and disease severity in COVID-19 patients. Our observations suggest, that apart from the degree of depletion of total lymphocytes and lymphocytes subsets, increased expression of CD38 on CD3+CD8+ cells alone or combined with increased expression of PD-1 on CD3+CD4+ cells, should be regarded as a risk factor of an unfavourable outcome in COVID-19 patients. Increased expression of PD-1 in the absence of an increased expression of Tim-3 on CD3+CD4+ and CD3+CD8+ cells suggests potential reversibility of ongoing immune paralysis in patients with the most severe course of COVID-19. [ABSTRACT FROM AUTHOR]

Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46–70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24–36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID‐19) has evolved into a pandemic infectious disease transmitted by the severe acute respiratory syndrome coronavirus (SARS‐CoV‐2). Allergists and other healthcare providers (HCPs) in the field of allergies and associated airway diseases are on the front line, taking care of patients potentially infected with SARS‐CoV‐2. Hence, strategies and practices to minimize risks of infection for both HCPs and treated patients have to be developed and followed by allergy clinics. Method: The scientific information on COVID‐19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet. Results: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID‐19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID‐19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies. Conclusions: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID‐19 pandemic. [ABSTRACT FROM AUTHOR]

Rescue ICS/SABA (under development as a single inhaler8 with favourable results of the pivotal studies just announced)9 would address many of these limitations as it could be used to overcome the current barriers to the ICQ generalizability at all treatment steps, irrespective of the type of background maintenance asthma therapy (if any). Anti-inflammatory treatment is the pharmacological cornerstone of asthma management. [Extracted from the article]