Biologics Reduce Symptoms of Alcohol Intolerance Better than Aspirin Desensitization in Patients with N-ERD and Nasal Polyps.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) exacerbated respiratory disease (N-ERD) is associated with chronic rhinosinusitis with nasal polyps (CRSwNP), asthma, and NSAID hypersensitivity. An overproduction of leukotrienes characterizes the pathomechanism of the disease. N-ERD patients often report breathing difficulties after consuming alcohol. These symptoms have been observed in patients receiving either aspirin therapy after desensitization (ATAD), therapy with the biologics dupilumab (anti-IL-4Ra antibody) and omalizumab (anti-IgE antibody), or intranasal corticosteroid treatment (INCS). METHODS: This retrospective, real-world study assessed the severity of alcohol-related and non-alcohol-related respiratory symptoms in CRSwNP/N-ERD patients 3-6 months after ATAD, biologic (dupilumab or omalizumab), or INCS therapy. A total of 171 patients (98 women and 73 men) were enrolled in the study. All groups received standard INCS therapy. Sixty-three patients were treated with ATAD; 48 received biologics (dupilumab n = 31; omalizumab n = 17); and 60 received INCS only and served as a control group. Alcohol-dependent symptoms and typical CRS symptoms (alcohol-independent) were quantified using visual analog scales (VAS). RESULTS: ATAD and biological therapy significantly reduced VAS scores for alcohol dependence and CRS symptoms. In the control group receiving INCS, only non-alcohol dependent CRS symptoms improved significantly (p < 0.05). The most significant differences in pre/post scores were observed in patients receiving dupilumab, with the most significant improvement in alcohol-dependent and CRS symptoms (dupilumab > omalizumab > ATAD). CONCLUSIONS: This real-world study shows that alcohol-related respiratory symptoms are a relevant parameter in CRSwNP/N-ERD patients. Patients benefit more from biologic therapy than from ATAD in terms of their alcohol-related symptoms and other CRS symptoms. Future studies should include placebo-controlled oral alcohol challenge.

A real-life comparison of pulmonary and nasal outcomes in patients with severe asthma and nasal polyposis treated with T2-biologics.

Background: Severe asthma (SA) with comorbid chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently associated with type 2 (T2) inflammatory endotype. Consequently, therapeutic targets are T2 biologics. The present retrospective study aimed to analyze and compare the clinical efficacy of mepolizumab, benralizumab, omalizumab, and dupilumab in patients with SA and comorbid CRSwNP. Methods: 115 adult patients with SA and CRSwNP receiving 1 of the 4 biologics (mepolizumab n = 31; benralizumab n = 27; dupilumab n = 27; omalizumab n = 30) were included in the retrospective open monocentric study. Pulmonary and rhinological parameters were evaluated by Asthma Control Test (ACT), FEV1%, GINA-severity grade, rhinological questionnaires (CRS VAS-scores and sinonasal QoL RSOM-31) before and after 4-6 months of therapy. Results: After 4-6 months of therapy, the Asthma Control Test and FEV1% significantly improved in all biologics groups (p < 0.01). GINA-score significantly improved in the omalizumab group only (p < 0.01). Overall, most nasal scores measured by VAS, total and nasal RSOM-31 subscores improved in all treatment groups (p < 0.05). Interestingly, the most significant differences in pre/post scores were observed in the patients receiving dupilumab, with the most notable improvement for all nasal symptoms, RSOM-31 total score, and RSOM-31 nasal subscore. There were no significant changes in the VAS scores loss of smell in the benralizumab group and postnasal drip in the mepolizumab group. Conclusion: T2-targeting biologics effectively treat asthma in patients with severe asthma and comorbid CRSwNP. However, the efficacy of T2 biologics differs regarding the outcome in CRSwNP.

Biologics for atopic diseases: Indication, side effect management, and new developments.

With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance.

Association of early life and acute pollen exposure with lung function and exhaled nitric oxide (FeNO). A prospective study up to adolescence in the GINIplus and LISA cohort.

BACKGROUND: Pollen exposure has both acute and chronic detrimental effects on allergic asthma, but little is known about its wider effects on respiratory health. This is increasingly important knowledge as ambient pollen levels are changing with the changing global climate. OBJECTIVE: To assess associations of pollen exposure with lung function and fractional exhaled nitric oxide (FeNO) at age 15 in two prospective German birth cohorts, GINIplus and LISA. METHODS: Background city-specific pollen exposure was measured in infancy (during the first three months of life), and contemporary (on the day of and 7 days prior to lung function measurement). Greenness levels within circular buffers (100-3000 m) around the birth and 15-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index. Regression models were used to assess the associations of grass and birch pollen with lung function and FeNO, and the modifying effects of residential greenness were explored. RESULTS: Cumulative early life exposure to grass pollen was associated with reduced lung function in adolescence (FEV1: -4.9 mL 95%CI: -9.2, -0.6 and FVC: -5.2 mL 95%CI: -9.8, -0.5 per doubling of pollen count). Acute grass pollen exposure was associated with increased airway inflammation in all children, with higher FeNO increases in children living in green areas. In contrast acute birch pollen exposure was associated with reduced lung function only in children sensitised to birch allergens. CONCLUSION: This study provides suggestive evidence that early pollen exposure has a negative effect on later lung function, which is in turn influenced by acute pollen exposures.

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA)A, Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI)B, Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI)D, Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI)E, Österreichische Gesellschaft für Pneumologie (ÖGP)F in co-operation with the German, Austrian, and Swiss ARIA groupsG, and the European Academy of Allergy and Clinical Immunology (EAACI)H.

BACKGROUND: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2. MATERIALS AND METHODS: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic. RESULTS: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future. CONCLUSION: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.

Tiered approach for the identification of Mal d 1 reduced, well tolerated apple genotypes.

A rising proportion of the world population suffers from food-related allergies, including incompatibilities to apples. Although several allergenic proteins have been found in apples, the most important proteins that cause allergic reactions to apples in Central-Northern Europe, and North America are the Mal d 1 proteins, which are homologues of the birch pollen allergen Bet v 1. As the demand for hypoallergenic fruits is constantly increasing, we selected apple genotypes with a low total content of Mal d 1 by enzyme-linked immunosorbent assay analysis from segregating populations and tested the tolerability of these fruits through a human provocation study. This tiered approach, which exploited the natural diversity of apples, led to the identification of fruits, which were tolerated by allergic patients. In addition, we found a significant correlation (coefficient >0.76) between the total Mal d 1 content and flavan-3-ol amount and show that the isoform composition of the Mal d 1 proteins, which was determined by LC-MS/MS has a decisive effect on the tolerability of apple genotypes. The approach presented can be applied to other types of fruit and to other allergenic proteins. Therefore, the strategy can be used to reduce the allergen content of other plant foods, thereby improving food safety for allergy subjects.

International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies.

Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking.

Abridged version of the AWMF guideline for the medical clinical diagnostics of indoor mould exposure: S2K Guideline of the German Society of Hygiene, Environmental Medicine and Preventive Medicine (GHUP) in collaboration with the German Association of Allergists (AeDA), the German Society of Dermatology (DDG), the German Society for Allergology and Clinical Immunology (DGAKI), the German Society for Occupational and Environmental Medicine (DGAUM), the German Society for Hospital Hygiene (DGKH), the German Society for Pneumology and Respiratory Medicine (DGP), the German Mycological Society (DMykG), the Society for Pediatric Allergology and Environmental Medicine (GPA), the German Federal Association of Pediatric Pneumology (BAPP), and the Austrian Society for Medical Mycology (ÖGMM).

This article is an abridged version of the AWMF mould guideline "Medical clinical diagnostics of indoor mould exposure" presented in April 2016 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with the above-mentioned scientific medical societies, German and Austrian societies, medical associations and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. Apart from allergic bronchopulmonary aspergillosis (ABPA) and mould-caused mycoses, only sufficient evidence for an association between moisture/mould damage and the following health effects has been established: allergic respiratory disease, asthma (manifestation, progression and exacerbation), allergic rhinitis, hypersensitivity pneumonitis (extrinsic allergic alveolitis), and increased likelihood of respiratory infections/bronchitis. In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitizing prevalence of 3-10% in the general population across Europe. Limited or suspected evidence for an association exist with respect to mucous membrane irritation and atopic eczema (manifestation, progression and exacerbation). Inadequate or insufficient evidence for an association exist for chronic obstructive pulmonary disease, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis and cancer. The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, above all the substrate. In the case of indoor moisture/mould damage, everyone can be affected by odour effects and/or mood disorders. However, this is not a health hazard. Predisposing factors for odour effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly with regard to an infection risk are persons on immunosuppression according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch- Institute (RKI) and persons with cystic fibrosis (mucoviscidosis); with regard to an allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma should be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections the reader is referred to the AWMF guideline "Diagnosis and Therapy of Invasive Aspergillus Infections". With regard to mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medicine standpoint it is important that indoor mould infestation in relevant dimension cannot be tolerated for precautionary reasons. With regard to evaluating the extent of damage and selecting a remedial procedure, the reader is referred to the revised version of the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

Visual analogue scales (VAS): Measuring instruments for the documentation of symptoms and therapy monitoring in cases of allergic rhinitis in everyday health care: Position Paper of the German Society of Allergology (AeDA) and the German Society of Allergy and Clinical Immunology (DGAKI), ENT Section, in collaboration with the working group on Clinical Immunology, Allergology and Environmental Medicine of the German Society of Otorhinolaryngology, Head and Neck Surgery (DGHNOKHC).

BACKROUND: Visual analogue scales (VAS) are psychometric measuring instruments designed to document the characteristics of disease-related symptom severity in individual patients and use this to achieve a rapid (statistically measurable and reproducible) classification of symptom severity and disease control. VAS can also be used in routine patient history taking and to monitor the course of a chronic disease such as allergic rhinitis (AR). More specifically, the VAS has been used to assess effectiveness of AR therapy in real life, both in intermittent and persistent disease. METHODS: This position paper takes a detailed look at the historical development of VAS and its method-specific principles. Particular focus is put on aspects of practical application in daily routine and on a critical discussion of the advantages and disadvantages of the individual methods. RESULTS: VAS are well validated for the measurement of AR symptoms and correlate well with the ARIA (allergic rhinitis and its impact on asthma) severity classification and also correlated well with rTNSS and RQLQ. Moreover, several treatment studies on AR have used VAS as an evaluation parameter. Thanks to the use of new (real-life and real-time) communication technologies, such as smartphone apps, Discussion: VAS can be used relatively simply and highly effectively to assess disease control. The VAS lends itself very well to digitization and has now been incorporated into a smartphone app (called Allergy Diary) to assess AR control and direct treatment decisions as part of an AR clinical decision support system (CDSS). MASK Rhinitis has developed this app, which is currently available in 15 different languages.

Medical diagnostics for indoor mold exposure.

In April 2016, the German Society of Hygiene, Environmental Medicine and Preventative Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin (GHUP)) together with other scientific medical societies, German and Austrian medical societies, physician unions and experts has provided an AWMF (Association of the Scientific Medical Societies) guideline 'Medical diagnostics for indoor mold exposure'. This guideline shall help physicians to advise and treat patients exposed indoors to mold. Indoor mold growth is a potential health risk, even without a quantitative and/or causal association between the occurrence of individual mold species and health effects. Apart from the allergic bronchopulmonary aspergillosis (ABPA) and the mycoses caused by mold, there is only sufficient evidence for the following associations between moisture/mold damages and different health effects: Allergic respiratory diseases, asthma (manifestation, progression, exacerbation), allergic rhinitis, exogenous allergic alveolitis and respiratory tract infections/bronchitis. In comparison to other environmental allergens, the sensitizing potential of molds is estimated to be low. Recent studies show a prevalence of sensitization of 3-10% in the total population of Europe. The evidence for associations to mucous membrane irritation and atopic eczema (manifestation, progression, exacerbation) is classified as limited or suspected. Inadequate or insufficient evidence for an association is given for COPD, acute idiopathic pulmonary hemorrhage in children, rheumatism/arthritis, sarcoidosis, and cancer. The risk of infections from indoor molds is low for healthy individuals. Only molds that are capable to form toxins can cause intoxications. The environmental and growth conditions and especially the substrate determine whether toxin formation occurs, but indoor air concentrations are always very low. In the case of indoor moisture/mold damages, everyone can be affected by odor effects and/or impairment of well-being. Predisposing factors for odor effects can be given by genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for impairment of well-being are environmental concerns, anxieties, conditioning and attributions as well as a variety of diseases. Risk groups that must be protected are patients with immunosuppression and with mucoviscidosis (cystic fibrosis) with regard to infections and individuals with mucoviscidosis and asthma with regard to allergies. If an association between mold exposure and health effects is suspected, the medical diagnosis includes medical history, physical examination, conventional allergy diagnosis, and if indicated, provocation tests. For the treatment of mold infections, it is referred to the AWMF guidelines for diagnosis and treatment of invasive Aspergillus infections. Regarding mycotoxins, there are currently no validated test methods that could be used in clinical diagnostics. From the perspective of preventive medicine, it is important that mold damages cannot be tolerated in indoor environments.

Risk of sensitization and allergy in Ragweed workers - a pilot study.

BACKGROUND: Due to its high allergenic potential Ambrosia artemisiifolia has become a health threat in many European countries during the last few decades. Hence, several cities and communities initiated ragweed eradication campaigns. In Berlin, Germany, so-called Ambrosia scouts are being assigned the task of finding and eliminating this weed. We sought to evaluate the potential risk of sensitization and allergy in these individuals. FINDINGS: In order to assess the risk of sensitization and allergy, we followed-up 20 Ambrosia scouts by skin-prick test with inhalant allergens, immunoserological and pulmonary function tests. Additionally, medical conditions were evaluated by a questionnaire especially designed for this study. Despite close contact to ragweed over a median duration of 13.8 months, none of the participants became sensitized or allergic to ragweed. One individual developed a clinical non-relevant sensitization towards the taxiconomically-related plant mugwort. A decline in relative FEV1 was most probably due to heavy smoking. CONCLUSIONS: Our surprising findings suggest that intensive contact and exposure to high ragweed pollen concentrations do not necessarily result in sensitization and/or allergy, meaning that the allergenic potential of this weed might be lower than hitherto expected. However, it is also conceivable that continuous exposure to high allergen levels induced tolerance in the ragweed workers. Due to the relatively small number of subjects studied, our results might be biased and therefore investigations on larger study groups are needed.

Asthma.

'Asthma' is derived from the Greek root ασθµαινω, meaning 'gasp for breath'. The term originally did not define a disease, but was employed to describe respiratory symptoms of a variety of pulmonary conditions. Over the centuries, several models have been proposed to understand the pathophysiologic abnormalities of asthma. By the beginning of the 20th century, asthma was seen to be a unique illness characterized by 'spasmodic afflictions of the bronchial tubes'. Consistent with the nature of asthma as a complex disease, the models for asthma pathogenesis have become increasingly complex. Research has moved from antiquated ideas to a descriptive functional approach to one that relies on pathophysiology in cellular and molecular biology, immunology, microbiology and genetics/genomics. As more advanced technologies for measuring lung function were developed, the features of asthma were steadily unraveled and its pathophysiology clarified. Asthma was shown to be associated with transient increases in airway resistance, reductions in forced expiratory volumes and flows, hyperinflation of the lungs and increased work of breathing, as well as abnormalities in the distribution of ventilation, perfusion and arterial blood gases. Today, asthma is seen as a chronic inflammatory disease which is not yet fully understood in its pathophysiology; therefore, therapy is still on the path to becoming optimal.