Bronchodilator Reversibility in the GAN Severe Asthma Cohort.

BACKGROUND AND OBJECTIVE: Positive bronchodilator reversibility (BDR) is a diagnostic criterion for asthma. However, patients with asthma may exhibit a negative BDR response. Aim: To describe the frequency of positive and Negative BDR response in patients with severe asthma and study associations with phenotypic characteristics. METHODS: A positive BDR response was defined as an increase in FEV1 >200 mL and >12% upon testing with a short-acting ß-agonist. RESULTS: BDR data were available for 793 of the 2013 patients included in the German Asthma Net (GAN) severe asthma registry. Of these, 250 (31.5%) had a positive BDR response and 543 (68.5%) a egative BDR response. Comorbidities significantly associated with a negative response were gastroesophageal reflux disease (GERD) (28.0% vs 40.0%, P<.01) and eosinophilic granulomatosis with polyangiitis (0.4% vs 3.0%; P<.05), while smoking history (active: 2.8% vs 2.2%; ex: 40.0% vs 41.7%) and comorbid chronic obstructive pulmonary disease (COPD) (5.2% vs 7.2%) were similar in both groups. Patients with a positive BDR response had worse asthma control (median Asthma Control Questionnaire 5 score, 3.4 vs 3.0, P<.05), more frequently reported dyspnea at rest (26.8% vs 16.4%, P<.001) and chest tightness (36.4% vs 26.2%, P<.001), and had more severe airway obstruction at baseline (FEV1% predicted, 56 vs 64, P<.001) and higher fractional exhaled nitric oxide (FeNO) levels (41 vs 33 ppb, P<0.05). There were no differences in diffusion capacity of the lung for carbon monoxide, single breath (% pred, 70% vs 71%). Multivariate linear regression analysis identified an association between positive BDR response and lower baseline FEV1% (P<.001) and chest tightness (P<.05) and a negative association between BDR and GERD (P<.05). CONCLUSION: In this real-life setting, most patients with severe asthma had a negative BDR response. Interestingly, this was not associated with smoking history or COPD, but with lower FeNO and presence of GERD.

[COVID-19 Vaccination in Asthma Patients Treated with Biologicals - Statement of the Austrian Society of Pneumology and German Respiratory Society]. / COVID-19-Impfungen bei Biologika-Therapie von Asthma bronchiale.

Patients with asthma should be vaccinated against COVID-19. This includes patients with severe asthma. Treatment with a biological for asthma is no contra-indication for vaccination against COVID-19.

[Guideline for the Diagnosis and Treatment of Asthma - Addendum 2020 - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma ­ Addendum 2020.

The present addendum of the guideline for the diagnosis and treatment of asthma (2017) complements new insights into the diagnosis and management of asthma as well as for the newly approved drugs for the treatment of asthma. Current, evidence-based recommendations on diagnostic and therapeutic approaches are presented for children and adolescents as well as for adults with asthma.

Clinical trials in allergen immunotherapy: current concepts and future needs.

Allergen immunotherapy (AIT) is a safe, effective treatment for allergic rhinoconjunctivitis and allergic asthma. However, AIT's clinical effect is still contested-primarily due to heterogeneity in clinical trial designs, study populations, therapeutic formulations, and efficacy criteria. After discussing current concepts and unmet needs, an international panel of experts made several recommendations: (i) explore and validate definitions for (clinical) responders in AIT trials; (ii) use of well-documented, standardized provocation tests prior to inclusion of subjects with relevant diseases in AIT trials; (iii) monitoring neo-sensitizations and occurrence of new allergy in extended AIT trials, and exclusion of polyallergic participants; (iv) validation of allergen exposure chambers with regard to natural exposure; (v) in studies of seasonal allergies, focus on peak exposure but also consider organizing two parallel, geographically distinct but otherwise identical trials; (vi) discuss adaptive trial designs with the regulatory authorities; (vii) use e-health and m-health technologies to capture more information on individual exposure to allergens; (viii) initiate research on potential psychological, biochemical, immune, neural, and even genomic markers of the placebo response; (ix) identify trial designs and primary endpoints that will give children with allergies easier, faster access to AIT formulations; and (x) promote and apply standardized methods for reporting systemic and local adverse events. The latest technologies and trial designs may provide novel, ethical ways of reducing bias and heterogeneity in AIT clinical trials. There is scope for physicians, patient organizations, companies, and regulators to improve clinical trials in AIT and, ultimately, to provide patients with better treatments.

The roadmap for allergology in Europe: The subspecialty of allergology as "stop-over" on the way to a full specialty. An EAACI position statement.

The vision of European Academy of Allergy and Clinical Immunology (EAACI) and the Union of European Medical Specialists Section and Board on allergology is to promote and to establish a full specialty of allergology in all European countries. In many European countries, a full specialty does not exist. In those countries, organ-based (sub)specialists or paediatricians and internists with an expertise in allergology may deliver allergy care. There are no generally accepted requirements for the training of subspecialists available. To fill the gap between the need and availability of experienced and accredited physicians who can deliver optimal care to the allergic patients, the EAACI Specialty Committee proposes the minimal requirements for training and certification of subspecialists in allergology. This paper describes the required theoretical knowledge, skills, competences and training facilities (staff and institution). The subspecialist as described in this paper should ideally show the necessary competence in providing good quality care to patients in an environment lacking those full specialists in allergology or tertiary care paediatric subspecialists in allergy.

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

Allergy in severe asthma.

It is well recognized that atopic sensitization is an important risk factor for asthma, both in adults and in children. However, the role of allergy in severe asthma is still under debate. The term 'Severe Asthma' encompasses a highly heterogeneous group of patients who require treatment on steps 4-5 of GINA guidelines to prevent their asthma from becoming 'uncontrolled', or whose disease remains 'uncontrolled' despite this therapy. Epidemiological studies on emergency room visits and hospital admissions for asthma suggest the important role of allergy in asthma exacerbations. In addition, allergic asthma in childhood is often associated with severe asthma in adulthood. A strong association exists between asthma exacerbations and respiratory viral infections, and interaction between viruses and allergy further increases the risk of asthma exacerbations. Furthermore, fungal allergy has been shown to play an important role in severe asthma. Other contributing factors include smoking, pollution and work-related exposures. The 'Allergy and Asthma Severity' EAACI Task Force examined the current evidence and produced this position document on the role of allergy in severe asthma.

Allergen immunotherapy for allergic rhinoconjunctivitis: A systematic review and meta-analysis.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing Guidelines on Allergen Immunotherapy (AIT) for Allergic Rhinoconjunctivitis. To inform the development of clinical recommendations, we undertook a systematic review to assess the effectiveness, cost-effectiveness, and safety of AIT in the management of allergic rhinoconjunctivitis. METHODS: We searched nine international biomedical databases for published, in-progress, and unpublished evidence. Studies were independently screened by two reviewers against predefined eligibility criteria and critically appraised using established instruments. Our primary outcomes of interest were symptom, medication, and combined symptom and medication scores. Secondary outcomes of interest included cost-effectiveness and safety. Data were descriptively summarized and then quantitatively synthesized using random-effects meta-analyses. RESULTS: We identified 5960 studies of which 160 studies satisfied our eligibility criteria. There was a substantial body of evidence demonstrating significant reductions in standardized mean differences (SMD) of symptom (SMD -0.53, 95% CI -0.63, -0.42), medication (SMD -0.37, 95% CI -0.49, -0.26), and combined symptom and medication (SMD -0.49, 95% CI -0.69, -0.30) scores while on treatment that were robust to prespecified sensitivity analyses. There was in comparison a more modest body of evidence on effectiveness post-discontinuation of AIT, suggesting a benefit in relation to symptom scores. CONCLUSIONS: AIT is effective in improving symptom, medication, and combined symptom and medication scores in patients with allergic rhinoconjunctivitis while on treatment, and there is some evidence suggesting that these benefits are maintained in relation to symptom scores after discontinuation of therapy.

[Current Practice of Pre- and Postnatal Screening and Future Developments for Evidence Based Guidelines]. / Aktueller Stand und zukünftige Entwicklung der prä- und postnatalen Vorsorge- bzw. Screeninguntersuchungen ­ Evidenz tut Not.

Objectives: In this selective review we provide an overview of the current pre- and postnatal screenings up to 18 years established in Germany to inform physicians of different medical fields (gynecologists, pediatricians, general practitioners, other medical specialists who treat children, adolescents or pregnant females). Current State: Research on screening for different types of cancer has frequently failed to show any benefit. Thus, there is a need to broaden the evidence basis related to medical screenings especially for children and adolescents. Outlook: Potential future developments of pre- and postnatal screenings are illustrated including their social impact. The lack of an early detection of mental health problems is pointed out. An interdisciplinary collaboration and research is required to accumulate evidence with regard to medical screenings and to consider health economic and ethical aspects.

[Guideline for the Diagnosis and Treatment of Asthma - Guideline of the German Respiratory Society and the German Atemwegsliga in Cooperation with the Paediatric Respiratory Society and the Austrian Society of Pneumology]. / S2k-Leitlinie zur Diagnostik und Therapie von Patienten mit Asthma.

The present guideline is a new version and an update of the guideline for the diagnosis and treatment of asthma, which replaces the previous version for german speaking countries from the year 2006. The wealth of new data on the pathophysiology and the phenotypes of asthma, and the expanded spectrum of diagnostic and therapeutic options necessitated a new version and an update. This guideline presents the current, evidence-based recommendations for the diagnosis and treatment of asthma, for children and adolescents as well as for adults with asthma.

[Vascular anomaly in the midcheek region of an infant--review of the diagnostic procedure]. / Gefäßanomalie in der Wangenregion eines Säuglings - Diagnostischer Prozess anhand einer Kasuistik.

Clinical history, physical examination, evolution and imaging findings (Colour Doppler sonography, MRI if available) are of pivotal importance in the diagnostic pathway of an infantile vascular anomaly. Histopathology with specific stains and markers is contributive in difficult cases. Differentiation between vascular tumors (hemangioma) and vascular malformations is now well known and integrated into the ISSVA classification. We report here a 6-months-old boy, who presented with a localized cutaneous and expansive vascular birthmark in the left cheek and developed bleedings at the age of 18 months. Diagnostic features of a hemangioma were not evident, and the final diagnosis of a venous malformation was confirmed by histopathology.

Observational Study on Less Invasive Surfactant Administration (LISA) in Preterm Infants<29 Weeks--Short and Long-term Outcomes.

BACKGROUND: A recent trial has demonstrated short-term benefits of a new minimal invasive procedure of surfactant administration in spontaneously breathing preterm infants ≥ 26 weeks (less invasive surfactant administration, LISA). AIM: To assess safety as well as short- and long-term outcomes of the LISA procedure in preterm infants between 23-28 weeks of gestation. STUDY DESIGN: Preterm infants born between 23+0 and 28+6 weeks gestational age during 2 periods, 18 months before (Period 1, n=44) and 18 months after introduction of LISA (Period 2, n=53), were analyzed for neonatal outcomes. 52% of discharged infants were assessed for neurodevelopmental outcome at corrected age of 3 years. RESULTS: In Period 2, 66% of the preterm infants needing surfactant were treated by the new method of LISA. In this period, fewer patient had to be ventilated during the first 3 days of life (42 vs. 77%, p<0.0005) and overall (55 vs. 77%, p=0.02). The median duration of mechanical ventilation was 2 vs. 3 days (p=0.056). Survival without BPD was 68% in period 1 and 74% in period 2 (p=0.29). In period 2, fewer infants received antibiotics after the third day of life (43 vs. 66%, p=0.04), systemic glucocorticoids were less frequently used (7.5 vs. 23%, p=0.04), and more infants received doxapram (34 vs. 2.3%, p<0.0001). Mental Developmental Index (89 vs. 98, p=0.16) and Physical Developmental Index (83 vs. 91, p=0.03) at 3 years improved between the 2 periods. CONCLUSION: Implementation of the LISA method on a neonatal ward was safe and feasible and was associated with less need for mechanical ventilation in infants >24 weeks. As our study was retrospective the observed trends for better pulmonary and neurocognitive outcomes should be interpreted with caution until results from randomized trials on the LISA procedure are available.

Therapeutic potential of larval excretory/secretory proteins of the pig whipworm Trichuris suis in allergic disease.

BACKGROUND: Gastrointestinal nematodes are currently being evaluated as a novel therapeutic in the treatment of chronic human inflammatory disorders, due to their unique ability to induce immunoregulatory pathways in their hosts. In particular, administration of ova from the pig whipworm Trichuris suis (T. suis; TSO) has been proposed for the treatment of allergic, inflammatory and autoimmune disorders. Despite these advances, the biological pathways through which TSO therapy modulates the host immune system in the context of human disease remain undefined. METHODS: We characterized the dominant proteins present in the excretory/secretory (E/S) products of first-stage (L1) T. suis larvae (Ts E/S) using LC-MS/MS analysis and examined the immunosuppressive properties of whole larval Ts E/S in vitro and in a murine model of allergic airway disease. RESULTS: Administration of larval Ts E/S proteins in vivo during the allergen sensitization phase was sufficient to suppress airway hyperreactivity, bronchiolar inflammatory infiltrate and allergen-specific IgE production. Three proteins in larval Ts E/S were unambiguously identified. The immunomodulatory function of larval Ts E/S was found to be partially dependent on the immunoregulatory cytokine IL-10. CONCLUSIONS: Taken together, these data demonstrate that the released proteins of larval T. suis have significant immunomodulatory capacities and efficiently dampen allergic airway hyperreactivity. Thus, the therapeutic potential of defined larval E/S proteins should be exploited for the treatment of human allergic disorders.

The role of lipocalins in airway disease.

The pathogenesis of allergic airway inflammation and disease is complex and still not fully understood. Many cells, factors and mediators are involved in the different aspects of induction, maintenance and persistence of airway inflammation. The heterogeneity and redundancy of this system is one of the main reasons why novel therapeutic targets focusing on the pathogenesis of asthma only hesitantly reach the market and clinical application. Thus, it seems mandatory that we proceed in our efforts to better understand this micro cosmos to succeed in the development of safe and effective drugs for the treatment of more severe and refractory forms of asthma and chronic obstructive pulmonary disease. One of the more recently discovered mediators in the context of airway inflammation are the lipocalins (Lcns). They are a family of proteins that share functional and structural similarities and are involved in the transport of small hydrophobic molecules such as steroids and lipids into the cell. Lcns are found in many different cell types from plants and bacteria through invertebrate cells to cells of vertebrate origin. The purpose of this review is to summarize the role of Lcns in airway diseases, focusing on allergic and infectious inflammation. In particular, we will summarize the present knowledge about Lipocalin 1 and Lipocalin 2, where exciting new discoveries in the recent years have highlighted their role in pulmonary disease and infection. This new class of proteins is another putative candidate for the development of novel drugs against airway inflammation.

EAACI position statement on asthma exacerbations and severe asthma.

Asthma exacerbations and severe asthma are linked with high morbidity, significant mortality and high treatment costs. Recurrent asthma exacerbations cause a decline in lung function and, in childhood, are linked to development of persistent asthma. This position paper, from the European Academy of Allergy and Clinical Immunology, highlights the shortcomings of current treatment guidelines for patients suffering from frequent asthma exacerbations and those with difficult-to-treat asthma and severe treatment-resistant asthma. It reviews current evidence that supports a call for increased awareness of (i) the seriousness of asthma exacerbations and (ii) the need for novel treatment strategies in specific forms of severe treatment-resistant asthma. There is strong evidence linking asthma exacerbations with viral airway infection and underlying deficiencies in innate immunity and evidence of a synergism between viral infection and allergic mechanisms in increasing risk of exacerbations. Nonadherence to prescribed medication has been identified as a common clinical problem amongst adults and children with difficult-to-control asthma. Appropriate diagnosis, assessment of adherence and other potentially modifiable factors (such as passive or active smoking, ongoing allergen exposure, psychosocial factors) have to be a priority in clinical assessment of all patients with difficult-to-control asthma. Further studies with improved designs and new diagnostic tools are needed to properly characterize (i) the pathophysiology and risk of asthma exacerbations, and (ii) the clinical and pathophysiological heterogeneity of severe asthma.

Prenatal allergen exposures prevent allergen-induced sensitization and airway inflammation in young mice.

BACKGROUND: Immune-modulation such as tolerance induction appears to be an upcoming concept to prevent development of atopic diseases. Pregnancy might present a critical period for preventing allergic sensitization of the progeny. We investigated the effect of maternal allergen exposures during pregnancy on allergen-induced sensitization and airway inflammation in the offspring in a murine model. METHODS: BALB/c mice were exposed to aerosolized ovalbumin (OVA) three times per week from day 7 of pregnancy until delivery (day 0). Offspring were systemically sensitized by six intraperitoneal injections with OVA between postnatal days 21 and 35, prior to airway allergen challenges on days 48, 49, and 50. Analyses were performed on day 52. To examine long-lasting effects of maternal OVA exposures some offspring were sensitized between days 115 and 129; analyses took place on day 147. RESULTS: Compared to maternal placebo exposures, maternal OVA exposures suppressed OVA-specific IgE serum levels and inhibited development of allergen-induced airway inflammation in the OVA-sensitized offspring on both days 52 and 147. This protective effect was associated with a shift from a predominant Th2 immune response toward a predominant production of the cytokines IFN-γ and IL-10. Further, maternal OVA exposures were associated with development of CD25(+) Foxp3(+) regulatory T cells (T(regs)) in the OVA-sensitized offspring. Depletion of T(regs) or neutralization of IL-10 prior to allergen sensitization re-established OVA-induced sensitization and eosinophilic airway inflammation in the OVA-sensitized offspring. CONCLUSIONS: In our model, maternal allergen exposures during pregnancy prevented later allergen-mediated sensitization and airway inflammation by allergen-specific tolerance induction in the offspring.

Questionnaire to preselect patients with a high probability of primary ciliary dyskinesia.

BACKGROUND: As diagnostic methods for primary ciliary dyskinesia are not generally available, we tested whether clinical criteria allow to preselect patients with a high probability of this disease, who should be further investigated in a specialized centre. PATIENTS AND METHODS: In patients with chronic cough we compared parameters of the case history with the finding of a reduced ciliary beat frequency (CBF). Data sheets of 323 patients (133 females, 190 males) aged 1 week through 40 years (median age 4.5 years) were available for analysis. Of these patients 46 (14%) had a reduced CBF. RESULTS: In this group the following features were found significantly more frequently compared to patients with normal CBF: neonatal respiratory disorder (odds ratio (OR) 9.0; 95% confidence interval (95% CI) 3.2;25), situs inversus (OR 8.1; 95% CI 2.5;26), retention of airway secretions (OR 6.7; 95% CI 2.4;19), recurrent pneumonia (OR 4.1; 95% CI 1.8;9.5), bronchiectasis (OR 3.5; 95% CI 1.2;11), asthma with poor response to treatment (OR 2.4; 95% CI 1.1;5.3). At least one of these potential indicators was present in 91% of the patients with reduced CBF. CONCLUSIONS: In patients with chronic cough specific parameters of the case history indicate a high probability of a reduced ciliary beat frequency which is an indicator for primary ciliary dyskinesia. If none of these findings is present, a reduced CBF is highly unlikely.

Ultrasound and colour Doppler in infantile subglottic haemangioma.

BACKGROUND: Subglottic haemangioma causes progressive and life-threatening stridor, typically manifesting at age 2-3 months. Standard diagnosis is by laryngoscopy. Larynx sonography is rarely used but allows assessment of the presence and extension of a mass that impinges on the subglottic airway. The additional use of colour Doppler enables demonstration of the vascular nature of such masses. OBJECTIVE: To compare US and endoscopic findings in infants with subglottic haemangioma and to evaluate accuracy of US and colour Doppler imaging in this diagnosis. MATERIALS AND METHODS: We report eight infants with subglottic haemangioma seen in our institution over the last decade. They presented with laryngeal stridor and were all investigated with both US and endoscopy. Six infants underwent colour Doppler sonography. RESULTS: US and endoscopic findings showed excellent anatomical correlation in lateral subglottic haemangioma. Colour Doppler imaging was deemed helpful in four infants. CONCLUSION: Larynx sonography with complementary colour Doppler imaging was non-invasive and helpful in the diagnosis of subglottic haemangioma.