1. Small airways dysfunction in asthma
2. Mechanism of epicutaneous immunotherapy for peanut allergens
3. Fatty-acids intake, air indoor pollution and severity of asthma
4. Benralizumab (B) for PDGFRA-negative hypereosinophilic syndrome
5. IL-33 drives influenza-induced ashtma exarcebations
Small airways dysfunction in asthma
D.S.Postma et al The Lancet Respiratory : 12 March 2019 online first
Small airways lung compartment defined by a diameter of 2mm or less, is well recognized in asthma and contributes to obstruction and ventilation heterogeneity. To assess which combination of biomarkers, physiological tests and imaging markers best measure the presence and extent of SAD, a group of physicians, recruited participants aged 18–65 years with and without asthma at 29 centers across nine countries (Brazil, China, Germany, Italy, Spain, the Netherlands, the UK, the USA, and Canada). 773 participants had received a diagnosis of asthma. Control group (99) aged 18–65 years, had no respiratory symptoms. All participants were assessed with spirometry, body plethysmography, impulse oscillometer, multiple breath nitrogen washout, Computer Tomography (in selected participants). A structural equation modelling in asthmatics was applied from which was defined clinical SAD and CT SAD scores, and patients classified into SAD groups with model-based clustering and compared.
2) Impulse oscillometry and spirometry results, which are used to assess dysfunction of small-sized to mid-sized airways, contributed most to the clinical SAD score; they are easy to use to assess the difference between the two SAD groups.
3) Participants in clinical SAD group 1 (n=452) had milder SAD than group 2. Participants in group 2 (n=312) had abnormal physiological results and had more severe asthma than group 1 and higher clinical SAD scores.
In conclusion of this excellent study, SAD is a complex and silent signature of all types of asthma, but particularly prevalent in severe disease and must be taken into account in its management.
No recognized therapy is available to date for peanut allergy (P.A). In several previous investigations, from a French-USA team, epicutaneous immunotherapy (EPIT) has shown a strongly increase of the threshold levels of patients allergic to PA (phase 2 b clinical trial) with an immune response marked by increase of IgG4 after one year of daily treatment by patches of Viaskin. In this meticulous study, baseline sensitization (specific IgE) was evaluated by ImmunoCAP and ISAC in 2 randomized groups (one Placebo) of 51 children 6 to 11 years. After 1 year of EPIT, strong increase of IgG4 was observed mainly to allergens Ara h2 and Ara h 6, stronger inducers of IgG4, even though they are present on the patch in lower amounts than Ara h 1 and Ara h 3. At the same time specific IgE which were increased during the 1st half year, decreased at one year to Ara h 1, 2 3 8 9. We must remember that other investigational therapies: Oral (OIT) or Sublingual (SLIT) showed induction of IgG4 to Ara h 1and mainly to Ara h 2 comparable or slightly lower than EPIT (between 10 fold to 25 fold the baseline) in quantity and specificity. The advantage of EPIT is through the patch, the low dose necessary to induce a humoral response to peanut allergens. Moreover, these findings confirm the important role of the major allergen Ara h6 and are encouragement to carry on new clinical trials.
Fatty-acids intake, Air Indoor Pollution and severity of AsthmaE.P Brigham et al AJRCCM 2019 29March In press
M.J Rosa and M.S Perzanowsky AJRCCM 2019 March 29 In press
Dietary intake of fatty acids, specifically omega-3 and omega-6, may modify pediatric asthma morbidity. The authors present at first, association between higher omega-6 intake and worse asthma severity in an urban cohort of 135 children with asthma from inner cities near Baltimore (USA). Data included at baseline 3 and 6 months, home indoor concentration of Particulate Matter PM 2,5 and PM 10, daily intake of fatty acids (specific questionnaire : 7 days) daily symptoms of asthma, criteria of severity, lung function and blood leucocytes.
· Higher intake of omega 6 was associated with increased odds of asthma severity (P=0.02 ) lower FEV/FVC ratio (P= 0.01) amplified effect of indoor PM and circulating neutrophil percentage.
· Further, higher omega-3 intake was associated with reduced harmful effect of indoor PM2.5 on respiratory symptoms.
This investigation represents the first evidence of a protective association between omega-3 and detrimental association between omega-6 and PM-induced asthma symptoms. It may provide opportunity for intervention to improve asthma. Rosa et al from New-York underline this intersection of environmental and dietary factors affecting asthma exacerbations.
F. L. Kuang et al NEJM 2109 380 April 4 1336-1346
Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. The American authors sought to use it in Hypereosinophilic syndrome: a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations (intractable pruritus, lung infiltrates endomyocardial fibrosis, thromboembolism). There is no treatment available apart from a myeloid subgroup which owns the gene encoding Platelet Derivative Growth Factor Receptor Alpha and is officially treated by imatinib mesylate.
In a randomized, double-blind, placebo-controlled, phase 2 trial, B was administered at series of three-monthly subcutaneous injections a dose of 30 mg to 20 symptomatic patients -PDGFRA negative, with eosinophil count of at least 1000 cells per cubic millimeter vs Placebo. The primary end point was a reduction of at least 50% in the absolute eosinophil count at week 12. This occurrence was observed in more patients in the B group than in the placebo group (9 of 10 patients vs. 3 of 10 patients P=0.02). During an open-label phase where therapy was more or less tapered, according to tolerance, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with B therapy.
Adverse events, such headache and an elevated lactate LDH level (32% of the patients) after the first dose of B and resolved within 48 hours, did not limit treatment.
L Ravanetti JACI Volume 143, Issue 4, April 2019, Pages 1355-1370
Influenza virus triggers severe asthma exacerbations through the cytokine IL-33, the levels of which correlate with exacerbation severity. The Dutch researchers aimed to dissect the mechanisms which underlie severe exacerbations and unveil the major source of IL-33 in the airways.
Patients with mild asthma were experimentally infected with rhinovirus. Mice were chronically exposed to house dust mite extract and then infected with influenza to resemble key features of exacerbations in human subjects. Interventions included the anti–IL-33 receptor ST2, anti–TSLP, or both.
They identified bronchial ciliated cells and type II alveolar cells as a major local source of IL-33 in human subjects and mice, respectively. By blocking ST2, they demonstrated that TSLP was not necessary to drive exacerbations. IL-33 enhanced airway hyper responsiveness and by suppressing innate and adaptive antiviral responses and by instructing epithelial cells and dendritic cells of house dust mite–sensitized mice to dampen IFN-β expression, prevent the TH1-promoting dendritic cell phenotype. IL-33 also halted cytolytic antiviral activities but did not affect the TH2 response.
In conclusion, given acute IL 33 response to virus, interventions targeting the IL-33/ST2 axis could prove an effective acute short-term therapy.
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