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Concept: Asthma

186

Background Many patients with severe asthma rely on oral glucocorticoids to manage their disease. We investigated whether benralizumab, a monoclonal antibody directed against the alpha subunit of the interleukin-5 receptor that significantly reduces the incidence of asthma exacerbations, was also effective as an oral glucocorticoid-sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. Methods In a 28-week randomized, controlled trial, we assessed the effects of benralizumab (at a dose of 30 mg administered subcutaneously either every 4 weeks or every 8 weeks [with the first three doses administered every 4 weeks]) versus placebo on the reduction in the oral glucocorticoid dose while asthma control was maintained in adult patients with severe asthma. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed. Results Of 369 patients enrolled, 220 underwent randomization and started receiving benralizumab or placebo. The two benralizumab dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group (P<0.001 for both comparisons). The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with benralizumab as with placebo. Among the secondary outcomes, benralizumab administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo (marginal rate, 0.83 vs. 1.83, P=0.003), and benralizumab administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo (marginal rate, 0.54 vs. 1.83, P<0.001). At 28 weeks, there was no significant effect of either benralizumab regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. The effects on various measures of asthma symptoms were mixed, with some showing significant changes in favor of benralizumab and others not showing significant changes. Frequencies of adverse events were similar between each benralizumab group and the placebo group. Conclusions Benralizumab showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1. (Funded by AstraZeneca; ZONDA ClinicalTrials.gov number, NCT02075255 .).

Concepts: Respiratory physiology, Effectiveness, Dose, Glucocorticoid, Immune system, Spirometry, Clinical trial, Asthma

180

Increased oxidative stress contributes to development and progression of several human chronic inflammatory diseases. Cherries are a rich source of polyphenols and vitamin C which have anti-oxidant and anti-inflammatory properties. Our aim is to summarize results from human studies regarding health benefits of both sweet and tart cherries, including products made from them (juice, powder, concentrate, capsules); all referred to as cherries here. We found 29 (tart 20, sweet 7, unspecified 2) published human studies which examined health benefits of consuming cherries. Most of these studies were less than 2 weeks of duration (range 5 h to 3 months) and served the equivalent of 45 to 270 cherries/day (anthocyanins 55-720 mg/day) in single or split doses. Two-thirds of these studies were randomized and placebo controlled. Consumption of cherries decreased markers for oxidative stress in 8/10 studies; inflammation in 11/16; exercise-induced muscle soreness and loss of strength in 8/9; blood pressure in 5/7; arthritis in 5/5, and improved sleep in 4/4. Cherries also decreased hemoglobin A1C (HbA1C), Very-low-density lipoprotein (VLDL) and triglycerides/high-density lipoprotein (TG/HDL) in diabetic women, and VLDL and TG/HDL in obese participants. These results suggest that consumption of sweet or tart cherries can promote health by preventing or decreasing oxidative stress and inflammation.

Concepts: Asthma, Antioxidant, Diabetes mellitus, Vitamin C, Nutrition, Atherosclerosis, Inflammation, Anti-inflammatory

180

Positive associations between having a pet dog and adult health outcomes have been documented; however, little evidence exists regarding the benefits of pet dogs for young children. This study investigates the hypothesis that pet dogs are positively associated with healthy weight and mental health among children.

Concepts: Asthma, Pet, Medical terms, Epidemiology, Dog, Public health, Medicine

180

To the Editor: Changing patterns of allergic sensitization to pollens have been noted around the world among schoolchildren. We report one associated with unusual winter allergic symptoms in Switzerland. Our group has gathered information on allergic symptoms and serologic findings among 15-year-olds attending school in Grabs, a village in eastern Switzerland,(1) from 1983 through 2007.(2) We measured IgE antibodies to 103 molecular allergens (using ImmunoCAP ISAC) in serum samples obtained from 54 students in 1986 and from 46 students in 2006.(3) In 2010, we retested 12 of the former students (then 39 years old) who in 1986 had had positive . . .

Concepts: Immunology, October 12, Ragweed, Antibody, Immunoglobulin E, Immune system, Asthma, Allergy

180

BACKGROUND: Studies on the association of birth by caesarean section (C/S) and allergies have produced conflicting findings. Furthermore, evidence on whether this association may differ in those at risk of atopy is limited. This study aims to investigate the association of mode of delivery with asthma and atopic sensitization and the extent to which any effect is modified by family history of allergies. METHODS: Asthma outcomes were assessed cross-sectionally in 2216 children at age 8 on the basis of parents' responses to the ISAAC questionnaire whilst skin prick tests to eleven aeroallergens were also performed in a subgroup of 746 children. Adjusted odds ratios of asthma and atopy by mode of delivery were estimated in multivariable logistic models while evidence of effect modification was examined by introducing interaction terms in the models. RESULTS: After adjusting for potential confounders, children born by C/S appeared significantly more likely than those born vaginally to report ever wheezing (OR 1.36, 95% CI 1.07-1.71), asthma diagnosis (OR 1.41, 95% CI 1.09-1.83) and be atopic (OR 1.67, 95% CI 1.08-2.60). There was modest evidence that family history of allergies may modify the effect of C/S delivery on atopy (p for effect modification=0.06) but this was not the case for the asthma outcomes. Specifically, while more than a two-fold increase in the odds of being a topic was observed in children with a family history of allergies if born by C/S (OR 2.62, 95% CI 1.38-5.00), no association was observed in children without a family history of allergies (OR 1.16, 95% CI 0.64-2.11). CONCLUSIONS: Birth by C/S is associated with asthma and atopic sensitization in childhood. The association of C/S and atopy appears more pronounced in children with family history of allergies.

Concepts: Allergen, Caesarean delivery on maternal request, Odds ratio, Hypersensitivity, Allergy, Atopy, Childbirth, Asthma

179

Chronic Obstructive Pulmonary Disease (COPD) is characterized by high morbidity and mortality. It remains unknown which aspect of lung function carries the most prognostic information and if simple spirometry is sufficient.Survival was assessed in COPD outpatients whose data had been added prospectively to a clinical audit database from the point of first full lung function testing including spirometry, lung volumes, carbon monoxide diffusion capacity and arterial blood gases. Variables univariately associated with survival were entered into a multivariate Cox proportional hazard model.604 patients were included (mean age 61.9±9.7 years, forced expiratory volume in 1 second 37±18.1%predicted, 62.9% males); 229(37.9%) died during a median follow-up of 83 months. Median survival was 91.9(80.8-103) months with survival rates at 3 and 5 years 0.83 and 0.66, respectively. Carbon monoxide diffusion capacity %predicted quartiles [(best quartile (>51%): HR=: 0.33; 95% CI: 0.96-0. and second quartile (51-37.3%): HR=0.52, versus lowest quartile (<27.9%))], age (HR=:1.04; 95% CI:1.02-1.06) and arterial oxygen partial pressure (HR=: 0.85;95% CI:0.77-0.94) were the only parameters independently associated with mortality.Measurement of diffusion capacity provides additional prognostic information compared to spirometry in patients under hospital follow-up and could be considered routinely.

Concepts: Respiratory therapy, Lung, Spirometry, Oxygen, Respiratory physiology, Chronic obstructive pulmonary disease, Pulmonology, Asthma

176

Coal workers' pneumoconiosis, also known as “black lung disease,” is an occupational lung disease caused by overexposure to respirable coal mine dust. Inhaled dust leads to inflammation and fibrosis in the lungs, and coal workers' pneumoconiosis can be a debilitating disease. The Federal Coal Mine Health and Safety Act of 1969 (Coal Act),* amended in 1977, established dust limits for U.S. coal mines and created the National Institute for Occupational Safety and Health (NIOSH)-administered Coal Workers' Health Surveillance Program with the goal of reducing the incidence of coal workers' pneumoconiosis and eliminating its most severe form, progressive massive fibrosis (PMF),(†) which can be lethal. The prevalence of PMF fell sharply after implementation of the Coal Act and reached historic lows in the 1990s, with 31 unique cases identified by the Coal Workers' Health Surveillance Program during 1990-1999. Since then, a resurgence of the disease has occurred, notably in central Appalachia (Figure 1) (1,2). This report describes a cluster of 60 cases of PMF identified in current and former coal miners at a single eastern Kentucky radiology practice during January 2015-August 2016. This cluster was not discovered through the national surveillance program. This ongoing outbreak highlights an urgent need for effective dust control in coal mines to prevent coal workers' pneumoconiosis, and for improved surveillance to promptly identify the early stages of the disease and stop its progression to PMF.

Concepts: Asthma, Anthracite, Kentucky, Pulmonology, Coal mining, Epidemiology, Coal, Occupational safety and health

174

BACKGROUND: Severe eczema in young children is associated with an increased risk of developing asthma and rhino-conjunctivitis. In the general population, however, most cases of eczema are mild to moderate. In an unselected cohort, we studied the risk of current asthma and the co-existence of allergy-related diseases at 6 years of age among children with and without eczema at 2 years of age. METHODS: Questionnaires assessing various environmental exposures and health variables were administered at 2 years of age. An identical health questionnaire was completed at 6 years of age. The clinical investigation of a random subsample ascertained eczema diagnoses, and missing data were handled by multiple imputation analyses. RESULTS: The estimate for the association between eczema at 2 years and current asthma at 6 years was OR=1.80 (95 % CI 1.10-2.96). Four of ten children with eczema at 6 years had the onset of eczema after the age of 2 years, but the co-existence of different allergy-related diseases at 6 years was higher among those with the onset of eczema before 2 years of age. CONCLUSIONS: Although most cases of eczema in the general population were mild to moderate, early eczema was associated with an increased risk of developing childhood asthma. These findings support the hypothesis of an atopic march in the general population.Trial registrationThe Prevention of Allergy among Children in Trondheim study has been identified as ISRCTN28090297 in the international Current Controlled Trials database.

Concepts: Data analysis, Epidemiology, Allergen, Expectation-maximization algorithm, Clinical trial, Asthma, Allergy, Eczema

173

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat ω-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE) specific to recombinant ω-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP), has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum ω-5 gliadin-specific serum IgE.

Concepts: Immunoglobulin E, Hypersensitivity, Allergology, Mast cell, Asthma, Wheat, Immune system, Allergy

172

For many years, pathogenetic concepts and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. However, there is now growing clinical and mechanistic evidence suggesting that treatment with the anti-IgE antibody omalizumab can be effective in patients with intrinsic asthma. Therefore, large and well-controlled clinical trials with anti-IgE are urgently warranted in patients with intrinsic asthma. In addition, there is a need to find new biomarkers which can identify patients with asthma who respond to anti-IgE treatment.

Concepts: Atopy, Hygiene hypothesis, Immunology, Clinical trial, Immunoglobulin E, Allergy, Asthma, Immune system