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Background Omalizumab is the recommended treatment for antihistamine‐refractory chronic spontaneous urticaria (CSU) and severe allergic asthma. In addition, it has been shown to reduce the frequency of viral respiratory infections in allergic asthma. Respiratory illness is a known trigger for asthma and CSU. Objectives To explore whether the antiviral effect of omalizumab may be extended to CSU patients independent of their atopic status. Methods We conducted a prospective parallel‐group pilot pragmatic trial including 30 non‐allergic and non‐atopic CSU patients (cases) under omalizumab 300 mg Q4‐weeks (due to refractory to H1‐antihistamines) and 30 age‐matched healthy controls. All CSU patients had to have a weekly urticaria activity score UAS7 <15 at least 4 weeks before recruitment. Using the self‐filled validated Jackson scale, we evaluated all study participants for common cold symptoms. All cases and controls rated weekly their respiratory symptoms. An increase in the symptom score of at least 4 points compared to baseline (defined as the minimum weekly report of symptoms) was considered an episode suggestive of a viral infection of the upper respiratory tract (URT). The patients were follow‐up every 4 weeks throughout the study period (10 months). Results CSU patients under omalizumab reported fewer episodes suggestive of an URT viral infection than the healthy controls (median of reported episodes: 0 vs. 1, inter‐quartile range 0–1 vs. 1–1, min–max: 0–3 vs. 0–4, respectively; p = 0.0095). The duration of each episode was the same in both cases and controls. Conclusions Omalizumab can reduce the number of common cold episodes in CSU patients and consequently may minimize viral‐related CSU exacerbations. This beneficial effect is exerted independently of the atopic status, even in non‐asthmatic individuals or non‐allergic patients without any evidence of respiratory susceptibility. Further large‐scale studies are needed to validate the current findings and elucidate the underlying relevant pathophysiology.

Doc number: 5 Abstract Background: The study of non-atopic asthma/wheeze in children separately from atopic asthma is relatively recent. Studies have focused on single risk factors and had inconsistent findings. Objective: To review evidence on factors associated with non-atopic asthma/wheeze in children and adolescents. Methods: A review of studies of risk factors for non-atopic asthma/wheeze which had a non-asthmatic comparison group, and assessed atopy by skin-prick test or allergen-specific IgE. Results: Studies of non-atopic asthma/wheeze used a wide diversity of definitions of asthma/wheeze, comparison groups and methods to assess atopy. Among 30 risk factors evaluated in the 43 studies only 3 (family history of asthma/rhinitis/eczema, dampness/mold in the household, and lower respiratory tract infections in childhood) showed consistent associations with non-atopic asthma/wheeze. No or limited period of breastfeeding was less consistently associated with non-atopic asthma/wheeze. The few studies examining the effects of overweight/obesity and psychological/social factors showed consistent associations. We used a novel graphical presentation of different risk factors for non-atopic asthma/wheeze, allowing a more complete perception of the complex pattern of effects. Conclusions: More research using standardized methodology is needed on the causes of non-atopic asthma.

Background The Causes And MEchanisms foR non-atopic Asthma in children (CAMERA) study was designed to investigate risk factors and mechanisms of non-atopic asthma in children and young adults in Brazil, Ecuador, Uganda, and New Zealand. Initial epidemiological analyses using existing datasets identified and compared risk factors for both atopic and non-atopic asthma. The focus of this paper is the protocol for sample collection and analysis of clinical data on possible non-atopic mechanisms. Methods In each of the four centres, the CAMERA study will enroll 160 participants aged 10–28 years, equally distributed among atopic asthmatics (AA), non-atopic asthmatics (NAA), atopic non-asthmatics and non-atopic non-asthmatics. Participants will be new recruits or returning World ASthma Phenotypes (WASP) study participants. Phase I consists of skin prick tests to define atopy, a general CAMERA questionnaire that covers respiratory and general health to identify asthma cases, followed by an asthma control questionnaire for asthmatics only. Phase II consists of a stress questionnaire and the following clinical assessments: lung function, nasal cytology, blood sampling, in vitro whole blood stimulation to assess IFN-γ production, hair cortisol concentration, dry air and capsaicin challenges, plus in a subset, cold air challenges. Analyses will compare inflammatory, physiological and clinical parameters across the four groups overall and by country. Discussion Here, we present the protocol for the CAMERA study, to provide relevant methodological details for CAMERA publications and to allow other centres globally to conduct similar analyses. The findings of this mechanistic multi-centre study will inform new and phenotype-specific prevention and treatment approaches. Clinical trial number Not applicable.

Upper respiratory tract infections (URTI) account for more than 80% of wheezing episodes in children with a high incidence of hospitalization in preschool age. Most children with symptoms of wheezing during an URTI are usually non-atopic. As the majority of wheezing episodes resulting from URTI are attributed to viral triggers, several studies have suggested the potential anti-inflammatory and antiviral properties of resveratrol. This study aims to identify the effect of resveratrol for pediatric non-atopic patients with recurrent wheezing triggered by URTIs. We conducted a prospective single-blind study to assess the effectiveness of a short course of nasal solutions incorporating resveratrol and carboxymethyl-β-glucan, administered for 7 days at the onset of URTIs, compared to standard nasal lavage with 0.9% saline solution. A total of 19 patients entered the active group, 20 patients were assigned to the placebo group. The comparison of overall wheezing days (p < 0.001), mean wheezing days per month (p < 0.01), and wheezing episodes per patient (p < 0.001) in the two groups showed a significant reduction in the group receiving resveratrol compared with the placebo group, with less hospital access (p < 0.001) and oral corticosteroid administration (p < 0.01). Our findings seem to suggest that, in non-atopic children with recurrent wheezing secondary to URTIs, nasal resveratrol could be effective to prevent or reduce the occurrence of wheezing, when started from the onset of upper airway symptoms.

A high body mass (BMI) index has repeatedly been associated with non-atopic asthma, but the biological mechanism linking obesity to asthma is still poorly understood. We aimed to test the hypothesis that inflammation and/or innate immunity plays a role in the obesity-asthma link. DNA methylome was measured in blood samples of 61 non-atopic participants with asthma and 146 non-atopic participants without asthma (non-smokers for at least 10 years) taking part in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) study. Modification by DNA methylation of the association of BMI or BMI change over 10 years with adult-onset asthma was examined at each CpG site and differentially methylated region. Pathway enrichment tests were conducted for genes in a priori curated inflammatory pathways and the NLRP3-IL1B-IL17 axis. The latter was chosen on the basis of previous work in mice. Inflammatory pathways including glucocorticoid/PPAR signaling (p = 0.0023), MAPK signaling (p = 0.013), NF-κB signaling (p = 0.031), and PI3K/AKT signaling (p = 0.031) were enriched for the effect modification of BMI, while NLRP3-IL1B-IL17 axis was enriched for the effect modification of BMI change over 10 years (p = 0.046). DNA methylation measured in peripheral blood is consistent with inflammation as a link between BMI and adult-onset asthma and with the NLRP3-IL1B-IL17 axis as a link between BMI change over 10 years and adult-onset asthma in non-atopic participants.

Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism of the beneficial action of inhalations of brine solution from the ‘Wieliczka’ Salt Mine, a Polish health resort, in a murine model of non-atopic asthma. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by an intratracheal challenge of cognate hapten. All animals underwent 12 inhalation sessions with brine solution, pure water or physiological saline. Control mice were not inhaled. We found that brine inhalations reduced, as compared to non-inhaled mice, the typical asthma-related symptoms, like airway hyperreactivity (AHR), the infiltration of pro-inflammatory cells into the bronchial tree, and the inflammation of the airways at the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6. The level of the anti-inflammatory IL-10 was elevated in brine-inhaled mice. Inhalations with pure water increased AHR, whereas saline had no influence, either on AHR or cytokine concentrations. These observations indicate that inhalations with a brine solution from the ‘Wieliczka’ Salt Mine diminish the asthma-related symptoms, mostly by reducing the inflammatory status and by decreasing AHR.

Allergen distribution has obvious geographical characteristics. Understanding local epidemiological data may provide evidence-based strategies for the prevention and management of disease. We investigated the distribution of allergen sensitization in patients with skin diseases in Shanghai, China. Data from tests for serum-specific immunoglobulin E were collected from 714 patients with three skin diseases who visited the Shanghai Skin Disease Hospital from January 2020 to February 2022. The prevalence of 16 allergen species, as well as age, sex, and disease-group differences in allergen sensitization, were investigated. and were the most common aeroallergen species to cause allergic sensitization in patients with skin diseases, whereas shrimp and crab were the most common food-allergen species. Children were more susceptible to various allergen species. With regard to sex differences, males were sensitized to more allergen species than females. Patients suffering from atopic dermatitis were sensitized to more allergenic species than patients with non-atopic eczema or urticaria. Allergen sensitization in patients with skin diseases in Shanghai differed by age, sex, and disease type. Knowing the prevalence of allergen sensitization across age, sex, and disease type may help facilitate diagnostic and intervention efforts, and guide the treatment and management of skin diseases in Shanghai.

We examined anti-inflammatory potency of hybrid peptide-PK20, composed of neurotensin (NT) and endomorphin-2 (EM-2) pharmacophores in a murine model of non-atopic asthma induced by skin sensitization with 2,4-dinitrofluorobenzene and intratracheal challenge of cognate hapten. Mice received intraperitoneally PK20, equimolar mixture of its structural elements (MIX), dexamethasone (DEX), or NaCl. Twenty-four hours following hapten challenge, the measurements of airway responsiveness to methacholine were taken. Bronchoalveolar lavage (BALF) and lungs were collected for further analyses. Treatment with PK20, similarly to dexamethasone, reduced infiltration of inflammatory cells, concentration of mouse mast cell protease, IL-1β, IL-12p40, IL-17A, CXCL1, RANTES in lungs and IL-1α, IL-2, IL-13, and TNF-α in BALF. Simple mixture of NT and EM-2 moieties was less potent. PK20, DEX, and MIX significantly decreased malondialdehyde level and secretory phospholipase 2 activity in lungs. Intensity of NF-κB immunoreactivity was diminished only after PK20 and DEX treatments. Neither PK20 nor mixture of its pharmacophores were as effective as DEX in alleviating airway hyperresponsiveness. PK20 effectively inhibited hapten-induced inflammation and mediator and signaling pathways in a manner seen with dexamethasone. Improved anti-inflammatory potency of the hybrid over the mixture of its moieties shows its preponderance and might pose a promising tool in modulating inflammation in asthma.

Background & objectives: High expression of arginase gene and its elevated level in serum and bronchial lavage reported in animal models indicated an association with the pathogenesis of asthma. This study was undertaken to assess the serum arginase activity in symptomatic asthma patients and healthy controls and to correlate it with cytokine levels [interleukin (IL)-4 and IL-13] and arginase I (ARG1) gene polymorphism. Methods: Asthma was confirmed by lung function test according to the GINA guidelines in patients attending Allergy and Pulmonology Clinic, Bhagwan Mahavir Hospital and Research Centre, Hyderabad, India, a tertiary care centre, during 2013-2015. Serum arginase was analyzed using a biochemical assay, total IgE and cytokine levels by enzyme-linked immunosorbent assay and genotyping of ARG1 for single-nucleotide polymorphisms (SNPs) rs2781666 and rs60389358 using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: There was a significant two-fold elevation in the arginase activity in asthmatics as compared to healthy controls which correlated with disease severity. Non-atopic asthmatics showed elevated activity of arginase compared to atopics, indicating its possible role in intrinsic asthma. Levels of serum IL-13 and IL-4 were significantly high in asthma group which correlated with disease severity that was assessed by spirometry. A positive correlation was observed between arginase activity and IL-13 concentration. Genetic analysis of ARG1 SNPs revealed that rs2781666 G/T genotype, T allele and C-T haplotype (rs60389358 and rs2781666) were associated with susceptibility to asthma. Interpretation & conclusions: This study indicated that high arginase activity and IL-13 concentration in the serum and ARG1 rs2781666 G/T genotype might increase the risk of asthma in susceptible population. Further studies need to be done with a large sample to confirm these findings.

► We studied 164 infants in a RCT who were randomized to prebiotics or placebo added to formula feeding. ► We examined their immunoglobulin-G concentrations specific to Hib and tetanus immunizations. ► Prebiotics supplementation has no effect on vaccination specific antibody levels in young infants. Previous studies have shown, that prebiotics can modulate the immune response in infants at risk for allergy, leading to a lower incidence of atopic dermatitis. Few studies have evaluated the effect of prebiotic carbohydrates alone on the vaccine-specific antibody response as a marker for the development of the immune system in healthy infants not at risk for allergy. This study evaluates the effect of adding a specific prebiotic mixture of short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosaccharides (lcFOS) ratio 9:1 and pectin-derived acidic oligosaccharides (pAOS) to formula feeding on the specific immunoglobulin responses to Haemophilus influenza type b (Hib) and tetanus immunization in healthy non-atopic infants during the first year of life. This substudy has been embedded in a multinational multicenter RCT (n=1130 children) to evaluate the effect of study prebiotics on the incidence of fever episodes during the first year of life. The study prebiotics were administered throughout the first year of life. This is a substudy on the vaccine-specific immunoglobulin responses to Hib and tetanus immunizations. Only data of the Dutch children, 80 in the prebiotics group and 84 in the control group, were used for this substudy. They all followed the national vaccination schedule leading to a homogeneous group. Blood was sampled at 6 and 12months of age. Hib immunizations: median values did not differ between groups at the age of 6 and 12months. At the age of 12months, 34 out of 37 (91.9%) infants in the prebiotics group and 31 out of 34 infants (91.2%) in the control group had Hib antibody levels >1.0μg/ml. Tetanus immunizations: median values did not differ between groups at the age of 6 and 12months and were above the cut-off value of 0.1IU/ml in all infants in both the prebiotics and the control group. No effect of prebiotics supplementation on vaccination specific antibody levels was found in children up to the age of 12months; the vaccine specific antibody levels in infants fed the study prebiotics or a control diet were similar during the first year of life. We hypothesize that this specific prebiotic mixture, which resembles the composition of oligosaccharides in human milk, mainly promotes Th1 and Treg dependent immune responses and induces a down regulation of IgE-mediated allergic responses, while the desired vaccine-specific serum antibody responses remain intact.