OBJECTIVE: To determine whether genetic variants in and around SPINK5 are associated with IgE-mediated food allergy.
METHOD: We genotyped 71 "tag" single nucleotide polymorphisms (tag-SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food-allergic, n=199 food-sensitized-tolerant and n=156 non-food-allergic controls) 12-month-old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran-Mantel-Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food-allergic, n=330 non-food-allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components.
RESULTS: SPINK5 variant rs9325071 (A⟶G) was associated with challenge-proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49-5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13-2.20) and by meta-analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype-tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also.
CONCLUSIONS: We report, for the first time, association between SPINK5 variant rs9325071 and challenge-proven IgE-mediated food allergy.
METHODS: We searched nine international biomedical databases for published, in-progress, and unpublished evidence.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.
METHOD: The scientific information on COVID-19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet.
RESULTS: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID-19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID-19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies.
CONCLUSIONS: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID-19 pandemic.
METHODS: Using data from the Global Burden of Diseases (GBD), Injuries, and Risk Factors Study 2019, we assessed the age-standardized prevalence, incidence, mortality, and disability-adjusted life years (DALYs) of both asthma and AD from 1990 to 2019, stratified by geographic region, age, sex, and socio-demographic index (SDI). DALYs were calculated as the sum of years lived with disability and years of life lost to premature mortality. Additionally, the disease burden of asthma attributable to high body mass index, occupational asthmagens, and smoking was described.
RESULTS: In 2019, there were a total of 262 million [95% uncertainty interval (UI): 224-309 million] cases of asthma and 171 million [95% UI: 165-178 million] total cases of AD globally; age-standardized prevalence rates were 3416 [95% UI: 2899-4066] and 2277 [95% UI: 2192-2369] per 100,000 population for asthma and AD, respectively, a 24.1% [95% UI: -27.2 to -20.8] decrease for asthma and a 4.3% [95% UI: 3.8-4.8] decrease for AD compared to baseline in 1990. Both asthma and AD had similar trends according to age, with age-specific prevalence rates peaking at age 5-9 years and rising again in adulthood. The prevalence and incidence of asthma and AD were both higher for individuals with higher SDI; however, mortality and DALYs rates of individuals with asthma had a reverse trend, with higher mortality and DALYs rates in those in the lower SDI quintiles. Of the three risk factors, high body mass index contributed to the highest DALYs and deaths due to asthma, accounting for a total of 3.65 million [95% UI: 2.14-5.60 million] asthma DALYs and 75,377 [95% UI: 40,615-122,841] asthma deaths.
CONCLUSIONS: Asthma and AD continue to cause significant morbidity worldwide, having increased in total prevalence and incidence cases worldwide, but having decreased in age-standardized prevalence rates from 1990 to 2019. Although both are more frequent at younger ages and more prevalent in high-SDI countries, each condition has distinct temporal and regional characteristics. Understanding the temporospatial trends in the disease burden of asthma and AD could guide future policies and interventions to better manage these diseases worldwide and achieve equity in prevention, diagnosis, and treatment.
METHODS: We developed mouse models representing three different phenotypes of allergic airway inflammation-eosinophilic, mixed, and neutrophilic asthma via different methods of house dust mite sensitization and challenge. Transcriptomic analysis of the lungs, followed by the RT-PCR, western blot, and confocal microscopy, was performed. Primary human bronchial epithelial cells cultured in air-liquid interface were used to study the mechanisms revealed in the in vivo models.
RESULTS: By whole-genome transcriptome profiling of the lung, we found that airway tight junction (TJ), mucin, and inflammasome-related genes are differentially expressed in these distinct phenotypes. Further analysis of proteins from these families revealed that Zo-1 and Cldn18 were downregulated in all phenotypes, while increased Cldn4 expression was characteristic for neutrophilic airway inflammation. Mucins Clca1 (Gob5) and Muc5ac were upregulated in eosinophilic and even more in neutrophilic phenotype. Increased expression of inflammasome-related molecules such as Nlrp3, Nlrc4, Casp-1, and IL-1β was characteristic for neutrophilic asthma. In addition, we showed that inflammasome/Th17/neutrophilic axis cytokine-IL-1β-may transiently impair epithelial barrier function, while IL-1β and IL-17 increase mucin expressions in primary human bronchial epithelial cells.
CONCLUSION: Our findings suggest that differential expression of TJ, mucin, and inflammasome-related molecules in distinct inflammatory phenotypes of asthma may be linked to pathophysiology and might reflect the differences observed in the clinic.