Severe asthma trajectories in adults: findings from the NORDSTAR cohort.

BACKGROUND: There is limited evidence on the pathways leading to severe asthma and we are presently unable to effectively predict the progression of the disease. We aimed to describe the longitudinal trajectories leading to severe asthma and to describe clinical events preceding disease progression in a nationwide population of patients with severe asthma. METHODS: We conducted an observational study based on Swedish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. We identified adult patients with severe asthma in 2018 according to the European Respiratory Society/American Thoracic Society definition and used latent class analysis to identify trajectories of asthma severity over a 10-year retrospective period from 2018. RESULTS: Among 169 128 asthma patients, we identified 4543 severe asthma patients. We identified four trajectories of severe asthma that were labelled as: trajectory 1 "consistently severe asthma" (n=389 (8.6%)), trajectory 2 "gradual onset severe asthma" (n=942 (20.7%)), trajectory 3 "intermittent severe asthma" (n=1685 (37.1%)) and trajectory 4 "sudden onset severe asthma" (n=1527 (33.6%)). "Consistently severe asthma" had a higher daily inhaled corticosteroid dose and more prevalent osteoporosis compared with the other trajectories. Patients with "gradual onset severe asthma" and "sudden onset severe asthma" developed type 2-related comorbidities concomitantly with development of severe asthma. In the latter group, this primarily occurred within 1-3 years preceding onset of severe asthma. CONCLUSIONS: Four distinct trajectories of severe asthma were identified illustrating different patterns of progression of asthma severity. This may eventually enable the development of better preventive management strategies in severe asthma.

Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis.

Asthma is one of the most common chronic diseases affecting both children and adults. We report a genome-wide association meta-analysis of 69,189 cases and 702,199 controls from Iceland and UK biobank. We find 88 asthma risk variants at 56 loci, 19 previously unreported, and evaluate their effect on other asthma and allergic phenotypes. Of special interest are two low frequency variants associated with protection against asthma; a missense variant in TNFRSF8 and 3' UTR variant in TGFBR1. Functional studies show that the TNFRSF8 variant reduces TNFRSF8 expression both on cell surface and in soluble form, acting as loss of function. eQTL analysis suggests that the TGFBR1 variant acts through gain of function and together with an intronic variant in a downstream gene, SMAD3, points to defective TGFßR1 signaling as one of the biological perturbations increasing asthma risk. Our results increase the number of asthma variants and implicate genes with known role in T cell regulation, inflammation and airway remodeling in asthma pathogenesis.

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma.

IL-33 is a tissue-derived cytokine that induces and amplifies eosinophilic inflammation and has emerged as a promising new drug target for asthma and allergic disease. Common variants at IL33 and IL1RL1, encoding the IL-33 receptor ST2, associate with eosinophil counts and asthma. Through whole-genome sequencing and imputation into the Icelandic population, we found a rare variant in IL33 (NM_001199640:exon7:c.487-1G>C (rs146597587-C), allele frequency = 0.65%) that disrupts a canonical splice acceptor site before the last coding exon. It is also found at low frequency in European populations. rs146597587-C associates with lower eosinophil counts (ß = -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids. The truncated IL-33 has normal intracellular localization but neither binds IL-33R/ST2 nor activates ST2-expressing cells. Together these data demonstrate that rs146597587-C is a loss of function mutation and support the hypothesis that IL-33 haploinsufficiency protects against asthma.

Overview on the current status of asthma genetics.

INTRODUCTION: Asthma is a complex heterogeneous and mutifactorial disease occurring at the interface of multiple genes that interact with various environmental stimuli insulting the immune system at different levels and different times of disease susceptibility. OBJECTIVE: The present paper is a review of the current status of the genetics of asthma. RESULTS: Sequence variants in hundreds of genes have been associated with asthma using both family-based and case control screening methods. CONCLUSION: As the number of genes known to be associated with asthma risk is rapidly growing, it is essential to begin integrating epidemiologic, genetic and genomic strategies to unravel the relationships between genotype and phenotype, and elucidate the pathogenesis of asthma with the goal to make clinical use of these discoveries.

[Yellow nail syndrome]. / Heilkenni gulra nagla.

We describe a 77 year old man with a prior history of recurrent airway infections, who presented with a history of cough, dyspnea and increased mucous production that had lasted several months. On chest X-ray a pleural effusion was observed. Subsequent thoracocentesis demonstrated an exudate with predominant eosinophils. An infectious cause was ruled out. The pleural effusion subsequently recurred and he was admitted for pleural biopsy, which revealed chronic pleuritis. On physical examination yellow nails on fingers and toes were noted. Subsequently, after exclusion of other diseases, a diagnosis of yellow nails syndrome was established. He was treated with corticosteroids, which were tapered over 6 months. One year later the eosinophilia had subsided, however the pleural effusion remained, although on a much smaller scale.

The effect of reducing levels of cat allergen (Fel d 1) on clinical symptoms in patients with cat allergy.

BACKGROUND: Treatment of cat allergy normally entails removal of the cat from the household, but cat owners are often unwilling to part with their pets, despite clinically relevant allergies. OBJECTIVE: To determine whether levels of Fel d 1 can be reduced without removal of the cat and whether this will affect symptoms of cat allergy. METHODS: Cat-allergic patients underwent randomization to either a group instructed in environmental control (EC) and a group with unchanged environment (UE). Dust samples were obtained and settled Fel d 1 measured by enzyme-linked immunosorbent assay. Patients recorded daily nasal inspiratory flow rates. At baseline, 3 months, and 8 months, patients underwent symptom evaluation. RESULTS: Eighteen patients were randomized to the EC group and 22 to the UE group; the final number completing the study was 31, 15 in the EC group, and 16 in the UE group. At 8 months, home Fel d 1 levels had diminished to 6.8% of baseline levels in the EC group, whereas no reduction in levels was noted in the UE group. In the EC group, significant improvements were found in nasal inspiratory flow rate and symptoms compared with the UE group. Patients did not have difficulties adhering to EC measures. CONCLUSION: A decrease in the allergen load was found in the EC group, which had a significant effect on symptoms of nasal allergy.