The exposome in respiratory diseases: multiple preventable risk factors from early life to adulthood

International audienceThe increasing global burden of respiratory diseases over the last decades raises questions about the impact of environmental factors during industrialisation and urbanisation. Although the knowledge of environmental epidemiology is growing, it is still unclear what the most critical exposure windows are for respiratory health. In addition, the relationships between different environmental exposures can be complex. The exposome approach investigating all non-genetic factors on health has been developed in recent years but has been little applied in respiratory health to date. This journal club article reviews three recent publications investigating the effects of environmental exposures, considered separately or in an exposome approach with different exposure windows, on respiratory health outcomes. These three studies highlight targets for action in primary and secondary prevention. Two studies, using data from the INMA and RHINESSA cohorts, support the regulation and reduction of phthalates and air pollution, respectively. Moreover, the exposome approach conducted in the NutriNet-Santé cohort emphasises that risk reduction must involve a multi-interventional approach targeting both specific early-life risk factors and promotion of a healthy lifestyle in adulthood. These three articles also present research perspectives in environmental epidemiology

The exposome in respiratory diseases: multiple preventable risk factors from early life to adulthood

The increasing global burden of respiratory diseases over the last decades raises questions about the impact of environmental factors during industrialisation and urbanisation. Although the knowledge of environmental epidemiology is growing, it is still unclear what the most critical exposure windows are for respiratory health. In addition, the relationships between different environmental exposures can be complex. The exposome approach investigating all non-genetic factors on health has been developed in recent years but has been little applied in respiratory health to date. This journal club article reviews three recent publications investigating the effects of environmental exposures, considered separately or in an exposome approach with different exposure windows, on respiratory health outcomes. These three studies highlight targets for action in primary and secondary prevention. Two studies, using data from the INMA and RHINESSA cohorts, support the regulation and reduction of phthalates and air pollution, respectively. Moreover, the exposome approach conducted in the NutriNet-Santé cohort emphasises that risk reduction must involve a multi-interventional approach targeting both specific early-life risk factors and promotion of a healthy lifestyle in adulthood. These three articles also present research perspectives in environmental epidemiology

Multiparameter analysis of vascular remodeling in post-acute sequelae of COVID-19

International audienceThe COVID-19 infection, a current worldwide health concern, manifests as an alveolar-interstitial pneumonia with unknown long-term evolution. It is also associated with vascular dysfunction and shows a vascular remodeling with a changed balance between small-and large-caliber vessels. In this study, we question the existence of residual vascular alteration in post-acute sequelae of COVID-19 (PASC) by investigating possible associations between vascular remodeling biomarkers extracted from CT and functional, radiological and morphological parameters. The used vascular biomarkers concern the blood volume ratio of vessels with cross-section area inferior to 5 mm 2 versus vessels of crosssection area inferior to 50 mm 2 (BV5/BV50), an index of local peripheral vascular density and a peripheral composite vascular remodeling index, both measured in the antero-postero-lateral lung periphery (excluding mediastinal region). As a functional parameter, diffusing capacity of the lung for carbon monoxide (DLCO) is a measure depending on the vascular perfusion and the amount of interstitial thickening, a decreased DLCO value suggesting altered vascular perfusion. Imaging biomarkers can be extracted from the analysis of perfusion lung scintigraphy or CT scan. Some of them are included in our study. Radiological features include CT attenuation as a measure of persistence of ground glass opacity and development of changes suggestive to look for fibrosis, such as reticulations. As additional morphological parameter, lung deformation observed between inspiration/expiration maneuvers may be suggestive of the presence of reticulations inducing lung stiffness and breathing deficiency. The investigation of associations between vascular remodeling biomarkers obtained from CT and the above functional, radiological and morphological parameters revealed moderate to strong correlations highlighting the ability to capture the persistence of vascular alterations in PASC in relation with the development of fibrotic patterns, which is a promising direction for future research

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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