Interindividual clinical variability in the course of SARS-CoV-2 infection is immense. We report that at least 101 of 987 patients with life-threatening COVID-19 pneumonia had neutralizing IgG auto-Abs against IFN-ω (13 patients), the 13 types of IFN-α (36), or both (52), at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1,227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 were men. A B cell auto-immune phenocopy of inborn errors of type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Clinical outcome upon infection with SARS-CoV-2 ranges from silent infection to lethal COVID-19. We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to influenza virus, in 659 patients with life-threatening COVID-19 pneumonia, relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally define LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying autosomal recessive or dominant deficiencies. We show that human fibroblasts with mutations affecting this pathway are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

Significance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population.

Introduction Tobacco use remains a major public health concern. Cigarette smoking is the single most preventable cause of death worldwide and has been linked to countless illnesses, chief among them cancer, cardiovascular and respiratory diseases [1-6]. As many as 9% of all deaths are attributable to tobacco consumption, making smoking cessation the most cost-effective strategy for reducing morbidity and mortality [7-9]. According to the World Health Organization (WHO), global tobacco use kills nearly 6 million people annually, more than the human immunodeficiency virus (HIV), tuberculosis and malaria combined. Unfortunately, despite recent favorable trends in developed nations, more than 8 million people are expected to die every year by 2030 [10]. Tobacco smoking has spread globally, and is currently increasing in many low-and middle-income countries. It is slowly but steadily decreasing in several high-income countries [11]. Paradoxically, death rates due to smoking-related illness are lower in low than in middle and high-income countries because of the delayed effects of cigarette smoking on health outcomes. Mortality in low and middle-income countries, especially for women, will therefore continue to rise in the foreseeable future, even if efforts to reduce smoking are successful [11]. The reduction of tobacco smoking over the past half century in most industrialized nations has not been evenly distributed among all smokers. Specifically, young adults, disadvantaged individuals, and women have experienced proportionally smaller declines [12, 13]. Many factors influence smoking trends, including individual-level variables such as socioeconomic status and education, as well as system-level factors such as regional economic development and tobacco control policies [14, 15]. Sociodemographic vulnerabilities may provide important clues for improving policy initiatives for tobacco control and regulation [16]. Smoking Prevalence Around the World Worldwide, approximately 23% of adults, including more than 1 billion males and 250 million females, smoke tobacco products. This gender gap is narrowing as the number of female smokers has been increasing. Unfortunately, smoking prevalence tends to be highest among those with the lowest levels of education and income. Nearly 80% of the world's smokers live in low and middle-income countries [17, 18]. Current projections indicate that globally the number of smokers will increase to 1.6 billion over the next 25 years. As a consequence, the number of tobacco-related deaths will surpass the combined mortality from AIDS, tuberculosis, automobile accidents, maternal deaths, homicide and suicide [19]. Consumption of tobacco products is increasing worldwide but unevenly; although it is decreasing in some high and upper middle-income countries, it is markedly increasing in developing regions [20]. Such a pattern reflects the commercial strategy of tobacco companies; as smoking becomes less acceptable and profitable in the developed world, countries with fewer public health warnings...

Low dose computed tomography (LDCT) screening, together with the recent advances in targeted and immunotherapies, have shown to improve non-small cell lung cancer (NSCLC) survival.Furthermore, screening has increased the number of early stage-detected tumors, allowing for surgical resection and multimodality treatments when needed. The need for improved sensitivity and specificity of NSCLC screening has led to increased interest in combining clinical and radiological data with molecular data. The development of biomarkers is poised to refine inclusion criteria for LDCT screening programs.Biomarkers may also be useful to better characterize the risk of indeterminate nodules found in the course of screening or to refine prognosis and help in the management of screening detected tumors. The clinical implications of these biomarkers are still being investigated and whether or not biomarkers will be included in further decision-making algorithms in the context of screening and early lung cancer management still needs to be determined. However, it seems clear that there is much room for improvement even in early stage lung cancer disease-free survival (DFS) rates; thus, biomarkers may be the key to refine risk-stratification and treatment of these patients. Clinicians' capacity to register, integrate, and analyze all the available data in both high risk individuals and early stage NSCLC patients will lead to a better understanding of the disease's mechanisms, and will have a direct impact in diagnosis, treatment, and follow up of these patients. In this review, we aim to summarize all the available data regarding the role of biomarkers in LDCT screening and early stage NSCLC from a multidisciplinary perspective. We have highlighted clinical implications, the need to combine risk stratification, clinical data, radiomics, molecular information and artificial intelligence in order to improve clinical decision-making, especially regarding early diagnostics and adjuvant therapy. We also discuss current and future perspectives for biomarker implementation in routine clinical practice.