Androgen receptor polyQ alleles and COVID-19 severity in men: A replication study.

BACKGROUND: Ample evidence indicates a sex-related difference in severity of COVID-19, with less favorable outcomes observed in men. Genetic factors have been proposed as candidates to explain this difference. The polyglutamine (polyQ) polymorphism in the androgen receptor gene has been recently described as a genetic biomarker of COVID-19 severity. OBJECTIVE: To test the association between the androgen receptor polyQ polymorphism and COVID-19 severity in a large cohort of COVID-19 male patients. MATERIALS AND METHODS: This study included 1136 male patients infected with SARS-CoV-2 as confirmed by positive PCR. Patients were retrospectively and prospectively enrolled from March to November 2020. Patients were classified according to their severity into three categories: oligosymptomatic, hospitalized and severe patients requiring ventilatory support. The number of CAG repeats (polyQ polymorphism) at the androgen receptor was obtained by PCR and patients were classified as either short (<23 repeats) or long (≥23 repeats) allele carriers. The association between polyQ alleles (short or long) and COVID-19 severity was assessed by Chi-squared (Chi2 ) and logistic regression analysis. RESULTS: The mean number of polyQ CAG repeats was 22 (±3). Patients were classified as oligosymptomatic (15.5%), hospitalized (63.2%), and severe patients (21.3%) requiring substantial respiratory support. PolyQ alleles distribution did not show significant differences between severity classes in our cohort (Chi2 test p > 0.05). Similar results were observed after adjusting by known risk factors such as age, comorbidities, and ethnicity (multivariate logistic regression analysis). DISCUSSION: Androgen sensitivity may be a critical factor in COVID-19 disease severity. However, we did not find an association between the polyQ polymorphism and the COVID-19 severity. Additional studies are needed to clarify the mechanism underlying the association between androgens and COVID-19 outcome. CONCLUSIONS: The results obtained in our study do not support the role of this polymorphism as biomarker of COVID-19 severity.

Age-dependent association of clonal hematopoiesis with COVID-19 mortality in patients over 60 years.

Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality. Genomic DNA extracted from peripheral blood of COVID-19 patients (n = 241 deceased, n = 239 survivors) was sequenced with the Myeloid Solutions™ panel of SOPHiA Genetics. The association between clonality and age and clonality and mortality was studied using logistic regression models adjusted for sex, ethnicity, and comorbidities. The association with mortality was performed with patients stratified into four groups of age according to the quartiles of the distribution: 60-74 years, 75-84 years, 85-91 years, and 92-101 years. Clonality was found in 38% of the cohort. The presence of CHIP variants, but not the number, significantly increased with age in the entire cohort of COVID-19 patients, as well as in the group of survivors (p < 0.001). When patients were stratified by age and the analysis adjusted, CHIP classified as pathogenic/likely pathogenic was significantly more represented in deceased patients compared with survivors in the group of 75-84 years (34.6% vs 13.7%, p = 0.020). We confirmed the well-established linear relationship between age and clonality in the cohort of COVID-19 patients and found a significant association between pathogenic/likely pathogenic CHIP and mortality in patients from 75 to 84 years that needs to be further validated.

[Prioritization of health resources in contexts of scarcity. SESPAS Report 2022]. / Priorización de recursos sanitarios en contextos de escasez. Informe SESPAS 2022.

The COVID-19 pandemic has been a clinical challenge, but also a legal and bioethical one. These three fundamental pillars are developed in the approach to prioritizing health resources in pandemic, clinical criteria, corresponding legal framework and applicable ethical principles. Initially, clinical criteria were applied to identify patients with the best survival prognosis, combining a clinical evaluation and the use of short-term and long-term prognostic variables. But the decision to prioritize the care of one patient over another has a legal-political burden, which poses a risk of falling into discrimination since fundamental rights are at stake. The prioritization criteria must be based on principles that reflect as a vehicle philosophy that which we have constitutionally assumed as a social and democratic State of Law, which did not respond to utilitarianism but to personalism. Any philosophy of resource distribution must bear in mind the scientific and constitutional perspective and, with them, those of fundamental rights and bioethical principles. In the prioritization of resources, ethical principles must be consolidated such as respect for the human dignity, the principle of necessity (equal need, equal access to the resource), the principle of equity (which advises prioritizing the most vulnerable population groups), transparency (fundamental in society's trust) and the principle of reciprocity (which requires protecting the sectors of the population that take more risks), among others.

Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID-19.

Rare variants affecting host defense against pathogens could be involved in COVID-19 severity and may help explain fatal outcomes in young and middle-aged patients. Our aim was to report the presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected group of COVID-19 patients under 65 years who required intubation or resulting in death (n = 44). To this end, different etiopathogenic mechanisms were explored using gene prioritization-based analysis in which genes involved in immune response, immunodeficiencies or blood coagulation were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of these variants were previously described as pathogenic and were located in genes mainly involved in immune response. A network analysis, including the 42 genes with candidate variants, showed three main components, consisting of 25 highly interconnected genes related to immune response and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA metabolism and repair processes. In conclusion, we have detected candidate variants that may potentially influence COVID-19 outcome in our cohort of patients. Further studies are needed to confirm the ultimate role of the genetic variants described in the present study on COVID-19 severity.

Bioethical Concerns During the COVID-19 Pandemic: What Did Healthcare Ethics Committees and Institutions State in Spain?

Objectives: Each new wave of the COVID-19 pandemic invites the possible obligation to prioritize individuals' access to vital resources, and thereby leads to unresolved and important bioethical concerns. Governments have to make decisions to protect access to the health system with equity. The prioritization criteria during a pandemic are both a clinical and legal-administrative decision with ethical repercussion. We aim to analyse the prioritization protocols used in Spain during the pandemic which, in many cases, have not been updated. Method: We carried out a narrative review of 27 protocols of prioritization proposed by healthcare ethics committees, scientific societies and institutions in Spain for this study. The review evaluated shared aspects and unique differences and proffered a bioethical reflection. Results: The research questions explored patient prioritization, the criteria applied and the relative weight assigned to each criterion. There was a need to use several indicators, being morbidity and mortality scales the most commonly used, followed by facets pertaining to disease severity and functional status. Although age was initially considered in some protocols, it cannot be the sole criterion used when assigning care resources. Conclusions: In COVID-19 pandemic there is a need for a unified set of criteria that guarantees equity and transparency in decision-making processes. Establishing treatment indications is not the aim of such criteria, but instead prioritizing access to care resources. In protocols of prioritization, the principle of efficiency must vary according to the principle of equity and the criteria used to guarantee such equity.