Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID

Abstract:

Introduction: There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity.

Methods: Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness.

Results: 205 consecutive patients, age 39 (IQR30.0-46.7) years, 84% male, were assessed 24 (IQR17.1-34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded ‘mild’. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness.

Conclusion: Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.

Source: Holdsworth DA, Chamley R, Barker-Davies R, O’Sullivan O, Ladlow P, Mitchell JL, Dewson D, Mills D, May SLJ, Cranley M, Xie C, Sellon E, Mulae J, Naylor J, Raman B, Talbot NP, Rider OJ, Bennett AN, Nicol ED. Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID. PLoS One. 2022 Jun 10;17(6):e0267392. doi: 10.1371/journal.pone.0267392. PMID: 35687603; PMCID: PMC9187094. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187094/ (Full text)

Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a disabling multi-system complex disorder with prevalence of 875 per 100,000 (up to 3.4 million people) in the United States. There are no known etiologic or risk factors and no approved treatments for ME/CFS. We conducted a molecular epidemiologic study to test the hypothesis that ME/CFS may be an autoimmune disease (AID) and explore the link between ME/CFS and cancer, specifically hematologic malignancies.Methods: Our clinic-based study involved carefully selected cases with confirmed diagnosis of ME/CFS (n=59) and healthy controls (n=54) frequency matched to cases on age, gender and ethnicity. During structured interviews, detailed multi-generation pedigrees, epidemiologic and medical questionnaires, and biospecimen were obtained on all subjects. Statistical analysis of pedigree data involved comparison of cases and controls with respect to the prevalence and cumulative incidence of AID and cancer among their first-degree relatives. For unadjusted analysis, risk ratios, 95% confidence intervals (CI), and p-values were calculated. For age-adjusted analyses, cumulative incidence estimates were compared using the log-rank test.

Results: The prevalence of AID was significantly higher among the first-degree relatives of cases compared to those of controls (OR=5.30; 95%CI: 1.83-15.38; p=0.001). The prevalence of AID among mothers was 14% for cases and 1.9% for controls (p=0.03). 11.2% of the first-degree relatives of cases had an AID compared to 3.1% of the relatives of controls (prevalence ratio=3.71; 95% CI: 1.74-7.88; p=0.0007). The cumulative incidence of AID among the first-degree relatives of ME/CFS cases was 9.4% compared to 2.7% for those of the controls (p=0.0025). First-degree relatives of ME/CFS cases had a significantly higher prevalence of any cancer compared to the relatives of unrelated controls (OR=4.06, 95%CI: 1.84-8.96, p=0.0005). Age-adjusted analysis revealed significantly higher (p=0.03) cumulative incidence of any cancer among the first-degree relatives of cases (20%) compared to the relatives of controls (15.4%). The cumulative incidence of hematologic cancers was also significantly higher among the relatives of cases (p<0.05).

Conclusions: We found statistically significant increased risks of AID and cancer among the first-degree relatives of ME/CFS cases. Our findings implicate immune dysregulation as an underlying mechanism, providing etiologic clues and leads for prevention. Given symptomatic similarities between ‘long COVID’ and ME/CFS, it is predicted that there will be a significant increase in incidence of ME/CFS as the result of COVID-19 pandemic. Our findings may enable defining a subset of COVID-19 patients who could be at risk of developing ME/CFS, and who may benefit from treatments used for certain AIDs.

Source: Roxana Moslehi, Anil Kumar, Amiran Dzutsev. Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 34. https://aacrjournals.org/cancerres/article/82/12_Supplement/34/700144

 

“Long COVID” results after hospitalization for SARS-CoV-2 infection

Abstract:

Long-term sequelae of symptomatic infection caused by SARS-CoV-2 are largely undiscovered. We performed a prospective cohort study on consecutively hospitalized Sars-CoV-2 patients (March-May 2020) for evaluating COVID-19 outcomes at 6 and 12 months. After hospital discharge, patients were addressed to two follow-up pathways based on respiratory support needed during hospitalization. Outcomes were assessed by telephone consultation or ambulatory visit.

Among 471 patients, 80.9% received no respiratory support during hospitalization; 19.1% received non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV). 58 patients died during hospitalization, therefore 413 were enrolled for follow-up. At 6 months, among 355 patients, the 30.3% had any symptoms, 18.0% dyspnea, 6.2% neurological symptoms. Fifty-two out of 105 had major damages in interstitial computed tomography images. NIV/IMV patients had higher probability to suffer of symptoms (aOR = 4.00, 95%CI:1.99-8.05), dyspnea (aOR = 2.80, 95%CI:1.28-6.16), neurological symptoms (aOR = 9.72, 95%CI:2.78-34.00). At 12 months, among 344, the 25.3% suffered on any symptoms, 12.2% dyspnea, 10.1% neurological symptoms. Severe interstitial lesions were present in 37 out of 47 investigated patients.

NIV/IMV patients in respect to no respiratory support, had higher probability of experiencing symptoms (aOR = 3.66, 95%CI:1.73-7.74), neurological symptoms (aOR = 8.96, 95%CI:3.22-24.90). COVID-19 patients showed prolonged sequelae up to 12 months, highlighting the need of follow-up pathways for post-COVID-19 syndrome.

Source: Rigoni M, Torri E, Nollo G, Donne LD, Rizzardo S, Lenzi L, Falzone A, Cozzio S. “Long COVID” results after hospitalization for SARS-CoV-2 infection. Sci Rep. 2022 Jun 10;12(1):9581. doi: 10.1038/s41598-022-13077-5. PMID: 35688830; PMCID: PMC9185134. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9185134/ (Full text)

Immunogenetic studies in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease that affects about 0.1-0.2% of the general population. The core symptoms are persistent debilitating fatigue, post-exertional malaise (PEM) and cognitive dysfunction. Most symptoms of ME/CFS are not disease specific. Additionally, there is a lack of both biomarkers and diagnostic tests for the disease, which makes accurate diagnosis difficult.

More than 20 different patient classifications and diagnostic criteria have emerged over the last four decades. Due to this, the patient population can be quite heterogeneous in terms of clinical symptoms and the extent to which the disease impacts quality of life.

There are several different theories that aim to explain the disease development of ME/CFS. In this thesis, we have taken as our starting point the growing evidence for an immunological background for ME/CFS pathogenesis. Several studies have pointed to altered NK cells, autoantibodies and T cell abnormalities in ME/CFS patients.

In addition, several genetic studies reported significant associations in various immunologically relevant genes. Most of these previous studies have been suboptimal and included heterogeneous patient populations and/or few patients in total.

Therefore, we aimed to gain a better understanding of the role of immunologically relevant genes and disease development of ME/CFS.

To do this, we employed known strategies from genetic studies in autoimmune disease and applied them to ME/CFS. We used strict quality control and included, to the best of our knowledge, the largest cohort diagnosed with the Canadian consensus criteria.

In paper I, the main goal was to follow up previously performed work by our group that reported associations between ME/CFS and HLA-C: 07: 04 and HLA-DQB1: 03: 03 alleles. The HLA (human leukocyte antigen) region consists a multitude of immunologically relevant genes in addition to the HLA genes, and there is extensive and complex linkage disequilibrium (LD) in the region.

The previously observed association signals in the HLA region were fine-mapped by genotyping five additional classical HLA loci and 5,342 SNPs (single nucleotide variants) in 427 Norwegian ME/CFS patients, diagnosed according to the Canadian consensus criteria, and 480 healthy Norwegian controls. The analysis revealed two independent association signals (p ≤ 0.001) represented by the genetic variants rs4711249 in the HLA class I region and rs9275582 in the HLA class II region.

The primary association signal in the HLA class II region was located in the vicinity of the HLA-DQ genetic region, most likely due to the HLA-DQB1 gene. In particular, amino acid position 57 (aspartic acid / alanine) in the peptide binding pit of HLA-DQB1, or an SNP upstream of HLA-DQB1 seemed to explain the association signal we observed in the HLA class II region.

In the HLA class I region, the putative primary locus was not as clear and could possibly lie outside the classical HLA genes (the association signal spans several genes DDR1, GTF2H4, VARS2, SFTA2 and DPCR1) with expression levels influenced by the ME/CFS associated SNP genotypes.

Interestingly, we also observed that > 60% of the patients who responded to cyclophosphamide treatment for ME/CFS had either the rs4711249 risk allele and/or DQB1* 03:03 versus 12% of the patients who did not respond to the treatment. Our findings suggest the involvement of the HLA region, and in particular the HLA-DQB1 gene, in ME/CFS.

Although our study is the largest to date, it is still a relatively small study in the context of genetic studies. Our findings need to be replicated in much larger, statistically more representative, cohorts.

In particular, it is necessary to investigate the involvement of HLA- 12 DQB1, a gene that contains alleles that increase the risk of several established autoimmune diseases such as celiac disease.

In paper II, we aimed to investigate immunologically relevant genes using a genotyping array (iChip) targeting immunological gene regions previously associated with different autoimmune diseases.

In addition to the Norwegian cohort of 427 ME/CFS patients (the Canadian consensus criteria), we also analyzed data from two replication cohorts, a Danish one of 460 ME/CFS patients (Canadian consensus criteria) and a data set from the UK Biobank of 2105 self-reported CFS patients.

To the best of our knowledge, this is the first ME/CFS genetic association study of this magnitude and it included more than 2,900 patients in total (of whom 887 are diagnosed according to Canadian consensus criteria).

We found no ME/CFS risk variants with a genome wide significance level (p<5×10-8), but we identified six gene regions (TPPP, LINC00333, RIN3. IGFBP/IGFBP3, IZUMO1/MAMSTR and ZBTB46/STMN3) with possible association with ME/CFS which require further follow-up in future studies in order to assess whether they are real findings or not.

Interestingly, these genes are expressed in disease-relevant tissue, e.g. brain, nerve, skeletal muscle and blood, including immune cells (subgroups of T cells, B cells, NK cells and monocytes).

Furthermore, several of the ME/CFS associated SNP genotypes are associated with differential expression levels of these genes. Although we could not identify statistically convincing associations with genetic variants across the three cohorts, we believe that our data sets and analysis represent an important step in the ME/CFS research field.

Our study demonstrated that for the future understanding of the genetic architecture of ME/CFS much larger studies are required to established reliable associations.

In paper III, we wanted to investigate previous findings from a genome wide association study of 42 ME/CFS patients who reported significant association with two SNPs in the T cell receptor alpha (TRA) locus (P-value<5×10-8).

In order to replicate these previously reported findings, we used a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK Biobank (2105 cases and 4786 controls). We examined a number of SNPs in the TRA locus, including the two previous ME/CFS-associated variants, rs11157573 and rs17255510. No statistically significant associations were observed in either the Norwegian cohort or UK biobank cohorts.

Nevertheless, other SNPs in the region showed weak signs of association (P-value <0.05) in the UK Biobank cohort and meta-analyzes of Norwegian and UK Biobank cohorts, but did not remain associated after applying correction for multiple testing. Thus, we could not confirm associations with genetic variants in the TRA locus in this study.

Source: Riad Hajdarevic. PhD thesis (University of Oslo) Electronic copies must be ordered. https://www.med.uio.no/klinmed/english/research/news-and-events/events/disputations/2022/hajdarevic-riad.html

Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease. While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases. The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.
Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison. Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.
Source: O’Neal AJ, Glass KA, Emig CJ, Vitug AA, Henry SJ, Shungu DC, Mao X, Levine SM, Hanson MR. Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Proteomes. 2022; 10(2):21. https://doi.org/10.3390/proteomes10020021 https://www.mdpi.com/2227-7382/10/2/21/htm (Full text)

SARS-CoV-2 infection and persistence throughout the human body and brain

Abstract:

COVID-19 is known to cause multi-organ dysfunction1-3 in acute infection, with prolonged symptoms experienced by some patients, termed Post-Acute Sequelae of SARS-CoV-2 (PASC)4-5. However, the burden of infection outside the respiratory tract and time to viral clearance is not well characterized, particularly in the brain3,6-14.
We performed complete autopsies on 44 patients with COVID-19 to map and quantify SARS-CoV-2 distribution, replication, and cell-type specificity across the human body, including brain, from acute infection through over seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, even among patients who died with asymptomatic to mild COVID-19, and that virus replication is present in multiple extrapulmonary tissues early in infection.
Further, we detected SARS-CoV-2 RNA in multiple anatomic sites, including regions throughout the brain, for up to 230 days following symptom onset. Despite extensive distribution of SARS-CoV-2 in the body, we observed a paucity of inflammation or direct viral cytopathology outside of the lungs. Our data prove that SARS-CoV-2 causes systemic infection and can persist in the body for months.
Source: Daniel Chertow, Sydney Stein, Sabrina Ramelli et al. SARS-CoV-2 infection and persistence throughout the human body and brain, 20 December 2021, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1139035/v1] https://www.researchsquare.com/article/rs-1139035/v1 https://www.nature.com/articles/s41586-022-05542-y (Full text)

Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

Abstract:

Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12-months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

Source: Lucette A. Cysique, David Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, Benjamin Heng, Sharron Chow, Mona Dehhaghi, Ananda Staats Pires, David R. Darley, Anthony Byrne, Chansavath Phetsouphanh, Anthony Kelleher, Gregory J. Dore, Gail V. Matthews, Gilles J Guillemin, Bruce J. Brew. Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study. medRxiv 2022.06.07.22276020; doi: https://doi.org/10.1101/2022.06.07.22276020 https://www.medrxiv.org/content/10.1101/2022.06.07.22276020v1.full-text (Full text)

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

Abstract:

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.

Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans.

As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

Source: Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain. 2022 Apr 29;145(3):1124-1138. doi: 10.1093/brain/awab408. PMID: 35323848; PMCID: PMC9050559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050559/ (Full text)

Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae

Abstract:

The diagnosis and management of post-acute sequelae of COVID-19 (PASC) poses an ongoing medical challenge. Identifying biomarkers associated with PASC would immensely improve the classification of PASC patients and provide the means to evaluate treatment strategies. We analyzed plasma samples collected from a cohort of PASC and COVID-19 patients (n = 63) to quantify circulating viral antigens and inflammatory markers. Strikingly, we detect SARS-CoV-2 spike antigen in a majority of PASC patients up to 12 months post-diagnosis, suggesting the presence of an active persistent SARS-CoV-2 viral reservoir. Furthermore, temporal antigen profiles for many patients show the presence of spike at multiple time points over several months, highlighting the potential utility of the SARS-CoV-2 full spike protein as a biomarker for PASC

Source: Zoe Swank, Yasmeen Senussi, Galit Alter, David R. Walt. Persistent circulating SARS-CoV-2 spike is associated with post-acute COVID-19 sequelae. medRxiv 2022.06.14.22276401; doi: https://doi.org/10.1101/2022.06.14.22276401 https://www.medrxiv.org/content/10.1101/2022.06.14.22276401v1 (Full text available as PDF file)

Novel genes and sex differences in COVID-19 severity

Abstract:

Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5×10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3×10-22 and p = 8.1×10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4×10-8).

In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7×10-8) and ARHGAP33 (p = 1.3×10-8), respectively.

The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1×10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE.

We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Source: Cruz R, Almeida SD, Heredia ML, Quintela I, Ceballos FC, Pita G, Lorenzo-Salazar JM, González-Montelongo R, Gago-Domínguez M, Porras MS, Castaño JAT, Nevado J, Aguado JM, Aguilar C, Aguilera-Albesa S, Almadana V, Almoguera B, Alvarez N, Andreu-Bernabeu Á, Arana-Arri E, Arango C, Arranz MJ, Artiga MJ, Baptista-Rosas RC, Barreda-Sánchez M, Belhassen-Garcia M, Bezerra JF, Bezerra MAC, Boix-Palop L, Brion M, Brugada R, Bustos M, Calderón EJ, Carbonell C, Castano L, Castelao JE, Conde-Vicente R, Cordero-Lorenzana ML, Cortes-Sanchez JL, Corton M, Darnaude MT, De Martino-Rodríguez A, Campo-Pérez V, Bustamante AD, Domínguez-Garrido E, Luchessi AD, Eirós R, Sanabria GME, Fariñas MC, Fernández-Robelo U, Fernández-Rodríguez A, Fernández-Villa T, Gil-Fournier B, Gómez-Arrue J, Álvarez BG, Quirós FGB, González-Peñas J, Gutiérrez-Bautista JF, Herrero MJ, Herrero-Gonzalez A, Jimenez-Sousa MA, Lattig MC, Borja AL, Lopez-Rodriguez R, Mancebo E, Martín-López C, Martín V, Martinez-Nieto O, Martinez-Lopez I, Martinez-Resendez MF, Martinez-Perez Á, Mazzeu JA, Macías EM, Minguez P, Cuerda VM, Silbiger VN, Oliveira SF, Ortega-Paino E, Parellada M, Paz-Artal E, Santos NPC, Pérez-Matute P, Perez P, Pérez-Tomás ME, Perucho T, Pinsach-Abuin ML, Pompa-Mera EN, Porras-Hurtado GL, Pujol A, León SR, Resino S, Fernandes MR, Rodríguez-Ruiz E, Rodriguez-Artalejo F, Rodriguez-Garcia JA, Ruiz-Cabello F, Ruiz-Hornillos J, Ryan P, Soria JM, Souto JC, Tamayo E, Tamayo-Velasco A, Taracido-Fernandez JC, Teper A, Torres-Tobar L, Urioste M, Valencia-Ramos J, Yáñez Z, Zarate R, Nakanishi T, Pigazzini S, Degenhardt F, Butler-Laporte G, Maya-Miles D, Bujanda L, Bouysran Y, Palom A, Ellinghaus D, Martínez-Bueno M, Rolker S, Amitrano S, Roade L, Fava F, Spinner CD, Prati D, Bernardo D, Garcia F, Darcis G, Fernández-Cadenas I, Holter JC, Banales JM, Frithiof R, Duga S, Asselta R, Pereira AC, Romero-Gómez M, Nafría-Jiménez B, Hov JR, Migeotte I, Renieri A, Planas AM, Ludwig KU, Buti M, Rahmouni S, Alarcón-Riquelme ME, Schulte EC, Franke A, Karlsen TH, Valenti L, Zeberg H, Richards B, Ganna A, Boada M, Rojas I, Ruiz A, Sánchez P, Real LM; SCOURGE Cohort Group; HOSTAGE Cohort Group; GRA@CE Cohort Group, Guillen-Navarro E, Ayuso C, González-Neira A, Riancho JA, Rojas-Martinez A, Flores C, Lapunzina P, Carracedo Á. Novel genes and sex differences in COVID-19 severity. Hum Mol Genet. 2022 Jun 16:ddac132. doi: 10.1093/hmg/ddac132. Epub ahead of print. PMID: 35708486.  https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac132/6607933  (Full text available as PDF file)