ABSTRACT
Background: The mechanisms driving SARS-CoV-2 susceptibility remain poorly understood, especially the factors determining why unvaccinated individuals remain uninfected despite high-risk exposures. Objective: to understand lipid and metabolite profiles related with COVID-19 susceptibility and disease progression. Methods: we collected samples from an exceptional group of unvaccinated healthcare workers heavily exposed to SARS-CoV-2 but not infected (‘non-susceptible’) and subjects who became infected during the follow-up (‘susceptible’), including non-hospitalized and hospitalized patients with different disease severity providing samples at early disease stages. Then, we analyzed their plasma metabolomic profiles using mass spectrometry coupled with liquid and gas chromatography. Results:we show specific lipids profiles and metabolites that could explain SARS-CoV-2 susceptibility and COVID-19 severity. More importantly, non-susceptible individuals show a unique lipidomic pattern characterized by the upregulation of most lipids, especially ceramides and sphingomyelin, which could be interpreted as markers of low susceptibility to SARS-CoV-2 infection. Conclusion: this study strengthens the findings of other researchers about the importance of studying lipid profiles as relevant markers of SARS-CoV-2 pathogenesis.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
Purpose To analyze the impact of SARS-COV-2-specific memory B cells (MBC) on the immune response after two doses of mRNA-based Comirnaty COVID-19 vaccine in seronegative health care workers. This study is seeking a rationale for boosting vaccines.Methods Longitudinal study including 31 seronegative health care workers with undetectable MBCs (IgG-MBC- group), 24 seronegative with detectable MBCs (IgG-MBC + group), and 24 seropositive with detectable MBCs (IgG + MBC + group). The level of neutralizing, anti-S IgG, IgA, and IgM antibodies was quantified by ELISA. In addition, specific memory B and T cells were quantified by flow cytometry.Results The level of specific MBCs, and isotypes, in the IgG-MBC- group was lower compared to that found in IgG-MBC+ (p = 0.0001) and IgG + MBC+ (p < 0.0001) groups, respectively. Neutralizing and anti-S IgG antibodies were at lower levels in the IgG-MBC- group after the vaccine. Specific MBCs directly correlated with specific CD4 + T cells (although not significant, p = 0.065), while no correlation was found with specific CD8 + T cells (p = 0.156) after the vaccine. In parallel, neutralizing antibodies only positively correlated with specific CD4 + T cells (p = 0.034).Conclusions IgG-MBC- individuals showed the worst humoral and cellular responses, both in frequency and magnitude, after vaccine. Individuals whose antibodies wane and become undetectable after a given period of time post vaccine and show no specific MBCs are less protected and hence are good candidates for boosting vaccine. On the other hand, seronegative individuals with specific MBC showed faster and higher responses compared to the IgG-MBC- group.
Subject(s)
COVID-19ABSTRACT
IntroductionSevere coronavirus disease 2019 (COVID-19) is associated with immune dysregulation and hyperinflammation (lymphocyte exhaustion and elevated IL-6). Pembrolizumab (P; immune-activating anti-PD-1 antibody) plus tocilizumab (TCZ; anti-IL6 receptor antibody) might interrupt the hyperinflammation and restore the cellular immunocompetence. We assessed the efficacy and safety of P + TCZ + standard of care [SOC] in high-risk, hospitalized, COVID-19 pneumonia patients without mechanical ventilation.MethodsRandomized, controlled, open-label, phase 2 trial in patients with severe SARS-CoV-2-infection to assess the hospitalization period to discharge.ResultsTwelve patients were randomized (P + TCZ + SOC, n = 7; SOC, n = 5). Nine (75%) were males, with a median age of 68 (41–79) years. Median time to discharge with P + TCZ + SOC and SOC was 10 and 47.5 days (p = 0.03), with 0 (n = 1 patient had P–related grade 5 myositis) and 2 COVID-19-related deaths, respectively.ConclusionsThe addition of P and TCZ to SOC reduced the hospitalization period, with higher and faster discharges without sequelae than SOC alone.
Subject(s)
COVID-19ABSTRACT
Despite of the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 early after symptom onset who were prospectively followed and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ( nonsusceptible). We found that the metabolite profile was predictive of the study group. We identified a total of 55 metabolites as biomarkers of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citrate, and BAIBA), energy production and amino acid catabolism (L-glycine, L-alanine, L-serine, L-proline, L-aspartic acid and L-histidine), endothelial dysfunction and thrombosis (citrulline, L-ADMA, 2-AB, and Neu5Ac), and we found interconnections between these pathways. In summary, in this first report of the metabolomic profile of individuals with severe COVID-19 and SARS-CoV-2 susceptibility by CE-MS, we define several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression that could be developed as biomarkers of COVID-19.
Subject(s)
COVID-19 , Hypoxia , Thrombosis , Liver DiseasesABSTRACT
Health care workers (HCW) are at an increased risk since they are directly exposed to SARS-CoV-2 infected patients, nevertheless, some remained without the development of anti-SARS-CoV-2 antibodies, suggesting lesser susceptibility to infection1-5. This study aimed to ascertain a potential specific cellular immune response to SARS-CoV-2 in these largely exposed HCWs.In this cross-sectional, case-control study, we analyzed 39 exposed uninfected HCWs and 17 convalescent HCWs. Cellular immune response was evaluated after SARS-CoV-2 stimulation with peptide pools (proteins S, M, and N), using bead-based multiplex assay (12 cytokines).Overall, 94.8% of uninfected HCWs had some degree of specific cellular response to SARS-CoV-2 structural proteins that could be classified, according to the number of cytokine production, as strong (61.5%), partial (33.3%), and weak/no response (5.1%). Strong responders showed a higher anti-inflammatory cytokine production (IL5 and IL10, p<0.001 and 0.002, respectively), and similar (IFN-γ and TNF-α, p=0.435 and 0.532, respectively) or higher (IL12, p=0.021) pro-inflammatory production compared to convalescents, resulted in a predominantly Th2 response. This study demonstrated a consistent and polyfunctional immune cellular response after stimulation with SARS-CoV-2 peptides in extensively exposed individuals that should be considered to establish the infection susceptibility, the impact in herd immunity, and the risk of relapses.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Background: Information about incidence, clinical characteristics and outcomes of HIV-infected individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is scarce. We characterized individuals with coronavirus disease 2019 (COVID-19) among a cohort of HIV-infected adults regularly followed-up at an HIV clinic in Madrid, Spain, one of the most affected cities worldwide.Methods: In this observational study, we included all consecutive HIV-infected individuals who were diagnosed of suspected or confirmed COVID-19 as of April 14, 2020. Demographic, clinical, treatment, and laboratory data, including HIV-specific information, were extracted from the electronic health records. We compared the characteristics of HIV-infected individuals with COVID-19 with a representative sample of HIV-infected individuals evaluated before the COVID-19 pandemic (n=1,302), and described the evolution and outcomes of individuals with COVID-19 according to baseline characteristics.Findings: Thirty-seven HIV-infected individuals (mean, 53·5 years; females, 16%) were diagnosed with COVID-19 (incidence, 1·3%, 95% confidence interval: 0·9-1·8%). Of them, 29 (78%) were laboratory confirmed cases, and 26 (70%) required hospitalization. Overall, 29 (78%) individuals had comorbidities, predominantly hypertension and diabetes, higher than that observed among HIV-infected individuals without COVID-19 ( P =0·006). Additionally, a significantly higher percentage of individuals with COVID-19 were receiving tenofovir prior to COVID-19 diagnosis compared to HIV-infected individuals without COVID-19 (70% versus 52%, P =0·030), and the rate of prior protease inhibitor use was similar in both groups (mostly darunavir, 19% versus 18%, P =0·830). Clinical, analytical and radiological presentation of COVID-19 in HIV-infected individuals was similar to that described in the general population: five (14%) were critically-ill, and two (5%) died. Two out of five critically ill individuals had CD4+ counts <200 cells/mm3.Interpretation: Our findings indicate that COVID-19 predominantly affects HIV-infected individuals with comorbidities. These data do not suggest a protective effect of CD4+ count or previous antiretroviral therapy on the rate of infection or outcomes.Funding Statement: None.Declaration of Interests: MJPE has received research grants or honoraria for lectures or for participation in advisory boards from Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, ViiV-Healthcare previously GlaxoSmithKline, Roche, and Janssen; and unrestricted grants from Abbott, ViiVHealthcare previously GlaxoSmithKline, Gilead Sciences and Janssen. For the remaining authors, none was declared.Ethics Approval Statement: The study protocol was approved by our Institutional Review Board (EC 110/20), and patients provided oral informed consent in order to minimize staff exposure.