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SARS-CoV-2-specific B- and T-cell immunity in a population-based study of young Swedish adults.
Björkander, S, Du, L, Zuo, F, Ekström, S, Wang, Y, Wan, H, Sherina, N, Schoutens, L, Andréll, J, Andersson, N, et al
The Journal of allergy and clinical immunology. 2022;(1):65-75.e8
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Abstract
BACKGROUND Young adults are now considered major spreaders of coronavirus disease 2019 (COVID-19) disease. Although most young individuals experience mild to moderate disease, there are concerns of long-term adverse health effects. The impact of COVID-19 disease and to which extent population-level immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exists in young adults remain unclear. OBJECTIVE We conducted a population-based study on humoral and cellular immunity to SARS-CoV-2 and explored COVID-19 disease characteristics in young adults. METHODS We invited participants from the Swedish BAMSE (Barn [Children], Allergy Milieu, Stockholm, Epidemiology) birth cohort (age 24-27 years) to take part in a COVID-19 follow-up. From 980 participants (October 2020 to June 2021), we here present data on SARS-CoV-2 receptor-binding domain-specific IgM, IgA, and IgG titers measured by ELISA and on symptoms and epidemiologic factors associated with seropositivity. Further, SARS-CoV-2-specific memory B- and T-cell responses were detected for a subpopulation (n = 108) by ELISpot and FluoroSpot. RESULTS A total of 28.4% of subjects were seropositive, of whom 18.4% were IgM single positive. One in 7 seropositive subjects was asymptomatic. Seropositivity was associated with use of public transport, but not with sex, asthma, rhinitis, IgE sensitization, smoking, or body mass index. In a subset of representative samples, 20.7% and 35.0% had detectable SARS-CoV-2 specific B- and T-cell responses, respectively. B- and T-cell memory responses were clearly associated with seropositivity, but T-cell responses were also detected in 17.2% of seronegative subjects. CONCLUSIONS Assessment of IgM and T-cell responses may improve population-based estimations of SARS-CoV-2 infection. The pronounced surge of both symptomatic and asymptomatic infections among young adults indicates that the large-scale vaccination campaign should be continued.
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Calcifediol Treatment and Hospital Mortality Due to COVID-19: A Cohort Study.
Alcala-Diaz, JF, Limia-Perez, L, Gomez-Huelgas, R, Martin-Escalante, MD, Cortes-Rodriguez, B, Zambrana-Garcia, JL, Entrenas-Castillo, M, Perez-Caballero, AI, López-Carmona, MD, Garcia-Alegria, J, et al
Nutrients. 2021;(6)
Abstract
CONTEXT Calcifediol has been proposed as a potential treatment for COVID-19 patients. OBJECTIVE To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized because of COVID-19. DESIGN Retrospective, multicenter, open, non-randomized cohort study. SETTINGS Hospitalized care. PATIENTS Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain. INTERVENTION Patients received calcifediol (25-hydroxyvitamin D3) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not. MAIN OUTCOME MEASURE In-hospital mortality during the first 30 days after admission. RESULTS A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80). CONCLUSION Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.
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The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts.
Maguire, D, Richards, C, Woods, M, Dolan, R, Wilson Veitch, J, Sim, WMJ, Kemmett, OEH, Milton, DC, Randall, SLW, Bui, LD, et al
PloS one. 2021;(5):e0251924
Abstract
BACKGROUND In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts. METHODS The aim of the present study was to compare the 4C mortality score, other measures of the systemic inflammatory response and clinicopathological characteristics in two consecutive cohorts of patients on admission with COVID-19. Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17/3/2020-1/5/2020) and (cohort 2: 18/5/2020-6/7/2020) were examined for routine clinical, laboratory and clinical outcome data. RESULTS Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). In cohort 2, age >70 (p<0.05), male gender (p<0.05), COPD (p<0.05), cognitive impairment (p<0.05), frailty (p<0.001), delirium (p = 0.001), CRP>150mg/L (p<0.05), albumin <30 g/L (p<0.01), elevated perioperative Glasgow Prognostic Score (p<0.05), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated PT (p<0.05), sodium <133 mmol/L (p<0.01) elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.001) and the 4C score (p<0.001) were associated with 30-day mortality. In multivariate analysis, greater frailty (CFS>3) (OR 11.3, 95% C.I. 2.3-96.7, p<0.05), low albumin (<30g/L) (OR 2.5, 95% C.I. 1.0-6.2, p<0.05), high NLR (≥3) (OR 2.2, 95% C.I. 1.5-4.5, p<0.05) and the 4C score (OR 2.4, 95% C.I. 1.0-5.6, p<0.05) remained independently associated with 30-day mortality. CONCLUSION In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19. TRIAL REGISTRATION clinicaltrials.gov: NCT04484545.
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Relation of Serum Copper Status to Survival in COVID-19.
Hackler, J, Heller, RA, Sun, Q, Schwarzer, M, Diegmann, J, Bachmann, M, Moghaddam, A, Schomburg, L
Nutrients. 2021;(6)
Abstract
The trace element copper (Cu) is part of our nutrition and essentially needed for several cuproenzymes that control redox status and support the immune system. In blood, the ferroxidase ceruloplasmin (CP) accounts for the majority of circulating Cu and serves as transport protein. Both Cu and CP behave as positive, whereas serum selenium (Se) and its transporter selenoprotein P (SELENOP) behave as negative acute phase reactants. In view that coronavirus disease (COVID-19) causes systemic inflammation, we hypothesized that biomarkers of Cu and Se status are regulated inversely, in relation to disease severity and mortality risk. Serum samples from COVID-19 patients were analysed for Cu by total reflection X-ray fluorescence and CP was quantified by a validated sandwich ELISA. The two Cu biomarkers correlated positively in serum from patients with COVID-19 (R = 0.42, p < 0.001). Surviving patients showed higher mean serum Cu and CP concentrations in comparison to non-survivors ([mean+/-SEM], Cu; 1475.9+/-22.7 vs. 1317.9+/-43.9 µg/L; p < 0.001, CP; 547.2.5 +/- 19.5 vs. 438.8+/-32.9 mg/L, p = 0.086). In contrast to expectations, total serum Cu and Se concentrations displayed a positive linear correlation in the patient samples analysed (R = 0.23, p = 0.003). Serum CP and SELENOP levels were not interrelated. Applying receiver operating characteristics (ROC) curve analysis, the combination of Cu and SELENOP with age outperformed other combinations of parameters for predicting risk of death, yielding an AUC of 95.0%. We conclude that the alterations in serum biomarkers of Cu and Se status in COVID-19 are not compatible with a simple acute phase response, and that serum Cu and SELENOP levels contribute to a good prediction of survival. Adjuvant supplementation in patients with diagnostically proven deficits in Cu or Se may positively influence disease course, as both increase in survivors and are of crucial importance for the immune response and antioxidative defence systems.
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Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality.
Snider, JM, You, JK, Wang, X, Snider, AJ, Hallmark, B, Zec, MM, Seeds, MC, Sergeant, S, Johnstone, L, Wang, Q, et al
The Journal of clinical investigation. 2021;(19)
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Abstract
There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
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Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.
Danlos, FX, Grajeda-Iglesias, C, Durand, S, Sauvat, A, Roumier, M, Cantin, D, Colomba, E, Rohmer, J, Pommeret, F, Baciarello, G, et al
Cell death & disease. 2021;(3):258
Abstract
The circulating metabolome provides a snapshot of the physiological state of the organism responding to pathogenic challenges. Here we report alterations in the plasma metabolome reflecting the clinical presentation of COVID-19 patients with mild (ambulatory) diseases, moderate disease (radiologically confirmed pneumonitis, hospitalization and oxygen therapy), and critical disease (in intensive care). This analysis revealed major disease- and stage-associated shifts in the metabolome, meaning that at least 77 metabolites including amino acids, lipids, polyamines and sugars, as well as their derivatives, were altered in critical COVID-19 patient's plasma as compared to mild COVID-19 patients. Among a uniformly moderate cohort of patients who received tocilizumab, only 10 metabolites were different among individuals with a favorable evolution as compared to those who required transfer into the intensive care unit. The elevation of one single metabolite, anthranilic acid, had a poor prognostic value, correlating with the maintenance of high interleukin-10 and -18 levels. Given that products of the kynurenine pathway including anthranilic acid have immunosuppressive properties, we speculate on the therapeutic utility to inhibit the rate-limiting enzymes of this pathway including indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase.
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Clinical Course and Risk Factors of Disease Deterioration in Critically Ill Patients with COVID-19.
Qin, W, Bai, W, Liu, K, Liu, Y, Meng, X, Zhang, K, Zhang, M
Human gene therapy. 2021;(5-6):310-315
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began in December 2019 and rapidly spread to other provinces in China as well as other countries. In this study, 262 patients diagnosed with moderate to severe SARS-CoV-2 pneumonia in Wuhan, China, were analyzed. Data were compared between survivors and nonsurvivors. Of all the 262 patients, 23 (8.8%) patients died and 239 (91.2%) were discharged. The median age was 63.5 years and 46.9% of patients were male. The main complaints were fever (83.6%), cough (63.4%), and fatigue (49.2%) in the surviving group, while there were more complaints of dyspnea (39.1%) and shortness of breath (56.5%) in the nonsurviving group. The main comorbidities were hypertension (35.5%), diabetes mellitus (16.4%), and coronary artery disease (9.9%). Morbidity is higher in elderly patients with more comorbidities. Patients were mainly treated with nasal cannula (93.9%), while the nonsurviving group received more invasive mechanical ventilation (39.1%). Arbidol (80.9%), ribavirin (36.6%), oseltamivir (38.9%), interferon (16.4%), and ganciclovir (14.5%) were used for the antiviral treatment. In the nonsurviving group, the number of white blood cells (WBC) was significantly increased and lymphocytes were decreased, and lymphopenia was more common. The levels of aspartate transaminase (AST), brain natriuretic peptide (BNP), creatine kinase isoenzyme MB (CK-MB), lactate dehydrogenase (LDH), and C-reactive protein (CRP) were also significantly increased in the nonsurviving group. The adjusted hazard ratios (HRs) for association of known variables for all-cause mortality due to the coronavirus disease 2019 were 2.467 (95% confidence interval [CI], 1.007-6.044; p = 0.048) for shortness of breath and 1.025 (95% CI, 1.001-1.049; p = 0.042) for AST. Elderly patients with more comorbidities and complaints of dyspnea and shortness of breath had increased risk of death. Patients with lymphopenia and high levels of WBC, AST, BNP, CK-MB, LDH, and CRP may be more likely to deteriorate.
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Distinct cytokine profiles associated with COVID-19 severity and mortality.
Dorgham, K, Quentric, P, Gökkaya, M, Marot, S, Parizot, C, Sauce, D, Guihot, A, Luyt, CE, Schmidt, M, Mayaux, J, et al
The Journal of allergy and clinical immunology. 2021;(6):2098-2107
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Abstract
BACKGROUND Markedly elevated levels of proinflammatory cytokines and defective type-I interferon responses were reported in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE We sought to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. METHODS Cytokine concentrations and severe acute respiratory syndrome coronavirus 2 antigen were measured at hospital admission in serum of symptomatic patients with COVID-19 (N = 115), classified at hospitalization into 3 respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS), and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal-component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N = 86). RESULTS At time of hospitalization, ECMO patients presented a dominant proinflammatory response with elevated levels of TNF-α, IL-6, IL-8, and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at 1 month was associated with higher levels of proinflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients, and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (risk ratio, 24.3; P < .0001). Severe acute respiratory syndrome coronavirus 2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with proinflammatory response or severity. CONCLUSIONS Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.
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Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19?
Saponaro, F, Franzini, M, Okoye, C, Antognoli, R, Campi, B, Scalese, M, Neri, T, Carrozzi, L, Monzani, F, Zucchi, R, et al
Frontiers in immunology. 2021;:745713
Abstract
BACKGROUND Hypovitaminosis D has been suggested to play a possible role in coronavirus disease 2019 (COVID-19) infection. METHODS The aim of this study is to analyze the relationship between vitamin D status and a biochemical panel of inflammatory markers in a cohort of patients with COVID-19. A secondary endpoint was to evaluate the correlation between 25OHD levels and the severity of the disease. Ninety-three consecutive patients with COVID-19-related pneumonia were evaluated from March to May 2020 in two hospital units in Pisa, in whom biochemical inflammatory markers, 25OHD levels, P/F ratio at nadir during hospitalization, and complete clinical data were available. RESULTS Sixty-five percent of patients presented hypovitaminosis D (25OHD ≤ 20 ng/ml) and showed significantly higher IL-6 [20.8 (10.9-45.6) vs. 12.9 (8.7-21.1) pg/ml, p = 0.02], CRP [10.7 (4.2-19.2) vs. 5.9 (1.6-8.1) mg/dl, p = 0.003], TNF-α [8.9 (6.0-14.8) vs. 4.4 (1.5-10.6) pg/ml, p = 0.01], D-dimer [0.53 (0.25-0.72) vs. 0.22 (0.17-0.35) mg/l, p = 0.002], and IL-10 [3.7 (1.8-6.9) vs. 2.3 (0.5-5.8) pg/ml, p = 0.03]. A significant inverse correlation was found between 25OHD and all these markers, even adjusted for age and sex. Hypovitaminosis D was prevalent in patients with severe ARDS, compared with the other groups (75% vs. 68% vs. 55%, p < 0.001), and 25OHD levels were lower in non-survivor patients. CONCLUSIONS The relationship between 25OHD levels and inflammatory markers suggests that vitamin D status needs to be taken into account in the management of these patients. If vitamin D is a marker of poor prognosis or a possible risk factor with beneficial effects from supplementation, this still needs to be elucidated.
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Multi-organ proteomic landscape of COVID-19 autopsies.
Nie, X, Qian, L, Sun, R, Huang, B, Dong, X, Xiao, Q, Zhang, Q, Lu, T, Yue, L, Chen, S, et al
Cell. 2021;(3):775-791.e14
Abstract
The molecular pathology of multi-organ injuries in COVID-19 patients remains unclear, preventing effective therapeutics development. Here, we report a proteomic analysis of 144 autopsy samples from seven organs in 19 COVID-19 patients. We quantified 11,394 proteins in these samples, in which 5,336 were perturbed in the COVID-19 patients compared to controls. Our data showed that cathepsin L1, rather than ACE2, was significantly upregulated in the lung from the COVID-19 patients. Systemic hyperinflammation and dysregulation of glucose and fatty acid metabolism were detected in multiple organs. We also observed dysregulation of key factors involved in hypoxia, angiogenesis, blood coagulation, and fibrosis in multiple organs from the COVID-19 patients. Evidence for testicular injuries includes reduced Leydig cells, suppressed cholesterol biosynthesis, and sperm mobility. In summary, this study depicts a multi-organ proteomic landscape of COVID-19 autopsies that furthers our understanding of the biological basis of COVID-19 pathology.