Individual blood concentrations of persistent organic pollutants and chemical elements, and COVID-19: A prospective cohort study in Barcelona.

BACKGROUND: There is wide, largely unexplained heterogeneity in immunological and clinical responses to SARS-CoV-2 infection. Numerous environmental chemicals, such as persistent organic pollutants (POPs) and chemical elements (including some metals, essential trace elements, rare earth elements, and minority elements), are immunomodulatory and cause a range of adverse clinical events. There are no prospective studies on the effects of such substances on the incidence of SARS-CoV-2 infection and COVID-19. OBJECTIVE: To investigate the influence of blood concentrations of POPs and elements measured several years before the pandemic on the development of SARS-CoV-2 infection and COVID-19 in individuals from the general population. METHODS: We conducted a prospective cohort study in 154 individuals from the general population of Barcelona. POPs and elements were measured in blood samples collected in 2016-2017. SARS-CoV-2 infection was detected by rRT-PCR in nasopharyngeal swabs and/or by antibody serology using eighteen isotype-antigen combinations measured in blood samples collected in 2020-2021. We analyzed the associations between concentrations of the contaminants and SARS-CoV-2 infection and development of COVID-19, taking into account personal habits and living conditions during the pandemic. RESULTS: Several historically prevalent POPs, as well as arsenic, cadmium, mercury, and zinc, were not associated with COVID-19, nor with SARS-CoV-2 infection. However, DDE (adjusted OR = 5.0 [95% CI: 1.2-21]), lead (3.9 [1.0-15]), thallium (3.4 [1.0-11]), and ruthenium (5.0 [1.8-14]) were associated with COVID-19, as were tantalum, benzo(b)fluoranthene, DDD, and manganese. Thallium (3.8 [1.6-8.9]), and ruthenium (2.9 [1.3-6.7]) were associated with SARS-CoV-2 infection, and so were lead, gold, and (protectively) iron and selenium. We identified mixtures of up to five substances from several chemical groups, with all substances independently associated to the outcomes. CONCLUSIONS: Our results provide the first prospective and population-based evidence of an association between individual concentrations of some contaminants and COVID-19 and SARS-CoV-2 infection. POPs and elements may contribute to explain the heterogeneity in the development of SARS-CoV-2 infection and COVID-19 in the general population. If the associations are confirmed as causal, means are available to mitigate the corresponding risks.

Comparison of hospitalized COVID-19 and influenza patients requiring supplemental oxygen in a cohort study: clinical impact and resource consumption.

BACKGROUND: To compare clinical characteristics, outcomes, and resource consumption of patients with COVID-19 and seasonal influenza requiring supplemental oxygen. METHODS: Retrospective cohort study conducted at a tertiary-care hospital. Patients admitted due to seasonal influenza between 2017 and 2019, or with COVID-19 between March and May 2020 requiring supplemental oxygen were compared. Primary outcome: 30-day mortality. Secondary outcomes: 90-day mortality and hospitalization costs. Attempted sample size to detect an 11% difference in mortality was 187 patients per group. RESULTS: COVID-19 cases were younger (median years, 67 (IQR 54-78) vs 76 (IQR 64-83); p < 0.001) and more frequently overweight whereas influenza cases had more hypertension, immunosuppression, and chronic heart, respiratory and renal disease. Compared to influenza, COVID-19 cases had more pneumonia (98% vs 60%, <0.001), higher MEWS and CURB-65 scores and were more likely to show worse progression on the WHO ordinal scale (33% vs 4%; p < 0.001). The 30-day mortality rate was higher for COVID-19 than for influenza: 15% vs 5% (p = 0.001). The median age of non-surviving cases was 81 (IQR 74-88) and 77.5 (IQR 65-84) (p = 0.385), respectively. COVID-19 was independently associated with 30-day (HR 4.6, 95%CI, 2-10.4) and 90-day (HR 5.2, 95%CI, 2.4-11.4) mortality. Sensitivity and subgroup analyses, including a subgroup considering only patients with pneumonia, did not show different trends. Regarding resource consumption, COVID-19 patients had longer hospital stays and higher critical care, pharmacy, and complementary test costs. CONCLUSIONS: Although influenza patients were older and had more comorbidities, COVID-19 cases requiring supplemental oxygen on admission had worse clinical and economic outcomes.

SARS-CoV-2 sculpts the immune system to induce sustained virus-specific naïve-like and memory B-cell responses.

OBJECTIVES: SARS-CoV-2 infection induces virus-reactive memory B cells expressing unmutated antibodies, which hints at their emergence from naïve B cells. Yet, the dynamics of virus-specific naïve B cells and their impact on immunity and immunopathology remain unclear. METHODS: We longitudinally profiled SARS-CoV-2-specific B-cell responses in 25 moderate-to-severe COVID-19 patients by high-dimensional flow cytometry and isotyping and subtyping ELISA. We also explored the relationship of B-cell responses to SARS-CoV-2 with the activation of effector and regulatory cells from the innate or adaptive immune system. RESULTS: We found a virus-specific antibody response with a broad spectrum of classes and subclasses during acute infection, which evolved into an IgG1-dominated response during convalescence. Acute infection was associated with increased mature B-cell progenitors in the circulation and the unexpected expansion of virus-targeting naïve-like B cells. The latter further augmented during convalescence together with virus-specific memory B cells. In addition to a transitory increase in tissue-homing CXCR3+ plasmablasts and extrafollicular memory B cells, most COVID-19 patients showed persistent activation of CD4+ and CD8+ T cells along with transient or long-lasting changes of key innate immune cells. Remarkably, virus-specific antibodies and the frequency of naïve B cells were among the major variables defining distinct immune signatures associated with disease severity and inflammation. CONCLUSION: Aside from providing new insights into the complexity of the immune response to SARS-CoV-2, our findings indicate that the de novo recruitment of mature B-cell precursors into the periphery may be central to the induction of antiviral immunity.

Calcifediol Treatment and COVID-19-Related Outcomes.

CONTEXT: COVID-19 is a major health problem because of saturation of intensive care units (ICU) and mortality. Vitamin D has emerged as a potential treatment able to reduce the disease severity. OBJECTIVE: This work aims to elucidate the effect of 25(OH)D3 (calcifediol) treatment on COVID-19-related outcomes. METHODS: This observational cohort study was conducted from March to May 2020, among patients admitted to COVID-19 wards of Hospital del Mar, Barcelona, Spain. A total of 930 patients with COVID-19 were included; 92 were excluded because of previous calcifediol intake. Of the remaining 838, a total of 447 received calcifediol (532 µg on day 1 plus 266 µg on days 3, 7, 15, and 30), whereas 391 were not treated at the time of hospital admission (intention-to-treat). Of the latter, 53 patients were treated later during ICU admission and were allocated in the treated group in a second analysis. In healthy individuals, calcifediol is about 3.2-fold more potent on a weight basis than cholecalciferol. Main outcome measures were ICU admission and mortality. RESULTS: ICU assistance was required by 102 (12.2%) participants. Out of 447 patients treated with calcifediol at admission, 20 (4.5%) required the ICU, compared to 82 (21%) out of 391 nontreated (P < .001). Logistic regression of calcifediol treatment on ICU admission, adjusted by age, sex, linearized 25-hydroxyvitamin D levels at baseline, and comorbidities showed that treated patients had a reduced risk of requiring the ICU (odds ratio [OR] 0.13; 95% CI 0.07-0.23). Overall mortality was 10%. In the intention-to-treat analysis, 21 (4.7%) out of 447 patients treated with calcifediol at admission died compared to 62 patients (15.9%) out of 391 nontreated (P = .001). Adjusted results showed a reduced mortality risk with an OR of 0.21 (95% CI, 0.10-0.43). In the second analysis, the obtained OR was 0.52 (95% CI, 0.27-0.99). CONCLUSION: In patients hospitalized with COVID-19, calcifediol treatment significantly reduced ICU admission and mortality.

Epigenome-wide association study of COVID-19 severity with respiratory failure.

BACKGROUND: Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities. METHODS: Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients. FINDINGS: The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease. INTERPRETATION: We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2. FUNDING: The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.

Effects of Environmental Factors on Severity and Mortality of COVID-19.

Background: Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. Methods: We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Findings: Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, p < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, p = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Interpretation: Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

CT imaging of pulmonary embolism in patients with COVID-19 pneumonia: a retrospective analysis.

OBJECTIVES: To describe imaging and laboratory findings of confirmed PE diagnosed in COVID-19 patients and to evaluate the characteristics of COVID-19 patients with clinical PE suspicion. Characteristics of patients with COVID-19 and PE suspicion who required admission to the intensive care unit (ICU) were also analysed. METHODS: A retrospective study from March 18, 2020, until April 11, 2020. Inclusion criteria were patients with suspected PE and positive real-time reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2. Exclusion criteria were negative or inconclusive RT-PCR and other chest CT indications. CTPA features were evaluated and severity scores, presence, and localisation of PE were reported. D-dimer and IL-6 determinations, ICU admission, and previous antithrombotic treatment were registered. RESULTS: Forty-seven PE suspicions with confirmed COVID-19 underwent CTPA. Sixteen patients were diagnosed with PE with a predominant segmental distribution. Statistically significant differences were found in the highest D-dimer determination in patients with PE and ICU admission regarding elevated IL-6 values. CONCLUSION: PE in COVID-19 patients in our series might predominantly affect segmental arteries and the right lung. Results suggest that the higher the D-dimer concentration, the greater the likelihood of PE. Both assumptions should be assessed in future studies with a larger sample size. KEY POINTS: • On CT pulmonary angiography, pulmonary embolism in COVID-19 patients seems to be predominantly distributed in segmental arteries of the right lung, an assumption that needs to be approached in future research. • Only the highest intraindividual determination of d-dimer from admission to CT scan seems to differentiate patients with pulmonary embolism from patients with a negative CTPA. However, interindividual variability calls for future studies to establish cut-off values in COVID-19 patients. • Further studies with larger sample sizes are needed to determine whether the presence of PE could increase the risk of intensive care unit (ICU) admission in COVID-19 patients.

COVID-19 in Grade 4-5 Chronic Kidney Disease Patients.

INTRODUCTION: Chronic kidney disease (CKD) increases the risk of mortality during coronavirus disease 2019 (COVID-19) episodes, and some reports have underlined the high incidence and severity of this infection in dialysis patients. Information on COVID-19 in nondialysis CKD patients is not available yet. CASE REPORTS: Here we present 7 patients with grade 4-5 CKD who developed symptomatic COVID-19; they comprise 2.6% of our 267 advanced CKD patients. The estimated GFR was between 12 and 20 mL/min during the month prior to COVID-19. The 3 major symptoms were fever, cough, and dyspnea, and 5 patients showed bilateral pneumonia. Hydroxychloroquine, azithromycin, ceftriaxone, and steroids were the most frequently prescribed drugs. Two patients needed noninvasive mechanical ventilation. All patients showed minimal to moderate kidney function deterioration during admission, with an eGFR decline below 5 mL/min in 6 cases. No patient required acute dialysis. Six patients were discharged alive and remained dialysis free athe t the time of reporting, and one 76-year-old patient died. CONCLUSIONS: COVID-19 affects grade 4-5 CKD patients, but prognosis may be acceptable if prompt supportive measures are applied. These findings should be confirmed in larger cohorts, and further observations will be needed to understand the full spectrum of clinical features and the optimal approach to COVID-19 in patients with advanced CKD.