Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19.

Temporal resolution of cellular features associated with a severe COVID-19 disease trajectory is needed for understanding skewed immune responses and defining predictors of outcome. Here, we performed a longitudinal multi-omics study using a two-center cohort of 14 patients. We analyzed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. Validation was performed in two independent cohorts of COVID-19 patients. Severe COVID-19 was characterized by an increase of proliferating, metabolically hyperactive plasmablasts. Coinciding with critical illness, we also identified an expansion of interferon-activated circulating megakaryocytes and increased erythropoiesis with features of hypoxic signaling. Megakaryocyte- and erythroid-cell-derived co-expression modules were predictive of fatal disease outcome. The study demonstrates broad cellular effects of SARS-CoV-2 infection beyond adaptive immune cells and provides an entry point toward developing biomarkers and targeted treatments of patients with COVID-19.

Regional spread of an atypical ESBL-producing Escherichia coli ST131H89 clone among different human and environmental reservoirs in Western Switzerland.

We describe the inter-regional spread of a novel ESBL-producing Escherichia coli subclone (ST131H89) in long-term care facility residents, general population, and environmental water sources in Western Switzerland between 2017 and 2020. The study highlights the importance of molecular surveillance for tracking emerging antibiotic-resistant pathogens in healthcare and community settings.

Pulmonary Surfactant Proteins Are Inhibited by Immunoglobulin A Autoantibodies in Severe COVID-19.

Rationale: Coronavirus disease 2019 (COVID-19) can lead to acute respiratory distress syndrome with fatal outcomes. Evidence suggests that dysregulated immune responses, including autoimmunity, are key pathogenic factors. Objectives: To assess whether IgA autoantibodies target lung-specific proteins and contribute to disease severity. Methods: We collected 147 blood, 9 lung tissue, and 36 BAL fluid samples from three tertiary hospitals in Switzerland and one in Germany. Severe COVID-19 was defined by the need to administer oxygen. We investigated the presence of IgA autoantibodies and their effects on pulmonary surfactant in COVID-19 using the following methods: immunofluorescence on tissue samples, immunoprecipitations followed by mass spectrometry on BAL fluid samples, enzyme-linked immunosorbent assays on blood samples, and surface tension measurements with medical surfactant. Measurements and Main Results: IgA autoantibodies targeting pulmonary surfactant proteins B and C were elevated in patients with severe COVID-19 but not in patients with influenza or bacterial pneumonia. Notably, pulmonary surfactant failed to reduce surface tension after incubation with either plasma or purified IgA from patients with severe COVID-19. Conclusions: Our data suggest that patients with severe COVID-19 harbor IgA autoantibodies against pulmonary surfactant proteins B and C and that these autoantibodies block the function of lung surfactant, potentially contributing to alveolar collapse and poor oxygenation.

Post-Acute Sequelae After Severe Acute Respiratory Syndrome Coronavirus 2 Infection by Viral Variant and Vaccination Status: A Multicenter Cross-Sectional Study.

BACKGROUND: Disentangling the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and vaccination on the occurrence of post-acute sequelae of SARS-CoV-2 (PASC) is crucial to estimate and reduce the burden of PASC. METHODS: We performed a cross-sectional analysis (May/June 2022) within a prospective multicenter healthcare worker (HCW) cohort in north-eastern Switzerland. HCWs were stratified by viral variant and vaccination status at time of their first positive SARS-CoV-2 nasopharyngeal swab. HCWs without positive swab and with negative serology served as controls. The sum of 18 self-reported PASC symptoms was modeled with univariable and multivariable negative-binomial regression to analyze the association of mean symptom number with viral variant and vaccination status. RESULTS: Among 2912 participants (median age: 44 years; 81.3% female), PASC symptoms were significantly more frequent after wild-type infection (estimated mean symptom number: 1.12; P < .001; median time since infection: 18.3 months), after Alpha/Delta infection (0.67 symptoms; P < .001; 6.5 months), and after Omicron BA.1 infections (0.52 symptoms; P = .005; 3.1 months) versus uninfected controls (0.39 symptoms). After Omicron BA.1 infection, the estimated mean symptom number was 0.36 for unvaccinated individuals versus 0.71 with 1-2 vaccinations (P = .028) and 0.49 with ≥3 prior vaccinations (P = .30). Adjusting for confounders, only wild-type (adjusted rate ratio [aRR]: 2.81; 95% confidence interval [CI]: 2.08-3.83) and Alpha/Delta infections (aRR: 1.93; 95% CI: 1.10-3.46) were significantly associated with the outcome. CONCLUSIONS: Previous infection with pre-Omicron variants was the strongest risk factor for PASC symptoms among our HCWs. Vaccination before Omicron BA.1 infection was not associated with a clear protective effect against PASC symptoms in this population.

Resistance development in Escherichia coli to delafloxacin at pHs 6.0 and 7.3 compared to ciprofloxacin.

Understanding the resistance mechanisms of antibiotics in the micro-environment of the infection is important to assess their clinical applicability and potentially prevent resistance development. We compared the laboratory resistance evolution of Escherichia coli to delafloxacin (DLX) compared to ciprofloxacin (CIP), the co-resistance evolution, and underlying resistance mechanisms at different pHs. Three clones from each of the eight clinical E. coli isolates were subjected to subinhibitory concentrations of DLX or CIP in parallel at either pH 7.3 or 6.0. Minimum inhibitory concentrations (MICs) were regularly tested (at respective pHs), and the antibiotic concentration was adjusted accordingly. After 30 passages, MICs were determined in the presence of the efflux pump inhibitor phenylalanine-arginine-ß-naphthylamide. Whole genome sequencing of the parental isolates and their resistant derivatives (n = 54) was performed. Complementation assays were carried out for selected mutations. Quantitative PCR and efflux experiments were carried out for selected derivatives. For DLX-challenged strains, resistance to DLX evolved much slower in acidic than in neutral pH, whereas for CIP-challenged strains, the opposite was the case. Mutations in the quinolone resistance-determining region were mainly seen in CIP-challenged E. coli, whereas a multifactorial mechanism including mutations in efflux-related genes played a role in DLX resistance evolution (predominantly at pH 6.0). This work provides novel insights into the resistance mechanisms of E. coli to delafloxacin and highlights the importance of understanding micro-environmental conditions at the infection site that might affect the true clinical efficacy of antibiotics and challenges our current antibiotic susceptibility-testing paradigm.

Autoreactive T cells targeting type II pneumocyte antigens in COVID-19 convalescent patients.

BACKGROUND: The role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease. OBJECTIVE: The aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease. METHODS: We collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells. RESULTS: We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells. CONCLUSIONS: Our data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance.

Elucidating climatic drivers of photosynthesis by tropical forests.

Tropical forests play a pivotal role in regulating the global carbon cycle. However, the response of these forests to changes in absorbed solar energy and water supply under the changing climate is highly uncertain. Three-year (2018-2021) spaceborne high-resolution measurements of solar-induced chlorophyll fluorescence (SIF) from the TROPOspheric Monitoring Instrument (TROPOMI) provide a new opportunity to study the response of gross primary production (GPP) and more broadly tropical forest carbon dynamics to differences in climate. SIF has been shown to be a good proxy for GPP on monthly and regional scales. Combining tropical climate reanalysis records and other contemporary satellite products, we find that on the seasonal timescale, the dependence of GPP on climate variables is highly heterogeneous. Following the principal component analyses and correlation comparisons, two regimes are identified: water limited and energy limited. GPP variations over tropical Africa are more correlated with water-related factors such as vapor pressure deficit (VPD) and soil moisture, while in tropical Southeast Asia, GPP is more correlated with energy-related factors such as photosynthetically active radiation (PAR) and surface temperature. Amazonia is itself heterogeneous: with an energy-limited regime in the north and water-limited regime in the south. The correlations of GPP with climate variables are supported by other observation-based products, such as Orbiting Carbon Observatory-2 (OCO2) SIF and FluxSat GPP. In each tropical continent, the coupling between SIF and VPD increases with the mean VPD. Even on the interannual timescale, the correlation of GPP with VPD is still discernable, but the sensitivity is smaller than the intra-annual correlation. By and large, the dynamic global vegetation models in the TRENDY v8 project do not capture the high GPP seasonal sensitivity to VPD in dry tropics. The complex interactions between carbon and water cycles in the tropics illustrated in this study and the poor representation of this coupling in the current suite of vegetation models suggest that projections of future changes in carbon dynamics based on these models may not be robust.

Seroprevalence trends of anti-SARS-CoV-2 antibodies and associated risk factors: a population-based study.

PURPOSE: We aimed to assess the seroprevalence trends of SARS-CoV-2 antibodies in several Swiss cantons between May 2020 and September 2021 and investigate risk factors for seropositivity and their changes over time. METHODS: We conducted repeated population-based serological studies in different Swiss regions using a common methodology. We defined three study periods: May-October 2020 (period 1, prior to vaccination), November 2020-mid-May 2021 (period 2, first months of the vaccination campaign), and mid-May-September 2021 (period 3, a large share of the population vaccinated). We measured anti-spike IgG. Participants provided information on sociodemographic and socioeconomic characteristics, health status, and adherence to preventive measures. We estimated seroprevalence with a Bayesian logistic regression model and the association between risk factors and seropositivity with Poisson models. RESULTS: We included 13,291 participants aged 20 and older from 11 Swiss cantons. Seroprevalence was 3.7% (95% CI 2.1-4.9) in period 1, 16.2% (95% CI 14.4-17.5) in period 2, and 72.0% (95% CI 70.3-73.8) in period 3, with regional variations. In period 1, younger age (20-64) was the only factor associated with higher seropositivity. In period 3, being aged ≥ 65 years, with a high income, retired, overweight or obese or with other comorbidities, was associated with higher seropositivity. These associations disappeared after adjusting for vaccination status. Seropositivity was lower in participants with lower adherence to preventive measures, due to a lower vaccination uptake. CONCLUSIONS: Seroprevalence sharply increased over time, also thanks to vaccination, with some regional variations. After the vaccination campaign, no differences between subgroups were observed.

Changes in socioeconomic resources and mental health after the second COVID-19 wave (2020-2021): a longitudinal study in Switzerland.

BACKGROUND: During the 2020/2021 winter, the labour market was under the impact of the COVID-19 pandemic. Changes in socioeconomic resources during this period could have influenced individual mental health. This association may have been mitigated or exacerbated by subjective risk perceptions, such as perceived risk of getting infected with SARS-CoV-2 or perception of the national economic situation. Therefore, we aimed to determine if changes in financial resources and employment situation during and after the second COVID-19 wave were prospectively associated with depression, anxiety and stress, and whether perceptions of the national economic situation and of the risk of getting infected modified this association. METHODS: One thousand seven hundred fifty nine participants from a nation-wide population-based eCohort in Switzerland were followed between November 2020 and September 2021. Financial resources and employment status were assessed twice (Nov2020-Mar2021, May-Jul 2021). Mental health was assessed after the second measurement of financial resources and employment status, using the Depression, Anxiety and Stress Scale (DASS-21). We modelled DASS-21 scores with linear regression, adjusting for demographics, health status, social relationships and changes in workload, and tested interactions with subjective risk perceptions. RESULTS: We observed scores above thresholds for normal levels for 16% (95%CI = 15-18) of participants for depression, 8% (95%CI = 7-10) for anxiety, and 10% (95%CI = 9-12) for stress. Compared to continuously comfortable or sufficient financial resources, continuously precarious or insufficient resources were associated with worse scores for all outcomes. Increased financial resources were associated with higher anxiety. In the working-age group, shifting from full to part-time employment was associated with higher stress and anxiety. Perceiving the Swiss economic situation as worrisome was associated with higher anxiety in participants who lost financial resources or had continuously precarious or insufficient resources. CONCLUSION: This study confirms the association of economic stressors and mental health during the COVID-19 pandemic and highlights the exacerbating role of subjective risk perception on this association.

Symptoms Compatible With Long Coronavirus Disease (COVID) in Healthcare Workers With and Without Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection-Results of a Prospective Multicenter Cohort.

BACKGROUND: The burden of long-term symptoms (ie, long COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCWs), frequency and risk factors for symptoms compatible with long COVID are assessed. METHODS: Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long COVID (including psychometric scores) were asked and compared between HCWs with positive NPS, seropositive HCWs without positive NPS (presumable asymptomatic/pauci-symptomatic infections), and negative controls. The effect of time since diagnosis and quantitative anti-spike protein antibodies (anti-S) was evaluated. Poisson regression was used to identify risk factors for symptom occurrence. RESULTS: Of 3334 HCWs (median, 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCWs with positive NPS more frequently reported ≥1 symptom compared with controls (73% vs 52%, P < .001); seropositive HCWs without positive NPS did not score higher than controls (58% vs 52%, P = .13), although impaired taste/olfaction (16% vs 6%, P < .001) and hair loss (17% vs 10%, P = .004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores. CONCLUSIONS: Seropositive HCWs without positive NPS are only mildly affected by long COVID. Exhaustion/burnout is common, even in noninfected HCWs. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

Risk and symptoms of COVID-19 in health professionals according to baseline immune status and booster vaccination during the Delta and Omicron waves in Switzerland-A multicentre cohort study.

BACKGROUND: Knowledge about protection conferred by previous Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and/or vaccination against emerging viral variants allows clinicians, epidemiologists, and health authorities to predict and reduce the future Coronavirus Disease 2019 (COVID-19) burden. We investigated the risk and symptoms of SARS-CoV-2 (re)infection and vaccine breakthrough infection during the Delta and Omicron waves, depending on baseline immune status and subsequent vaccinations. METHODS AND FINDINGS: In this prospective, multicentre cohort performed between August 2020 and March 2022, we recruited hospital employees from ten acute/nonacute healthcare networks in Eastern/Northern Switzerland. We determined immune status in September 2021 based on serology and previous SARS-CoV-2 infections/vaccinations: Group N (no immunity); Group V (twice vaccinated, uninfected); Group I (infected, unvaccinated); Group H (hybrid: infected and ≥1 vaccination). Date and symptoms of (re)infections and subsequent (booster) vaccinations were recorded until March 2022. We compared the time to positive SARS-CoV-2 swab and number of symptoms according to immune status, viral variant (i.e., Delta-dominant before December 27, 2021; Omicron-dominant on/after this date), and subsequent vaccinations, adjusting for exposure/behavior variables. Among 2,595 participants (median follow-up 171 days), we observed 764 (29%) (re)infections, thereof 591 during the Omicron period. Compared to group N, the hazard ratio (HR) for (re)infection was 0.33 (95% confidence interval [CI] 0.22 to 0.50, p < 0.001) for V, 0.25 (95% CI 0.11 to 0.57, p = 0.001) for I, and 0.04 (95% CI 0.02 to 0.10, p < 0.001) for H in the Delta period. HRs substantially increased during the Omicron period for all groups; in multivariable analyses, only belonging to group H was associated with protection (adjusted HR [aHR] 0.52, 95% CI 0.35 to 0.77, p = 0.001); booster vaccination was associated with reduction of breakthrough infection risk in groups V (aHR 0.68, 95% CI 0.54 to 0.85, p = 0.001) and H (aHR 0.67, 95% CI 0.45 to 1.00, p = 0.048), largely observed in the early Omicron period. Group H (versus N, risk ratio (RR) 0.80, 95% CI 0.66 to 0.97, p = 0.021) and participants with booster vaccination (versus nonboosted, RR 0.79, 95% CI 0.71 to 0.88, p < 0.001) reported less symptoms during infection. Important limitations are that SARS-CoV-2 swab results were self-reported and that results on viral variants were inferred from the predominating strain circulating in the community at that time, rather than sequencing. CONCLUSIONS: Our data suggest that hybrid immunity and booster vaccination are associated with a reduced risk and reduced symptom number of SARS-CoV-2 infection during Delta- and Omicron-dominant periods. For previously noninfected individuals, booster vaccination might reduce the risk of symptomatic Omicron infection, although this benefit seems to wane over time.

Is living in a household with children associated with SARS-CoV-2 seropositivity in adults? Results from the Swiss national seroprevalence study Corona Immunitas.

BACKGROUND: We aimed to determine whether living in a household with children is associated with SARS-CoV-2 seropositivity in adults and investigated interacting factors that may influence this association. METHODS: SARS-CoV-2 serology testing was performed in randomly selected individuals from the general population between end of October 2020 and February 2021 in 11 cantons in Switzerland. Data on sociodemographic and household characteristics, employment status, and health-related history was collected using questionnaires. Multivariable logistic regression was used to examine the association of living with children <18 years of age (number, age group) and SARS-CoV-2 seropositivity. Further, we assessed the influence of reported non-household contacts, employment status, and gender. RESULTS: Of 2393 working age participants (18-64 years), 413 (17.2%) were seropositive. Our results suggest that living with children and SARS-CoV-2 seropositivity are likely to be associated (unadjusted odds ratio (OR) 1.22, 95% confidence interval [0.98-1.52], adjusted OR 1.25 [0.99-1.58]). A pattern of a positive association was also found for subgroups of children aged 0-11 years (OR 1.21 [0.90-1.60]) and 12-17 years (OR 1.14 [0.78-1.64]). Odds of seropositivity were higher with more children (OR 1.14 per additional child [1.02-1.27]). Men had higher risk of SARS-CoV-2 infection when living with children than women (interaction: OR 1.74 [1.10-2.76]). CONCLUSIONS: In adults from the general population living with children seems associated with SARS-CoV-2 seropositivity. However, child-related infection risk is not the same for every subgroup and depends on factors like gender. Further factors determining child-related infection risk need to be identified and causal links investigated. TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN18181860 .

Remdesivir in Coronavirus Disease 2019 patients treated with anti-CD20 monoclonal antibodies: a case series.

PURPOSE: COVID-19 patients on anti-CD20 treatment can suffer a delayed viral clearance and worse clinical outcome. We aim to present our experience with remdesivir treatment in anti-CD20-treated patients with prolonged symptoms, a patient population for which no data from randomized controlled trials are available. METHODS: From the beginning of the pandemic until February 2021, we included all consecutive patients from our healthcare network on anti-CD20 treatment with prolonged COVID-19 symptoms, who received remdesivir. Patient informed consent was gathered and patients' charts were reviewed to collect baseline data, COVID-19 history including time of symptom onset, diagnosis, data on treatment and disease course. Patients or their next of kin were contacted in March 2022 to assess long-term outcomes. RESULTS: We included 11 patients, who received remdesivir at a median of 33 days after diagnosis. Eight patients showed clinical improvement along with reductions in viral loads, one patient with relapsing infection recovered after administration of convalescent plasma, and two patients died. No clinical relapses were reported (median follow-up 13 months), while follow-up PCRs were not performed. One patient died of underlying malignancy 8 months after recovery from COVID-19. CONCLUSIONS: We observed a benefit of antiviral therapy in a majority of COVID-19 patients on anti-CD20 treatment, without any clinical relapses in the 1-year follow-up. Although these data suggest that remdesivir might be a promising management option in patients with delayed viral clearance, the lack of a control group is an important limitation of the study design. TRIAL REGISTRATION: Ethikkommission Ostschweiz, Scheibenackerstrasse 4, CH-9000 St. Gallen approved this case series. Project-ID 2021-00349 EKOS 21/027.

TROPOMI reveals dry-season increase of solar-induced chlorophyll fluorescence in the Amazon forest.

Photosynthesis of the Amazon rainforest plays an important role in the regional and global carbon cycles, but, despite considerable in situ and space-based observations, it has been intensely debated whether there is a dry-season increase in greenness and photosynthesis of the moist tropical Amazonian forests. Solar-induced chlorophyll fluorescence (SIF), which is emitted by chlorophyll, has a strong positive linear relationship with photosynthesis at the canopy scale. Recent advancements have allowed us to observe SIF globally with Earth observation satellites. Here we show that forest SIF did not decrease in the early dry season and increased substantially in the late dry season and early part of wet season, using SIF data from the Tropospheric Monitoring Instrument (TROPOMI), which has unprecedented spatial resolution and near-daily global coverage. Using in situ CO2 eddy flux data, we also show that cloud cover rarely affects photosynthesis at TROPOMI's midday overpass, a time when the forest canopy is most often light-saturated. The observed dry-season increases of forest SIF are not strongly affected by sun-sensor geometry, which was attributed as creating a pseudo dry-season green-up in the surface reflectance data. Our results provide strong evidence that greenness, SIF, and photosynthesis of the tropical Amazonian forest increase during the dry season.

Severe Coronavirus Disease 2019 (COVID-19) is Associated With Elevated Serum Immunoglobulin (Ig) A and Antiphospholipid IgA Antibodies.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) frequently entails complications that bear similarities to autoimmune diseases. To date, there are little data on possible immunoglobulin (Ig) A-mediated autoimmune responses. Here, we aim to determine whether COVID-19 is associated with a vigorous total IgA response and whether IgA antibodies are associated with complications of severe illness. Since thrombotic events are frequent in severe COVID-19 and resemble hypercoagulation of antiphospholipid syndrome, our approach focused on antiphospholipid antibodies (aPL). METHODS: In this retrospective cohort study, clinical data and aPL from 64 patients with COVID-19 were compared from 3 independent tertiary hospitals (1 in Liechtenstein, 2 in Switzerland). Samples were collected from 9 April to 1 May 2020. RESULTS: Clinical records of 64 patients with COVID-19 were reviewed and divided into a cohort with mild illness (mCOVID; 41%), a discovery cohort with severe illness (sdCOVID; 22%) and a confirmation cohort with severe illness (scCOVID; 38%). Total IgA, IgG, and aPL were measured with clinical diagnostic kits. Severe illness was significantly associated with increased total IgA (sdCOVID, P = .01; scCOVID, P < .001), but not total IgG. Among aPL, both cohorts with severe illness significantly correlated with elevated anticardiolipin IgA (sdCOVID and scCOVID, P < .001), anticardiolipin IgM (sdCOVID, P = .003; scCOVID, P< .001), and anti-beta 2 glycoprotein-1 IgA (sdCOVID and scCOVID, P< .001). Systemic lupus erythematosus was excluded from all patients as a potential confounder. CONCLUSIONS: Higher total IgA and IgA-aPL were consistently associated with severe illness. These novel data strongly suggest that a vigorous antiviral IgA response, possibly triggered in the bronchial mucosa, induces systemic autoimmunity.

Household Transmission of Carbapenemase-producing Enterobacterales in Ontario, Canada.

BACKGROUND: Data on household transmission of carbapenemase-producing Enterobacterales (CPE) remain limited. We studied risk of CPE household co-colonization and transmission in Ontario, Canada. METHODS: We enrolled CPE index cases (identified via population-based surveillance from January 2015 to October 2018) and their household contacts. At months 0, 3, 6, 9, and 12, participants provided rectal and groin swabs. Swabs were cultured for CPE until September 2017, when direct polymerase chain reaction (PCR; with culture of specimens if a carbapenemase gene was detected) replaced culture. CPE risk factor data were collected by interview and combined with isolate whole-genome sequencing to determine likelihood of household transmission. Risk factors for household contact colonization were explored using a multivariable logistic regression model with generalized estimating equations. RESULTS: Ninety-five households with 177 household contacts participated. Sixteen (9%) household contacts in 16 (17%) households were CPE-colonized. Household transmission was confirmed in 3/177 (2%) cases, probable in 2/177 (1%), possible in 9/177 (5%), and unlikely in 2/177 (1%). Household contacts were more likely to be colonized if they were the index case's spouse (odds ratio [OR], 6.17; 95% confidence interval [CI], 1.05-36.35), if their index case remained CPE-colonized at household enrollment (OR, 7.00; 95% CI, 1.92-25.49), or if they had at least 1 set of specimens processed after direct PCR was introduced (OR, 6.46; 95% CI, 1.52-27.40). CONCLUSIONS: Nine percent of household contacts were CPE-colonized; 3% were a result of household transmission. Hospitals may consider admission screening for patients known to have CPE-colonized household contacts.

Impact of baseline SARS-CoV-2 antibody status on syndromic surveillance and the risk of subsequent COVID-19-a prospective multicenter cohort study.

BACKGROUND: In a prospective healthcare worker (HCW) cohort, we assessed the risk of SARS-CoV-2 infection according to baseline serostatus. METHODS: Baseline serologies were performed among HCW from 23 Swiss healthcare institutions between June and September 2020, before the second COVID-19 wave. Participants answered weekly electronic questionnaires covering information about nasopharyngeal swabs (PCR/rapid antigen tests) and symptoms compatible with coronavirus disease 2019 (COVID-19). Screening of symptomatic staff by nasopharyngeal swabs was routinely performed in participating facilities. We compared numbers of positive nasopharyngeal tests and occurrence of COVID-19 symptoms between HCW with and without anti-nucleocapsid antibodies. RESULTS: A total of 4812 HCW participated, wherein 144 (3%) were seropositive at baseline. We analyzed 107,807 questionnaires with a median follow-up of 7.9 months. Median number of answered questionnaires was similar (24 vs. 23 per person, P = 0.83) between those with and without positive baseline serology. Among 2712 HCW with ≥ 1 SARS-CoV-2 test during follow-up, 3/67 (4.5%) seropositive individuals reported a positive result (one of whom asymptomatic), compared to 547/2645 (20.7%) seronegative participants, 12 of whom asymptomatic (risk ratio [RR] 0.22; 95% confidence interval [CI] 0.07 to 0.66). Seropositive HCWs less frequently reported impaired olfaction/taste (6/144, 4.2% vs. 588/4674, 12.6%, RR 0.33, 95% CI 0.15-0.73), chills (19/144, 13.2% vs. 1040/4674, 22.3%, RR 0.59, 95% CI 0.39-0.90), and limb/muscle pain (28/144, 19.4% vs. 1335/4674, 28.6%, RR 0.68 95% CI 0.49-0.95). Impaired olfaction/taste and limb/muscle pain also discriminated best between positive and negative SARS-CoV-2 results. CONCLUSIONS: Having SARS-CoV-2 anti-nucleocapsid antibodies provides almost 80% protection against SARS-CoV-2 re-infection for a period of at least 8 months.

Characteristics of patients with Coronavirus Disease 2019 (COVID-19) and seasonal influenza at time of hospital admission: a single center comparative study.

BACKGROUND: In the future, co-circulation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses A/B is likely. From a clinical point of view, differentiation of the two disease entities is crucial for patient management. We therefore aim to detect clinical differences between Coronavirus Disease 2019 (COVID-19) and seasonal influenza patients at time of hospital admission. METHODS: In this single-center observational study, we included all consecutive patients hospitalized for COVID-19 or influenza between November 2019 and May 2020. Data were extracted from a nationwide surveillance program and from electronic health records. COVID-19 and influenza patients were compared in terms of baseline characteristics, clinical presentation and outcome. We used recursive partitioning to generate a classification tree to discriminate COVID-19 from influenza patients. RESULTS: We included 96 COVID-19 and 96 influenza patients. Median age was 68 vs. 70 years (p = 0.90), 72% vs. 56% (p = 0.024) were males, and median Charlson Comorbidity Index (CCI) was 1 vs. 2 (p = 0.027) in COVID-19 and influenza patients, respectively. Time from symptom onset to hospital admission was longer for COVID-19 (median 7 days, IQR 3-10) than for influenza patients (median 3 days, IQR 2-5, p < 0.001). Other variables favoring a diagnosis of COVID-19 in the classification tree were higher systolic blood pressure, lack of productive sputum, and lack of headache. The tree classified 86/192 patients (45%) into two subsets with ≥80% of patients having influenza or COVID-19, respectively. In-hospital mortality was higher for COVID-19 patients (16% vs. 5%, p = 0.018). CONCLUSION: Discriminating COVID-19 from influenza patients based on clinical presentation is challenging. Time from symptom onset to hospital admission is considerably longer in COVID-19 than in influenza patients and showed the strongest discriminatory power in our classification tree. Although they had fewer comorbidities, in-hospital mortality was higher for COVID-19 patients.

Antimicrobial resistance and antibiotic consumption in intensive care units, Switzerland, 2009 to 2018.

BackgroundIntensive care units (ICU) constitute a high-risk setting for antimicrobial resistance (AMR).AimWe aimed to describe secular AMR trends including meticillin-resistant Staphylococcus aureus (MRSA), glycopeptide-resistant enterococci (GRE), extended-spectrum cephalosporin-resistant Escherichia coli (ESCR-EC) and Klebsiella pneumoniae (ESCR-KP), carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa (CRPA) from Swiss ICU. We assessed time trends of antibiotic consumption and identified factors associated with CRE and CRPA.MethodsWe analysed patient isolate and antibiotic consumption data of Swiss ICU sent to the Swiss Centre for Antibiotic Resistance (2009-2018). Time trends were assessed using linear logistic regression; a mixed-effects logistic regression was used to identify factors associated with CRE and CRPA.ResultsAmong 52 ICU, MRSA decreased from 14% to 6% (p = 0.005; n = 6,465); GRE increased from 1% to 3% (p = 0.011; n = 4,776). ESCR-EC and ESCR-KP increased from 7% to 15% (p < 0.001, n = 10,648) and 5% to 11% (p = 0.002; n = 4,052), respectively. CRE, mostly Enterobacter spp., increased from 1% to 5% (p = 0.008; n = 17,987); CRPA remained stable at 27% (p = 0.759; n = 4,185). Antibiotic consumption in 58 ICU increased from 2009 to 2013 (82.5 to 97.4 defined daily doses (DDD)/100 bed-days) and declined until 2018 (78.3 DDD/100 bed-days). Total institutional antibiotic consumption was associated with detection of CRE in multivariable analysis (odds ratio per DDD: 1.01; 95% confidence interval: 1.0-1.02; p = 0.004).DiscussionIn Swiss ICU, antibiotic-resistant Enterobacterales have been steadily increasing over the last decade. The emergence of CRE, associated with institutional antibiotic consumption, is of particular concern and calls for reinforced surveillance and antibiotic stewardship in this setting.

Frequency of serological non-responders and false-negative RT-PCR results in SARS-CoV-2 testing: a population-based study.

Objectives The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p<0.05). The antibody titer from quantitative immunoassays was positively associated with the number of disease symptoms and disease duration (p<0.001). Conclusions RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays.