Health-care workers in gastrointestinal endoscopy are at higher risk for SARS-CoV-2 infection compared to other aerosol-generating disciplines (preprint)

ObjectiveHealthcare workers (HCW) are at high risk of SARS-CoV-2 infection due to exposure to potentially infectious material, especially during aerosol-generating procedures (AGP). We aimed to investigate the prevalence of infection among HCW in medical disciplines with AGP. DesignA nationwide questionnaire-based study in in- and outpatient settings was conducted between 12/16/2020 and 01/24/2021. Data on SARS-CoV-2 infections among HCW and potential risk factors were investigated. Results2,070 healthcare facilities with 25,113 employees were included in the study. Despite a higher rate of pre-interventional testing, clinics treated three times more confirmed SARS-CoV-2 cases than private practices (28.8% vs. 88.4%, p<0.001). Overall infection rate among HCW accounted for 4.7%. Multivariate analysis revealed that ZIP-regions having comparably higher incidences were significantly associated with increased risk of infection. Furthermore, clinical setting and the GIE specialty have more than double the risk of infection (OR 2.63; 95% CI 2.501-2.817, p<0.01 and OR 2.35; 95% CI 2.245-2.498, p<0.01). The number of procedures performed per day was also significantly associated with an increased risk of infection (OR 1.01; 95% CI 1.007-1.014), p<0.01). No treatment of confirmed SARS-CoV-2 cases was tending to lower the risk of infection (OR 0.72; 95% CI 0.507-1.025, p=0.068). ConclusionHCW in GIE seem to be at higher risk of infection than those in other AGP, especially in the clinical setting. Regions having comparably higher incidences as well as the number of procedures performed per day were also significantly associated with increased risk of infection. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSHealth care workers, especially those exposed to aerosol generating procedures, are assumed to have an increased risk of SARS-CoV-2 infection. However, data confirming this are lacking, especially for the outpatient care setting. What are the new findings?Health care workers in gastrointestinal endoscopy have a higher risk of SARS-CoV-2-infection than in other AGPs. This risk is particularly higher - in clinical settings compared to private practices - in regions having comparably higher incidences - the more procedures are performed per day How might it impact on clinical practice in the foreseeable future?Our study suggests making additional efforts to protect HCW in the gastrointestinal work field.

Autoantibodies against Progranulin and IL-1 receptor antagonist due to immunogenic posttranslational isoforms contribute to hyperinflammation in critically ill COVID-19 (preprint)

Hyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, associated with autoantibodies in a proportion of patients, lead to severe courses of disease. In addition, hyperactive responses of the humoral immune system have been described. In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from adult patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-1-Ra, IL-10, IL-18BP, IL-22BP, IL-36-Ra, CD40, IFN-α2, IFN-γ, IFN-ω and serpinB1. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. In a discovery cohort with severe to critical COVID-19 high titers of PGRN-autoantibodies were detected in 11 of 30 (36.7%), and of IL-1-Ra-autoantibodies in 14 of 30 (46.7%) patients. In a validation cohort of 64 patients with critical COVID-19 high-titer PGRN-Abs were detected in 25 (39%) and IL-1-Ra-Abs in 32 of 64 patients (50%). PGRN-Abs and IL-1-Ra-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-Ra-Abs were detected in low frequency (i.e. in < 5% of patients) and at low titers. Neither PGRN- nor IL-1-Ra-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2 or 188 unvaccinated healthy controls. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins nor against IL-1-Ra. Plasma levels of both free PGRN and free IL-1-Ra were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID-19 controls. In vitro PGRN-Abs from patients functionally reduced PGRN-dependent inhibition of TNF-α signaling, and IL-1-Ra-Abs from patients reduced IL-1-Ra- or anakinra-dependent inhibition of IL-1ß signaling. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a hyperphosphorylated IL-1-Ra isoform was only found in patients with high-titer IL-1-Ra-Abs. Thr111 was identified as the hyperphophorylated amino acid of IL-1-Ra. In longitudinally collected samples hyperphosphorylated isoforms of both PGRN and IL-1-Ra emerged transiently, and preceded the appearance of autoantibodies. In hospitalized patients, the presence of IL-1-Ra-Abs or IL-1-Ra-Abs in combination with PGRN-Abs was associated with a higher morbidity and mortality.To conclude, neutralizing autoantibodies to IL-1-Ra and PGRN occur in a significant portion of patients with critical COVID-19, with a concomitant decrease in circulating free PGRN and IL-1-Ra, indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical hyperphosphorylated isoforms of both antigens, whose appearances precede autoantibody induction. Our data suggest that these immunogenic secondary modifications are induced by the SARS-CoV-2-infection itself or the inflammatory environment evoked by the infection and predispose for a critical course of COVID-19.

Autoantibodies against Progranulin and IL-1 receptor antagonist in critically ill COVID-19 (preprint)

INTRODUCTION: Hyperinflammation is frequently observed in patients with severe COVID-19. Inadequate and defective IFN type I responses against SARS-CoV-2, caused by autoantibodies in a proportion of patients, lead to severe courses. In addition, hyperactive responses of the humoral immune system have been described so far. RATIONALE: In the current study we investigated a possible role of neutralizing autoantibodies against anti-inflammatory mediators. Plasma from patients with severe and critical COVID-19 was screened by ELISA for antibodies against PGRN, IL-10, IL-18BP, IL-22BP and IL-1-RA. Autoantibodies were characterized and the antigens were analyzed for immunogenic alterations. RESULTS: PGRN-autoantibodies were detected with high titers in 11 of 30 (36.7%), and IL 1-RA-autoantibodies in 14 of 30 (46.7%) patients of a discovery cohort with severe to critical COVID-19. In a validation cohort of 41 patients with critical COVID-19 high-titered PGRN-Abs were detected in 12 (29.3%) and IL-1-RA-Abs in 19 of 41 patients (46.2%). PGRN-Abs and IL-1-RA-Abs belonged to IgM and several IgG subclasses. In separate cohorts with non-critical COVID-19, PGRN-Abs and IL-1-RA-Abs were detected significantly less frequently and at low titers. Neither PGRN- nor IL-1-RA-Abs were found in 40 healthy controls vaccinated against SARS-CoV-2. PGRN-Abs were not cross-reactive against SARS-CoV-2 structural proteins or against IL-1-RA. Plasma levels of both free PGRN and IL-1-RA were significantly decreased in autoantibody-positive patients compared to Ab-negative and non-COVID controls. Functionally, PGRN-Abs from patients reduced PGRN-dependent inhibition of TNF- signaling in vitro. The pSer81 hyperphosphorylated PGRN isoform was exclusively detected in patients with high-titer PGRN-Abs; likewise, a yet unidentified hyperphosphorylated IL-1-RA isoform was only found in patients with high-titer IL-1-RA-Abs. No autoantibodies against IL-10, IL-18BP or IL-22BP were found. CONCLUSION: To conclude, neutralizing autoantibodies to IL-1-RA and PGRN occur in a significant proportion of patients with critical COVID-19, with a concomitant decrease in circulating PGRN and IL-1-RA, which is indicative of a misdirected, proinflammatory autoimmune response. The break of self-tolerance is likely caused by atypical isoforms of both antigens due to hyperphosphorylation. It remains to be determined whether these secondary modifications are induced by the SARS-CoV-2-infection itself, or are preexisting and predispose for a critical course.

Therapeutic application of alpha-1-antitrypsin in COVID-19 (preprint)

Rationale: The treatment options for COVID-19 patients are sparse and do not show sufficient efficacy. Alpha-1-antitrypsin (AAT) is a multi-functional host-defense protein with anti-proteolytic and anti-inflammatory activities. Objectives: The aim of the present study was to evaluate whether AAT is a suitable candidate for treatment of COVID-19. Methods: AAT and inflammatory markers were measured in the serum of COVID-19 patients. Human cell cultures were employed to determine the cell-based anti-protease activity of AAT and to test whether AAT inhibits the host cell entry of vesicular stomatitis virus (VSV) particles bearing the spike (S) protein of SARS-CoV-2 and the replication of authentic SARS-CoV-2. Inhaled and / or intravenous AAT was applied to nine patients with mild-to-moderate COVID-19. Measurements and Main Results: The serum AAT concentration in COVID-19 patients was increased as compared to control patients. The relative AAT concentrations were decreased in severe COVID-19 or in non-survivors in ratio to inflammatory blood biomarkers. AAT inhibited serine protease activity in human cell cultures, the uptake of VSV-S into airway cell lines and the replication of SARS-CoV-2 in human lung organoids. All patients, who received AAT, survived and showed decreasing respiratory distress, inflammatory markers, and viral load. Conclusion: AAT has anti-SARS-CoV-2 activity in human cell models, is well tolerated in patients with COVID-19 and together with its anti-inflammatory properties might be a good candidate for treatment of COVID-19.

Pre-endoscopy SARS-CoV-2 testing strategy during COVID-19 pandemic: The care must go on (preprint)

Background: In response to the COVID-19 pandemic, endoscopic societies have recommended reduction of endoscopic procedures. In particular non-urgent endoscopies should be postponed. However, this might lead to unnecessary delay in diagnosing gastrointestinal conditions. Methods: Retrospectively we analysed the gastrointestinal endoscopies performed at the Central Endoscopy Unit of Saarland University Medical Center during seven weeks from 23 March to 10 May 2020 and present our real-world single-center experience with an individualized rtPCR-based pre-endoscopy SARS-CoV-2 testing ("PECo") strategy. Results: Altogether 359 gastrointestinal endoscopies were performed. The PECo strategy enabled us to conservatively handle endoscopy program reduction (44% reduction as compared 2019). The results of COVID-19 rtPCR from nasopharyngeal swabs were available in 89% of patients prior to endoscopies. Apart from six patients with known COVID-19, all other tested patients were negative. The frequencies of endoscopic therapies and clinically significant findings did not differ between patients with or without SARS-CoV-2 tests. Conclusion: A reasonable reduction of the endoscopy program in the setting of structured SARS-CoV-2 testing is feasible and safe. The PECo strategy allows continuation of endoscopic procedures in a region with intermediate frequency of COVID-19 when hospital capacities are not overwhelmed by the pandemic. Thus, the study might help to develop new strategies during future waves of COVID-19 or local outbreaks.

Are German endoscopy units prepared for the COVID-19 pandemic? A nationwide survey (preprint)

Objective: The COVID-19 pandemic challenges health care systems worldwide. In this situation, guidelines for health care professionals in endoscopy units with increased risk of infection from inhalation of airborne droplets, conjunctival contact and faeces are urgently needed. Recently, the European Society of Gastrointestinal Endoscopy (ESGE) and the German Society for Pneumology (DGP) issued recommendations. However, real-world data on the conditions and requirements of endoscopy units to adhere to this guidance are missing. Design: We conducted an internet-based survey among German endoscopy units from all levels of care from April 1st to 7th, 2020. The survey comprised 33 questions and was distributed electronically by the German Society of Gastroenterology, Digestive and Metabolic Diseases (DGVS) and the DGP. Results: In total, 656 endoscopy units completed the survey. Overall, 253 units (39%) cancelled fewer than 40% of their procedures. Of note, private practices cancelled less procedures than hospital-based units. Complete separation of high-risk and COVID-19 positive patients was achieved in only 20% of the units. Procedural measures were well adopted, with 91% of the units systematically identifying patients at risk and 85% using risk-adapted personal protective equipment (PPE). For the future, shortages in PPE (81%), staff (69%) and relevant financial losses (77%) were expected. Conclusion: Concise definitions of non-urgent, elective interventions and endoscopic surveillance strategies are needed to better guide endoscopic activity and intervention cancellations. In the short term, a lack of PPE can constitute considerable impairment of endoscopy units' operability and patient outcomes.