ABSTRACT
Autoantibodies neutralizing the antiviral action of type I interferons (IFNs) have been associated with pre-disposition to severe COVID-19. Here, we screened for such autoantibodies in 103 critically-ill COVID-19 patients in a tertiary intensive care unit in Switzerland. Eleven patients (10.7%), but no healthy donors, had neutralizing anti-IFN or anti-IFN/anti-IFN{omega} IgG in plasma/serum, but anti-IFN IgM or IgA was rare. One patient had non-neutralizing anti-IFN IgG. Strikingly, all patients with plasma anti-IFN IgG also had anti-IFN IgG in tracheobronchial secretions, identifying these autoantibodies at anatomical sites relevant for SARS-CoV-2 infection. Longitudinal analyses revealed patient heterogeneity in terms of increasing, decreasing, or stable anti-IFN IgG levels throughout the length of hospitalization. Notably, presence of anti-IFN autoantibodies in this critically-ill COVID-19 cohort appeared to predict herpesvirus (herpes simplex viruses types 1 and 2, HSV-1/-2; and/or cytomegalovirus, CMV) reactivations, which are linked to worse clinical outcomes. Indeed, all seven tested COVID-19 patients with anti-IFN IgG in our cohort (100%) suffered from one or more herpesvirus reactivations, and analysis revealed that these patients were substantially more likely to experience CMV reactivation than COVID-19 patients without anti-IFN autoantibodies, even when adjusting for systemic steroid treatment (odds ratio 7.28, 95%-CI 1.14-46.31, p=0.036). As the IFN system deficiency caused by neutralizing anti-IFN autoantibodies likely directly and indirectly exacerbates herpesvirus reactivations in critically-ill patients, early diagnosis of anti-IFN IgG could be rapidly used to inform risk-group stratification and treatment options.
ABSTRACT
Objectives While superinfections are associated with unfavourable disease course, their impact on clinical outcomes in critically ill COVID-19 patients remains largely unknown. We aimed to investigate the burden of superinfections in COVID-19 patients. Methods In this prospective single centre cohort study in an intensive care setting patients aged [≥] 18 years with COVID-19 acute respiratory distress syndrome were assessed for concomitant microbial infections by longitudinal analysis of tracheobronchial secretions, bronchoalveolar lavages and blood. Our primary outcome was ventilator-free survival on day 28 in patients with and without clinically relevant superinfection. Further outcomes included the association of superinfection with ICU length of stay, incidence of bacteremia, viral reactivations, and fungal colonization. Results In 45 critically ill COVID-19 patients, we identified 19 patients with superinfections (42.2%) by longitudinal analysis of 433 TBS, 35 BAL and 455 blood samples, respectively. On average, superinfections were detected on day 10 after ICU admission. The most frequently isolated clinically relevant bacteria were Enterobacteriaceae, Streptococcus pneumoniae, and Pseudomonas aeruginosa. Ventilator-free survival was substantially lower in patients with superinfection (subhazard ratio 0.37, 95%-CI 0.15-0.90, p=0.028). Patients with pulmonary superinfections more often had bacteraemia, virus reactivations, yeast colonization, and needed ICU treatment for a significantly longer time. Conclusions The detection of superinfections was frequent and associated with reduced ventilator-free survival. Despite empirical antibiotic therapy, superinfections lead to an extended ICU stay in COVID 19 patients. Longitudinal microbiological sampling in COVID-19 patients could allow targeted antimicrobial therapy, and therefore minimize the use of broad-spectrum and reserve antibiotics.
