ABSTRACT
Cardiac microthrombi are postulated to underlie cardiac injury in critical COVID-19. To determine pathogenic mechanism(s) of cardiac injury in fatal COVID-19, we conducted a single-center prospective cohort study of 69 consecutive COVID-19 decedents. Microthrombi was the most commonly detected acute cardiac histopathologic feature (n=48, 70%). We tested associations of cardiac microthrombi with biomarkers of inflammation, cardiac injury, and fibrinolysis and with inhospital antiplatelet therapy, therapeutic anticoagulation, and corticosteroid treatment, while adjusting for multiple clinical factors, including COVID-19 therapies. Higher peak ESR and CRP during hospitalization were independently associated with higher odds of microthrombi (ESR, Pnonlinearity 0.015, Passociation=0.008;CRP per 20mg/L increase, OR 1.17, 95%CI 1.00-1.36). Using single nuclei RNA-sequence analysis, we discovered an enrichment of prothrombotic, anti-fibrinolytic, and extracellular matrix signaling amongst cardiac fibroblasts in microthrombi-positive COVID-19 hearts, compared with microthrombi-negative COVID-19 hearts and non-COVID-19 donor hearts. Our cumulative findings identify these specific transcriptomic changes in cardiac fibroblasts as salient features of COVID-19-associated cardiac microthrombi.
ABSTRACT
Background: Patients with COVID-19 may be at increased risk for secondary bacterial infections. At our quaternary care hospital in New York City, the rapid escalation of COVID-19 cases was accompanied by a massive surge in the need for hospital and critical care capacity. During this time, we noted a increase in infections caused by carbapenemase-producing Enterobacterales (CPE). Methods: We retrospectively assessed microbiology data to identify patients with positive testing for SARS-CoV-2 who had clinical cultures with meropenem-resistant and/or carbapenemase gene-positive Enterobacterales. We obtained microbiological and clinical data by manual chart review. Available clinical isolates underwent long-range genomic sequencing using the MinION (Oxford) for rapid genotyping, resistance gene detection, and phylogenetic analysis. Results: From March 1 to May 18, we identified 33 CPE isolates from 13 patients, including 29 Klebsiella pneumonia and four Enterobacter cloacae. Most patients (11/13) had a positive respiratory culture, and 7/13 developed bacteremia. All patients had prolonged, complex hospitalizations with extensive antibiotic exposure. We performed long-range sequencing on 19 isolates from 12 patients. 15/16 K. pneumoniae isolates belonged to sequence type (ST) 258 encoding KPC (14 KPC-2;1 KPC-3);one ST70 isolate encoded KPC-2. All four E. cloacae isolates belonged to ST270 and encoded NDM-1. Phylogenetic analysis of ST258 isolates including historical isolates from our hospital revealed a distinct lineage of isolates from COVID-19 patients (72% bootstrap support), with expected clustering of isolates from the same patient and patients that were cohorted together. Conclusion: While CPE have declined substantially in New York City in recent years, increased detection in patients with COVID-19 may signal a reemergence of these highly resistant pathogens in the wake of the global pandemic. System-level factors, such as the rapid scale-up of critical care capacity, while clearly needed to address the unprecedented reach of COVID-19, may have contributed to isolate clustering in these patients. Increased surveillance and antimicrobial stewardship efforts will be needed to mitigate the impact of CPE in the future.