Increasing Rates of Intensive Care Unit Bloodstream Infections During the Second COVID-19 Pandemic Wave, Particularly Primary Endogenous Enterococcus faecium, with High Crude Mortality and Associated with Introduction of Immunomodulatory Therapy (preprint)

Background: Reports indicate that COVID-19 patients have more bloodstream infections (BSI) on the intensive care unit (ICU) potentially due to lapses in infection control practice or other factors.Methods: Retrospective single-site study of ICU-BSIs in mechanically ventilated (MV) COVID-19 patients during the first pandemic year. Clinical, demographic and laboratory data including targeted pathogen genome sequencing was analysed during first (March 13th - May 31st 2020) and second (October 1st 2020 - March 15th 2021) pandemic waves.Findings: There were 305 MV-ICU patients in wave one and 440 in wave two with peak occupancy of 113 and 155 patients, respectively. The BSI rate was higher during both waves than pre-pandemic, but more in wave-two than wave-one, particularly during the first 28 days on ICU (14.1 vs. 9.4/1000 bed days; p=0.03) and with E. faecium (3.57 vs. 0.47/1000 bed days; p=0.0067). 22/28 (77%) of E. faecium BSIs had no microbiologically definable focus and the high wave-two rate could not be explained by transmission. Wave-two BSI-patients received more corticosteroids and tocilizumab and had higher crude hospital mortality compared with non-BSI patients (41% vs. 21% p<0.0001), a phenomenon not seen in wave one (32% vs. 27% p=0.551). Interpretation: MV-COVID-19 patients had a greater BSI-burden in wave two associated with the emergence of primary endogenous E. faecium. Identifying mechanisms and causal links between admission COVID-19 disease severity, immunomodulation, BSI and death could help identify new approaches to improving outcomes for COVID-19 patients.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses (preprint)

It is unclear whether prior endemic coronavirus infections affect COVID-19 severity. Here, we show that in cases of fatal COVID-19, antibody responses to the SARS-COV-2 spike are directed against epitopes shared with endemic beta-coronaviruses in the S2 subunit of the SARS-CoV-2 spike protein. This immune response is associated with the compromised production of a de novo SARS-CoV-2 spike response among individuals with fatal COVID-19 outcomes.

A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR) (preprint)

BACKGROUNDIncreasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19. METHODSWe conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60. RESULTSOverall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI -0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19. CONCLUSIONSAlthough not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).

Application of respiratory metagenomics for COVID-19 patients on the intensive care unit to inform appropriate initial antimicrobial treatment and rapid detection of nosocomial transmission (preprint)

Background. Clinical metagenomics (CMg) is being evaluated for translation from a research tool into routine diagnostic service, but its potential to significantly improve management of acutely unwell patients has not been demonstrated. The SARS-CoV-2 pandemic provides impetus to determine that benefit given increased risk of secondary infection and nosocomial transmission by multi-drug resistant (MDR) pathogens linked with expansion of critical care capacity. Methods. Prospective evaluation of CMg using nanopore sequencing was performed on 43 respiratory samples over 14 weeks from a cohort of 274 intubated patients across seven COVID-19 intensive care units. Results. Bacteria or fungi were cultured from 200 (73%) patients, with a predominance of Klebsiella spp. (31%) and C. striatum (7%) amongst other common respiratory pathogens. An 8 hour CMg workflow was 93% sensitive and 81% specific for bacterial identification compared to culture, and reported presence or absence of {beta}-lactam resistance genes carried by Enterobacterales that would modify initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus (4 positive and 39 negative samples). Single nucleotide polymorphism (SNP)-typing using 24 hour sequence data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak potentially involving 14 patients across three ICUs. Conclusion. CMg testing for ICU patients provides same-day pathogen detection and antibiotic resistance prediction that significantly improves initial treatment of nosocomial pneumonia and rapidly detects unsuspected outbreaks of MDR-pathogens.