Evaluating the effectiveness of rapid SARS-CoV-2 genome sequencing in supporting infection control teams: the COG-UK hospital-onset COVID-19 infection study (preprint)

Introduction Viral sequencing of SARS-CoV-2 has been used for outbreak investigation, but there is limited evidence supporting routine use for infection prevention and control (IPC) within hospital settings. Methods We conducted a prospective non-randomised trial of sequencing at 14 acute UK hospital trusts. Sites each had a 4-week baseline data-collection period, followed by intervention periods comprising 8 weeks of 'rapid' (<48h) and 4 weeks of 'longer-turnaround' (5-10 day) sequencing using a sequence reporting tool (SRT). Data were collected on all hospital onset COVID-19 infections (HOCIs; detected [≥]48h from admission). The impact of the sequencing intervention on IPC knowledge and actions, and on incidence of probable/definite hospital-acquired infections (HAIs) was evaluated. Results A total of 2170 HOCI cases were recorded from October 2020-April 2021, with sequence reports returned for 650/1320 (49.2%) during intervention phases. We did not detect a statistically significant change in weekly incidence of HAIs in longer-turnaround (IRR 1.60, 95%CI 0.85-3.01; P=0.14) or rapid (0.85, 0.48-1.50; P=0.54) intervention phases compared to baseline phase. However, IPC practice was changed in 7.8% and 7.4% of all HOCI cases in rapid and longer-turnaround phases, respectively, and 17.2% and 11.6% of cases where the report was returned. In a per-protocol sensitivity analysis there was an impact on IPC actions in 20.7% of HOCI cases when the SRT report was returned within 5 days. Conclusion While we did not demonstrate a direct impact of sequencing on the incidence of nosocomial transmission, our results suggest that sequencing can inform IPC response to HOCIs, particularly when returned within 5 days.

SARS-CoV-2 lineage B.1.1.7 is associated with greater disease severity among hospitalised women but not men (preprint)

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.1.7 has been associated with an increased rate of transmission and disease severity among subjects testing positive in the community. Its impact on hospitalised patients is less well documented. Methods We collected viral sequences and clinical data of patients admitted with SARS-CoV-2 and hospital-onset COVID-19 infections (HOCIs), sampled 16/11/2020 - 10/01/2021, from eight hospitals participating in the COG-UK-HOCI study. Associations between the variant and the outcomes of all-cause mortality and intensive therapy unit (ITU) admission were evaluated using mixed effects Cox models adjusted by age, sex, comorbidities, care home residence, pregnancy and ethnicity. Results Sequences were obtained from 2341 inpatients (HOCI cases = 786) and analysis of clinical outcomes was carried out in 2147 inpatients with all data available. The hazard ratio (HR) for mortality of B.1.1.7 compared to other lineages was 1.01 (95% CI 0.79-1.28, P=0.94) and for ITU admission was 1.01 (95% CI 0.75-1.37, P=0.96). Analysis of sex-specific effects of B.1.1.7 identified increased risk of mortality (HR 1.30, 95% CI 0.95-1.78) and ITU admission (HR 1.82, 95% CI 1.15-2.90) in females infected with the variant but not males (mortality HR 0.82, 95% CI 0.61-1.10; ITU HR 0.74, 95% CI 0.52-1.04). Conclusions In common with smaller studies of patients hospitalised with SARS-CoV-2 we did not find an overall increase in mortality or ITU admission associated with B.1.1.7 compared to other lineages. However, women with B.1.1.7 may be at an increased risk of admission to intensive care and at modestly increased risk of mortality.

Severe COVID-19 pneumonia in an intensive care setting and comparisons with historic severe viral pneumonia due to other viruses (preprint)

Purpose Severe viral pneumonia is associated with significant morbidity and mortality. Recent COVID-19 pandemic continues to impose significant health burden worldwide and individual pandemic waves often leads to a large surge in the ICU admissions for respiratory support. Comparisons of severe SARS-CoV-2 pneumonia with other seasonal and non-seasonal severe viral infections are rarely studied in an intensive care setting.Methods A retrospective cohort study comparing patients admitted to ICU with COVID-19 between March-June 2020 and those with viral pneumonias between January-December 2019. We compared patient specific demographic variables, duration of illness, ICU organ supportive measures and outcomes between both groups.Results Analysis of 93 COVID-19 (group 1) and 52 other viral pneumonia patients (group 2) showed an increased proportion of obesity (42% vs 23%, p = 0.02), non-white ethnicities (41% vs 6%, p < 0.001) and diabetes mellitus (30% vs 13%, p = 0.03) in group 1, with lower prevalence of COPD/asthma (16% vs 34%, p = 0.02). In group 1, the neutrophil to lymphocyte ratio was much lower (6.7 vs 10, p = 0.006) and invasive mechanical ventilation (58% vs 26%, p < 0.001) was more common. Length of ICU (8 vs 4, p < 0.001) and hospital stay (22 vs 11, p < 0.001) was prolonged in group 1, with no significant difference in mortality. Influenza A and rhinovirus were the most common pathogens in group 2 (26% each).Conclusions Key differences were identified within demographics (obesity, ethnicity, age, ICU scores, co-morbidities) and organ support. Despite these variations, there was no significant differences in mortality between both groups. Further studies with larger sample sizes would allow for further assessment of clinical parameters in these patients.

Mid-Regional pro-Adrenomedullin (MR-proADM), C-Reactive Protein (CRP) and Other Biomarkers in the Early Identification of Disease Progression in COVID-19 Patients in the Acute NHS Setting (preprint)

Background: There is a lack of biomarkers validated for assessing clinical deterioration in COVID-19 patients upon presentation to secondary or tertiary care. This evaluation looked at the potential clinical application of a range of biomarkers, including C-Reactive Protein (CRP) and Procalcitonin (PCT) and Mid-Regional pro-adrenomedullin (MR-proADM), and White Cell Count to support prediction of clinical outcomes. Methods: Adult patients presenting to Hampshire Hospitals NHS Foundation Trust between April and June 2020 confirmed to have COVID-19 via RT-qPCR were included. Biomarkers were measured in blood samples taken within 24 hours of admission and logistic regression and area under the receiver operating characteristic (AUROC) curves were used to predict disease progression. The endpoints assessed were 30-day all-cause mortality, intubation and ventilation, admission to critical care and non-invasive ventilation (NIV) use. Findings: A total of 135 adult patients were identified. Elevated levels of MR-proADM were shown to have the greatest ability to predict 30-day mortality adjusting for age, cardiovascular disease, renal disease and neurological disease. A significant association was also noted between raised MR-proADM and CRP concentrations and the requirement for critical care admission and non-invasive ventilation, when controlling for covariates. Interpretation: The measurement of biomarkers, particularly MR-proADM and CRP in patients with confirmed COVID-19 infection upon admission to secondary care shows significant potential to support clinicians in the early identification of those at increased risk of disease progression and need for higher level care, subsequently enabling prompt escalation in clinical interventions and treatment.

C-reactive protein guided use of procalcitonin in COVID-19 (preprint)

Low procalcitonin (PCT) concentrations (<0.5ng/mL) can facilitate exclusion of bacterial co-infection in viral infections, including COVID-19. However, costs associated with PCT measurement preclude universal adoption, indicating a need to identify settings where PCT provides clinical information beyond that offered by other inflammatory markers, such as C-reactive protein (CRP) and white cell count (WCC). In an unselected cohort of 299 COVID-19 patients, we tested the hypothesis that PCT<0.5ng/mL was associated with lower levels of CRP and WCC. We demonstrated that CRP values below the geometric mean of the entire patient population had a negative predictive value for PCT<0.5ng/mL of 97.6% and 100% at baseline and 48 hours into admission respectively, and that this relationship was not confounded by intensive care admission or microbiological findings. CRP-guided PCT testing algorithms can reduce costs and support antimicrobial stewardship strategies in COVID-19.

Can a Quantitative Assessment of SARS-CoV-2 PCR Predict Degree of Severity and Outcomes in Critical Care Patients with COVID-19 (preprint)

Real-Time polymerase chain reaction (qPCR) is the gold standard diagnostic method for acute SARS-CoV-2 infection. Cycle threshold (Ct) is defined as the number of heating and cooling cycles required during the PCR process. Ct-values are inversely proportional to the amount of target nucleic acid in a sample. Our aim in this retrospective study was to determine the impact of serial SARS-CoV-2 qPCR Ct-values, among critically ill COVID-19 patients both prior and during intensive care unit (ICU) stay, on: mortality, need for mechanical ventilation (MV) and development of acute kidney injury (AKI). There was a continuous increment in Ct-values over the ICU stay from 1st-week through to 3rd-week. Although not significant, lower ICU 1st-week Ct-values were associated with Black ethnicity, increased need for MV and mortality. However, patients who had developed AKI at any stage of their illness had significantly lower Ct-values compared to those with normal renal function. When ICU 1st-week Ct-values are subcategorised as <20, 20-30 and >30 the 28-day survival probability was less for patients with Ct-values of <20.To our knowledge this is the first report showing the impact of Ct-values and outcomes, especially AKI, among patients at different time point’s prior to and during ICU stay.