Has a change in established care pathways during the first wave of the COVID-19 pandemic led to an excess death rate in the fragility fracture population? A longitudinal cohort study of 1846 patients.

OBJECTIVE: During the first wave of the COVID-19 pandemic, changes to established care pathways and discharge thresholds for patients with fragility fractures were made. This was to increase hospital bed capacity and minimise the inpatient risk of contracting COVID-19. This study aims to identify the excess death rate in this population during the first wave of the pandemic. DESIGN: A longitudinal cohort study of patients with fragility fractures identified by specific International Classification of Diseases (ICD)-10 codes. The first wave of the pandemic was defined as the 3-month period between 1 March and 1 June 2020. The control group presented between 1 March and 1 June 2019. SETTING: Two acute National Health Service hospitals within the East Midlands region of England. PARTICIPANTS: 1846 patients with fragility fractures over the aforementioned two specified matched time points. PRIMARY AND SECONDARY OUTCOME MEASURES: Four-month mortality of all patients with fragility fractures with a subanalysis of patients with fragility hip fractures. RESULTS: 832 patients with fragility fracture were admitted during the pandemic period (104 diagnosed with COVID-19). 1014 patients presented with fragility fractures in the control group. Mortality in patients with fragility fracture without COVID-19 was significantly higher among pandemic period admissions (14.7%) than the pre-pandemic cohort (10.2%) (HR=1.86; 95% CI 1.41 to 2.45; p<0.001) adjusted for age and sex. Length of stay was shorter during the pandemic period (effect size=-4.2 days; 95% CI -5.8 to -3.1, p<0.001). Subanalysis of patients with fragility hip fracture revealed a mortality of 8.4% in the pre-pandemic cohort, and 15.48% during pandemic admissions with no COVID-19 diagnosis (HR=2.08; 95% CI 1.11 to 3.90; p=0.021). CONCLUSIONS: There is a significant increase in excess death, not explained by confirmed COVID-19 infections. Altered care pathways and aggressive discharge criteria during the pandemic are likely responsible for the increase in excess deaths.

HLA-DR polymorphism in SARS-CoV-2 infection and susceptibility to symptomatic COVID-19.

SARS-CoV-2 infection results in different outcomes ranging from asymptomatic infection to mild or severe disease and death. Reasons for this diversity of outcome include differences in challenge dose, age, gender, comorbidity and host genomic variation. Human leukocyte antigen (HLA) polymorphisms may influence immune response and disease outcome. We investigated the association of HLAII alleles with case definition symptomatic COVID-19, virus-specific antibody and T-cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS-CoV-2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T-cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA-DRB1*13:02 was associated with a 6·7-fold increased risk of case definition symptomatic COVID-19. In terms of immune responsiveness, HLA-DRB1*15:02 was associated with lower nucleocapsid T-cell responses. There was no association between DRB1 alleles and anti-spike antibody titres after two COVID vaccine doses. However, HLA DRB1*15:01 was associated with increased spike T-cell responses following both first and second dose vaccination. Trial registration: NCT04318314 and ISRCTN15677965.

Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection.

Understanding the impact of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the response to vaccination is a priority for responding to the coronavirus disease 2019 (COVID-19) pandemic. In particular, it is necessary to understand how prior infection plus vaccination can modulate immune responses against variants of concern. To address this, we sampled 20 individuals with and 25 individuals without confirmed previous SARS-CoV-2 infection from a large cohort of health care workers followed serologically since April 2020. All 45 individuals had received two doses of the Pfizer-BioNTech BNT162b2 vaccine with a delayed booster at 10 weeks. Absolute and neutralizing antibody titers against wild-type SARS-CoV-2 and variants were measured using enzyme immunoassays and pseudotype neutralization assays. We observed antibody reactivity against lineage A, B.1.351, and P.1 variants with increasing antigenic exposure, through either vaccination or natural infection. This improvement was further confirmed in neutralization assays using fixed dilutions of serum samples. The impact of antigenic exposure was more evident in enzyme immunoassays measuring SARS-CoV-2 spike protein­specific IgG antibody concentrations. Our data show that multiple exposures to SARS-CoV-2 spike protein in the context of a delayed booster expand the neutralizing breadth of the antibody response to neutralization-resistant SARS-CoV-2 variants. This suggests that additional vaccine boosts may be beneficial in improving immune responses against future SARS-CoV-2 variants of concern.

Longitudinal assessment of symptoms and risk of SARS-CoV-2 infection in healthcare workers across 5 hospitals to understand ethnic differences in infection risk.

BACKGROUND: : Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics. METHODS: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314. FINDINGS: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups. INTERPRETATION: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role.