To What Extent do Social Determinants of Health Modulate Presentation, ITU Admission and Outcomes among Patients with SARS-COV-2 Infection? An Exploration of Household Overcrowding, Air Pollution, Housing Quality, Ethnicity, Comorbidities and Frailty.

Background: Internationally, researchers have called for evidence to support tackling health inequalities during the severe acute respiratory syndrome coronavirus 2 (COVID19) pandemic. Despite the 2020 Marmot review highlighting growing health gaps between wealthy and deprived areas, studies have not explored social determinants of health (ethnicity, frailty, comorbidities, household overcrowding, housing quality, air pollution) as modulators of presentation, intensive care unit (ITU) admissions and outcomes among COVID19 patients. There is an urgent need for studies examining social determinants of health including socioenvironmental risk factors in urban areas to inform the national and international landscape. Methods: An in-depth retrospective cohort study of 408 hospitalized COVID19 patients admitted to the Queen Elizabeth Hospital, Birmingham was conducted. Quantitative data analyses including a two-step cluster analysis were applied to explore the role of social determinants of health as modulators of presentation, ITU admission and outcomes. Results: Patients admitted from highest Living Environment deprivation indices were at increased risk of presenting with multi-lobar pneumonia and, in turn, ITU admission whilst patients admitted from highest Barriers to Housing and Services (BHS) deprivation Indies were at increased risk of ITU admission. Black, Asian and Minority Ethnic (BAME) patients were more likely, than Caucasians, to be admitted from regions of highest Living Environment and BHS deprivation, present with multi-lobar pneumonia and require ITU admission. Conclusion: Household overcrowding deprivation and presentation with multi-lobar pneumonia are potential modulators of ITU admission. Air pollution and housing quality deprivation are potential modulators of presentation with multi-lobar pneumonia. BAME patients are demographically at increased risk of exposure to household overcrowding, air pollution and housing quality deprivation, are more likely to present with multi-lobar pneumonia and require ITU admission. Irrespective of deprivation, consideration of the Charlson Comorbidity Score and the Clinical Frailty Score supports clinicians in stratifying high risk patients.

COVID-19 neutrophils show elevated migration and NETosis, which is reduced by PI3K inhibition

Rational: Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics. Cell functions are interwoven pathways, so understanding the effect of COVID-19 across neutrophil function may identify therapeutic targets. We examined neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia (CAP) patients. Method(s): Isolated neutrophils underwent ex vivo analyses for migration, phagocytosis and NETosis, and the effect of PI3K inhibition. Circulating DNAse 1 activity and levels of cfDNA were measured. Result(s): Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397, A) and NETosis (p=0.0366, B), but impaired phagocytosis (p=0.0236, C) associated with impaired ROS generation (p<0.0001). COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001, D). Ex vivo inhibition of PI3K gamma and delta reduced NET release by COVID-19 neutrophils (p=0.0156). Conclusion(s): COVID-19 is associated with neutrophil dysfunction across all main effector functions, with elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function via PI3k may help modulate COVID-19 severity. (Figure Presented).

Dysfunctional neutrophil response in COVID-19 infection vary by subtype

S94 Figure 1Comparison of neutrophil effector functions between COVID-19 variants (alpha n=33, delta n=13, omicron n-14). A.% change in phagocytosis significantly increased between alpha and delta patients (p=0.0162). B. Fold change in cells migrated through a transwell pore to IL8 compared to vehicle control significantly reduced in omicron patients compared alpha and delta (vs alpha p=0.0018, vs delta p=0.0370). C. Neutrophil extracellular trap production after stimulation with PMA compared to vehicle control significantly reduced in omicron patients compared to alpha (p=0.0396)[Figure omitted. See PDF]DiscussionOur results showing changes in neutrophil „function and phenotype differ between variants of COVID-19 infection, potentially reflect viral evolution. This change in neutrophil function may contribute to the evolving clinical phenotype observed in patients. Our population of ward-based COVID-19 patients represents the majority of inpatient hospital burden where early intervention may prevent clinical deterioration. Targeting neutrophil function may be an effective way of improving infection outcome in the future.ReferenceBelchamber K, et al. Altered neutrophil phenotype and function in non-ICU hospitalised COVID-19 patients correlated with disease severity. medRxiv, 2021: p. 2021.06.08.21258535.

Increased mortality of hospitalised community acquired pneumonia in winter 2020/21 compared to 2019/20

IntroductionCommunity acquired pneumonia is a leading cause of admission to hospital during the winter months. In the winter of 2020–21 the United Kingdom remained under social distancing measures to limit transmission of COVID-19. These measures should also limit transmission of other respiratory pathogens and therefore reduce admission to hospital. Work to date has demonstrated reduced hospital attendances. We aimed to investigate whether hospitalised cases of non-COVID-19 community acquired pneumonia differed between winter 2019–20 and winter 2020–21.MethodsCommunity acquired pneumonia hospital admissions were compared between 01/09/2019–31/01/2020 and 01/09/2020–31/01/2021 using Pioneer the Health Data Research Hub in Acute Care. Data were collected to compare demographics, severity, complications, and outcomes. Cases were identified using ICD coding. For the winter 20–21 cohort, all cases had a negative COVID PCR on admission to hospital.ResultsAdmissions fell by 16% in the 20/21 time period with 2073 admissions in 19/20 and 1757 in 20/21. The median age of cases was similar across both timepoints (74 in 19/20 and 72 in 20/21). Length of stay was similar between the two timepoints. However, mortality significantly increased from 13.5% in 19/20 to 21.6% in 20/21 (p<0.001). Admission to ICU did not change significantly during the time periods (21.2 vs. 24.6%).ConclusionWe demonstrate that changes in social distancing guidance impacts non COVID CAP in keeping with other studies. The increased mortality seen in winter 20/21 is likely multi-factorial but may be related to perceived reduced access to healthcare by patients resulting in delayed treatment. Additionally, we show that intensive care admission was unchanged despite the increased mortality and therefore severity of cases, suggesting that accessing critical care may have been more challenging in the winter of 20/21 than previous years. Further analyses to characterise the difference in cases and understand increase in mortality are underway.

Elevated NETosis and migration but impaired anti-microbial responses in neutrophils from non-ICU, hospitalized COVID-19 patients

RationalInfection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based predominantly on transcriptomics or single functional assays. Cell functions are interwoven pathways, and so understanding the effect of COVID-19 across the spectrum of neutrophil function may identify therapeutic targets to treat disease.ObjectivesExamine neutrophil phenotype and functional capacity in COVID-19 patients versus age-matched controls (AMC).MethodsIsolated neutrophils from 41 non-ICU COVID-19 patients and 23 AMC underwent ex vivo analyses for migration, phagocytosis of Streptococcus pneumoniae, reactive oxygen species (ROS) generation, neutrophil extracellular trap formation (NETosis) and cell surface receptor expression. Serum DNAse 1 activity was measured, alongside circulating levels of cell-free (cf)DNA, myeloperoxidase (MPO), VEGF, IL-6 and sTNFRI. All measurements were correlated to clinical outcome. Serial sampling on day 3–5 post hospitalisation were also measured.ResultsCompared to AMC, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397) and NETosis (p=0.0366), but impaired phagocytosis (p=0.0236) associated with impaired ROS generation (p<0.0001). Surface expression of CD54 (p<0.0001) and CD11c (p=0.0008) was significantly increased and CD11b significantly decreased (p=0.0229) on COVID-19 patient neutrophils. On day 3–5 follow-up, levels of senescent neutrophils increased compared to day 1 (indicated by decreased CXCR2 and elevated CXCR4 expression (p=0.0332)). COVID-19 patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001). MPO, VEGF, sTNFRI, and IL-6 (p<0001) were elevated in COVID-19, which positively correlated with disease severity by 4C score.ConclusionCOVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function may help modulate COVID-19 severity.Please refer to page A189 for declarations of interest related to this abstract.

L12 To what extent are social determinants of health, including household overcrowding, air pollution and housing quality deprivation, modulators of presentation, ITU admission and outcomes among patients with SARS-COV-2 infection in an urban catchment area in Birmingham, United Kingdom?

BackgroundInternationally, researchers have called for evidence to support tackling health inequalities during the COVID19 pandemic. UK Office for National Statistics data suggests that patients in regions of most deprived overall Index of Multiple Deprivation Score (IMDS) are twice as likely to die of COVID19 than other causes. The Intensive Care National Audit and Research Centre (ICNARC) report that Black, Asian and Minority Ethnic (BAME) patients account for 34% of critically ill COVID19 patients nationally despite constituting 14% of the population. This paper is the first to explore the roles of social determinants of health, including specific IMDS sub-indices with indicators for household overcrowding deprivation (Barriers to Housing and Services subindex (BHS)), indoor housing quality deprivation and outdoor air pollution deprivation (Living Environment subindex (LE)) as modulators of presentation, Intensive Care Unit(ITU) admission and outcomes among COVID19 patients of all ethnicities.MethodsAn in-depth retrospective cohort study of 408 hospitalised COVID19 patients admitted to Queen Elizabeth Hospital, Birmingham was conducted. Quantitative data analyses including two-step cluster analyses were applied.ResultsPatients admitted from highest LE deprivation sub-indices were at increased risk of presenting with multi-lobar pneumonia and, in turn, ITU admission. Patients admitted from highest BHS deprivation sub-indices were at increased risk of ITU admission. BAME patients were more likely, than white patients, to present with multi-lobar pneumonia, be admitted to ITU and be admitted from highest BHS and LE deprivation indices. Comorbidities and frailty significantly increased the risk of death among COVID19 patients irrespective of deprivation.ConclusionsAir pollution and housing quality deprivation are potential modulators of presentation with multi-lobar pneumonia. Household overcrowding deprivation and presentation with multi-lobar pneumonia are potential modulators of ITU admission. Patents of BAME ethnicity are more likely to be admitted from regions of highest air pollution, housing quality and household overcrowding deprivation;this is likely to contribute an explanation towards the higher ITU admissions reported among COVID19 BAME patients. Consideration of Charlson Comorbidity and Clinical Frailty Scores on admission supports clinicians in stratifying high risk patients. These findings have urgent implications for supporting front line clinical decisions, disseminating practical advice around applying social distancing messages at the household level and informing wider pandemic strategy.This study has been cited by several national and international public bodies including Public Health England and UK Parliament as evidence to support the COVID19 strategic response.