Evaluation of S/F94 as a proxy for COVID-19 severity (preprint)

Optimising statistical power in early-stage trials and observational studies accelerates discovery and improves the reliability of results. Ideally, intermediate outcomes should be continuously distributed and lie on the causal pathway between an intervention and a definitive outcome such as mortality. In order to optimise power for an intermediate outcome in the RECOVERY trial, we devised and evaluated a modification to a simple, pragmatic measure of oxygenation function - the SaO2/FIO2 (S/F) ratio. We demonstrate that, because of the ceiling effect in oxyhaemoglobin saturation, S/F ceases to reflect pulmonary oxygenation function at high values of SaO2. Using synthetic and real data, we found that the correlation of S/F with a gold standard (PaO2/FIO2, P/F ratio) improved substantially when measurements with SaO2 > 0.94 are excluded(Spearman r, synthetic data: S/F: 0.31; S/F94: 0.85). We refer to this measure as S/F94. In order to test the underlying assumptions and validity of S/F94 as a predictor of a definitive outcome (mortality), we collected an observational dataset including over 39,000 hospitalised patients with COVID-19 in the ISARIC4C study. We first demonstrated that S/F94 is predictive of mortality in COVID-19. We then compared the sample sizes required for trials using different outcome measures (S/F94, the WHO ordinal scale, sustained improvement at day 28 and mortality at day 28) ensuring comparable effect sizes. The smallest sample size was needed when S/F94 on day 5 was used as an outcome measure. To facilitate future study design, we provide an online user interface to quantify realworld power for a range of outcomes and inclusion criteria, using a synthetic dataset retaining the population-level clinical associations in real data accrued in ISARIC4C https://isaric4c.net/endpoints. We demonstrated that S/F94 is superior to S/F as a measure of pulmonary oxygenation function and is an effective intermediate outcome measure in COVID-19. It is a simple and non-invasive measurement, representative of disease severity and provides greater statistical power to detect treatment differences than other intermediate endpoints.

Long Covid in adults discharged from UK hospitals after Covid-19: A prospective, multicentre cohort study using the ISARIC WHO Clinical Characterisation Protocol. (preprint)

Structured Abstract Objectives: The long-term consequences of severe Covid-19 requiring hospital admission are not well characterised. The objective of this study was to establish the long-term effects of Covid-19 following hospitalisation and the impact these may have on patient reported outcome measures. Design: A multicentre, prospective cohort study with at least 3 months follow-up of participants admitted to hospital between 5th February 2020 and 5th October 2020. Setting: 31 hospitals in the United Kingdom. Participants: 327 hospitalised participants discharged alive from hospital with confirmed/high likelihood SARS-CoV-2 infection. Main outcome measures and comparisons: The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, new or increased disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). We compared these outcome measures across age, comorbidity status and in-hospital Covid-19 severity to identify groups at highest risk of developing long-term difficulties. Multilevel logistic and linear regression models were built to adjust for the effects of patient and centre level risk factors on these outcomes. Results: In total 53.7% (443/824) contacted participants responded, yielding 73.8% (327/443) responses with follow-up of 90 days or more from symptom onset. The median time between symptom onset of initial illness and completing the participant questionnaire was 222 days (Interquartile range (IQR) 189 to 269 days). In total, 54.7% (179/327) of participants reported they did not feel fully recovered. Persistent symptoms were reported by 93.3% (305/325) of participants, with fatigue the most common (82.8%, 255/308), followed by breathlessness (53.5%, 175/327). 46.8% (153/327) reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24.2% (79/327) of participants. Overall (EQ5D-5L) summary index was significantly worse at the time of follow-up (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. Conclusions: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present even in young, previously healthy working age adults, and were most common in younger females. Policymakers should fund further research to identify effective treatments for long-Covid and ensure healthcare, social care and welfare support is available for individuals with long-Covid.

Relation of severe COVID-19 in Scotland to transmission-related factors and risk conditions eligible for shielding support: REACT-SCOT case-control study (preprint)

* Objectives - To investigate:(1) the risk of severe COVID-19 in those eligible for shielding, and (2) the relation of severe COVID-19 to transmission-related factors in those in shielding and the general population. * Design - Matched case-control study (REACT-SCOT). * Setting - Population of Scotland from 1 March 2020 to 28 January 2021. * Participants - All 160307 diagnosed cases of COVID-19 and 1564782 controls matched for age, sex and primary care practice, linked with all 204913 individuals identified as eligible for shielding by Public Health Scotland. * Main outcome measure - Severe COVID-19, defined as cases that entered critical care or were fatal. * Results - With those without risk conditions as reference category, the univariate rate ratio for severe COVID-19 was 5.3 (95% CI 5.0 to 5.7, p=4 x 10-527) in those with moderate risk conditions and 7.6 (95% CI 7.1 to 8.3, p=1 x 10-527) in those eligible for shielding. The highest rate was in solid organ transplant recipients: rate ratio 13.6 (95% CI 9.6 to 19.2, p=8 x 10-50). In both the shielded and the general population, the risk of severe COVID-19 increased with the number of adults but decreased with the number of school-age children in the household. Severe COVID-19 was strongly associated with recent exposure to hospital (defined as 5 to 14 days before presentation date): rate ratio 12.6 (95% CI 11.7 to 13.6, p=2 x 10-989) overall. In a case-crossover analysis with less recent exposure only (15 to 24 days before first testing positive) as reference category, the rate ratio associated with recent exposure only was 6.3 (95% CI 3.6 to 11.1, p=2 x 10-10). Among those eligible for shielding, the population attributable risk fraction (PARF) of severe cases for recent exposure to hospital was 36%. In the general population the PARF for recent exposure to hospital peaked at 46% in May 2020 and again at 64% in December 2020. * Conclusions - The effectiveness of shielding vulnerable individuals was limited by the inability to control transmission in hospital and from other adults in the household. For solid organ transplant recipients, in whom the efficacy of vaccines is uncertain, these results support a policy of offering vaccination to household contacts. Mitigating the impact of the epidemic requires control of nosocomial transmission.

Influence of Socioeconomic Deprivation on Interventions and Outcomes for Patients Admitted with COVID-19 to Critical Care Units in Scotland: A National Cohort Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) can lead to significant respiratory failure with between 14% and 18% of hospitalised patients requiring critical care admission. This study describes the impact of socioeconomic deprivation on 30-day survival following critical care admission for COVID-19, and the impact of the COVID-19 pandemic on critical care capacity in Scotland.Methods: This cohort study used linked national hospital records including ICU, virology testing and national death records to identify and describe patients with COVID-19 admitted to a critical care unit in Scotland. Multivariable logistic regression was used to assess the impact of deprivation on 30-day mortality. Critical care capacity was described by reporting the percentage of baseline ICU bed utilisation required.Results: There were 735 patients with COVID-19 admitted to critical care units across Scotland from 1/3/2020 to 20/6/2020. There was a higher proportion of patients from more deprived areas, with 183 admissions (24.9%) from the most deprived quintile and 100 (13.6%) from the least deprived quintile. 30-day mortality was 34.8%. After adjusting for age, sex and ethnicity, mortality was significantly higher in patients from the most deprived quintile (OR 1.97, 95%CI 1.13, 3.41, p=0.016). ICUs serving populations with higher levels of deprivation spent a greater amount of time over their baseline ICU bed capacity.Conclusion: Patients with COVID-19 living in areas with greater socioeconomic deprivation had a higher frequency of critical care admission and a higher adjusted 30-day mortality. ICUs in health boards with higher levels of socioeconomic deprivation had both higher peak occupancy and longer duration of occupancy over normal maximum capacity.Funding Statement: None.Declaration of Interests: All authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; NL is Director of Research, Intensive Care Society; JM is funded by a THIS.Institute (University of Cambridge) Research Fellowship (PD-2019-02-16). Ethics Approval Statement: The Scottish Intensive Care Society Audit Group in Public Health Scotland has a legislative remit to process personal data in relation to public health. Linkage to additional datasets was approved following scrutiny by the Public Benefit and Privacy Panel for Health and Social Care (ref 1920-0093). Access and use of the data for the purpose of this work were approved following a Public Health Scotland information governance review of linking additional internal datasets to identify patients with COVID-19. Only analysts working in Public Health Scotland had access to the linked patient data which could only be accessed via an NHS secure network.

What is the recovery rate and risk of long-term consequences following a diagnosis of COVID-19? - A harmonised, global longitudinal observational study (preprint)

Introduction Very little is known about possible clinical sequelae that may persist after resolution of the acute Coronavirus Disease 2019 (COVID-19). A recent longitudinal cohort from Italy including 143 patients recovered after hospitalisation with COVID-19 reported that 87% had at least one ongoing symptom at 60 day follow-up. Early indications suggest that patients with COVID-19 may need even more psychological support than typical ICU patients. The assessment of risk factors for longer term consequences requires a longitudinal study linked to data on pre-existing conditions and care received during the acute phase of illness. Methods and analysis This is an international open-access prospective, observational multi-site study. It will enrol patients following a diagnosis of COVID-19. Tier 1 is developed for following up patients day 28 post-discharge, additionally at 3 to 6 months intervals. This module can be used to identify sub-sets of patients experiencing specific symptomatology or syndromes for further follow up. A Tier 2 module will be developed for in-clinic, in-depth follow up. The primary aim is to characterise physical consequences in patients post-COVID-19. Secondary aim includes estimating the frequency of and risk factors for post-COVID- 19 medical sequalae, psychosocial consequences and post-COVID-19 mortality. A subset of patients will have sampling to characterize longer term antibody, innate and cell-mediated immune responses to SARS-CoV-2. Ethics and dissemination This collaborative, open-access study aims to characterize the frequency of and risk factors for long-term consequences and characterise the immune response over time in patients following a diagnosis of COVID-19 and facilitate standardized and longitudinal data collection globally. The outcomes of this study will inform strategies to prevent long term consequences; inform clinical management, direct rehabilitation, and inform public health management to reduce overall morbidity and improve outcomes of COVID-19.

Associations of severe COVID-19 with polypharmacy in the REACT-SCOT case-control study (preprint)

Objectives -- To investigate the relation of severe COVID-19 to prior drug prescribing. Design -- Matched case-control study (REACT-SCOT) based on record linkage to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. Setting -- Scottish population. Main outcome measure -- Severe COVID-19, defined by entry to critical care or fatal outcome. Participants -- All 4272 cases of severe COVID-19 in Scotland since the start of the epidemic, with 36948 controls matched for age, sex and primary care practice. Results -- Severe COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in care homes, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.7, 13.2), and was not accounted for by treatment of conditions designated as conferring increased risk. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19. The largest effect was for antipsychotic agents: rate ratio 4.14 (3.39, 5.07). Other drug classes with large effects included proton pump inhibitors (rate rato 2.19 (1.70, 2.80) for >= 2 defined daily doses/day), opioids (3.62 (2.65, 4.94) for >= 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates, and were stronger with recent than with non-recent exposure. Conclusions -- Severe COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression or dyskinesia, have anticholinergic effects or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Although the evidence for causality is not conclusive, these results support existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy as a potential means of reducing COVID-19 risk. Registration -- ENCEPP number EUPAS35558

COVID-19 in patients undergoing renal replacement therapy in Scotland: findings and experience from the Scottish Renal Registry (preprint)

IntroductionInfection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has led to a worldwide pandemic with coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2, overwhelming healthcare systems globally. Preliminary reports suggest a high incidence of infection and mortality with SARS-CoV-2 in patients receiving renal replacement therapy (RRT). The aims of this study are to report characteristics, rates and outcomes of all patients affected by infection with SARS-CoV-2 undergoing RRT in Scotland. MethodsStudy design was an observational cohort study. Data were linked between the Scottish Renal Registry, Health Protection Scotland and the Scottish Intensive Care Society Audit Group national data sets using a unique patient identifier (Community Health Index (CHI)) for each individual by the Public Health and Intelligence unit of Public Health, Scotland. Descriptive statistics and survival analyses were performed. ResultsDuring the period 1st March 2020 to 31st May 2020, 110 patients receiving RRT tested positive for SARS-CoV-2 amounting to 2% of the prevalent RRT population. Of those affected, 87 were receiving haemodialysis or peritoneal dialysis and 24 had a renal transplant. Patients who tested positive were older and more likely to reside in more deprived postcodes. Mortality was high at 26.7% in the dialysis patients and 29.2% in the transplant patients. ConclusionThe rate of detected SARS-CoV-2 in people receiving RRT in Scotland was relatively low but with a high mortality for those demonstrating infection. Although impossible to confirm, it appears that the measures taken within dialysis units coupled with the national shielding policy, have been effective in protecting this population from infection.

COVID-19 Disease in People with Diabetes in Scotland: Incidence, Severity and Risk Stratification Using Matched Case-Control and Prospective Cohort Studies (preprint)

Background: The risks of, and risk factors for, COVID-19 disease associated with diabetes are poorly quantified. Methods: We identified as cases all those in Scotland with a positive SARS-CoV-2 nucleic acid test in the national laboratory database and anyone else with a death certificate mentioning COVID-19. Seven controls matched for age, sex and general practice were selected per case. Data were linked to the national diabetes register, hospitalisation and critical care unit (CCU) databases. Analyses focused on those with COVID-19 requiring critical care or dying. Analyses were by conditional and unconditional logistic regression. Findings: 0.3% (n=845) of those with diabetes had developed severe or fatal COVID-19, representing rate ratios of 3.86 (2.74, 5.45) in type 1 and 1.69 (1.56, 1.84) in type 2 diabetes. Rates were almost threefold in the most versus least socioeconomically deprived quintiles of the population. Most (77%) cases had another recognised co-morbidity such as heart or lung disease (OR 2.6). Diabetes specific factors associated with increased risk included; HbA1c odds ratio (OR) >85 mmol/mol versus <53: 1.96(1.55,2.48);p-value <0.001, prior diabetic ketoacidosis: OR 2.44(1.41,4.20);p-value 0.001 and hypoglycaemia hospitalisations: OR 3.28(2.41,4.46);p-value <0.001. Chronic retinal and renal complications were also associated with increased risk. A cross-validated predictive model of severe or fatal disease had a C-statistic of 0.83. Interpretations: Relative risks of severe or fatal COVID-19 are substantially elevated in both types of diabetes. Risk scores based on prior clinical history should be useful for identifying those with diabetes needing tailored protective measures.Funding Statement: There was no specific funder for this study.Declaration of Interests: The authors declare no conflicts of interest.Ethics Approval Statement: This research was conducted with approval from the Public Benefit Privacy Protection Panel (PBPP ref. 1617- 0147), originally set up under PAC 33/11, with approval from the Scotland A Research Ethics Committee (ref. 11/AL/0225). All datasets were de-identified before analysis.

Higher clinical acuity and 7-day hospital mortality in non-COVID-19 acute medical admissions: prospective observational study. (preprint)

ObjectivesTo understand the effect of COVID-19 lockdown measures on severity of illness and mortality in non-COVID-19 acute medical admissions. DesignA prospective observational study Setting3 large acute medical receiving units in NHS Lothian, Scotland. Participants: Non-covid-19 acute admissions (n = 1756) were examined over the first 31 days after the implementation of the COVID-19 lockdown policy in the United Kingdom on 23rd March 2019. Patients admitted over a matched interval in the previous 5 years were used as a comparator cohort (n = 14961). Main outcome measuresPatient demography, biochemical markers of clinical acuity and 7-day hospital inpatient mortality. ResultsNon-covid-19 acute medical admissions reduced by a mean 43.8% (95% CI 27.3, 59.4) across all 3 sites in comparison to the mean of the preceding 5 years P < 0.001. The reduction in admissions predominated in the over 75 age category and a greater proportion arrived by emergency ambulance transport. Non-covid-19 admissions during lockdown had a greater incidence of severe renal injury, hyperlactataemia and over twice the risk of hospital death within 7 days 5.01% vs 2.49% which persisted after adjustment for confounders (OR 2.17, 95% CI 1.70,2.73, P < 0.0001) ConclusionsThese data support current fears that patients are delaying seeking medical attention for acute illness which is associated with worsening clinical parameters and a higher risk of death following admission.

Rapid Epidemiological Analysis of Comorbidities andTreatments as risk factors for COVID-19 in Scotland(REACT-SCOT): a population-based case-control study (preprint)

BackgroundThe objectives of this study were to identify risk factors for severe COVID-19 and to lay the basis for risk stratification based on demographic data and health records. Methods and FindingsThe design was a matched case-control study. Severe COVID-19 was defined as either a positive nucleic acid test for SARS-CoV-2 in the national database followed by entry to a critical care unit or death within 28 days, or a death certificate with COVID-19 as underlying cause. Up to ten controls per case matched for sex, age and primary care practice were selected from the population register. All diagnostic codes from the past five years of hospitalisation records and all drug codes from prescriptions dispensed during the past nine months were extracted. Rate ratios for severe COVID-19 were estimated by conditional logistic regression. There were 4272 severe cases. In a logistic regression using the age-sex distribution of the national population, the odds ratios for severe disease were 2.87 for a 10-year increase in age and 1.63 for male sex. In the case-control analysis, the strongest risk factor was residence in a care home, with rate ratio (95% CI) 21.4 (19.1, 23.9). Univariate rate ratios (95% CIs) for conditions listed by public health agencies as conferring high risk were 2.75 (1.96, 3.88) for Type 1 diabetes, 1.60 (1.48, 1.74) for Type 2 diabetes, 1.49 (1.37, 1.61) for ischemic heart disease, 2.23 (2.08, 2.39) for other heart disease, 1.96 (1.83, 2.10) for chronic lower respiratory tract disease, 4.06 (3.15, 5.23) for chronic kidney disease, 5.4 (4.9, 5.8) for neurological disease, 3.61 (2.60, 5.00) for chronic liver disease and 2.66 (1.86, 3.79) for immune deficiency or suppression. 78% of cases and 52% of controls had at least one listed condition (NA of cases and NA of controls under age 40). Severe disease was associated with encashment of at least one prescription in the past nine months and with at least one hospital admission in the past five years [rate ratios 3.10 (2.59, 3.71)] and 2.75 (2.53, 2.99) respectively] even after adjusting for the listed conditions. In those without listed conditions significant associations with severe disease were seen across many hospital diagnoses and drug categories. Age and sex provided 2.58 bits of information for discrimination. A model based on demographic variables, listed conditions, hospital diagnoses and prescriptions provided an additional 1.25 bits (C-statistic 0.825). A limitation of this study is that records from primary care were not available. ConclusionsAlong with older age and male sex, severe COVID-19 is strongly associated with past medical history across all age groups. Many comorbidities beyond the risk conditions designated by public health agencies contribute to this. A risk classifier that uses all the information available in health records, rather than only a limited set of conditions, will more accurately discriminate between low-risk and high-risk individuals who may require shielding until the epidemic is over. Author summaryMost people infected with the SARS-CoV-2 coronavirus do not become seriously ill. It is The risk of severe or fatal illness is higher in older than in younger people, and is higher in people with conditions such as asthma and diabetes than in people without these conditions. Using Scotlands capability for linking electronic health records, we report the first systematic study of the relation of severe or fatal COVID-19 to pre-existing health conditions and other risk factors. We show that the strongest risk factor, apart from age, is residence in a care home. The conditions associated with increased risk include not only those already designated by public health agencies - asthma, diabetes, heart disease, disabling neurological disease, kidney disease - but many other diagnoses, associated with frailty and poor health. This lays a basis for constructing risk scores based on electronic health records that can be used to advise people at high risk of severe disease to shield themselves when there cases in their neighbourhood.