Associations of comorbidities and medications with COVID-19 outcome: A retrospective analysis of real-world evidence data

BackgroundHundreds of thousands of deaths have already been recorded for patients with the severe acute respiratory syndrome coronavirus (SARS-CoV-2; aka COVID-19). Understanding whether there is a relationship between comorbidities and COVID-19 positivity will not only impact clinical decisions, it will also allow an understanding of how better to define the long-term complications in the groups at risk. In turn informing national policy on who may benefit from more stringent social distancing and shielding strategies. Furthermore, understanding the associations between medications and certain outcomes may also further our understanding of indicators of vulnerability in people with COVID-19 and co-morbidities. MethodsElectronic healthcare records (EHR) from two London hospitals were analysed between 1st January and 27th May 2020. 5294 patients presented to the hospitals in whom COVID status was formally assessed; 1253 were positive for COVID-19 and 4041 were negative. This dataset was analysed to identify associations between comorbidities and medications, separately and two outcomes: (1) presentation with a COVID-19 positive diagnosis, and (2) inpatient death following COVID-19 positive diagnosis. Medications were analysed in different time windows of prescription to differentiate between short-term and long-term medications. All analyses were done with controls (without co-morbidity) matched for age, sex, and number of admissions, and a robustness approach was conducted to only accept results that consistently appear when the analysis is repeated with different proportions of the data. ResultsWe observed higher COVID-19 positive presentation for patients with hypertension (1.7 [1.3-2.1]) and diabetes (1.6 [1.2-2.1]). We observed higher inpatient COVID-19 mortality for patients with hypertension (odds ratio 2.7 [95% CI 1.9-3.9]), diabetes (2.2 [1.4-3.5]), congestive heart failure (3.1 [1.5-6.4]), and renal disease (2.6 [1.4-5.1]). We also observed an association with reduced COVID-19 mortality for diabetic patients for whom anticoagulants (0.11 [0.03-0.50]), lipid-regulating drugs (0.15 [0.04-0.58]), penicillins (0.20 [0.06-0.63]), or biguanides (0.19 [0.05-0.70]) were administered within 21 days after their positive COVID-19 test with no evidence that they were on them before, and for hypertensive patients for whom anticoagulants (0.08 [0.02-0.35]), antiplatelet drugs (0.10 [0.02-0.59]), lipid-regulating drugs (0.15 [0.05-0.46]), penicillins (0.14 [0.05-0.45]), or angiotensin-converting enzyme inhibitors (ARBs) (0.06 [0.01-0.53]) were administered within 21 days post-COVID-19-positive testing with no evidence that they were on them before. Moreover, long-term antidiabetic drugs were associated with reduced COVID-19 mortality in diabetic patients (0.26 [0.10-0.67]). ConclusionsWe provided real-world evidence for observed associations between COVID-19 outcomes and a number of comorbidities and medications. These results require further investigation and replication in other data sets.

Early risk assessment for COVID-19 patients from emergency department data using machine learning

BackgroundSince its emergence in late 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic, with more than 4.8 million reported cases and 310 000 deaths worldwide. While epidemiological and clinical characteristics of COVID-19 have been reported, risk factors underlying the transition from mild to severe disease among patients remain poorly understood. MethodsIn this retrospective study, we analysed data of 820 confirmed COVID-19 positive patients admitted to a two-site NHS Trust hospital in London, England, between January 1st and April 23rd, 2020, with a majority of cases occurring in March and April. We extracted anonymised demographic data, physiological clinical variables and laboratory results from electronic healthcare records (EHR) and applied multivariate logistic regression, random forest and extreme gradient boosted trees. To evaluate the potential for early risk assessment, we used data available during patients initial presentation at the emergency department (ED) to predict deterioration to one of three clinical endpoints in the remainder of the hospital stay: A) admission to intensive care, B) need for mechanical ventilation and C) mortality. Based on the trained models, we extracted the most informative clinical features in determining these patient trajectories. ResultsConsidering our inclusion criteria, we have identified 126 of 820 (15%) patients that required intensive care, 62 of 808 (8%) patients needing mechanical ventilation, and 170 of 630 (27%) cases of in-hospital mortality. Our models learned successfully from early clinical data and predicted clinical endpoints with high accuracy, the best model achieving AUC-ROC scores of 0.75 to 0.83 (F1 scores of 0.41 to 0.56). Younger patient age was associated with an increased risk of receiving intensive care and ventilation, but lower risk of mortality. Clinical indicators of a patients oxygen supply and selected laboratory results were most predictive of COVID-19 patient trajectories. ConclusionAmong COVID-19 patients machine learning can aid in the early identification of those with a poor prognosis, using EHR data collected during a patients first presentation at ED. Patient age and measures of oxygenation status during ED stay are primary indicators of poor patient outcomes.

COVID-19 genomic susceptibility: Definition of ACE2 variants relevant to human infection with SARS-CoV-2 in the context of ACMG/AMP Guidance

BackgroundMortality remains very high and unpredictable in CoViD-19, with intense public protection strategies tailored to preceived risk. Males are at greater risk of severe CoViD-19 complications. Genomic studies are in process to identify differences in host susceptibility to SARS-CoV-2 infection. MethodsGenomic structures were examined for the ACE2 gene that encodes angiotensin-converting enzyme 2, the obligate receptor for SARS-CoV-2. Variants in 213,158 exomes/genomes were integrated with ACE2 protein functional domains, and pathogenicity criteria from the American Society of Human Genetics and Genomics/Association for Molecular Pathology. Results483 variants were identified in the 19 exons of ACE2 on the X chromosome. All variants were rare, including nine loss-of-function (potentially SARS-CoV-2 protective) alleles present only in female heterozygotes. Unopposed variant alleles were more common in males (262/3596 [7.3%] nucleotides) than females (9/3596 [0.25%] nucleotides, p<0.0001). 37 missense variants substituted amino acids in SARS-CoV-2 interacting regions or critical domains for transmembrane ACE2 expression. Four upstream open reading frames with 31 associated variants were identified. Excepting loss-of-function alleles, variants would not meet minimum criteria for classification as Likely Pathogenic/beneficial if differential frequencies emerged in patients with CoViD-19. ConclusionsMales are more exposed to consequences from a single variant ACE2 allele. Common risk/beneficial alleles are unlikely in regions subject to evolutionary constraint. ACE2 upstream open reading frames may have implications for aminoglycoside use in SARS-CoV-2-infected patients. For this SARS-CoV-2-interacting protein with pre-identified functional domains, pre-emptive functional and computational studies are encouraged to accelerate interpretations of genomic variation for personalised and public health use.

Risk factors for clinical progression in patients with COVID-19: a retrospective study of electronic health record data in the United Kingdom

BackgroundThe novel coronavirus disease 2019 (COVID-19) outbreak presents a significant threat to global health. A better understanding of patient clinical profiles is essential to drive efficient and timely health service strategies. In this study, we aimed to identify risk factors for a higher susceptibility to symptomatic presentation with COVID-19 and a transition to severe disease. MethodsWe analysed data on 2756 patients admitted to Chelsea & Westminster Hospital NHS Foundation Trust between 1st January and 23rd April 2020. We compared differences in characteristics between patients designated positive for COVID-19 and patients designated negative on hospitalisation and derived a multivariable logistic regression model to identify risk factors for predicting risk of symptomatic COVID-19. For patients with COVID-19, we used univariable and multivariable logistic regression to identify risk factors associated with progression to severe disease defined by: 1) admission to the hospitals AICU, 2) the need for mechanical ventilation, 3) in-hospital mortality, and 4) at least one measurement of elevated D-dimer ([≥]1,000 g/L) indicative of increased risk of venous thromboembolism. ResultsThe patient population consisted of 1148 COVID-19 positive and 1608 COVID-19 negative patients. Age, sex, self-reported ethnicity, C-reactive protein, white blood cell count, respiratory rate, body temperature, and systolic blood pressure formed the most parsimonious model for predicting risk of symptomatic COVID-19 at hospital admission. Among 1148 patients with COVID-19, 116 (10.1%) were admitted to the AICU, 71 (6.2%) required mechanical ventilation, 368 (32.1%) had at least one record of D-dimer levels [≥]1,000 g/L, and 118 patients died. In the multivariable logistic regression, age (OR = 0.953 per 1 year, 95% CI: 0.937-0.968) C-reactive protein (OR = 1.004 per 1 mg/L, 95% CI: 1.002-1.007), and white blood cell counts (OR = 1.059 per 109/L, 95% CI: 1.010-1.111) were found to be associated with admission to the AICU. Age (OR = 0.973 per 1 year, 95% CI: 0.955-0.990), C-reactive protein (OR = 1.003 per 1 mg/L, 95% CI: 1.000-1.006) and sodium (OR = 0.915 per 1 mmol/L, 0.868-0.962) were associated with mechanical ventilation. Age (OR = 1.023 per 1 year, 95% CI: 1.004-1.043), CRP (OR = 1.004 per 1 mg/L, 95% CI: 1.002-1.006), and body temperature (OR = 0.723 per 1{degrees}C, 95% CI: 0.541-0.958) were associated with elevated D-dimer. For mortality, we observed associations with age (OR = 1.060 per 1 year, 95% CI: 1.040-1.082), female sex (OR = 0.442, 95% CI: 0.442, 95% CI: 0.245-0.777), Asian ethnic background (OR = 2.237 vs White ethnic background, 95% CI: 1.111-4.510), C-reactive protein (OR = 1.004 per 1 mg/L, 95% CI: 1.001-1.006), sodium (OR = 1.038 per 1 mmol/L, 95% CI: 1.001-1.006), and respiratory rate (OR = 1.054 per 1 breath/min, 95% CI: 1.024-1.087). ConclusionOur analysis suggests there are several demographic, clinical and laboratory findings associated with a symptomatic presentation of COVID-19. Moreover, significant associations between patient deterioration were found with age, sex and specific blood markers, chiefly C-reactive protein, and could help early identification of patients at risk of poorer prognosis. Further work is required to clarify the extent to which our observations are relevant beyond current settings.

Early detection of severe COVID-19 disease patterns define near real-time personalised care, bioseverity in males, and decelerating mortality rates.

BackgroundCOVID-19 is a global health emergency. Recent data indicate a 50% mortality rate across UK intensive care units. MethodsA single institution, two-centre retrospective analysis following implementation of a Decision Support tool and real-time data dashboard for early detection of patients requiring personalised enhanced care, focussing on respiratory rate, diastolic blood pressure, oxygenation indices, C-reactive protein, D-dimer and ferritin. Protocols differing from conventional practice included high-dose prophylactic anticoagulation for all COVID-19 positive patients and prescription of antioxidants. ResultsBy 22/04/2020, 923 patients tested COVID-19 positive. 569 patients (61.7%) were male. The majority presented with advanced disease: interquartile ranges were C-reactive protein 44.9-179mg/L, D-dimer 1070-3802ng/mL, and ferritin 261-1208{micro}g/L. Completed case fatality rates were 25.1% [95% CI 20.0, 30.0] in females, 40.5% [95% CI 35.9, 45.0] in males. 139 patients were admitted to intensive care where current death rates are 16.2% [95% CI 3.8, 28.7] in females, 38.2% [95% CI 28.6, 47.8] in males with no trends for differences based on ethnicity. A real-time traffic lights dashboard enabled rapid assessment of patients using critical parameters to accelerate adjustments to management protocols. In total 513 (55.6%) of patients were flagged as high risk for thromboembolic disease, exceeding the numbers flagged for respiratory deteriorations (N=391, 42.4%), or cytokine storm (N=68, 7.4%). There was minimal evidence that age was associated with disease severity, but males had higher levels of all dashboard indices, particularly C-reactive protein and ferritin (p<0.0001) which displayed no relationship with age. ConclusionsSurvival rates are encouraging. Protocols employed (traffic light-driven personalised care, protocolised early therapeutic anticoagulation based on D-dimer >1,000ng/mL and/or CRP>200 mg/L, personalised ventilatory strategies and antioxidants) are recommended to other units. Males are at greater risk of severe disease, most likely as the obligate SARS-CoV-2 receptor is encoded by the X-chromosome, and require especially close, and early attention.