Discussion and conclusions
Here we report on a large cohort of patients diagnosed with COVID-19 over a 6-week period in a multisite NHS Trust in London. In our cohort, multivariate analysis revealed male gender, increased age, increased frailty and lower platelet count were independently associated with increased risk of ICU admission and/or death within 30 days of COVID-19 diagnosis, while taking antiplatelet medication was associated with a lower risk of poor outcome. Within the subset of our cohort with diabetes (96% type 2 and 4% type 1), multivariate analysis demonstrated pre-existing IHD, advancing age and lower platelet count were associated with increased risk of ICU admission and/or death.
Prior to the COVID-19 pandemic, data from the National Diabetes Inpatient Audit indicate the prevalence of diabetes among hospital inpatients in England and Wales was 18%,18 reflecting a generalized increased risk of hospitalization among people with diabetes. Using data from a UK primary care database, Barron et al19 reported that people with both type 1 and type 2 diabetes had multiply adjusted increased odds of dying in hospital with COVID-19 compared with those without diabetes. Our results show that people with diabetes are at increased risk of severe or life-threatening COVID-19, although this was driven by its tendency to coexist with other conditions, particularly IHD. The relative proportions of patients admitted with COVID-19 with type 1 and type 2 diabetes were similar to the population we serve, suggesting no difference in susceptibility based on diabetes type.
Hyperglycemia is a modifiable factor that may influence outcome in COVID-19, especially in people with diabetes. In our cohort, recent HbA1c was not a significant predictor of poor outcome, which is similar to some cohort studies12 but not others.13 In patients with diabetes (and in patients without diabetes), our data demonstrate that blood glucose ≥10 mmol/L (at the time of COVID-19 diagnosis and on average during the 72 hours following COVID-19 diagnosis) is associated with increased risk of death/ICU admission. Similar findings have been reported by groups from England,13 France12 and China.11 20 This association is not sustained on multivariate analysis in our patients with diabetes and there is no prospective study to address whether maintaining blood glucose <10 mmol/L would improve outcomes for patients with diabetes with COVID-19. Furthermore, maintaining blood glucose <10 mmol/L may become even more challenging to achieve as the use of dexamethasone in the management of severe COVID-19 becomes more widespread, following publication of beneficial reports of its use in this context.21
It is now well established that patients with more severe manifestations of COVID-19 (including those that need to be escalated to ICU care and those that die) are much more likely to have a diagnosis of diabetes than those who are documented as having a mild form of the infection.2 19 22 Some people have recommended that patients with diabetes need to be more actively shielded, and diabetes may be associated with a higher risk of viral infection.23 Evidence of increased risk of contracting COVID-19 in people with diabetes is lacking, with similar adult prevalence of diabetes (10.1%) and prevalence of diabetes in patients with COVID-19 (10.9%) reported by the Centers for Disease Control in America.24 However, it is important to note that here we show that diabetes alone is not a major factor contributing to the risk of death/ICU admission, but rather its association with other consequences of the metabolic syndrome, particularly IHD, confers a higher risk of a poor outcome. For instance, patients (in our cohort) with diabetes have a 33% increased risk of death/ICU admission if they also have IHD.
In line with our observations that it is multimorbidity per se and not any single particular diagnosis that confers a strong increased risk of poorer outcomes in COVID-19 infection, we show that the CFS score is a robust, independent predictor of poor outcome on multivariate analysis. This is consistent with (COVID-19 and non-COVID-19) studies that show that as the CFS score increases, the likelihood of mortality increases.25 26 However, we have also shown that the CFS score is much less useful in younger age groups. We chose death or ICU admission as our primary outcome measure as this incorporated all patients with severe/life-threatening COVID-19. Our cohort also included those who, with unfavorable chances of tolerating and surviving invasive ventilation, would not have been admitted to ICU due to pre-existing multimorbidity.
We report a strongly significant and independent risk of death/ICU admission as platelet count at presentation decreases. The inverse relationship between platelet count and risk of death/ICU admission with COVID-19 has also been reported by several other studies.22 27 28 As microvascular and macrovascular thrombosis is increasingly being reported as a feature of severe COVID-19,29–31 reduced platelet count may reflect consumptive coagulopathy (D-dimers were significantly higher in the primary outcome group), possibly in conjunction with direct effects of the virus on thrombopoiesis or platelet survival. We note that patients with coexisting diabetes and IHD are at particular risk of poorer outcomes with COVID-19, and that in these patients the protective benefits of antiplatelet usage are abrogated. Differing recommendations about the use of anticoagulants in hospitalized patients with COVID-19 have been made in recently published international guidelines,32 while several prospective randomized trials evaluating the effects of anticoagulation on COVID-19 mortality are currently underway.
Strengths of our study include a diverse population of patients and indepth characterization, including CFS and numerous prehospital and presentation factors. We selected a statistical approach focused on a primary outcome measure with no selection bias for the multivariate analysis that produced intuitive results, which survived robust sensitivity analysis.
Large population studies (of millions of patients), using primary care databases in England, have reported increased mortality risk among patients with COVID-19 who have diabetes.19 33 Similarly, several meta-analyses (of thousands of patients) have reported increased risk of poor outcomes and/or death in people with COVID-19 who have diabetes.34 35 In our cohort, diabetes per se was not associated with an increased risk of ICU admission and/or death on multivariate analysis (which included 37 variables including presenting clinical features as well as pre-existing comorbidities). It is clear that patients with diabetes are over-represented among those that have the poorest outcomes with COVID-19, and our findings suggest that this is extensively driven by the association of diabetes with cardiovascular disease.
In conclusion, this study contributes further to understanding the drivers of poor outcomes in patients with diabetes admitted to hospital with COVID-19. Advancing age, multimorbidity (as crystallized in the CFS) and lower platelet count are important predictors of poor outcome in patients with COVID-19 admitted to hospital. The protective benefits of usage of antiplatelet agents are lost in patients with diabetes. There is no clear evidence that dysglycemia drives the increased risk of death/ICU admission among patients with diabetes, but rather the association of diabetes with other common medical conditions confers excess risk of poor outcomes.