Early in the COVID pandemic, several baseline characteristics emerged as risk factors for in-hospital mortality among persons with COVID-19. Although a growing list of other comorbidities has since entered the discussion, these core risk factors, which included advanced age (>65 years), male sex, and the comorbidities obesity and diabetes, have remained relatively static over time.
From a practical perspective, identifying age, the Y chromosome, obesity and diabetes with COVID-19 in-hospital mortality doesn't seem particularly useful. All are known to increase the likelihood of death among hospitalized persons whether or not SARS-CoV-2 is present. However, a number of recent studies suggest that in the context of COVID-19, these risk factors have unexpected attributes and odd interactions with one another and within affected population subsets.
The findings of two international clinical trials in patients with atrial fibrillation, ARISTOTAL and RE-LY, for example, offer a possible (if yet conclusive) explanation for the elevated risk of COVID deaths among males, the aged and diabetic patients. In these trials, researchers found all three populations to have elevated levels of angiotensin-converting enzyme 2 (ACE2), the membrane-bound surface receptor by which SARS-CoV-2 enters cells in the respiratory system and elsewhere. There is evidence, as well, that ACE2 plays a role in the etiology of obesity.
Obesity is a recognized risk factor for in-hospital mortality in COVID-19, but several studies suggest that this risk is specific to younger patients, a tendency noted in a retrospective study of more than 7500 patients at 88 US hospitals. This evaluation found the association between BMI and death or mechanical ventilation to be strongest in adults ≤50 years, intermediate in adults 51 to 70 years, and weakest in adults >70 years. Severe obesity (BMI ≥40 kg/m2) was associated with an increased risk of in-hospital death only in those ≤50 years.
These results are echoed, in part, in a study conducted at the University of Maryland where obesity as an independent risk factor was found to differ in magnitude of effect by age, with patients 20-39 years of age having the highest relative risk. The study, which analyzed ~67,000 patients with COVID-19 at more than 600 geographically diverse hospitals, considered age, sex, hypertension and diabetes (in addition to obesity) as risk factors for death in hospitalized patients.
The outcomes for diabetes and hypertension in this study had unexpected results. After analysis, the researchers excluded uncomplicated diabetes (i.e., without chronic end-organ complications, including heart disease, renal disease, and/or vascular manifestations) as a risk factor at any age, and found uncomplicated hypertension (similarly defined) to be a risk factor only among persons aged 20-39. Patients 20-39 years-old were identified with the highest relative risk for diabetes and hypertension with chronic complications.
The association of old age and risk of COVID-19 death would seem to be intuitive, but researchers in the UK wondered whether the phenomenon was more complicated than chronological age alone. To assess this hypothesis (which has application as an attribute for in-hospital mortality), more than 500,000 non-hospitalized participants aged 37 to 73 years (47 to 85 years) were recruited and a comprehensive accounting of non-age-related characteristics catalogued, including demographic and medical information. This information was then analyzed for potential confounding factors and other parameters and the variables categorized for interpretation.
In the end, chronological age remained a predominant factor, but BMI, systolic blood pressure, low FEV1, frailty and multi-morbidity were found to have an exponential association with COVID-related death, as well. The researchers postulated that the association between concomitant morbidities and increased risk of COVID-19 in the aged could be related to shared biological pathways (e.g., chronic low-grade inflammation) and attenuated immune response.
Multi-morbidity as an independent factor for mortality was identified in 92% of hospitalized COVID patients in a cohort study of ~2500 COVID patients at more than 150 US hospitals, with hypertension, obesity and diabetes (chronic metabolic disease) most frequently documented. The study, which also noted the prevalence of age and male sex as factors for in-hospital mortality, added renal disease, immunosuppression, chronic lung disease, cardiovascular disease and neurologic disorders to the core repertory of risk factors.
A caveat: Because many of the reports of risk-factors for COVID in-hospital mortality arise from retrospective cohort evaluations or meta-analyses of observational studies, selection bias and information on confounding and mediating factors may be issues. These types of study design are not unusual for assessment of in-hospital mortality risk, however. A number of case control trials considering the in-hospital mortality risks identified with specific conditions or patient practices (i.e., hemodialysis, infusion therapy) have been conducted and will be considered in future articles.