The main findings of this study were that patients with diabetes constituted around half of critically ill patients with MERS; MERS patients with diabetes presented with dyspnea and sputum production and had respiratory failure requiring mechanical ventilation more often than those with no diabetes; viral shedding was prolonged but of similar duration in patients with diabetes and no diabetes and diabetes was an independent predictor of mortality in MERS.
Diabetes is a global health problem and may lead to significant complications that increase the risk morbidity and development of critical illness. Saudi Arabia is among the countries with the highest prevalence rates (> 30%). This may partly explain the high prevalence of diabetes in our cohort of critically ill MERS patients. A Korean cohort of 186 patients with confirmed MERS patients, diabetes was present in 18.8%. In our study, patients with diabetes presented with more severe respiratory symptoms and hypoxia, needed mechanical ventilation more frequently and were given nitric oxide as rescue therapy more often. They also required vasopressors more often. Multiple antivirals were provided. These included ribavirin and interferon alone or in combination. These antivirals have not been associated with improved outcomes in MERS.
Diabetes is associated with reduced neutrophil chemotaxis after stimulation and blunted inflammatory response to endotoxemia. These abnormalities are thought to be the reasons why diabetics have increased risk of infections. These include infection of the urinary tract, skin and soft tissue and lower respiratory tract. For viral infections, diabetes has been associated with increased risk for hospitalization after H1N1 infection, ICU admission, and death. Comorbidities, including diabetes, have been associated with increased mortality in MERS patients. In a small cohort from two hospitals in Saudi Arabia, diabetes was present in 10.5% of survivors and 70,0% of nonsurvivors (p=0.002). A study that evaluated MERS cases during the Korean outbreak found that diabetes was a risk factor for mortality on multivariate Cox-regression analysis (OR, 2.47; 95% CI, 1.06-5.72). Analysis of 1743 MERS cases found that patients with comorbidity (diabetes mellitus, cardiovascular disease, renal disease, or pulmonary disease) had higher mortality risk (adjusted hazard ratio, of 3.7; 95% CI, 2.6-5.7). In SARS, diabetes (OR, 3.0; 95% CI, 1.4-6.3) and fasting blood glucose ≥ 7.0 mmol/l (OR, 3.3; 95%, CI 1.4- 7.7) were independent predictors of death.
Studies on diabetes prevalence in COVID-19 and its association with disease severity and outcomes have yielded variable results. The prevalence was 5.3-19.5% in studies from China, > 30% in studies from Italy and 10.9-58.0% in studies from the United States. In a study of 140 COVID-19 patients from Wuhan, China, diabetes was prevalent in 12.1% and was not associated with more severe disease (respiratory frequency ≥ 30/min, oxygen saturation ≤ 93% at rest, and oxygenation index ≤ 300 mm Hg). No mortality data were reported. One report of 72314 COVID-19 cases found an overall case-fatality rate of 2.3%. This rate was higher in patients with preexisting comorbid conditions and was 7.3% for diabetes. Another study that included 1099 patients with confirmed COVID-19, diabetes was present in 5.7% of non-severe cases, 16.2% of severe cases and 26.9% in those who had ICU admission, needed mechanical ventilation, or died. However, a metanalysis of eight studies (N=46,248), the risk of severe COVID-19 was not significantly increased in patients with diabetes (OR, 2.07; 95% CI, 0.89-4.82), unlike hypertension and cardiovascular disease. In a study of 191 patients from two hospitals in Wuhan, China, hypertension was the most common comorbidity (30.4%) followed by diabetes (18.8%). The mortality rate was 28.3% with diabetes being associated with mortality on univariate but not multivariable analysis. Similarly, another study from Wuhan (N=201) found no significant increased mortality risk with diabetes (hazard ratio, 1.58; 95% CI, 0.80-3.13, p = 0.19) in a bivariate cox regression analysis.
It remains unclear clear how diabetes may contribute to increased disease severity and outcome in people infected with MERS-CoV. In a mouse model of MERS-CoV infection, diabetic mice had a prolonged phase of severe disease and delayed recovery compared to non-diabetic mice. This was associated with delayed inflammation which lasted through 21 days after infection. Diabetic mice exhibited fewer inflammatory monocyte/macrophages and CD4+ T cells and lower levels of TNF-a, IL-6 and IL-12b. This may explain the findings of severe MERS in patients with diabetes. The worse outcome among diabetic patients could be due to the higher prevalence of comorbid underlying medical conditions.
Viral shedding was relatively prolonged in our MERS patients. The time to clearance of rt-PCR for MERS-CoV was similar in patients with diabetes and no diabetes (median: 23 versus 21 days, respectively). Prolonged shedding has been reported in MERS patients in other studies, and has been associated with corticosteroid use. In SARS, early use of hydrocortisone was associated with delayed viral clearance compared with a control group (median: 12 days (range: 11-20 days) versus 8 days (8-15 days), respectively; p=0.11). In 191 COVID-19 patients, the median duration of viral shedding was 20.0 days (Q1, Q3: 17,0-24.0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors (median:18.5 days; Q1, Q3: 15·0-22·0).
The findings of this study should be interpreted in the light of its strengths and weakness. The strengths include that it is the largest cohort of MERS critically ill patients. The limitations include diabetes diagnosis by history, absence of data on glycemic measures such hemoglobin A1c, glucose control during hospitalization and prior or current diabetes medications. In addition, glucose levels in the patients with no diabetes were elevated, suggesting that some patients had stress hyperglycemia or undiagnosed diabetes.