Our study demonstrates that patients with diabetes constituted around half of the critically ill patients with MERS; MERS patients with diabetes presented with dyspnea and sputum production and were more likely to have respiratory failure requiring mechanical ventilation more often than those with no diabetes; and diabetes was an independent predictor of mortality in MERS. Viral shedding duration was similar in patients with diabetes and no diabetes
Diabetes is a global health problem and leads to significant complications that increase the risk of morbidity and development of critical illness. Saudi Arabia is among the countries with high prevalence rates (> 30%) [19]. This may partly explain the high prevalence of diabetes in our cohort of critically ill MERS patients. In a Korean cohort of 186 patients with confirmed MERS patients, diabetes was present in 18.8% [9]. In our study, patients with diabetes presented with more severe respiratory symptoms and hypoxia, required mechanical ventilation more frequently, and were given nitric oxide as rescue therapy more often. They also required vasopressors more often. These patients were more likely to receive ribavirin and interferon (alpha or beta-1a) alone or in combination; these antivirals have not been associated with improved outcomes in MERS [20]. Recently, the MIRACLE trial demonstrated reduction in mortality with combination of lopinavir-ritonavir and interferon beta-1b; but none of patients in this cohort had received this combination.[21]
Diabetes is associated with reduced neutrophil chemotaxis after stimulation [22] and blunted inflammatory response to endotoxemia [23]. These abnormalities are thought to be the reasons why diabetics have an increased risk of various infections [24]. For viral infections, diabetes has been associated with increased risk for hospitalization after H1N1 infection [25], ICU admission [25], and death [26]. Comorbidities, including diabetes, have been associated with increased mortality in MERS patients [27]. In a small cohort from two hospitals in Saudi Arabia, diabetes was present in 10.5% of survivors and 70.0% of non-survivors (p=0.002) [28]. A study that evaluated MERS cases during the Korean outbreak found that diabetes was a risk factor for mortality on multivariate analysis (OR, 2.47; 95% CI, 1.06-5.72) [9]. 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) [13]. In Severe Acute Respiratory Syndrome (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 [29].
Diabetes is also prevalent among COVID-19 patients and its association with disease severity and outcomes have yielded variable results [30-32]. 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 [30]. In 140 COVID-19 patients from Wuhan, China, diabetes was present in 12.1% and was not associated with more severe disease [31]. In a 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 [33]. However, in a metanalysis of eight studies (N=46248), 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 [34]. In a study of 72314 COVID-19 cases, the case-fatality rate was in higher patients with diabetes (7.3%) compared with an overall fatality of 2.3% [35]. In two studies, the multivariable logistic regression analysis did that found an association between diabetes and morality in COVID-19 [32, 36].
It remains unclear clear how diabetes may contribute to increased disease severity and mortality 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 [14]. This was associated with delayed inflammation which lasted through 21 days after infection [14]. Diabetic mice exhibited fewer inflammatory monocyte/macrophages and CD4+ T cells and lower levels of TNF-a, IL-6, and IL-12b [14]. This may explain the findings of severe MERS in patients with diabetes.
Viral shedding was relatively prolonged in our MERS patients. However, the time to clearance of MERS-CoV RNA was similar in patients with diabetes and no diabetes. Prolonged shedding has been reported in MERS patients in other studies [37], and has been associated with corticosteroid use [38]. Corticosteroids were used more commonly in patients with diabetes in the current study.
The findings of this study should be interpreted in light of its strengths and weaknesses. The strengths include that it is the largest cohort of critically ill patients with MERS. The limitations are related to the nature of the database and include diabetes diagnosis by history and absence of data on glycemic measures, such as type of diabetes, hemoglobin A1c, glucose control during hospitalization, and prior or current diabetes medications. In addition, glucose levels in patients with no diabetes were elevated, suggesting that some patients had stress hyperglycemia or undiagnosed diabetes. This may affect the associations between diabetes and various outcomes. Given the high prevalence of diabetes in Saudi Arabia, the results of our study may not be generalizable to populations of lower diabetes prevalence.