Diabetes mellitus and COVID-19: The ominous duo

Field: Medicine (Health Sciences)

The novel coronavirus disease (COVID-19) has scourged the world ever since its outbreak in December 2019 in Wuhan, China. As of August 30, 2020, COVID-19 has affected more than 25 million people and inflicted over 800,000 casualties in more than 200 nations worldwide.[1] The majority of the cases of COVID-19 are mild/asymptomatic, however, critical disease are seen in 5% of the patients.[2] The overall global case-fatality rate due to COVID-19 stands at 3.2%.[1] The mortality rate is especially higher in patients with advancing age and those with underlying comorbidities, notably, hypertension, cardiovascular disease, obesity, and chronic obstructive pulmonary disease.[3] Likewise, diabetes mellitus (DM) has emerged as a distinct comorbidity associated with severe disease, acute respiratory distress syndrome (ARDS), and mortality in COVID-19.[456] In addition, there are theoretical concerns that patients with uncontrolled DM may be at a high risk of reinfections with COVID-19.[7] In a retrospective study from China, patients with diabetes had more severe pneumonia; a subgroup of 24 patients with DM had greater mortality compared to 26 patients without DM (16.5% vs. 0%).[8] In a prospective cohort study of COVID-19 patients from New York, the prevalence of DM was higher in individuals admitted to the hospital than those who did not require admission (34.7% vs. 9.7%).[9] In a meta-analysis of eight studies, COVID-19 patients with DM had a higher risk of admission to the intensive care unit.[10] Despite a poor prognosis, patients with DM do not appear to be at an increased risk of acquiring COVID-19 infection.[611] Most of the available data pertain to patients with type 2 diabetes mellitus (T2DM); however, patients with type 1 diabetes mellitus (T1DM) also appear to be at a high risk of poor prognosis with COVID-19. A survey done in the United Kingdom showed that out of 23,804 patients with COVID-19 dying in hospital, 32% had T2DM and 1.5% had T1DM, with the odds ratio of dying being 2.03 and 3.5 times compared with patients without DM, respectively.[12] Another study from England showed that the adjusted hazard ratio (HR) for mortality in COVID-19 patients with T1DM with glycated hemoglobin (HbA1c) >10% compared with HbA1c6.5%–7% was 2.19.[13] The adverse outcome associated with DM in patients with COVID-19 is multifactorial. Patients with T2DM tend to be old; advancing age itself is a risk factor for poor prognosis in COVID-19.[3] However, DM was found to be an independent predictor of admission to the intensive care unit or invasive ventilation or death in COVID-19 (HR 1.59, 95% confidence interval [CI]: 1.03–2.45), even after the adjustment for age.[14] Various pathophysiological explanations have been proposed supporting the association between DM and COVID-19 severity. The innate immune system, the primary line of defense against SARS-CoV-2, is compromised in patients with uncontrolled DM. Moreover, DM is characterized by an underlying pro-inflammatory state that is responsible for an inappropriate and exaggerated cytokine response; this has been depicted in COVID-19 patients in whom serum levels of interleukin-6, ferritin, and C-reactive protein were significantly higher in patients with DM compared with those without DM. This makes COVID-19 patients with underlying DM more susceptible to cytokine storm eventually, leading to ARDS, shock, rapid deterioration, and death.[6] Besides, COVID-19 patients with DM have higher D-dimer levels than those without DM, perhaps signifying overactivation of the hemostatic system.[8] Amid an already underlying pro-thrombotic hypercoagulable state predisposed by the presence of DM, overactivation of the coagulation cascade in COVID-19 can lead to fatal thromboembolic complications and eventual mortality.[515] Besides, obesity, which is common in patients with T2DM, is itself a risk factor for severe COVID-19.[16] DM is associated with reduced expression of angiotensin-converting enzyme 2 (ACE2). Under normal physiological conditions, ACE2 degrades angiotensin-II (Ang-II) and to a little extent Ang-I to smaller peptides, namely Ang (1–7) and Ang (1–9), respectively. The pulmonary ACE2/Ang (1–7) system plays a vital anti-inflammatory and antioxidant role; ACE2 is known to be protective against lethal avian influenza A H5N1 infection.[17] Accordingly, low ACE2 expression in DM might explain the increased incidence of severe lung injury and ARDS in patients with COVID-19.[418] On the contrary, overexpression of ACE2, as seen in patients on angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), commonly used in patients with DM, can also be counterproductive. SARS-CoV-2 uses ACE2 as a receptor for entry into the host pneumocytes; thus, ACE2 upregulation would facilitate entry and subsequent proliferation of the coronavirus. However, once the virus uses the enzyme to gain entry into the host tissue, ACE2 gets downregulated and it is unable to protect against lung injury.[4] Keeping in mind the fact that patients with DM are at a high risk of grave complications and mortality with COVID-19, patients with DM must take extra precautions amid the ongoing pandemic. They should strictly follow the government advisories of social distancing, hand hygiene, and use of face masks.[19] However, a recently conducted telephonic as well as a nationwide online survey in India had shown that the knowledge and awareness about COVID-19 among young adults with T1DM are at best, modest.[2021] Hence, improving patient awareness through social and print media is the need of the hour. Besides, good glycemic control should also be ensured.[19] In an adjusted model, the HR for in-hospital death was greater in patients with HbA1c ≥ 7.5% (3.36, 95% CI 2.18–2.56) than in those with lower HbA1c (1.50, 1.40–1.60).[22] All antidiabetic drugs can be used amid the ongoing pandemic, although there are theoretical concerns that pioglitazone and liraglutide can upregulate ACE2 and increase the risk of infection/disease severity with COVID-19.[2324] Regarding the use of ACEi/ARBs, all the international organizations recommend the continuation of these drugs for the control of hypertension. COVID-19 can also lead to worsening of hyperglycemia via cytokine mediated exacerbation of insulin resistance as well as by direct damage to the pancreatic ß-cells. Besides, drugs used in the management of COVID-19, namely, corticosteroids, lopinavir/ritonavir and remdesivir can further worsen hyperglycemia in COVID-19 patients with DM.[5] Vitamin D deficiency is more common in T2DM. During the COVID-19 pandemic, the chances of hypovitaminosis D are further exaggerated due to limited outdoor activity and continuous use of face masks. Vitamin D sufficiency is associated with better innate and cell-mediated immunity. The deficiency of vitamin D in T2DM might predispose to increased morbidity and mortality with COVID-19 due to impaired immunity. All individuals of DM should be optimally replaced with vitamin D to achieve target levels of vitamin D (>30 ng/ml). In conclusion, it is well accepted that T2DM and associated comorbidities are linked to increased morbidity and mortality with COVID-19. Every individual with DM should try to achieve optimum glucose control and take full precautions to avoid contracting the disease.