COVID-19 in Diabetics

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Anahita Deylamsalehi, M.D.[2]

Historical Perspective

• On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.
• Diabetes mellitus, specifically type 2 diabetes has been recognized as one of the most common comorbidities of COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). It has been estimated that 20-25% of patients with COVID-19 had diabetes.

Classification

• There is no classification for COVID-19 in diabetes mellitus.

Pathophysiology

• COVID-19 is caused by a virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) belong to the order nidovirale, family coronaviridae.
• Diabetes mellitus, specifically type 2 diabetes has been recognized as one of the most common comorbidities of COVID-19.
• Abnormal production of adipokines and cytokines like Tumor necrosis factor-alpha and interferon in diabetic patients have been associated with impairment in immune system and increased susceptibility to infections.
• The following factors have been demonstrated as responsible mechanisms which increase the risk of infections in diabetes:
  • Reduction of Interleukin production
  • Decreased phagocytic activity and chemotaxis
  • Immobilized granulocytes
  • Poor circulation, especially with concurrent peripheral vascular disease (PVD)

Causes

Disease name] may be caused by [cause1], [cause2], or [cause3].

Differentiating [disease name] from other Diseases

• [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:

Epidemiology and Demographics

• It has been estimated that 20-25% of patients with COVID-19 had diabetes.
• Based on a Meta-analysis, the prevalence of diabetes among Chinese population with COVID-19 was 9·7%.
• A study done on 1317 participants reported that 88.5% of patients with COVID-19 had concurrent diabetes mellitus type 2.

Age

• Diabetic patients of all age groups may develop COVID-19, although older age has higher prevalence and been related to higher mortality rate with exception of Korean population, which reported higher rate of COVID-19 among individuals aged 20–29 years.
• Studies have been demonstrated an association between old age and worse outcome, furthermore this association has been speculated to be more strong in diabetic patients.
• Individuals older than 80 years old have 12-times higher chance of worse outcome, compared to those aged 50-59 years old.

Gender

• Male sex has been linked to higher prevalence of COVID-19.
• Chance of worse outcome has been estimated twice in male sex, compared to females.

Race

• There are some data supporting that non-white ethnic groups have higher chance of developing COVID-19.
• An analysis reported that African Americans included 33% of individuals admitted to hospital with COVID-19 in the US.
• Even though only 28% of New York city population consisted of Hispanic or Latin individuals, 34% of COVID-19 deaths of New York were consisted of these minorities.
• The higher chance of COVID-19 in these ethnic minority groups has been speculated to be due to both biological and environmental circumstances, as well as socioeconomic and life style related factors.

Risk Factors

• Some possible factors that lead to more severe COVID-19 in diabetic patient have been summarized in the table below:

Confirmed factors	hypothesized factors
1- Glycemic instability 2- Immune deficiency (specially T-cell response) 3- Related comorbidities, like obesity and cardiac and renal disease	1- Chronic inflammation (elevated interleukin-6) 2- Elevated plasmin 3- Reduced ACE2 4- Increased furin (involved in virus entry into cell)

• HbA1C more than 86 mmol/mol (10%) has been related to worst outcome and higher chance of death, compared to HbA1C less than 48 mmol/mol (6·5%), which further confirms the importance of desirable glycemic control.

Natural History, Complications and Prognosis

Complications

• Diabetic patients with SARS-CoV-2 infection had higher rate of the following complications:
  • Acute Respiratory Distress Syndrome (ARDS)
  • Septic Shock
  • Acute kidney injury
  • Acute heart injury
  • Requirement of oxygen inhalation
  • Multi-organ failure
  • Both non-invasive and invasive ventilation (eg, extracorporeal membrane oxygenation (ECMO)).
• Optimal metabolic control reduces the chance of complications in concurrent diabetes mellitus and COVID-19 in outpatients.
• COVID-19 has been related to high coagulation activity, probably due to hypoxia related endothelial dysfunction. The latter COVID-19 consequence will be more augmented by the prothrombotic state in diabetic patients, which can lead to more unwanted complications.

Prognosis

• SARS-CoV-2 infection has been linked with higher rate of hospitalization and mortality in diabetic patients compared to non-diabetics.
• Records from the Centers for Disease Control and Prevention (CDC) and other national health centers and hospitals state that diabetic patients with COVID-19 have up to 50% higher chance of death compared to non diabetics with this infection.]]
• Another study done in the US reports more than fourfold mortality rate elevation in COVID-19 in diabetic patients.
• Study on COVID-19 patients in intensive care unit showed a twofold increase in incidence of diabetes, compared to non-intensive care patients.
• Another study done among 1561 patients with COVID-19 in Wuhan demonstrated that diabetic patients had higher rate of intensive care unit (ICU) admission and death, compared to nondiabetics.
• A cohort study done on 5693 patients in England demonstrated higher chance of death among patients with uncontrolled diabetes.
• Complications of diabetes and higher prevalence of comorbidities such as hypertension, cardiovascular disease, cerebrovascular disease, Pulmonology and chronic kidney disease.
• Estimated GFR less than 60 mL/min per 1·73 m2 at the time of admission is correlated to higher rate of early death in diabetic patients with COVID-19.

Diagnosis

History and Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

Laboratory Findings

• Diabetic patients with SARS-CoV-2 infection have lower levels of the following, compared to non-diabetics:
  • Lymphocytes
  • Red blood cells (RBC)
  • Albumin
  • Hemoglobin
• Diabetic patients with SARS-CoV-2 infection have higher levels of the following, compared to non-diabetics:
  • Neutrophils
  • Erythrocyte sedimentation rate (ESR)
  • D-dimer
  • A-hydroxybutyrate dehydrogenase
  • Lactic dehydrogenase
  • Alanine aminotransferase (ALT)
  • Fibrinogen
  • C reactive protein
  • Ferritin
  • Interleukin-6 (IL-6)
  • Interleukin-10 (IL-10)
  • γ-glutamyl transferase
  • Procalcitonin
• High C-reactive protein (CPR) level is one of the risk factors that increase mortality rate in diabetic patients who become infected with SARS-CoV-2. Therefore, A study suggests usage of C-reactive protein (CRP) as a tool to identify patients with higher chance of dying during hospitalization. Based on a prospective cohort study, C-reactive protein higher than 200 mg/L and Ferritin more than 2500 ng/mL at the time of admission have been related to more severe COVID-19.
• Sever COVID-19 in diabetic patients were related to higher levels of serum amyloid A (SAA) and low CD4+ T lymphocyte counts.
• There is a J-curve association between HbA1c and risk of infections in general, particularly respiratory tract infections.

Electrocardiogram

There are no ECG findings associated with [disease name].

X-ray

There are no x-ray findings associated with [disease name].

Echocardiography or Ultrasound

There are no echocardiography/ultrasound findings associated with [disease name].

CT scan

There are no CT scan findings associated with [disease name].

MRI

There are no MRI findings associated with [disease name].

Other Imaging Findings

There are no other imaging findings associated with [disease name].

Other Diagnostic Studies

There are no other diagnostic studies associated with [disease name].

Treatment

Medical Therapy

• Treatment with insulin was associated with poor prognosis in diabetic patients with COVID-19. Although, Insulin is the choice agent to control blood glucose in hospitalized diabetic patients with COVID-19.
  • Possible β cell damage caused by SARS-CoV-2 can cause to insulin deficiency, which explain increased insulin requirement in these patients. Due to elevated insulin consumption, intravenous infusion must be considered.
  • Although angiotensin-converting enzyme II (ACE) expression has been reduced in COVID-19, treatment with ACE inhibitors (ACEI) or angiotensin II type-I receptor blockers (ARB) in diabetic patient with hypertension had no significant difference compared to other anti-hypertensive treatments based on one study. On the other hand, another study done on diabetic patients showed higher risk of SARS-CoV-2 infection with ACE2-increasing drugs. Elevated ACE2 level can ease the entry of virus. Therefore It is hypothesized that medications like, Angiotensin-converting-enzyme inhibitors (ACEI), angiotensin II type-I receptor blockers (ARB), thiazolidinediones and ibuprofen augment the risk of a severe and lethal SARS-CoV-2 infection.
  • Due to increased risk of chronic kidney disease and acute kidney injury, renal function should be monitored in patients who take metformin. There is also a recommendation to stop Metformin use in a patient with poor oral intake and vomiting. There are other data that suggest metformin as a possibly helpful anti-diabetic agent in concurrent SARS-CoV-2 infection. Since metformin leads to less elevation in interleukin-6 level, compared to other anti-diabetic agents. These data also assert an association between metformin use and albumin level elevation and a lower COVID-19 related death in patients who took metformin.
  • A hypothesis state that since Sodium glucose cotransporter 2 (SGLT-2) inhibitors decrease lactate production and subsequently increase the cytosolic pH, they interfere with virus entry into the cells. Conversely, based on another study Sodium glucose cotransporter 2 (SGLT-2) inhibitors are also indirectly responsible for high ACE2 level, which is attributed as a risk factor for SARS-CoV-2 infection. High ACE2 level can be further elevated by concurrent Angiotensin-converting-enzyme inhibitors (ACEI) use. Current database suggests benefit from discontinuation of Sodium glucose cotransporter 2 (SGLT-2) inhibitors in diabetic patient with COVID-19.
  • Initiation of Sodium-glucose-co-transporter 2 inhibitors should be avoided in respiratory illnesses.
  • Although lactic acidosis due to metformin use and euglycaemic or moderate hyperglycaemic diabetic ketoacidosis associated with Sodium-glucose-co-transporter 2 inhibitors are rare, their usage has not been recommended. Nevertheless, there is no need to stop these medications prophylactically in diabetic patients with no sign of COVID-19.
  • Dipeptidyl peptidase-4 inhibitors has been well tolerated in some diabetic patients with concurrent SARS-CoV-2 infection. It can be continue in mild to moderate COVID-19, nevertheless it is better to be discontinued in sever cases.
  • Use of thiazolidinediones has been linked with increased fluid retention and congestive heart failure in diabetic patients with SARS-CoV-2 infection. Pioglitazone use can be continued in mild or moderate COVID-19.
  • Dehydration in diabetic patients with COVID-19 should be avoided. Based on a practical recommendation, medications with possible dehydration side effect like Metformin, Sodium-glucose-co-transporter 2 inhibitors and Glucagon-like peptide-1 receptor agonists should be avoided to prevent further complications.
  • A summary of anti-diabetic medications in diabetic patients with SARS-CoV-2 infection:

Anti-diabetic medication	Relation to ACE2 expression	Advantage	Disadvantage
Metformin	None	Lower level of IL-6 Higher albumin level Lower COVID-19 related death Potential cardiovascular benefits	Higher chance of lactic acidosis and renal dysfunction higher chance of dehydration
Pioglitazone	Increased ACE2 production in animal models	Reduction in proinflammatory cytokines Lower chance of lung injury	Increased chance of SARS-CoV-2 infection due to ACE2 overexpression
Sulfonylurea	None	No specific advantage has been found in patients with COVID-19	Higher chance of hypoglycemia
Dipeptidyl peptidase-4 inhibitors	None	Some anti-inflammatory properties are reported	No specific disadvantage has been found in patients with COVID-19
Sodium-glucose-co-transporter 2 inhibitors	Increased ACE2 production by kidney in human studies	Decreased oxidative stress Anti-inflammatory effects	Higher chance of hypovolemia
Glucagon-like peptide-1 receptor agonists	Liraglutide has been linked with elevated ACE2 production in lung and heart in animal models	Potential cardiovascular benefits	Higher chance of dehydration higher chance of gastrointestinal side effects
Insulin	Increased Renal ACE2 production in animal models	Anti-inflammatory effects	No specific disadvantage has been found in patients with COVID-19

Management Considerations:

• Evaluation of electrolytes, blood glucose, blood PH, blood ketones or beta-hydroxybutyrate should be considered in patients in intensive care unit (ICU). Since hypokalemia is a feature of COVID-19 (possibly as a result of high angiotensin 2 concentration and consequent hyperaldosteronism), potassium level should be checked. Specially in concurrent insulin treatment.
• Plasma glucose concentration goal for diabetic outpatients infected with SARS-CoV-2 is 72-144 mg/dl, while plasma glucose concentration of patients in intensive care unit is recommended to be maintained between 72 and 180 mg/dl.
• The glycemic control during hospital stay plays an important role in the overall outcome of diabetic patients with COVID-19. Based on a study done on 1122 patients with COVID-19 in the US, hyperglycaemia during the hospitalization has been associated with four time increase in mortality rate, compared to normoglycemia.
• The importance of a careful glycemic control is further supported by a study done in china, which demonstrated that patients with blood glucose concentration median less than 6·4 mmol/L during their hospital stay had higher rate of lymphopenia. These patients also had lower chance of neutrophilia, high C-reactive protein and procalcitonin levels.

Prevention

• There are no primary preventive measures available for [disease name].