Angiotensin-Converting-Enzyme 2 and Renin-Angiotensin System Inhibitors in COVID-19: An Update.

Ever since its outbreak, Corona Virus Disease 2019(COVID-19) caused by SARS-CoV-2 has affected more than 26 million individuals in more than 200 countries. Although the mortality rate of COVID-19 is low, but several clinical studies showed, patients with diabetes mellitus (DM) or other major complication at high risk of COVID-19 and reported more severe disease and increased fatality. The angiotensin-converting-enzyme 2 (ACE2), a component of renin-angiotensin-system (RAS); acts on ACE/Ang-II/AT1recptor axis, and regulates pathological processes like hypertension, cardiac dysfunction, Acute Respiratory Distress Syndrome (ARDS) etc. The progression of T2DM and hypertension show decreased expression and activity of ACE2. There are several treatment strategies for controlling diabetes, hypertension, etc; like ACE2 gene therapies, endogenous ACE2 activators, human recombinant ACE2 (hrACE2), Angiotensin-II receptor blockers (ARBs) and ACE inhibitors (ACEi) medications. ACE2, the receptors for SARS-CoV2, facilitates virus entry inside host cell. Clinicians are using two classes of medications for the treatment of COVID-19; one targets the SARS-CoV-2-ACE2 interaction, while other targets human immune system. The aim of this review is to discuss the role of ACE2 in diabetes and in COVID-19 and to provide an analysis of data proposing harm and benefit of RAS inhibitor treatment in COVID-19 infection as well as showing no association whatsoever. This review also highlights some candidate vaccines which are undergoing clinical trials.

Cortisol level dysregulation and its prevalence-Is it nature's alarm clock?

This review examines the stress hormone cortisol which plays an important role in regulating and supporting different bodily functions. Disruption in cortisol production has an impact on health and this review looks at a wide range of papers where cortisol has been indicated as a factor in numerous chronic conditions-especially those which are classed as "noncommunicable diseases" (NCDs). Timely detection, screening, and treatment for NCDs are vital to address the growing problem of NCDs worldwide-this would have health and socioeconomic benefits. Interestingly, many of the papers highlight the pro-inflammatory consequences of cortisol dysregulation and its deleterious effects on the body. This is particularly relevant given the recent findings concerning COVID-19 where pro-inflammatory cytokines have been implicated in severe inflammation.

Haemoglobin A1c is a predictor of COVID-19 severity in patients with diabetes.

AIM: Poor outcomes of coronavirus disease 2019 (COVID-19) have been linked to diabetes, but its relation to pre-infection glycaemic control is still unclear. MATERIALS AND METHODS: To address this question, we report here the association between pre-infection Haemoglobin A1c (HbA1c) levels and COVID-19 severity as assessed by need for hospitalization in a cohort of 2068 patients with diabetes tested for COVID-19 in Leumit Health Services (LHSs), Israel, between 1 February and 30 April 2020. Using the LHS-integrated electronic medical records system, we were able to collect a large amount of clinical information including age, sex, socio-economic status, weight, height, body mass index, HbA1c, prior diagnosis of ischaemic heart disease, depression/anxiety, schizophrenia, dementia, hypertension, cerebrovascular accident, congestive heart failure, smoking, and chronic lung disease. RESULTS: Of the patients included in the cohort, 183 (8.85%) were diagnosed with COVID-19 and 46 were admitted to hospital. More hospitalized patients were female, came from higher socio-economic background and had a higher baseline HbA1c. A prior diagnosis of cerebrovascular accident and chronic lung disease conferred an increased risk of hospitalization but not obesity or smoking status. In a multivariate analysis, controlling for multiple prior clinical conditions, the only parameter associated with a significantly increased risk for hospitalization was HbA1c ≥ 9%. CONCLUSION: Using pre-infection glycaemic control data, we identify HbA1c as a clear predictor of COVID-19 severity. Pre-infection risk stratification is crucial to successfully manage this disease, efficiently allocate resources, and minimize the economic and social burden associated with an undiscriminating approach.

Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era?

Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.

Clinical characteristics and outcomes of coronavirus disease 2019 infections among diabetics: A retrospective and multicenter study in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) emerged in December 2019 and has spread globally. Diabetics are at increased risk of infections caused by a variety of pathogens including viruses. The present research aims to describe clinical characteristics and outcomes of COVID-19 patients with diabetes. METHODS: A retrospective multicenter study of COVID-19 patients with diabetes was conducted in four hospitals in Wuhan, Shanghai, and Anhui Province. Reverse transcription polymerase chain reaction or next-generation sequencing was carried out to confirm the existence of severe acute respiratory syndrome coronavirus 2 from respiratory specimens. RESULTS: A total of 54 diabetics (10.36%) were recruited from among 521 COVID-19 patients, with a median age of 63 (interquartile range, 52-70) years. Among them, 51 had been previously diagnosed with diabetes and 3 had been newly diagnosed based on glycosylated hemoglobin over 6.5%. For COVID-19, 47 of the 54 patients had an exposure history. Fever (47/54, 87.04%), dry cough (36/54, 66.67%), and expectoration (21/53, 39.62%) were among the top three symptoms. Lung infiltration was bilateral (46/52, 88.46%) and multilobe (47/52, 90.38%), and ground-glass opacity (36/37, 97.30%) was the most common pattern in radiological images. Moreover, COVID-19 patients with diabetes were prone to be classified as severe or critical cases (46.30%, 25/54) and had complications such as acute lung injury, acute respiratory distress syndrome, and acute kidney injury. The proportions of intensive care unit (ICU) admissions and deaths among the COVID-19 diabetics were 14.81% (8/54) and 12.96% (7/54), respectively. CONCLUSIONS: With older age, diabetics diagnosed as having COVID-19 were prone to develop into severe cases and exhibited a high rate of ICU admission and mortality.

Analysis of the lymphocyte count in type 2 diabetic patients with coronavirus disease (COVID-19): A retrospective study in a centralized treatment center.

OBJECTIVE: To investigate the characteristics of lymphocytes in type 2 diabetic patients with coronavirus disease (COVID-19). METHODS: Patients with COVID-19 admitted to hospital in Wuxi, China from January 29 to March 15 were included in the study. Lymphocytes were measured and recorded at admission and during treatment. Hospitalization days, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid positive days, minimal lymphocyte count, and occurrence time were collected and comparatively analyzed. Correlations between minimal lymphocyte count and hospitalization days as well as SARS-CoV-2 nucleic acid positive days were analyzed. RESULTS: A total of 63 patients were included in the study, with 16 in the diabetic group and 47 in the non-diabetic group. After adjusting for potential confounding factors, we observed lower minimal lymphocyte count (0.67 ± 0.36 * 109/L vs. 1.30 ± 0.54 * 109/L, adjusted P = 0.001), earlier occurrence of the minimal lymphocyte count (2.68 ± 2.33 days vs. 5.29 ± 4.95 days, adjusted P = 0.042), and longer hospitalization time (20.44 ± 5.24 days vs. 17.11 ± 4.78 days, adjusted P = 0.047) in the diabetic group than in the non-diabetic group. There was a negative correlation between minimal lymphocyte count and hospitalization days (R = -0.600, P < 0.05) as well as SARS-CoV-2 nucleic acid positive days (R = -0.420, P < 0.05). CONCLUSIONS: The diabetic group with COVID-19 had lower lymphocyte count, reached the minimal count faster, and had longer hospital stays than the non-diabetic group. Hospitalization days and SARS-CoV-2 nucleic acid positive days were negatively correlated with the minimal lymphocyte count.

A metabolic handbook for the COVID-19 pandemic.

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.

Hypoglycemia at the time of Covid-19 pandemic.

BACKGROUND: Hypoglycemia is the limiting factor in the glycemic management of diabetes, which need to be addressed critically to avoid complications. Lockdown because of new coronavirus strain (COVID-19) pandemic has further complicated the issue of hypoglycemia due to limitations in access to food, outpatient clinics, pathological services and medicines. AIM: To assess the factors associated with the risk of hypoglycemia during April-May 2020 lockdown in people with type 2 diabetes mellitus. METHODOLOGY: We analyzed the data retrospectively from 146 patients of type 2 diabetes mellitus (T2DM) reporting to the emergency department (ED) during lockdown period with symptoms suggestive of hypoglycemia. RESULTS: The majority of patients were male (90/146) with a mean age of 59.88 ± 10.09 years and a mean random blood glucose level of 57.67 ± 9.00 mg/dL. Two-third of patients (70.83%) had level 1 hypoglycemia, while level 2 hypoglycemia was reported in 29.16% of patients. A combination of Metformin and Sulfonylureas (SU) was most commonly associated with the risk of hypoglycemia (65.75%) followed by insulin (33.56%). Subjects who received insulin reported a lower blood glucose value (50.75 ± 8.20 mg/dL) as compared to those receiving a combination of metformin and SU (60.95 ± 7.10 mg/dl). 330.56% of patients who had received prophylaxis hydroxychloroquine (HCQ) 400 mg twice a day along with the routine anti-hyperglycemic agents without their dose adjustment reported hypoglycemia. Patients with hypertension, micro-vascular, macro-vascular complications, and coexistent with each other had a higher propensity to the risk of hypoglycemia (46.58%, 33.56%, 23.29%, and 32.88%) respectively. CONCLUSION: The COVID-19 lockdown has shown to influence the risk of hypoglycemia in patients with T2DM, especially those receiving SU, insulin, HCQ especially in patients with associated co-morbidities. Patient education, support, and telemedicine plays a pivotal role to prevent hypoglycemia.

A case presentation for positive SARS-CoV-2 RNA recurrence in a patient with a history of type 2 diabetes that had recovered from severe COVID-19.

Coronavirus disease 2019 (COVID-19) is considered to be spread primarily by people who have tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss a patient with severe COVID-19 and a history of type 2 diabetes who had a recurrence of positive SARS-CoV-2 ribonucleic acid (RNA) after recovering. The patient was initially discharged after two consecutive negative SARS-CoV-2 RNA tests and partially absorbed bilateral lesions on chest computed tomography (CT). However, at his first follow-up, reverse transcription-polymerase chain reaction (RT-PCR) assay with an oropharyngeal swab sample was positive for SARS-CoV-2. Despite this, he displayed no obvious clinical symptoms and improved chest CT. The patient was prescribed anti-viral medication. Eight consecutive RT-PCR assays on oropharyngeal swab specimens were conducted after he was re-admitted to our hospital. The results tested positive on the 12th, 14th, 19th, 23rd and 26th of March and negative on the 28th of March, and 6th and 12th of April. After his second discharge, he has tested negative for 5 weeks. This case highlights the importance of active surveillance of SARS-CoV-2 RNA during the follow-up period so that an infectivity assessment can be made.

The impact of type 2 diabetes and its management on the prognosis of patients with severe COVID-19.

BACKGROUND: Although type 2 diabetes mellitus (T2DM) patients with coronavirus disease 2019 (COVID-19) develop a more severe condition compared to those without diabetes, the mechanisms for this are unknown. Moreover, the impact of treatment with antihyperglycemic drugs and glucocorticoids is unclear. METHODS: From 1584 COVID-19 patients, 364 severe/critical COVID-19 patients with clinical outcome were enrolled for the final analysis, and patients without preexisting T2DM but elevated glucose levels were excluded. Epidemiological data were obtained and clinical status evaluation carried out to assess the impact of T2DM and its management on clinical outcomes. RESULTS: Of 364 enrolled severe COVID-19 inpatients, 114 (31.3%) had a history of T2DM. Twenty-seven (23.7%) T2DM patients died, who had more severe inflammation, coagulation activation, myocardia injury, hepatic injury, and kidney injury compared with non-DM patients. In severe COVID-19 patients with T2DM, we demonstrated a higher risk of all-cause fatality with glucocorticoid treatment (adjusted hazard ratio [HR], 3.61; 95% CI, 1.14-11.46; P = .029) and severe hyperglycemia (fasting plasma glucose ≥11.1 mmol/L; adjusted HR, 11.86; 95% CI, 1.21-116.44; P = .034). CONCLUSIONS: T2DM status aggravated the clinical condition of COVID-19 patients and increased their critical illness risk. Poor fasting blood glucose (≥ 11.1 mmol/L) and glucocorticoid treatment are associated with poor prognosis for T2DM patients with severe COVID-19.

Coronavirus infection in patients with diabetes.

Diabetes mellitus is a complex, multifactorial, chronic disease characterized by impaired metabolism of glucose, fats and proteins. Patients who suffer from it frequently have hyperglycemia and coronary artery disease is the leading cause of death. The comorbidities associated with diabetes are overweight and obesity, systemic arterial hypertension, atherogenic dyslipidemia and in some patients peripheral vascular disease, kidney damage, neuropathy and retinopathy. Chronic lack of control of the disease is associated with increased susceptibility to infections, which generally have few symptoms, but hyperglycemia is generally magnified, which worsens the course of infections. Since December 2019, when the disease caused by one of the coronaviruses (coronavirus 2 of severe acute respiratory syndrome, SARS-CoV-2) was identified and has been called coronavirus disease 2019 (COVID-19), there have been some reports that associate the presence of diabetes with an increased risk of mortality. In this review article we have focused on four specific points: 1) epidemiology of the prevalence and mortality of COVID 19 in the general population and in the population with type 2 diabetes mellitus; 2) pathophysiology related to the binding of SARS-CoV-2 to receptors in subjects with diabetes; 3) the immune response induced by SARS-CoV-2, and 4) the outpatient and hospital treatment recommended in patients with diabetes who become infected with SARS-CoV-2.

La diabetes mellitus es una enfermedad crónica, compleja, multifactorial, que se caracteriza por alteración en el metabolismo de la glucosa, las grasas y las proteínas. Los pacientes que la padecen con frecuencia cursan con hiperglucemia y la enfermedad arterial coronaria es la principal causa de muerte. Las comorbilidades que se asocian a la diabetes son: sobrepeso y obesidad, hipertensión arterial sistémica, dislipidemia aterogénica y en algunos pacientes enfermedad vascular periférica, daño renal, neuropatía y retinopatía. El descontrol crónico de la enfermedad se asocia a mayor susceptibilidad a infecciones, las cuales generalmente cursan con pocos síntomas, pero generalmente se magnifica la hiperglucemia, lo cual empeora el curso de las infecciones. Desde diciembre de 2019, cuando se identificó la enfermedad producida por uno de los coronavirus (coronavirus 2 del síndrome respiratorio agudo grave, SARS-CoV-2) y que ha sido llamada enfermedad por coronavirus 2019 (COVID-19), ha habido algunos reportes que asocian la presencia de diabetes con un mayor riesgo de mortalidad. En este artículo de revisión nos hemos enfocado en cuatro puntos específicos: 1) epidemiología de la prevalencia y de la mortalidad de COVID 19 en la población general y en la población con diabetes mellitus tipo 2; 2) fisiopatología relacionada con la unión del SARS-CoV-2 a los receptores en sujetos con diabetes; 3) la respuesta inmunológica inducida por el SARS-CoV-2, y 4) el tratamiento ambulatorio y hospitalario que se recomienda en los pacientes con diabetes que se infectan con SARS-CoV-2.