|Ahead of print publication
COVID-19, hypertension, and diabetes – Hunt for the link!
Kaustav Saha, Shatavisa Mukherjee
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
|Date of Submission||01-May-2020|
|Date of Decision||20-Jun-2020|
|Date of Acceptance||17-Aug-2020|
|Date of Web Publication||07-Jun-2021|
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata - 700 073, West Bengal
Source of Support: None, Conflict of Interest: None
The recent pandemic outbreak of coronavirus disease 2019 (COVID-19) has left everyone baffled. The exponential rise in deaths worldwide, with such an extensive rapid spread, has made it a public health emergency. While the scientists at the frontier are untiringly putting their utmost efforts to come up with evidence-based pharmacological interventions, attempts have also been made to demystify the disease link with associated comorbidities and further risk prognostication. The presence of comorbidities has been documented to be associated with increased risk of developing acute respiratory diseases. Older hypertensives have been posed to be at greater risk of being affected, with associated complications and severity in grade. Diabetic and obese individuals have also been shown to be in increased risk of infections and other complications. Cytokine storm, a major complication of this disease, has also led to adverse renal outcomes. The present review aimed to probe the possible link between COVID-19 and various comorbidities.
Keywords: Comorbidities, coronavirus disease 2019, diabetes, hypertension
| Introduction|| |
In late December 2019, the first pneumonia cases of unknown origin were identified in Wuhan, the capital city of Hubei province in Central China. The causative pathogen was identified as a novel enveloped RNA betacoronavirus. Owing to the phylogenetic similarity to the previously isolated severe acute respiratory syndrome coronavirus (SARS-CoV), the new virus has been named SARS-CoV-2. The rapid outbreak of coronavirus disease 2019 (COVID-19) has now become a public health emergency of international concern contributing to a huge adverse impact globally. There have been 3,221,029 laboratory-confirmed cases and 228,252 deaths globally as of April 30, 2020, with figures on an exponential rise daily. The World Health Organization (WHO) declared COVID-19 a pandemic health emergency. Person-to-person transmission of this virus occurs mainly through close contact with an infected person, primarily via respiratory droplets and after touching contaminated objects. The clinical spectrum of SARS-CoV-2 infection appears to be wide and heterogeneous, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and even death. With severity varying from mild to moderate, mostly symptoms mainly include fever, tiredness, and dry cough, however, people have also experienced aches and pains, nasal congestion, runny nose, sore throat, and diarrhea. Current evidence suggests that the incubation period may last for 1–14 days, with a mean duration of 5–7 days. The peak viremia occurs at the end of the incubation period and before the onset of symptoms, suggesting that transmission begins 1–2 days before the onset of symptoms. One of the putative mechanisms of viral entry depends on the binding of the viral spike (S) proteins to angiotensin-converting enzyme 2 (ACE2) cellular receptors and on the S protein priming by the host cellular serine protease TMPRSS2. The understanding of the host-virus immunologic interaction is still incomplete.
The infection spread has been on exponential rise due to transmission potential by asymptomatic or minimally symptomatic patients. India in combating this situation has mainly focused on containment strategy which involves quarantining individuals coming from a high transmission area, isolation of infected individuals, contact tracing as well as reducing the movement of people in areas that have a high caseload. Regarded as a voluntary measure taken up by a person himself or in advice of his/her health-care professionals, self-isolation is a condition when a person experiencing any cardinal symptoms stays at home and does not go to work, school, or public places. For all confirmed cases, self-isolation for 14 days, even after the disappearance of symptoms, has been advocated as a precautionary measure. However, owing to the unknown nature of the virus, it is quite unknown as to how long people remain infectious even after they have recovered. Abiding by the national advice in such cases has been advocated. For reduction of SARS-CoV-2 transmission, nonpharmacological interventions comprising repeated hand hygiene, respiratory etiquettes, and social distancing have been advocated. The WHO recommended maintaining at least a 1-m (3 feet) distance between oneself and others, as a protective measure.
As reported till date, severity of this illness has been observed to be majorly skewed toward the geriatric population, with a higher prevalence of cardiovascular (CV) complications such as hypertension and diabetes. Since this culprit virus largely infects human cells via ACE2 receptor that acts on the renin–angiotensin–aldosterone system (RAAS), sufficient suspicion upsurges a keen hunt for link between hypertension and severe COVID-19 infection. This present narrative review tried to explore possible links between COVID-19 and other CV risks. An extensive literature search was conducted using the main online databases (PubMed, Google Scholar, MEDLINE, UpToDate, Embase, and Web of Science) with keywords such as “COVID-19,” “SARS-CoV-2,” “Hypertension,” “Diabetes,” and “Obesity.” ;
| COVID and Comorbidities|| |
Studies have demonstrated that the presence of any commodities has been associated with a 3.4-fold increased risk of developing this acute respiratory distress syndrome (ARDS) in affected patients. Patients with at least one comorbidities have been associated with poor clinical outcomes. The most common comorbidities associated with poorer prognosis included diabetes, hypertension, respiratory diseases, cardiac diseases, pregnancy, renal diseases, and malignancy. Huang et al. reported the clinical features of 41 confirmed patients and indicated that 32% of them had underlying diseases including cardiovascular disease (CVD), diabetes, hypertension, and chronic obstructive pulmonary disease (COPD). Subsequently, Wang et al. reported findings from 138 cases of COVID-19 of which 46.4% had comorbidities. Almost 72.2% admitted to the intensive care units had comorbidities, thus suggesting that comorbidities may be risk factors for adverse outcomes. Like other avian influenza, COVID-19 is more readily predisposed to respiratory failure and death in susceptible patients. Older age and male sex have been some of the significant clinical predictors of worse COVID-19 prognosis. Studies commenting on the association suggest that hypertension carries a nearly 2.5-fold higher risk of developing severe disease or dying from SARS-CoV-2 infection. This is in comparison to other comorbidities, such as COPD (over 5-fold higher risk) or chronic kidney disease (over 3-fold higher risk). Researches indicated that SARS-CoV infections led to immune dysregulation which explains the escalated risk of cardiac diseases, bone diseases, and malignancy, thus suggesting immune dysregulation and prolonged inflammation to be potential drivers of the poor clinical outcomes in COVID-19 patients, though it awaits robust verification with further studies. Thus, assessment of the prevalence of various underlying conditions is the basis for mitigating complications in patients infected with SARS-CoV-2.
Data collected by the newly created COVID-19-Associated Hospitalization Surveillance Network (COVID-NET) showed that almost 90% of hospitalized patients have some type of underlying condition, with the hospitalization rate being 4.6 per 100,000 populations. The hospitalization rate is shown to be increasing with increasing patients' age, and those aged 65 years and older also were the most likely to have one or more underlying conditions. Women are less likely to be affected by many bacteria and viruses than men, partly because of their more robust innate and adaptive immune responses. Elderly people and severe patients are more susceptible to SARS-CoV-2, which may be associated with a higher frequency of comorbidities.
| Hypertension|| |
Hypertension was the most common comorbidity among the oldest patients, with a high prevalence rate of 72.6%, followed by CVD at 50.8% and obesity at 41%. In the two younger groups, obesity was the condition most often seen in COVID-19 patients, with prevalences of 49% in 50–64-year-olds and 59% in those aged 18–49 years. A meta-analysis of the comorbidities suggested that hypertension was prevalent in approximately 21.1% of the patients, while diabetes, CVD, and respiratory system disease were present in 9.7%, 8.4%, and 1.5% of the cases, respectively. Older hypertensive individuals are at greater risk of being affected with COVID-19, with associated complications and severity in grade. However, it is unclear whether uncontrolled blood pressure is a risk factor for acquiring COVID-19, or whether controlled blood pressure among patients with hypertension is or is not less of a risk factor.
| Diabetes|| |
Diabetes is a risk factor for hospitalization and mortality of the COVID-19 infection. Studies have suggested that diabetes has been comorbidity in 22% of 32 nonsurvivors in a study of 52 intensive care patients. In another study of 173 cases with severe disease, 16.2% had diabetes, and in further study of 140 hospitalized patients, 12% had diabetes. When comparing intensive care and nonintensive care patients with COVID-19, there appears to be a two-fold increase in the incidence of patients in intensive care having diabetes. Individuals with diabetes are at increased risk of infections, including influenza, and for related complications such as secondary bacterial pneumonia. The same can be postulated as diabetes patients have impaired immune response to infection both in relation to cytokine profile and to changes in immune responses including T-cell and macrophage activation. Poor glycemic control impairs several aspects of the immune response to viral infection and also to the potential bacterial secondary infection in the lungs. Moreover, diabetic complications such as diabetic kidney disease and ischemic heart disease may complicate the situation in COVID patients, increasing the severity and the need for acute dialysis. Furthermore, COVID-19 could cause acute myocardial injury with heart failure, leading to impaired circulation.
Both hypertension and diabetes are often treated with ACE inhibitors. There has been a considerable uproar in finding links between the use of ACE inhibitors and COVID-19.
| COVID–Hypertension–Diabetes – Angiotensin-Converting Enzyme Inhibitors Linked?|| |
SARS-CoV and SARS-CoV-2 bind to their target cells through ACE2, expressed by epithelial cells of the lung, intestine, kidney, and blood vessels. In patients with hypertension or type 1/2 diabetes, who are treated with ACE inhibitors and angiotensin II type I receptor blockers (ARBs), the expression of ACE2 receptor are substantially increased. ACE2 receptor can also be increased by antidiabetic agents like thiazolidinediones and nonsteroidal anti-inflammatory drug like ibuprofen. Studies thus hypothesized that treatment with ACE2-stimulating drugs increases the binding of SARS-Cov-2 to the lung surface and in this way leads to lung injury and risk of developing severe and fatal COVID-19. On the contrary, experimental studies have shown ACE2 to be protective against lung injury. ACE2 forms angiotensin 1–7 from angiotensin II, and thus reduces the inflammatory action of angiotensin II, and increases the potential of the anti-inflammatory effects of angiotensin 1–7. Accordingly, by reducing either formation of angiotensin II in the case of ACE inhibitors, or by antagonizing the action of angiotensin II by blocking angiotensin AT1 receptors in the case of ARBs, these agents could actually contribute to reduced inflammation systemically and particularly in the lung, heart, and kidney. Hence, drugs acting on RAAS may reduce the potential for development of complications such as ARDS, acute kidney injury (AKI), and myocarditis in COVID-19 patients., In fact, ARBs have been suggested as a treatment for COVID-19 and its complications. Increased soluble ACE2 in the circulation could bind SARS-CoV-2, reducing its ability to injure the lungs and other ACE2-bearing organs. Recombinant ACE2 could be a potential therapeutic approach in reducing viral load by binding circulating SARS-CoV-2 and reducing their potential attachment to tissue ACE2. None of these possibilities have, however, been demonstrated in patients yet. A study from China included 42 hospitalized COVID-19 patients on antihypertensive therapy. Results showed that those on ACE inhibitor/ARB therapy had a lower rate of severe disease and a trend toward a lower level of interleukin (IL)-6 in peripheral blood. In addition, patients on ACE inhibitor/ARB therapy had increased CD3+ and CD8+ T-cell counts in peripheral blood and decreased peak viral load compared with other antihypertensive drugs.
A study by Juyi Li published in JAMA Cardiology reported on a case series of 1178 patients hospitalized with COVID-19 at the Central Hospital of Wuhan in China, between January 15 and March 15, 2020. Of the 1178 patients, 30.7% had a diagnosis of hypertension. These patients were older in age and had a greater prevalence of chronic diseases. Patients with hypertension also had more severe manifestations of COVID-19 compared to those without hypertension, including higher rates of ARDS and inhospital mortality. 31.8% of total hypertension cases were on ACE inhibitors or ARBs and had similar comorbidities to those not taking these medications, with similar laboratory profile results including blood counts, inflammatory markers, renal and liver function tests, and cardiac biomarkers, although those taking ACE inhibitors/ARBs had higher levels of alkaline phosphatase.
Researchers are also probing genetic predisposition for an increased risk of SARS-CoV-2 infection, which might be due to ACE2 polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in Asian populations. Monitoring of ACE2-modulating medications, such as ACE inhibitors or ARBs, has been suggested in patients with CV comorbidities on ACE2-increasing drugs who might be at higher risk for severe COVID-19 infection.
| Obesity|| |
Many patients with type 2 diabetes are obese, and obesity is also a risk factor for severe infection. It was illustrated during the influenza A H1N1 epidemic in 2009 that the disease was more severe and had a longer duration in about two-fold more patients with obesity who were then treated in intensive care units compared with the background population. Especially, metabolic active abdominal obesity is associated with higher risk. The abnormal secretion of adipokines and cytokines such as tumor necrosis factor-alpha and interferon characterizes a chronic low-grade in abdominal obesity and may induce an impaired immune response. People with severe abdominal obesity also have mechanical respiratory problems, with reduced ventilation of the basal lung sections increasing the risk of pneumonia as well as reduced oxygen saturation of blood. Obese patients also have an increased asthma risk, and those patients with obesity and asthma have more symptoms, more frequent and severe exacerbations, and reduced response to several asthma medications. Preliminary data suggest that people with obesity are at increased risk of severe COVID-19. However, as data on metabolic parameters in patients with COVID-19 are scarce, increased reporting is needed to improve the understanding of COVID-19 and the care of affected patients. For better estimating the risk of complications in patients with COVID-19, in addition to evaluation of standard hospital parameters, the measurement of anthropometrics and metabolic parameters is crucial. These parameters include body mass index, waist and hip circumferences, and levels of glucose and insulin.,
| Chronic Obstructive Pulmonary Disease|| |
COVID-19 is an acute respiratory disease that can lead to respiratory failure and death. Previous epidemics of novel coronavirus diseases, such as SARS and Middle East respiratory syndrome, were associated with similar clinical features and outcomes. One might anticipate that patients with chronic respiratory diseases, particularly COPD and asthma, would be at increased risk of SARS-CoV-2 infection and more severe presentations of COVID-19. However, it is striking that both diseases appear to be under-represented in the comorbidities reported for patients with COVID-19, compared with the global burden of disease estimates of the prevalence of these conditions. The lower reported prevalence of asthma and COPD in patients diagnosed with COVID-19 might be due to one or a number of factors like underdiagnosis and varied immune response elicited by the chronic disease itself. However, this theory is not supported by the finding that among those with COVID-19 who have COPD as comorbidity, mortality is increased, as would otherwise be expected.
Another possibility is that the therapies used by patients with chronic respiratory diseases can reduce the risk of infection or of developing symptoms leading to diagnosis. In vitro studies have shown inhaled corticosteroids alone or in combination with bronchodilators suppressing coronavirus replication and cytokine production. A case series in Japan demonstrated improvement seen in three patients with COVID-19 requiring oxygen, but not ventilatory support, after being given inhaled ciclesonide; however, no control group was used and it is not known whether these patients would have improved spontaneously. More robust evidence can embark on the same.
| Renal Failure|| |
Emerging evidence suggests the possibility of a direct cytopathic effect of SARS-CoV-2. ACE2 and members of the serine protease family, essential for viral uptake by host cells, are highly expressed on podocytes and tubule epithelial cells. Reports of albuminuria and hematuria along with viral RNA isolation from the urine further support potential viral tropism for the kidney. Cytokine release syndrome (CRS), also termed “cytokine storm,” can occur in various conditions including sepsis, hemophagocytic syndrome, and chimeric antigen receptor (CAR) T-cell therapy. The occurrence of CRS in COVID-19 has also been documented. In patients with CRS, AKI might occur as a result of intrarenal inflammation, increased vascular permeability, volume depletion, and cardiomyopathy, which can lead to type 1 cardiorenal syndrome. Pro-inflammatory IL-6 is considered to be the most important causative cytokine in CRS. Among patients with COVID-19, the plasma concentration of IL-6 is increased in those with ARDS. Tocilizumab, an anti-IL-6 monoclonal antibody, is widely used to treat CRS in patients who have undergone CAR T-cell therapy and is thus being used now as an empiric approach in patients with severe COVID-19. However, extracorporeal membrane oxygenation, invasive mechanical ventilation, and continuous kidney replacement therapy can also contribute to cytokine generation and have been proposed beneficial in critically ill COVID-19 patients as cytokine removal could prevent CRS-induced organ damage.
| Cancer|| |
Liang et al. in a prospective cohort of 1571 patients with COVID-19 reported 18 of them having a prior history of cancer had a higher incidence of severe events. However, it did not establish a definitive increase in incidence of COVID-19 infection.
| Conclusion|| |
Studies as of now have postulated that laboratory-confirmed cases of COVID-19 with one or more comorbidities have yielded poorer clinical outcomes than those without. With older age and male sex being a significant clinical predictor of COVID-19, the most prevalent comorbidities were hypertension, followed by diabetes. Studies have probed the association and found hypertensive, diabetic, and renal patients at greater risk of COVID-19. Increased incidence has been observed in obese individuals in intensive care. However, considering the dynamic behavior of the virus, more research findings can test the hypothesis and embark on the definitive mechanism underlying the same. A thorough assessment of comorbidities may help establish risk stratification of patients with COVID-19 upon hospital admission.
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Conflicts of interest
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