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Potential Anti-SARS-CoV-2 Therapeutics That Target the Post-Entry Stages of the Viral Life Cycle: A Comprehensive Review.
Al-Horani, RA, Kar, S
Viruses. 2020;12(10)
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The covid-19 pandemic has required the identification of therapies to prevent infection and limit severity. A previous paper by the same authors reviewed therapies that block the virus in the early stages of its lifecycle. This very large review of over 300 papers aimed to summarise therapeutics which are aimed at blocking the lifecycle of the virus after it has entered the body’s cells. The authors began by reviewing the lifecycle of the covid-19 virus explaining how it enters the body’s cells, replicates inside and then is released to infect new cells. Several antivirals, antimalarials and natural products were then reviewed. Of note, Remdesivir is being trialled in covid-19 patients, with mixed results, however, is being recommended in the US for the treatment of hospitalised covid-19 patients with severe disease. Ribavirin, which is being trialled in combination with other antivirals is also showing promising results in shortening hospitalisation times in covid-19 patients. It was concluded that any stage of the covid-19 lifecycle could be a target for therapeutics and combining therapies is likely to be more successful than monotherapy. This paper could be used by health care professionals to understand the most recent therapeutic research for covid-19.
Abstract
The coronavirus disease-2019 (COVID-19) pandemic continues to challenge health care systems around the world. Scientists and pharmaceutical companies have promptly responded by advancing potential therapeutics into clinical trials at an exponential rate. Initial encouraging results have been realized using remdesivir and dexamethasone. Yet, the research continues so as to identify better clinically relevant therapeutics that act either as prophylactics to prevent the infection or as treatments to limit the severity of COVID-19 and substantially decrease the mortality rate. Previously, we reviewed the potential therapeutics in clinical trials that block the early stage of the viral life cycle. In this review, we summarize potential anti-COVID-19 therapeutics that block/inhibit the post-entry stages of the viral life cycle. The review presents not only the chemical structures and mechanisms of the potential therapeutics under clinical investigation, i.e., listed in clinicaltrials.gov, but it also describes the relevant results of clinical trials. Their anti-inflammatory/immune-modulatory effects are also described. The reviewed therapeutics include small molecules, polypeptides, and monoclonal antibodies. At the molecular level, the therapeutics target viral proteins or processes that facilitate the post-entry stages of the viral infection. Frequent targets are the viral RNA-dependent RNA polymerase (RdRp) and the viral proteases such as papain-like protease (PLpro) and main protease (Mpro). Overall, we aim at presenting up-to-date details of anti-COVID-19 therapeutics so as to catalyze their potential effective use in fighting the pandemic.
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Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents.
Khadke, S, Ahmed, N, Ahmed, N, Ratts, R, Raju, S, Gallogly, M, de Lima, M, Sohail, MR
Virology journal. 2020;17(1):154
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Severe manifestations of COVID-19 infection and mortality are associated with a cytokine storm. This is an excessive inflammatory response to the infection leading to an overproduction of pro-inflammatory signalling molecules, which consequently contributes to tissue and organ damage. This literature review summarised current knowledge, as of June 2020, about virus-associated cytokine storm, virus-host interactions and immunological mechanism, to gain a better understanding of the phenomena observed in COVID-19 infections and devise better treatment strategies. The review briefly outlines the epidemiology of COVID-19, predictors of severity of disease, mode of transmission, testing, viral structure, mechanism of invasion of the host cell, replication and immune invasion and the progression of the four stages of the cytokine storm. The second part of the review discusses antiviral therapeutics of interest with a table summarising drugs, mechanism and available data. This article may be of interest to those who like to delve further into the mechanisms and immune components involved in a cytokine storm and gain an oversight of the pathways targeted by allopathic agents that have been put forward as treatment options.
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, previously named 2019-nCov), a novel coronavirus that emerged in China in December 2019 and was declared a global pandemic by World Health Organization by March 11th, 2020. Severe manifestations of COVID-19 are caused by a combination of direct tissue injury by viral replication and associated cytokine storm resulting in progressive organ damage. DISCUSSION We reviewed published literature between January 1st, 2000 and June 30th, 2020, excluding articles focusing on pediatric or obstetric population, with a focus on virus-host interactions and immunological mechanisms responsible for virus associated cytokine release syndrome (CRS). COVID-19 illness encompasses three main phases. In phase 1, SARS-CoV-2 binds with angiotensin converting enzyme (ACE)2 receptor on alveolar macrophages and epithelial cells, triggering toll like receptor (TLR) mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ƙB) signaling. It effectively blunts an early (IFN) response allowing unchecked viral replication. Phase 2 is characterized by hypoxia and innate immunity mediated pneumocyte damage as well as capillary leak. Some patients further progress to phase 3 characterized by cytokine storm with worsening respiratory symptoms, persistent fever, and hemodynamic instability. Important cytokines involved in this phase are interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α. This is typically followed by a recovery phase with production of antibodies against the virus. We summarize published data regarding virus-host interactions, key immunological mechanisms responsible for virus-associated CRS, and potential opportunities for therapeutic interventions. CONCLUSION Evidence regarding SARS-CoV-2 epidemiology and pathogenesis is rapidly evolving. A better understanding of the pathophysiology and immune system dysregulation associated with CRS and acute respiratory distress syndrome in severe COVID-19 is imperative to identify novel drug targets and other therapeutic interventions.
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Dissecting the interaction between COVID-19 and diabetes mellitus.
Chee, YJ, Tan, SK, Yeoh, E
Journal of diabetes investigation. 2020;11(5):1104-1114
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Several countries have reported higher death rates and more severe cases of covid-19 amongst individuals with chronic diseases such as type 2 diabetes. This review of 100 papers aimed to investigate the interconnecting factors which may contribute to poorer prognosis in individuals with covid-19 and type 2 diabetes. Although the evidence suggests that patients with type 2 diabetes have poorer outcomes after contracting covid-19, they are not more susceptible to infection. The paper reported that mechanisms which may increase severity in type 2 diabetics are abnormal immune function, increased susceptibility to inflammation, the increased adherence of the virus to target cells and reduced ability to fight infection. It is important to manage blood sugars when suffering from covid-19. The paper reviewed the use of several medications such as metformin, dipeptidyl peptidase-4 inhibitors (DPP4), glucagon-like peptide-1 agonists and insulin in the context of individuals suffering from covid-19, with insulin being the treatment of choice in the acutely ill patient. Current treatments of covid-19 were also reviewed such as chloroquine and hydroxychloroquine, Lopinavir-ritonavir, IL-6 receptor agonists, type 1 interferon and remdesivir. It was concluded that clinicians should be aware of the risks in patients with type 2 diabetes and covid-19. However as new data is made available, the chronic and long-term implications will become clearer. This study could be used by health care professionals to ensure that patients with type 2 diabetes do everything they can to avoid covid-19 infection and that if contracted these patients are closely monitored for severe disease.
Abstract
Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have shown higher morbidity and mortality among individuals with chronic metabolic diseases, such as diabetes mellitus. In this review, we explore the contributing factors for poorer prognosis in these individuals. As a significant proportion of patients with COVID-19 also have diabetes mellitus, this adds another layer of complexity to their management. We explore potential interactions between antidiabetic medications and renin-angiotensin-aldosterone system inhibitors with COVID-19. Suggested recommendations for the use of antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We also review pertinent clinical considerations in the management of diabetic ketoacidosis in COVID-19 patients. In addition, we aim to increase clinicians' awareness of the metabolic effects of promising drug therapies for COVID-19. Finally, we highlight the importance of timely vaccinations for patients with diabetes mellitus.
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A systematic review on COVID-19 pandemic with special emphasis on curative potentials of Nigeria based medicinal plants.
Oladele, JO, Ajayi, EI, Oyeleke, OM, Oladele, OT, Olowookere, BD, Adeniyi, BM, Oyewole, OI, Oladiji, AT
Heliyon. 2020;6(9):e04897
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At the time of writing, there were no known vaccines or treatments for Covid-19. This systematic review article aimed to investigate how Covid-19 works in the body and any Nigerian based medicinal plants that could mitigate this. The paper first began by discussing that the highly contagious nature and susceptibility of the population has ensured that Covid-19 has spread to all continents and that men may be more susceptible than women. How the virus enters the body’s cells, and the extreme inflammatory reaction it causes was extensively discussed. The paper went on to explain that Covid-19 had a higher infectivity and was more easily transmitted but a lower death rate in comparison to other coronaviruses such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The authors then go on to extensively review plants that may be of benefit to individuals with Covid-19 due to their anti-inflammatory, anti-viral, antioxidant, and cell membrane and immune boosting properties. Finally, plants used in the treatment of other respiratory infections such as cold and flu were reviewed. It was concluded that although plants have been effective in the treatment of symptoms of Covid-19, research is needed to prove their abilities and that combining plants as a treatment regimen may be more effective. This study could be used by healthcare professionals to understand the mode of action of Covid-19 and how natural therapies could be included in a treatment plan.
Abstract
Despite the frightening mortality rate associated with COVID-19, there is no known approved drug to effectively combat the pandemic. COVID-19 clinical manifestations include fever, fatigue, cough, shortness of breath, and other complications. At present, there is no known effective treatment or vaccine that can mitigate/inhibit SARS-CoV-2. Available clinical intervention for COVID-19 is only palliative and limited to support. Thus, there is an exigent need for effective and non-invasive treatment. This article evaluates the possible mechanism of actions of SARS-CoV-2 and present Nigeria based medicinal plants which have pharmacological and biological activities that can mitigate the hallmarks of the pathogenesis of COVID-19. SARS-CoV-2 mode of actions includes hyper-inflammation characterized by a severe and fatal hyper-cytokinaemia with multi-organ failure; immunosuppression; reduction of angiotensin-converting enzyme 2 (ACE2) to enhance pulmonary vascular permeability causing damage to the alveoli; and further activated by open reading frame (ORF)3a, ORF3b, and ORF7a via c-Jun N- terminal kinase (JNK) pathway which induces lung damage. These mechanisms of action of SARS-CoV-2 can be mitigated by a combination therapy of medicinal herbs based on their pharmacological activities. Since the clinical manifestations of COVID-19 are multifactorial with co-morbidities, we strongly recommend the use of combined therapy such that two or more herbs with specific therapeutic actions are administered to combat the mediators of the disease.
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Effects of Plant-Based Diets on Weight Status: A Systematic Review.
Tran, E, Dale, HF, Jensen, C, Lied, GA
Diabetes, metabolic syndrome and obesity : targets and therapy. 2020;13:3433-3448
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Being overweight or obese is a huge risk factor for many detrimental conditions. It is estimated that around one-third of the world’s population will be overweight or obese by 2025. Hence there is a need to look at dietary strategies in the prevention and treatment of overweight and obesity. Plant-based diets have always existed, however interest in the topic has increased recently and more research is being done on the health-related effects of different plant-based diets. There are many reasons why someone might convert to a plant-based diet, possible health benefits such as weight management are among the most common. The purpose of this review was to evaluate intervention studies assessing the effects of different plant-based diets on body mass index and weight. The results suggest that plant-based diets may improve weight status in some patient groups. It should be noted that only one study out of the 19 included in the review had normal weight, clinically healthy participants. The study populations for the rest were overweight, obese or had type 2 diabetes. Future research should aim to include a representative study population and apply study diets without dietary restrictions.
Abstract
There is an increasing number of people who convert to a plant-based diet. The desire for health benefits, including weight management, is often a contributing factor behind this dietary choice. The purpose of this review was to evaluate intervention studies assessing the effects of different plant-based diets on body mass index and weight. A literature search was conducted in PubMed until December 2019. Twenty-two publications from 19 studies were included. The majority of them were randomized controlled trials comparing a low-fat vegan diet to an omnivore diet in participants with overweight, type 2 diabetes mellitus and/or cardiovascular disease. All studies reported weight reductions, of which seven revealed significant differences, and four revealed non-significant differences between the intervention and the control groups. The results suggest that plant-based diets may improve weight status in some patient groups. Due to restrictions in fat intake in many studies, followed by reduced energy intake, the effects of the different interventions differ depending on the specific plant-based diets investigated. Future research should aim to include a representative study population and apply study diets without dietary restrictions.
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Vitamin C: an essential "stress hormone" during sepsis.
Marik, PE
Journal of thoracic disease. 2020;12(Suppl 1):S84-S88
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Most mammals can synthesise vitamin C, except humans, other primates and guinea pigs, who lost this ability through a mutation. It is estimated that goats produce 2-4g of vitamin C per day, but significantly more when stressed. Vitamin C is thought to play an important role in our stress response. This short review articles discusses the importance of vitamin C during stress, in particular the stress of sepsis. The adrenal glands, our “stress organs”, contain very high levels of vitamin C which is released when the hypothalamus-pituitary-adrenal (HPA) axis (which deals with our response to stressors) is stimulated. In animals, there is an inverse relationship between vitamin C internal manufacture and cortisol release under stress: the less vitamin C an animal can produce, the more cortisol they release. A number of vitamin C’s biological actions including antioxidant, anti-inflammatory, immune function, synthesis of the stress hormones adrenaline and noradrenaline and wound healing, may play an important role during a stress response. During sepsis vitamin C gets used up at alarming rate. Sepsis is a complex disease and vitamin C’s biological actions can affect many of the underlying pathophysiological processes. Preclinical and clinical studies have shown a beneficial effect of vitamin C in patients with sepsis and synergistic effects are seen with thiamine (vitamin B1), corticosteroids and antibiotics.
Abstract
The stress response is a preserved evolutionary response that functions to enhance the survival of the species. In mammals, the stress response is characterized by activation of the HPA axis and sympathoadrenal system (SAS) as well as the increased synthesis and secretion of vitamin C. Cortisol, catecholamines, and vitamin C act synergistically to increase hemodynamic reserve, maintain immune function and protect the host against excessive oxidant injury. Humans (and anthropoid apes) have lost the ability to synthesize vitamin C and therefore have an impaired stress response. The inability to produce vitamin C has serious implications in septic humans. Treatment with vitamin C appears to restore the stress response and improve the survival of stressed humans.
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Immediate and long-term consequences of COVID-19 infections for the development of neurological disease.
Heneka, MT, Golenbock, D, Latz, E, Morgan, D, Brown, R
Alzheimer's research & therapy. 2020;12(1):69
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Covid-19 may cause brain dysfunction evidenced by symptoms individuals experience once they have contracted the disease. Loss of smell, taste and confusion have all been reported by patients and a number of severe cases have reported incidences of stroke. These are all of concern, as Covid-19 can severely affect the elderly who ordinarily are the most likely to suffer from brain disorders. This small review paper of 27 studies stated that there are four possible ways in which Covid-19 may affect the brain, which put Covid-19 sufferers at an increased risk of long-term brain disorders. This was supported by findings, which showed one third of Covid-19 patients leave hospital with evidence of brain dysfunction. Inflammation was heavily reviewed by the authors as a possible causal factor. It was concluded that patients who survive Covid-19 infection are at an increased risk for developing brain disorders such as Alzheimer's disease, however it was acknowledged that further studies are required. Clinicians could use this study to understand the possible need for both short-term and long-term monitoring of brain function in individuals who have survived Covid-19, especially if they are elderly.
Abstract
Increasing evidence suggests that infection with Sars-CoV-2 causes neurological deficits in a substantial proportion of affected patients. While these symptoms arise acutely during the course of infection, less is known about the possible long-term consequences for the brain. Severely affected COVID-19 cases experience high levels of proinflammatory cytokines and acute respiratory dysfunction and often require assisted ventilation. All these factors have been suggested to cause cognitive decline. Pathogenetically, this may result from direct negative effects of the immune reaction, acceleration or aggravation of pre-existing cognitive deficits, or de novo induction of a neurodegenerative disease. This article summarizes the current understanding of neurological symptoms of COVID-19 and hypothesizes that affected patients may be at higher risk of developing cognitive decline after overcoming the primary COVID-19 infection. A structured prospective evaluation should analyze the likelihood, time course, and severity of cognitive impairment following the COVID-19 pandemic.
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Bariatric and metabolic surgery during and after the COVID-19 pandemic: DSS recommendations for management of surgical candidates and postoperative patients and prioritisation of access to surgery.
Rubino, F, Cohen, RV, Mingrone, G, le Roux, CW, Mechanick, JI, Arterburn, DE, Vidal, J, Alberti, G, Amiel, SA, Batterham, RL, et al
The lancet. Diabetes & endocrinology. 2020;8(7):640-648
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Bariatric surgery has been proven for weight loss in people with severe obesity. However, during the covid-19 pandemic, surgery has been postponed for many individuals. Under normal conditions, patients who are awaiting bariatric surgery are prioritised based on weight, however this does not necessarily reflect severity of their condition. This review paper aimed to develop new criteria in order to help prioritise individuals who are awaiting bariatric surgery. The authors began by reviewing the reasons for delaying bariatric surgery and the need for beds, the risks of covid-19 transmission during the procedure and the severe covid-19 complications that individuals with obesity can experience were discussed. A recommendation was made that all patients having bariatric surgery be tested for Covid-19. Solutions were proposed for those awaiting surgery such as diets, exercise, optimal blood sugar control and the potential use of weight loss medications. Prioritisation of surgery should focus on clinical need; it should be accessible and minimise harm from delays. Individuals with obesity and type 2 diabetes should be prioritised based on those who have an increased risk of death, determined by whether the individual; has poor blood sugar control despite maximal use of medications to control it, uses insulin, has previous heart disease, has liver disease or if they have other risk factors. It was concluded that weight alone is inadequate to prioritise candidates for bariatric surgery. Disease severity should be at the centre of decisions, especially when access to surgery is reduced, as is during the Covid -19 pandemic. This paper could be used by healthcare professionals to understand how to prioritise their obese and type 2 diabetic patients who are awaiting bariatric surgery.
Abstract
The coronavirus disease 2019 pandemic is wreaking havoc on society, especially health-care systems, including disrupting bariatric and metabolic surgery. The current limitations on accessibility to non-urgent care undermine postoperative monitoring of patients who have undergone such operations. Furthermore, like most elective surgery, new bariatric and metabolic procedures are being postponed worldwide during the pandemic. When the outbreak abates, a backlog of people seeking these operations will exist. Hence, surgical candidates face prolonged delays of beneficial treatment. Because of the progressive nature of obesity and diabetes, delaying surgery increases risks for morbidity and mortality, thus requiring strategies to mitigate harm. The risk of harm, however, varies among patients, depending on the type and severity of their comorbidities. A triaging strategy is therefore needed. The traditional weight-centric patient-selection criteria do not favour cases based on actual clinical needs. In this Personal View, experts from the Diabetes Surgery Summit consensus conference series provide guidance for the management of patients while surgery is delayed and for postoperative surveillance. We also offer a strategy to prioritise bariatric and metabolic surgery candidates on the basis of the diseases that are most likely to be ameliorated postoperatively. Although our system will be particularly germane in the immediate future, it also provides a framework for long-term clinically meaningful prioritisation.
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Non-Systematic Review of Diet and Nutritional Risk Factors of Cardiovascular Disease in Obesity.
Rychter, AM, Ratajczak, AE, Zawada, A, Dobrowolska, A, Krela-Kaźmierczak, I
Nutrients. 2020;12(3)
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Nutrition is a major factor influencing obesity associated heart disease risk, however many people with this disease do not follow nutritional recommendations. This review of 155 studies aimed to summarise dietary aspects of heart disease prevention. The paper began by outlining the role of obesity through the development of other disorders that contribute to heart disease, such as type 2 diabetes, high blood pressure and blood sugar imbalance. The quantity and distribution of fat tissue also can contribute to heart disease risk, especially if it is located within the heart or around the major organs of the body. Dietary factors which can increase heart disease risk were described as an increased intake of processed foods, sugar, salt and certain fats and low intakes of fruit, vegetables, fibre, whole grains, beans and nuts. The Mediterranean diet, the dietary approaches to stop hypertension (DASH) diet, plant-based diets, the portfolio dietary pattern and low carbohydrate diets were all reviewed and although mixed results were stated for low carbohydrate diets, most of the diets reviewed reported improved heart disease outcomes. The role of intestinal microbiota in heart disease were also reviewed and the influence of a poor diet was implicated in imbalanced gut microbiota and the development of heart disease. It was concluded that an unhealthy diet can contribute to heart disease and that dietary patterns such as the Mediterranean diet and plant-based diets may be favourable for its management. This study could be used by healthcare professionals to individualise dietary recommendations for patients with heart disease or who are at risk of it.
Abstract
Although cardiovascular disease and its risk factors have been widely studied and new methods of diagnosis and treatment have been developed and implemented, the morbidity and mortality levels are still rising-cardiovascular disease is responsible for more than four million deaths each year in Europe alone. Even though nutrition is classified as one of the main and changeable risk factors, the quality of the diet in the majority of people does not follow the recommendations essential for prevention of obesity and cardiovascular disease. It demonstrates the need for better nutritional education in cardiovascular disease prevention and treatment, and the need to emphasize dietary components most relevant in cardiovascular disease. In our non-systematic review, we summarize the most recent knowledge about nutritional risk and prevention in cardiovascular disease and obesity.
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Comorbid Chronic Diseases are Strongly Correlated with Disease Severity among COVID-19 Patients: A Systematic Review and Meta-Analysis.
Liu, H, Chen, S, Liu, M, Nie, H, Lu, H
Aging and disease. 2020;11(3):668-678
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Symptomatic COVID-19 infection is accompanied by a cluster of flu-like symptoms and life-threatening severe illnesses including acute respiratory distress syndrome, acute kidney injury, myocarditis, and organ failure. The aim of this study was to provide a systematic evaluation and detailed estimate on the prevalence and effects of pre-existing chronic conditions in COVID-19 patients. This study is a systemic review and meta-analysis of 24 studies (with a total of 10948 COVID-19 patients) for qualitative and quantitative synthesis. Results show that: - male participants were more susceptible to COVID-19. - both sexes exhibited clinical presentations similar in symptomatology. - diabetes and coronary artery disease/cardiovascular disease were prevalent in 10.0% and 8.0% of the patients, respectively. - pre-existing chronic diseases were strongly correlated with the increased disease severity and increased admittance to ICU. Authors conclude that patients with pre-existing chronic diseases may have a higher risk for developing severe COVID-19 and should be given close attention.
Abstract
Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity and mortality worldwide since December 2019. In order to explore the effects of comorbid chronic diseases on clinical outcomes of COVID-19, a search was conducted in PubMed, Ovid MEDLINE, EMBASE, CDC, and NIH databases to April 25, 2020. A total of 24 peer-reviewed articles, including 10948 COVID-19 cases were selected. We found diabetes was present in 10.0%, coronary artery disease/cardiovascular disease (CAD/CVD) was in 8.0%, and hypertension was in 20.0%, which were much higher than that of chronic pulmonary disease (3.0%). Specifically, preexisting chronic conditions are strongly correlated with disease severity [Odds ratio (OR) 3.50, 95% CI 1.78 to 6.90], and being admitted to intensive care unit (ICU) (OR 3.36, 95% CI 1.67 to 6.76); in addition, compared to COVID-19 patients with no preexisting chronic diseases, COVID-19 patients who present with either diabetes, hypertension, CAD/CVD, or chronic pulmonary disease have a higher risk of developing severe disease, with an OR of 2.61 (95% CI 1.93 to 3.52), 2.84 (95% CI 2.22 to 3.63), 4.18 (95% CI 2.87 to 6.09) and 3.83 (95% CI 2.15 to 6.80), respectively. Surprisingly, we found no correlation between chronic conditions and increased risk of mortality (OR 2.09, 95% CI 0.26 to16.67). Taken together, cardio-metabolic diseases, such as diabetes, hypertension and CAD/CVD were more common than chronic pulmonary disease in COVID-19 patients, however, each comorbid disease was correlated with increased disease severity. After active treatment, increased risk of mortality in patients with preexisting chronic diseases may reduce.