Clinical determinants of the severity of COVID-19: A systematic review and meta-analysis




We aimed to systematically identify the possible risk factors responsible for severe cases.


We searched PubMed, Embase, Web of science and Cochrane Library for epidemiological studies of confirmed COVID-19, which include information about clinical characteristics and severity of patients’ disease. We analyzed the potential associations between clinical characteristics and severe cases.


We identified a total of 41 eligible studies including 21060 patients with COVID-19. Severe cases were potentially associated with advanced age (Standard Mean Difference (SMD) = 1.73, 95% CI: 1.34–2.12), male gender (Odds Ratio (OR) = 1.51, 95% CI:1.33–1.71), obesity (OR = 1.89, 95% CI: 1.44–2.46), history of smoking (OR = 1.40, 95% CI:1.06–1.85), hypertension (OR = 2.42, 95% CI: 2.03–2.88), diabetes (OR = 2.40, 95% CI: 1.98–2.91), coronary heart disease (OR: 2.87, 95% CI: 2.22–3.71), chronic kidney disease (CKD) (OR = 2.97, 95% CI: 1.63–5.41), cerebrovascular disease (OR = 2.47, 95% CI: 1.54–3.97), chronic obstructive pulmonary disease (COPD) (OR = 2.88, 95% CI: 1.89–4.38), malignancy (OR = 2.60, 95% CI: 2.00–3.40), and chronic liver disease (OR = 1.51, 95% CI: 1.06–2.17). Acute respiratory distress syndrome (ARDS) (OR = 39.59, 95% CI: 19.99–78.41), shock (OR = 21.50, 95% CI: 10.49–44.06) and acute kidney injury (AKI) (OR = 8.84, 95% CI: 4.34–18.00) were most likely to prevent recovery. In summary, patients with severe conditions had a higher rate of comorbidities and complications than patients with non-severe conditions.


Patients who were male, with advanced age, obesity, a history of smoking, hypertension, diabetes, malignancy, coronary heart disease, hypertension, chronic liver disease, COPD, or CKD are more likely to develop severe COVID-19 symptoms. ARDS, shock and AKI were thought to be the main hinderances to recovery.

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Hyperglycemia in Acute COVID-19 is Characterized by Adipose Tissue Dysfunction and Insulin Resistance

Authors: Reiterer MRajan MGómez-Banoy NLau JDGomez-Escobar LGGilani AAlvarez-Mulett SSholle ETChandar VBram YHoffman KRubio-Navarro AUhl SShukla APGoyal PtenOever BRAlonso LCSchwartz RESchenck EJSafford MM


COVID-19 has proven to be a metabolic disease resulting in adverse outcomes in individuals with diabetes or obesity. Patients infected with SARS-CoV-2 and hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality compared to those who do not develop hyperglycemia. Nevertheless, the pathophysiological mechanism(s) of hyperglycemia in COVID-19 remains poorly characterized. Here we show that insulin resistance rather than pancreatic beta cell failure is the prevalent cause of hyperglycemia in COVID-19 patients with ARDS, independent of glucocorticoid treatment. A screen of protein hormones that regulate glucose homeostasis reveals that the insulin sensitizing adipokine adiponectin is reduced in hyperglycemic COVID-19 patients. Hamsters infected with SARS-CoV-2 also have diminished expression of adiponectin. Together these data suggest that adipose tissue dysfunction may be a driver of insulin resistance and adverse outcomes in acute COVID-19.

The deadly COVID-19 pandemic is underscored by the high morbidity and mortality rates seen in certain vulnerable populations, including patients with diabetes mellitus (DM), obesity, cardiovascular disease, and advanced age, with the latter associated with many chronic cardiometabolic diseases 14 . Hyperglycemia with or without a history of DM is a strong predictor of in-hospital adverse outcomes, portending a 7-fold higher mortality compared to patients with well-controlled blood glucose levels 5 . Hyperglycemia may be seen as a biomarker that predicts poor prognosis. A retrospective study that compared hyperglycemic patients that were treated with insulin against those who were not showed increased mortality in those receiving insulin 6 . However, it remains unclear whether insulin treatment is a surrogate for increased hyperglycemia and overall morbidity, or whether it is an actual causative factor for death. There is thus uncertainty regarding specific treatments for hyperglycemia in acute COVID-19 7 .

Despite our early recognition of the association between hyperglycemia and perilous outcomes, the pathophysiological mechanisms that underlie hyperglycemia in COVID-19 remain undefined 8,9 . Hypotheses have included a broad range of pathologies from direct infection of islets leading to beta cell failure (BCF) and to inflammation and glucocorticoids leading to insulin resistance (IR). Although COVID-19 is primarily a respiratory tract infection, SARS-CoV-2 is known to infect other cell types and often leads to extrapulmonary consequences 10,11 ACE2 and other entry receptors for SARS-CoV-2 can be expressed on pancreatic islet cells and endocrine cells differentiated from human pluripotent stem cells are permissive to infection 12 . Early reports of unexpected diabetic ketoacidosis (DKA) in COVID-19 patients fuelled concerns for a novel form of acute onset beta cell failure. For example, one case described a patient with new onset diabetic ketoacidosis (DKA) who was found to be autoantibody negative for type 1 DM (T1DM) but showed evidence of prior SARS-CoV-2 infection based on serology results, suggesting the possibility of pancreatic beta cell dysfunction or destruction as a result of COVID-19 13 . However, given the high rates of COVID-19 during this pandemic coupled with low background rates of new onset T1DM, the connection between these two events in this case could be “true, true, and unrelated.” Recent studies disagree on whether ACE2 is expressed on pancreatic beta cells or whether the SARS-CoV-2 virus is found in pancreatic beta cells of deceased individuals with COVID-19 1416 . Conversely, the well-known connection between obesity and insulin resistance might lead to impaired immunity and more severe SARS-CoV-2 infection 17 . In fact, population level studies have reported higher risk of complications in obese patients with COVID-19 1820 . Viral infection may lead to systemic insulin resistance and worsened hyperglycemia. In sum, despite much attention, the pathophysiology of hyperglycemia in COVID-19 remains unknown.

Dexamethasone substantially reduces mortality in patients with severe COVID-19 infection requiring oxygen or invasive mechanical ventilation 21 . Glucocorticoids can also provoke hyperglycemia by inducing insulin resistance and beta cell dysfunction. The widespread usage of dexamethasone in severe SARS-CoV-2 infection is sure to exacerbate both the incidence and severity of hyperglycemia in COVID-19.

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Severe COVID-19: what have we learned with the immunopathogenesis?


The COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global major concern. In this review, we addressed a theoretical model on immunopathogenesis associated with severe COVID-19, based on the current literature of SARS-CoV-2 and other epidemic pathogenic coronaviruses, such as SARS and MERS. Several studies have suggested that immune dysregulation and hyperinflammatory response induced by SARS-CoV-2 are more involved in disease severity than the virus itself.

Immune dysregulation due to COVID-19 is characterized by delayed and impaired interferon response, lymphocyte exhaustion and cytokine storm that ultimately lead to diffuse lung tissue damage and posterior thrombotic phenomena.

Considering there is a lack of clinical evidence provided by randomized clinical trials, the knowledge about SARS-CoV-2 disease pathogenesis and immune response is a cornerstone to develop rationale-based clinical therapeutic strategies. In this narrative review, the authors aimed to describe the immunopathogenesis of severe forms of COVID-19.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA-enveloped virus, is the causative agent of coronavirus disease 2019 (COVID-19), being first identified in Wuhan, China, in December 2019. Previously, other epidemic coronavirus such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and the middle-east respiratory syndrome coronavirus (MERS-CoV) in 2012, had serious impact on human health and warned the world about the possible reemergence of new pathogenic strains [1]. Despite being a new virus, several common morpho-functional characteristics have been reported between SARS-CoV and the SARS-CoV-2, including the interaction of the viral spike (S) glycoprotein with the human angiotensin converting enzyme 2 (ACE2). These similarities may help understanding some pathophysiological mechanisms and pointing out possible therapeutic targets.

The first step for SARS-CoV-2 entry into the host cell is the interaction between the S glycoprotein and ACE2 on cell surface. Since the latter acts as a viral receptor, the virus will only infect ACE2 expressing cells, notably type II pneumocytes. These cells represent 83% of the ACE2-expressing cells in humans, but cells from other tissues and organs, such as heart, kidney, intestine and endothelium, can also express this receptor [2]. A host type 2 transmembrane serine protease, TMPRSS2, facilitates virus entry by priming S glycoprotein. TMPRSS2 entails S protein in subunits S1/S2 and S2´, allowing viral and cellular membrane fusion driven by S2 subunit [3]. Once inside the cell viral positive sense single strand RNA is translated into polyproteins that will form the replicase-transcriptase complex. This complex function as a viral factory producing new viral RNA and viral proteins for viral function and assembly [4]. Considering these particularities, the infection first begins on upper respiratory tract mucosa and then reaches the lungs. The primary tissue damage is related to the direct viral cytopathic effects. At this stage, the virus has the potential to evade the immune system, where an inadequate innate immune response can occur, depending on the viral load and other unknown genetic factors. Subsequently, tissue damage is induced by additional mechanisms derived from a dysregulated adaptive immune response [5].

Although most of COVID-19 cases have a mild clinical course, up to 14% can evolve to a severe form, with respiratory rate ≥ 30/min, hypoxemia with pulse oxygen saturation ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 and/or pulmonary infiltrates involving more than 50% of lung parenchyma within 24 to 48 h. Up to 5% of the cases can be critical, evolving with respiratory failure, septic shock and/or multiple organ dysfunction, presumably driven by a cytokine storm [6]. Host characteristics, including aging (immunosenescence) and comorbidities (hypertension, diabetes mellitus, lung and heart diseases) may influence the course of the disease [7]. The false paradox between inflammation and immunodeficiency is highlighted by the severe form of COVID-19. Thus, severe pneumonia caused by SARS-CoV-2 is marked by immune system dysfunction and hyperinflammation leading to acute respiratory distress syndrome (ARDS), macrophage activation, hypercytokinemia and coagulopathy [8].

Herein, we aim to review the factors related to the dysregulated immune response against the SARS-CoV-2, along with its relation with severe forms of COVID-19, namely ARDS and cytokine storm (CS).

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COVID-19: A Mitochondrial Perspective

Authors: Pankaj Prasun 1

Coronavirus disease 2019 (COVID-19) is the worst public health crisis of the century. Although we have made tremendous progress in understanding the pathogenesis of this disease, a lot more remains to be learned. Mitochondria appear to be important in COVID-19 pathogenesis because of its role in innate antiviral immunity, as well as inflammation. This article examines pathogenesis of COVID-19 from a mitochondrial perspective and tries to answer some perplexing questions such as why the prognosis is so poor in those with obesity, metabolic syndrome, or type 2 diabetes. Although effective vaccines and antiviral drugs will be the ultimate solution to this crisis, a better understanding of disease mechanisms will open novel avenues for treatment and prevention.

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