In addition to exocrine damage, there is much debate regarding the impact of COVID-19 on the endocrine pancreas and its subsequent effect on glucose regulation. Progression to Multisystem Organ Failure One of the key hallmarks of COVID-19 severity is the progression to systemic disease characterized by multisystem organ damage or failure. Many groups have suggested extrapulmonary involvement in COVID-19 is a direct result of unrestrained inflammation. However, other contributing mechanisms have been proposed and are explored below (FIGURE 3). Open in a separate window FIGURE 3. Laboratory/clinical profile and key potential mechanisms underlying extrapulmonary manifestations observed in severe COVID-19 patients NT-proBNP, NH2-terminal-proB-type natriuretic peptide; ALT, alanine aminotransferase; AST, aspartate aminotransferase; aPTT, activated partial thromboplastin time; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; ESR, erythrocyte sedimentation rate. Cardiovascular Complications Significant cardiovascular damage has been observed in severe COVID-19 patients. Several studies have demonstrated significantly elevated levels of classical markers of cardiac injury and failure [i.e., cardiac troponin and brain natriuretic peptides (BNP)] in patients with greater disease severity (53a, 78). Notably, increasing cardiac troponin levels have been correlated to other inflammatory markers, such as CRP, ferritin, and IL-6, Rabbit Polyclonal to ATP5D suggesting inflammatory damage as opposed to primary myocardial injury (28). Maladaptive cytokine release is known to directly affect cardiomyocytes as well as to lead to endothelial cell reprogramming and dysfunction, supporting their causative role in COVID-19 cardiovascular manifestations (71, 131). However, it is important to note that a handful of studies have described patients presenting with primary cardiac symptoms, suggesting myocarditis and stress-related cardiomyopathy due to respiratory failure and hypoxemia (60, 63, 152). Currently, there is insufficient evidence to support direct viral infection of cardiomyocytes, although SARS-CoV-2 genomes have been effectively detected in endomyocardial biopsies, mostly involving immune cell infiltrates (40, 149). Previous data from the SARS epidemic suggests 35% of heart specimens showed presence of viral RNA in the myocardium. Given the homology between these viruses, such direct viral invasion should not be Cyclopamine discounted (100, 106). Renal Injury and Failure In addition to cardiovascular damage, renal involvement is frequently observed in COVID-19, varying from mild proteinuria and minor serum creatinine elevations to acute kidney injury (AKI) and renal failure. Initial studies have reported varying incidences (3C15%) of AKI during illness (20, 22, 155). Now considered a valuable prognostic indicator for COVID-19 survival, Cyclopamine AKI is estimated to affect 20C40% of critically ill patients in intensive care, necessitating renal replacement therapy and extracorporeal support therapies such as blood purification (112, 155). An understanding of the complex and likely multifactorial pathophysiological mechanisms behind kidney failure in COVID-19 is thus needed for early recognition and appropriate treatment selection. Direct renal infection and damage presents one potential contributing mechanism. ACE2 is expressed in the kidney, and although previous studies suggested absence of viral particles in postmortem renal specimens from SARS patients (27), electron microscopic examination of 26 postmortem COVID-19 patients demonstrated direct virulence in tubular epithelium and podocytes (126). Direct SARS-CoV-2 infection of the renal epithelium is estimated to result in mitochondrial dysfunction, acute tubular necrosis, and protein leakage (72, 118). In addition to direct infection, uncontrolled cytokine release, thrombosis, and ischemia can also result in further kidney dysfunction, Cyclopamine characterized by intrarenal inflammation, increased vascular permeability, and volume depletion (88). Cytokine-mediated inflammatory AKI has been described previously in the literature in other clinical contexts such as CAR-T-cell treatment in cancer patients (102, 104, 117). Gastrointestinal, Hepatic, and Pancreatic Manifestations The involvement of the gastrointestinal (GI) tract and hepatic system in COVID-19 disease progression is being increasingly reported. The most common GI manifestations reported in both adult. Cyclopamine
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