Table 1 |.
Future directions for research pertaining to various organ systems affected by COVID-19
| General | |
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| Pathophysiological | Clinical |
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| • How long does infectious SARS-CoV-2 persist in the upper airway of an infected patient? • How does SARS-CoV-2 disseminate in extrapulmonary tissues? Is hematogenous spread of the virus required for the direct cytotoxic effects to occur? • Do other organs serve as sites of viral infection and persistence? • Is extrapulmonary involvement dependent on viral load? • Is extrapulmonary involvement dependent on mutations of SARS-CoV-2 or ACE2 polymorphisms? • What role do host factors such as genetics (Toll-like receptors or complement components) or post-transcriptional modifications have in extrapulmonary SARS-CoV-2 infection? Are there biologically relevant factors (in addition to social factors) that explain the observed race disparities in incidence and outcomes? • What is the predominant mechanism underlying the multiple organ dysfunction; is it direct virus-induced tissue damage, systemic cytokine-release syndrome, or the synergistic effects of both? What is the role of other proposed mechanisms such as RAAS dysregulation and endothelialitis? |
• What is the impact of COVID-19 on the capacity to care for competing patients without COVID-19? • What is the efficacy, safety, and proper timing for the use of antiviral and anti-inflammatory therapies currently under investigation? • How should these therapies be best used in conjunction with each other to maximize efficacy while considering safety profiles? • Is there a role for recombinant ACE2 in treatment of patients with COVID-19? |
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| Hematologic | |
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| Pathophysiological | Clinical |
| • What are the mechanisms of viral entry into lymphocytes? • Does SARS-CoV-2 exert direct effects on coagulation and complement pathways, and if so, which ones? • In addition to IL-6, which cytokines and chemokines may act as therapeutic targets for COVID-19? • How is interferon signaling modulated by SARS-CoV-2? Are there differences in interferon responses in the early stages versus the late stages of COVID-19? |
• Do novel measurements of hypercoagulability offer improved assessment of thrombotic risk? • Is there a role for empiric higher-intensity (prophylactic or therapeutic dose) anticoagulation in patients who do not have documented thromboembolic events? • Does post-hospitalization extended thromboprophylaxis improve patient outcomes? • Does targeting inflammatory pathways and cytokine storm result in a reduction in the rate of thrombotic complications in COVID-19? • Which patients, if any, would benefit from empiric thrombolytic therapy? |
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| Cardiovascular | |
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| Pathophysiological | Clinical |
| • Does direct cardiac viral toxicity contribute substantially to myocardial dysfunction? • Are the mechanisms that result in myocardial injury and MI substantially different from those that are observed with other viral and bacterial infections? • What are the mechanisms of cardiac arrhythmias in patients with COVID-19? |
• What is the optimal antithrombotic regimen (including antiplatelets and anticoagulants) in patients presenting with COVID-19 with evidence of myocardial injury or MI? • Do statins have a protective role in patients with COVID-19, given the ability of statins to downregulate ACE2, as well as their anti-inflammatory and other pleiotropic effects? • Among the patients who develop right ventricular dysfunction in COVID-19, what proportion have pulmonary embolism and what proportion are due to the development of pulmonary hypertension or isolated right ventricular failure due to other causes? • What strategies should be used to assess and treat acute right ventricular dysfunction in patients with COVID-19 without pulmonary embolism? Can this dysfunction be temporized with mechanical circulatory support or pulmonary vasodilators? |
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| Renal | |
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| Pathophysiological | Clinical |
| • How does SARS-COV-2 induce renal tubular injury? • What is the mechanism of the development of electrolyte abnormalities and proteinuria in patients with COVID-19? • Does SARS-CoV-2 act as a 'second hit' that potentiates the glomerular damage attributed to APOL1 risk genotypes, as seen with development of collapsing-variant focal segmental glomerulosclerosis in some cases? |
• What is the optimal volume-management strategy in patients with COVID-19 who are at high risk of AKI, while also at risk of ARDS and myocardial injury? • What is the frequency of renal recovery in patients who develop renal failure? • Is there a role for cytokine removal through hemofiltration in patients with severe COVID-19? |
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| Gastrointestinal and hepatobiliary | |
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| Pathophysiological | Clinical |
| • What is the duration and extent of fecal shedding of SARS-CoV-2? • Does fecal shedding have a role in viral transmission? • What is the role of intestinal entry by the virus? Can the microbiome alter susceptibility to SARS-CoV-2 infection? • What are the predominant mechanisms of hepatocellular damage in COVID-19? |
• Do the hematologic abnormalities associated with COVID-19 increase the likelihood of developing gastrointestinal bleeding? How can this risk be best balanced with the risk for coagulopathy and thrombotic complications? • Do antihistaminic agents (e.g., famotidine) have a role in prophylaxis against gastrointestinal pathology, including bleeding events? Do these agents have antiviral efficacy against SARS-CoV-2? |
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| Endocrinologic | |
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| Pathophysiological | Clinical |
| • Is the COVID-19-induced metabolic disarray a direct consequence of viral action? • Does SARS-CoV-2 cause metabolic disarray by indirect effects such as altered nutrient utilization, cytokines and inflammation, and counter-regulatory hormones? • Is ACE2 expressed uniformly in pancreatic β-cells and endocrine islets? • If there is evidence of direct viral damage in pancreas, what is the nature of islet damage? • Is there evidence of impairment of insulin action in patients with COVID-19? |
• Do metabolic differences contribute to the racial disparities seen with COVID-19? • Do the anti-inflammatory properties of agents used to treat diabetes mellitus or metabolic syndrome (e.g., metformin) have a protective effect in patients with COVID-19 and stable renal function? |
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| Neurologic | |
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| Pathophysiological | Clinical |
| • Does SARS-CoV-2 directly infect neurons, and if so, which neuron types? • Does SARS-CoV-2 have a tropism for the brainstem and its medullary respiratory centers, and does this contribute to respiratory failure? |
• Do the neurologic and neuroimaging features of stroke differ in patients with COVID-19? • Are there long-term neurological complications in people who recover from SARS-CoV-2 infection? |