CSA Online First

CSA Online First is a weekly blog featuring insights from CSA members themselves.

Edited by Rita Agarwal, MD, FAAP, with contributions from CSA’s Committee on Professional and Public Communications, Online First is a place where knowledge and opinion from any one of our 3200 plus physician-anesthesiologist members can be shared, discussed and deliberated to advance the specialty of anesthesiology, the practice of medicine and society in general.

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Effect of COVID-19 Throughout the Body: Part I

  • Jain, Uday, MD
| Sep 16, 2020

Uday-JainIntroduction & Background

SARS-CoV-2 virus binds to angiotensin converting enzyme 2 (ACE2) receptors present in vascular endothelial cells, lungs, heart, brain, kidneys, intestine, liver, pharynx, and other tissue [1]. Injury to all these and other organs are discussed.

Inflammation and Endotheliitis

Compared to other health conditions, COVID-19 can lead to a much greater production of cytokines by white blood cells [2]. A surge of catecholamines may precede and contribute to cytokine storm, also called hypercytokinemia or cytokine release syndrome. This maladaptive response can lead to systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), multi-organ injury, shock, and death. The inflammatory response may continue to increase even when the viral load is diminishing.

SARS-CoV-2 infects the endothelial cells in multiple organs and causes diffuse lymphocytic endotheliitis, leading to vasoconstriction [3]. Accompanying inflammation, hypercoagulability, and edema, cause hypoperfusion leading to organ ischemia.

However, patients with preexisting immune-mediated inflammatory disease being treated with anticytokine biologics and other immunomodulatory therapies are not at an increased risk due to COVID-19 [4].

Effect on Coagulation

Bleeding is not common in COVID-19. Deep vein thrombosis (DVT), venous thromboembolism, pulmonary embolism (PE) and cor pulmonale, systemic and pulmonary arterial thrombosis and embolism, ischemic stroke and myocardial infarction (MI) are reported [5-12]. DVT & PE are common among the dead [9]. This is caused by inflammation, platelet activation, hypercoagulability, endothelial dysfunction, constriction of blood vessels, stasis, hypoxia, muscle immobilization, and disseminated intravascular coagulation (DIC) [13,14].

Fever and inflammation cause hypercoagulability and impair fibrinolysis. Cytokine interleukin-6 (IL-6) levels correlate with hypercoagulability and disease severity.

Elevated antiphospholipid antibodies are associated with thrombosis [15]. The liver increases production of procoagulant substances. Prothrombin time and activated partial thromboplastin time are moderately prolonged. Moderate thrombocytopenia is observed. C-reactive protein is elevated. Cytokine storm and excessive systemic inflammation are associated with lymphocytopenia, elevated D-dimer, elevated fibrin degradation products (FDP), and DIC. D-dimer levels and DIC are prognostic.

Guidelines recommend thromboprophylaxis [16,17]. Prophylaxis with low-molecular- weight or regular heparin, fondaparinux, or a direct oral anticoagulant such as apixaban or rivaroxaban should be considered. Heparins bind tightly to COVID-19 spike proteins impeding the entry of the virus into cells. Heparins also downregulate IL-6 and reduce immune activation. A non-randomized study suggests that among patients requiring mechanical ventilation, systemic anticoagulation may be associated with reduced mortality without increasing major bleeding [18]. However, systemic anticoagulation has not proven to be beneficial in ARDS due to other etiologies. After hospital discharge extended prophylaxis may be beneficial.

Pulmonary Effects

Autopsy studies indicate that in the acute phase the patients have classic diffuse alveolar damage (DAD) without organization and fibrosis [19-21]. DAD is caused by disruption of endothelial and alveolar cells. This leads to fluid and cellular exudation and hyaline membrane formation. Acute fibrinous and organizing pneumonia (AFOP) is also observed [22]. It consists of alveolar fibrin aggregation. Airway inflammation is present. Increased capillary permeability causes alveolar and interstitial edema. Vascular angiogenesis is a distinguishing feature of COVID-19 [23,24].

On chest computed tomography, findings of subpleural and peripheral areas of ground- glass opacity and consolidation are present in patients with COVID-19. Most of the patients have bilateral distribution. On chest radiographs, patchy infiltrates are observed that may be distributed asymmetrically.

Several modalities are available for managing respiratory insufficiency [25-28]. Oxygen via high-flow nasal cannula is one of the therapies utilized in these patients. Prone positioning may improves oxygenation [29-33].

Cardiac Effects

In COVID-19, cardiac complications can precede and can occur in the absence of pulmonary and other complications [34,35]. Ischemic cardiac injury can occur in patients with established coronary artery disease (CAD), those with latent CAD, and those without CAD. The primary cause of the former two is plaque rupture and thrombosis.

The last one is due to inadequate oxygen supply and mimics a myocardial infarction. For acute coronary syndrome due to plaque rupture, antiplatelet and anticoagulation therapy may be beneficial. Fibrinolytic therapy and percutaneous coronary intervention may be considered. However, the reported incidence of acute myocardial infarction has declined in the COVID-19 period [36].

Invasion of myocytes by the virus is observed in some patients. Systemic inflammatory response such as cytokine storm can cause myocarditis without direct viral infiltration. It can cause heart failure and arrhythmias. This can occur even after the acute phase of the infection has resolved and in the absence of lung damage.

About one-half of the non-survivors have acute cardiac injury and heart failure. Respiratory failure dominates in the early phases of the disease whereas cardiac injury becomes more critical in the later phases. Vascular risk factors of diabetes, obesity, age, and hypertension have greater association with mortality than does respiratory disease. In Britain one-quarter of the COVID-19 deaths occurred among diabetics, whereas 15% occurred among patients with chronic pulmonary disease.

Heart failure and elevation of brain-type natriuretic peptide (BNP) is observed. Elevated troponin and BNP levels are associated with mortality. Pulmonary embolism can cause elevation of troponin as well as BNP. For older patients with existing CAD or hypertension, heart failure may be caused by worsening demand-supply relationship. Myocarditis is more likely the cause in younger patients. Arrhythmias include tachycardia, bradycardia, and asystole. They can be due to inflammation, myocarditis, hypoxemia, metabolic abnormalities, or medications.

Cardiovascular complications may occur long after viral clearance and recovery. Inflammation can persist and evolve silently. As an example, dyslipidemia, pulmonary fibrosis, and avascular necrosis evolved over the long term in many survivors of severe acute respiratory syndrome (SARS), which is closely related to COVID-19.

Commonly used medications including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers have not been demonstrated to increase the risk of COVID-19 infection or its complications and should not be discontinued [37-40].

Renal Effects

COVID-19 complicates the management of patients on dialysis and with kidney transplantation [41]. In Britain about 15% of the patients who expired had chronic kidney disease. ACE2 receptors are present in kidneys [42]. The virus is found in glomerular cells, tubular epithelium, and podocytes of kidneys. Acute kidney injury (AKI) is commonly secondary to systemic abnormalities including diabetes, hypertension, chronic kidney disease, hypoxemia, and coagulopathy. Cytokine storms can cause drastic hypoperfusion and AKI.

AKI is also caused by rhabdomyolysis due to hyperventilation or medications including antivirals such as remdesivir. In New York, about 90% of patients who were on mechanical ventilation developed AKI [43]. AKI occurs in temporal association with respiratory failure.

Due to shortage of continuous renal replacement therapy and other hemodialysis equipment and supplies, there is greater utilization of peritoneal dialysis. The latter is suboptimal in hospitalized patients, especially if they are unstable. The catheter for peritoneal dialysis is usually placed in the anterior abdomen. It is less effective in patients who are being proned because of respiratory failure. Placing the catheter on the side of the abdomen alleviates the problem.

Among kidney transplant recipients, initially fever is present in only about one-half and diarrhea is present in about one-quarter of the patients [44]. Compared to a matched cohort they have a faster progression of disease and a higher mortality.



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