Months into the COVID-19 pandemic, there is forever growing evidence to support the theory that the novel coronavirus can infect blood vessels which could explain not only the prevalence of blood clots, strokes, heart attacks, and multi-organ dysfunction but also provide an answer for the diverse set of head-to-toe symptoms that have emerged. This milestone discovery could cause a significant change in the prognosis and therapeutic approach to this complex disease. To know it all, read this article till the end.
WHAT DO WE ALREADY KNOW?
Coronavirus disease 2019 (COVID -19), an infectious disease caused by Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA coronavirus that was first identified in Wuhan, Hubei, China has resulted in the ongoing global pandemic. Since then, researchers and doctors around the world have been trying to understand the pathophysiology and therapeutic possibilities of the disease.
SARS-CoV-2 is spread primarily via small droplets from coughing, sneezing, and talking. It enters the lung tissue through ACE 2 receptors in type II alveolar cells, where it destroys the tissue causing diffuse alveolar damage and hyper inflammation and this is when people start coughing. It further causes viral pneumonia resulting in acute respiratory failure in up to 20% of symptomatic patients.
But that’s not it. In April, researchers found that blood clots emerged as one of the mysterious symptoms attributed to COVID. Most of the COVID-associated complications were a mystery. There’s blood clotting, kidney damage, inflammation of heart, encephalitis (swelling of the brain), a whole myriad of a seemingly unconnected phenomenon that is ironically not seen with SARS or H1N1 or, frankly, most of the infectious diseases.
Findings also include high viral loads and extensive inflammation in kidneys, liver, heart, and brain, which indicates direct viral tissue damage. This dissemination of virus and Multi-Organ Dysfunction Syndrome (MODS) is now conferred to as ‘Viral sepsis’
If you start to put all the emerging data together, it turns out that this is not a respiratory illness alone but is actually a vascular illness that kills people through the involvement of vasculature. The problem here is, a respiratory virus infecting blood cells and circulating through the body is virtually unheard of. Influenza (H1N1) and original SARS (sister to corona) are limited only to the lungs. Though viruses like Ebola, Dengue damage the endothelium, they are very different in structure from those affecting lungs.
Later, studies have shown that though SARS and SARS CoV-2 dock onto cells through ACE 2 receptors, another protein is required to release genetic material into infected cells. This protein, in the case of SARS, is present only in the lungs while for SARS CoV-2, protein furin, is present in all cells.
Another point to be noted here is, though ACE-2 is present in most of the cells (of the endothelium, intestine, lungs, heart, liver, eye, pancreas, etc) it doesn’t necessarily imply SARS-CoV-2 invasion in all organs. It depends on the binding of the viral spike (S proteins) to cellular receptors and S protein priming by host cells.
WHAT PIECES OF EVIDENCE SUGGEST ENDOTHELIAL INFECTION?
German COVID-19 autopsy data recorded thromboembolism seen as ‘congested and heavy lungs’ as a common, unsuspected finding with no preclinical evidence. All the patients showed either of massive pulmonary embolism, fresh DVT, fresh thrombus in prostatic venous plexus, or a combination.
The most consistent hemostatic abnormalities were mild thrombocytopenia and increased D-dimer levels, with increased chances of the requirement of mechanical ventilation, ICU admission, and death. Other tests are less certain and often contra indicatory. 71% of COVID-19 nonsurvivors fulfilled ISTH criteria for DIC compared to 0.6% in survivors.
The doubt was if these hemostatic changes were the effect of SARS-CoV-2 or the cytokine storm that causes SIRS.
Studies also show a 31% incidence of thrombotic complications in COVID-19 patients in ICU. 23% of acute pulmonary embolism associated with COVID-19 pneumonia was detected by Pulmonary CT Pulmonary Angiography. Acute pulmonary edema in critical COVID-19 patients with occlusion and micro thrombosis of small pulmonary vessels was observed.
Acute Respiratory Distress Syndrome (ARDS), which is the most common complication of the disease is actually a reflection of severe mEC dysfunction (microvascular Endothelial Cells). A pattern of Atypical ARDS is observed in COVID-19 patients in which the lungs have near-normal compliance with severe hypoxemia which indicates impaired hypoxic pulmonary vasoconstriction (HPV) and Ventilation/ Perfusion (V/Q) mismatch. There is also persistent hypotension which clearly indicates that the primary insult is to the pulmonary endothelium.
40% of deaths from COVID-19 are due to cardiovascular complications. Patients with cardiovascular disease are at more risk of adverse events. Large vessel stroke was observed in many young patients of COVID-19. Most of the comorbidities that are associated with systemic endothelial dysfunction (Hypertension, Diabetes, Obesity) are also associated with a higher rate of death in COVID-19 patients.
Chinese observational studies confirmed that the serum level of IL-6 is directly proportional to the severity of the disease and is a major inducible pro-inflammatory cytokine that plays a major role in Endothelial Cell activation. IL-2 activation by T helper cells plays an important role in the pathophysiology of COVID-19 because Pulmonary endothelial cells have a large number of IL-2 Receptors (IL-2 R) on their surfaces which on IL-2 binding leads to pulmonary edema.
Histological pieces of evidence have shown viral inclusions in Endothelial cells with inflammation and recruitment of neutrophils, lymphocytic endotheliitis in multiorgan failure. Lung biopsies have shown vascular injury as a prominent feature. The typical picture shows endothelial injury with cytoplasmic vacuolization and cell detachment in small to medium-sized pulmonary arteries, which is different because it shows fewer signs of viral cytopathic or fibroproliferative change.
WHAT CAN BE CONCLUDED?
COVID-19 is not just a pulmonary syndrome but also a multi-organ dysfunction syndrome, a manifest of disease of blood vessels, arterial, and venous thrombotic events. Once it has damaged the lung tissue, it infects endothelial cells and causes local immune response and inflammation. Vascular endothelial injury attracts neutrophils leading to further injury to the endothelium-epithelium barrier. Various receptors for viral entry into the cells (ACE 2, TMPRSS2, Sialic acid, Basigin) are also present in endothelial cells. Thus, once it is present in circulation, it can easily spread through the body. The mechanisms are shown in detail in the image below.
EC dysfunction activates these thrombo-inflammatory processes that ultimately result in COVID-19 vasculopathy, ventilation/ perfusion mismatch, and a clinical phenotype of refractory ARDS. Many questions and problems can be raised following this conclusion:Ventilation, which is a major therapeutic process in severe COVID-19, is only one part of the equation. The exchange of O2 and CO2 with the rest of the body is as important.
Doctors don’t routinely test for injury to endothelial cells. So, we are battling on two fronts; first is understanding the endothelial involvement and taking into account, the markers of endothelial injury and second is devising pharmacotherapy for that target.
Does all this mean the best antiviral therapy is not actually an antiviral therapy in this case?
One thing is for sure; studies focusing on endothelial dysfunction in COVID-19 patients are warranted to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.
WHAT CAN CHANGE?
Various biomarkers and evaluations that indicate the severity of endothelial dysfunction could be used to assess the severity of COVID-19 too:
- Circulating biomarkers like endothelin-1, E and P selectins, vWF, and soluble adhesion molecules that signify endothelial dysfunction can act as early biomarkers for viral infection and probable organ dysfunction.
- Circulating Endothelial Progenitor Cells (EPCs) can indicate disease severity and progression and could also be new pharmacological targets.
- Evaluation of angiogenic factors and soluble receptors (SVEGFR-2 and angiopoietin-2) has prognostic significance.
- Increased ratio of angiogenic factor, soluble Fms-like Tyrosine Kinase-1 (sFLT-1) to Placental Growth Factor (PLGF) in COVID-19 could be a tool to stratify the intensity of endothelial dysfunction.
- Recent reports indicate that Neutrophil Extracellular Traps (NETs) are increased in hospitalized COVID-19 patients receiving mechanical ventilation. Their use as markers of severity needs further assessment and studies.
To date, COVID-19 patients management has been either symptomatic or palliative treatment. Ongoing trials, directly and indirectly, target COVID-19 related endothelial dysfunctions and immune organs:
- Soluble recombinant ACE 2 (rACE-2) has high therapeutic potential but fast clearance. rACE-2 fused with the Fc region of Human IgG has better pharmacological properties and helps in the balance between circulating ACE-2 and membrane-bound ACE-2 which is crucial to prevent SARS-CoV-2 entry into target cells.
- Dexamethasone and other steroids inhibit endothelial activation and levels of soluble VCAM and E selectins in both in vitro and in vivo models of sepsis (Precise effects warrants in-depth investigations).
- Statins have a direct anti-inflammatory effect and are proved to be protective.
- Targeting NETs as mentioned above could be a therapeutic option to rescue lung endothelium.
- Targeted inhibition of cytokines (inflammasome-IL-1β-IL-6 pathway) Example;
The recombinant form of endogenous IL-1 receptor antagonist, Anakinra, blocks IL-1α, and IL-1β.
Conakinumab is a selective IL-1β antibody and has a much longer half-life.
Tocilizumab is also a potential immunomodulatory treatment option.
Anti-cytokine therapies may entail an increased risk of superinfection.
- Fingolimod (immunomodulating agent) can decrease reperfusion injury and increase outcomes in patients with acute ischaemic stroke.
As said in an article in European Heart Journal “In sum, we can envisage COVID-19 as a disease of the endothelium, certainly with respect to its complications. This unifying hypothesis can help to understand the complex pathophysiology of this current plague and may also help to improve our therapeutic approaches to combatting consequences of SARS-CoV-2 infection”
For my readers,
Attached below is the link for article from European Heart Journal mentioned above.
Special Thanks to Soundarajan Sir, dept. of Physiology, JIPMER for reviewing this article.