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dcyphr | Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases

Abstract

This research team studied the lung and skin tissue of 5 patients with lung failure due to COVID-19. They found damage to the capillaries in the lungs surrounding the alveoli. There were also Neutrophils, a type of white blood cell, found in the capillaries. Molecules from the complement system were also found. These molecules are membrane attack complex (C5b-9), C4d, and mannose binding lectin-associated serine protease 2 (MASP2). In the skin, C5b-9 and C4d were also found. This suggests that severe cases of COVID-19 are influenced by damage due to the complement system.


Introduction

SARS-CoV-2 is one of many existing coronaviruses. Many coronaviruses cause respiratory failure, and may develop into acute respiratory distress syndrome (ARDS). Early studies of COVID-19 showed that the virus could cause ARDS, but more recent studies have shown that the effects of COVID-19 are actually different from ARDS. The patients in the study had microvascular thrombosis, which is when the immune system tries to stop the travel of the pathogen by narrowing the vessels. It can cause a purple coloring to the skin. Microvascular thrombosis can be caused by the complement system.  Since MASP2 binds to the spike protein of SARS-CoV in mice, it is likely that MASP2 binds to the spike protein of SARS-CoV-2 in humans. There are several different pathways that the complement system can use to function. Based on the molecules that were found, the alternative pathway (AP) and the lectin pathway (LP) are the two that scientists could target to treat severe cases of COVID-19. C5b-9, C4d, and MASP2 are all components or byproducts of the complement system. So finding these molecules in the tissue tells us that the complement system is active and could be damaging the tissues. Finding fibrin can show that the vessel walls were damaged and are trying to heal.


Methods

The patients who were tested in this study were tested wit PCR to make sure they were COVID-19 positive and negative for any other infection that could influence their condition. The researchers used antibodies and a light microscope to test if C5b-9, C4d, and MASP2 were present in the tissue samples. They used another stain specific for the SARS-CoV-2 spike protein to detect if it was present in the tissue samples since it may bind to MASP2.


Results

Case 1

This 62 year old patient came into the emergency room with low oxygen levels and high blood pressure. He had coronary artery disease, diabetes, heart failure, and kidney disease. This patient passed away a few hours after coming to the ER. When they looked at the tissue, the researchers found a protein called fibrin in his capillaries of his lungs. Fibrin is a protein that helps clot blood when there is a wound. The vessel walls were dying, and were full of white blood cells. Most of the lung damage was actually to the capillaries, and the actual lung cells were not damaged. C5b-9 and C4d were found in the capillaries of the lungs.


Case 2

This 72 year old patient came to the ER with a fever, rapid breathing rate, and very low oxygen level. He had a history of smoking, obesity, and prediabetes. The patient was put on a ventilator right away and soon developed an irregular heart rhythm and kidney failure. The carbon dioxide rose in his blood and he passed away 4 days after he came to the ER. When analyzing the tissue, fibrin was found in the capillaries and in the alveoli. This patient had more damage to the lung tissue compared to Patient 1 because this patient was on the ventilator for four days. C5b-9 was found in unhealthy lung tissue, healthy lung tissue and the trachea. C4d and MASP2 were only found in the capillaries.


Case 3

This 32 year old man came to the ER after a week of coughing and a fever. He had a history of obesity, sleep apnea, steroid use, and using testosterone supplements. He had respiratory failure and was placed on a ventilator. He spent three weeks on the ventilator. He was treated with hydroxychloroquine, azithromycin, and remdesivir. He had tissue death on the skin of the buttocks. A biopsy of the dying tissue was taken and the capillaries were full of white blood cells and C5b-9.


Case 4

This 66 year old female came to the ER with fever, cough, diarrhea, and chest pain. She had low oxygen levels and was admitted to the hospital. She was given hydroxychloroquine and other medications. After three days, she had to be put on a ventilator. She had a purple rash on her hands from blood leaking out of the capillaries. This tissue was biopsied, and there were high levels of C5b-9 and C4d in the capillaries. The patient lost blood supply to many parts of her brain during ventilation and was in a coma.


Case 5

A 40 year old female came to the ER with a cough, fever, body aches, diarrhea, and difficulty breathing. She had been diagnosed with COVID-19 a week earlier, but was feeling worse. She then had to be put on ventilation for respiratory failure. She had the purple rash around her chest, legs, and arms. These were biopsied and there were high levels of C5b-9 and C4d in the capillaries.


Discussion

Microvascular thrombosis in severe COVID-19 cases can cause damage to the skin and the lungs. C5b-9, C4d, and MASP2 were found in both the damaged purple rashes and the healthy tissue near the rash. Early studies showed COVID-19 caused ARDS. But this study shows that severe COVID-19 effects are caused by microvascular thrombosis. The complement system is causing damage to the wall of the vessels, which is why the clotting factor fibrin was found in some of the capillaries. In another study, mice were genetically modified so they didn’t have a functioning complement system (C3 -/- knockout mice). When infected with SARS-CoV, the C3 -/- knockout mice did not become as severe as the regular mice. The regular mice had worse lung function, more white blood cells in the capillaries, more inflammation, and more weight loss. This shows that a potential treatment for COVID-19 is stopping the complement system. Stopping the complement system will not stop the virus from spreading, but it can decrease the most severe symptoms of COVID-19.


This study has some limitations. It was a case study that only followed 5 patients, which is a small sample size. The virus also binds to ACE2 to enter the cell, which may account for some of the results of this study. Binding to ACE2 can cause inflammation and damage to the vessels similar to the complement system. More research should be done to confirm the complement system as a potential method of treatment for COVID-19.