Long COVID continues to be a lingering problem for more and more coronavirus patients in the months following their infection. Now, a new study contends that the life-threatening inflammation many patients experience — causing long-term damage to their health — is turning COVID-19 into a chronic condition.
“When someone has a cold or even pneumonia, we usually think of the illness being over once the patient recovers. This is different from a chronic disease, like congestive heart failure or diabetes, which continue to affect patients after an acute episode. We may similarly need to start thinking of COVID-19 as having ongoing effects in many parts of the body after patients have recovered from the initial episode,” says first author Professor Arch G. Mainous III, vice chair for research in the Department of Community Health and Family Medicine at the University of Florida Gainesville, in a media release.
“Once we recognize the importance of ‘long COVID’ after seeming ‘recovery’, we need to focus on treatments to prevent later problems, such as strokes, brain dysfunction, and especially premature death.”
COVID inflammation increases risk of death one year later
The study finds COVID patients experiencing severe inflammation while in the hospital saw their risk of death skyrocket by 61 percent over the next year post-recovery.
Inflammation raising the risk of death after an illness is a seemingly confusing concept. Typically, inflammation is a natural part of the body’s immune response and healing process. However, some illnesses including COVID-19 cause this infection-fighting response to overshoot. Previous studies call this the “cytokine storm,” an event where the immune system starts attacking healthy tissue.
“COVID-19 is known to create inflammation, particularly during the first, acute episode. Our study is the first to examine the relationship between inflammation during hospitalization for COVID-19 and mortality after the patient has ‘recovered’,” Prof. Mainous says.
“Here we show that the stronger the inflammation during the initial hospitalization, the greater the probability that the patient will die within 12 months after seemingly ‘recovering’ from COVID-19.”
There is a way to stop harmful inflammation
The study examined the health records of 1,207 adults hospitalized for COVID-19 in the University of Florida health system between 2020 and 2021. Researchers followed them for at least one year after discharge — keeping track of their C-reactive protein (CRP) levels. This protein is secreted by the liver and is a common measure of systemic inflammation.
Results show patients with a more severe case of the virus and those needing oxygen or ventilation had higher CRP levels during their hospitalization. The patients with the highest CRP concentrations had a 61-percent increased risk of death over the next year after their release from the hospital.
However, the team did find that prescribing anti-inflammatory steroids after hospitalization lowered the risk of death by 51 percent. Study authors say their findings show that the current recommendations for care after a coronavirus infection need to change. Researchers recommend more widespread use of orally taken steroids following a severe case of COVID.
Here’s how to detox from the COVID spike protein – from the jab or the virus
Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs, but the World Council for Health has compiled a list of medications to prevent this.
Thu Dec 23, 2021 – 10:38 am EST
Note: This article is an opinion and the treatments that are recommended in it have not been proven as an effective means to eliminate the spike protein from COVID or mRNA vaccines. Damage to endothelial linings of vessels and organs by the COVID-19 spike protein and how to reverse it requires new research and randomized clinical trials to determine if any treatment can detox the body of the spike protein that causes Long-haul diseases.
If you had COVID-19 or received a COVID-19 injection, you may have dangerous spike proteins circulating in your body
Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs
The World Council for Health has released a spike protein detox guide, which provides straightforward steps you can take to potentially lessen the effects of toxic spike protein in your body
Spike protein inhibitors and neutralizers include pine needles, ivermectin, neem, N-acetylcysteine (NAC) and glutathione
The top 10 spike protein detox essentials include vitamin D, vitamin C, nigella seed, quercetin, zinc, curcumin, milk thistle extract, NAC, ivermectin and magnesium
(Mercola) – Have you had COVID-19 or received a COVID-19 injection? Then you likely have dangerous spike proteins circulating in your body. While a spike protein is naturally found in SARS-CoV-2, no matter the variant, it’s also produced in your body when you receive a COVID-19 shot. In its native form in SARS-CoV-2, the spike protein is responsible for the pathologies of the viral infection.
In its wild form it’s known to open the blood-brain barrier, cause cell damage (cytotoxicity) and, as Dr. Robert Malone – the inventor of the mRNA and DNA vaccine core platform technology – said in a commentary on News Voice, the protein “is active in manipulating the biology of the cells that coat the inside of your blood vessels — vascular endothelial cells, in part through its interaction with ACE2, which controls contraction in the blood vessels, blood pressure and other things.”
It’s also been revealed that the spike protein on its own is enough to cause inflammation and damage to the vascular system, even independent of a virus.
Now, the World Council for Health (WCH) – a worldwide coalition of health-focused organizations and civil society groups that seek to broaden public health knowledge – has released a spike protein detox guide, which provides straightforward steps you can take to potentially lessen the effects of toxic spike protein. You can view their full guide of natural remedies, including dosages, at the end of this article.
Why should you consider a spike protein detox?
Spike proteins can circulate in your body after infection or injection, causing damage to cells, tissues and organs. “Spike protein is a deadly protein,” Dr. Peter McCullough, an internist, cardiologist and trained epidemiologist, says in a video. It may cause inflammation and clotting in any tissue in which it accumulates.
For instance, Pfizer’s biodistribution study, which was used to determine where the injected substances end up in the body, showed the COVID spike protein from the shots accumulated in “quite high concentrations” in the ovaries.
Further, a Japanese biodistribution study for Pfizer’s jab found that vaccine particles move from the injection site to the blood, after which circulating spike proteins are free to travel throughout the body, including to the ovaries, liver, neurological tissues and other organs. WCH noted:
“The virus spike protein has been linked to adverse effects, such as: blood clots, brain fog, organizing pneumonia, and myocarditis. It is probably responsible for many of the Covid-19 [injection] side effects … Even if you have not had any symptoms, tested positive for Covid-19, or experienced adverse side effects after a jab, there may still be lingering spike proteins inside your body.
In order to clear these after the jab or an infection, doctors and holistic practitioners are suggesting a few simple actions. It is thought that cleansing the body of spike protein … as soon as possible after an infection or jab may protect against damage from remaining or circulating spike proteins.”
Spike protein inhibitors and neutralizers
A group of international doctors and holistic practitioners who have experience helping people recover from COVID-19 and post-injection illness compiled natural options for helping to reduce your body’s spike protein load. The following are spike protein inhibitors, which means they inhibit the binding of the spike protein to human cells:
Dandelion leaf extract
Ivermectin, for example, docks to the SARS-CoV-2 spike receptor-bending domain attached to ACE2, which may interfere with its ability to attach to the human cell membrane. They also compiled a list of spike protein neutralizers, which render it unable to cause further damage to cells. This includes:
Star anise tea
Pine needle tea
St. John’s wort
The plant compounds in the table above contain shikimic acid, which may counteract blood clot formation and reduce some of the spike protein’s toxic effects. Nattokinase, a form of fermented soy, may also help to reduce the occurrence of blood clots.
How to protect your ACE2 receptors and detox IL-6
Spike protein attaches to your cells’ ACE2 receptors, impairing the receptors’ normal functioning. This blockage may alter tissue functioning and could be responsible for triggering autoimmune disease or causing abnormal bleeding or clotting, including vaccine-induced thrombotic thrombocytopenia.
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Ivermectin, hydroxychloroquine (with zinc), quercetin (with zinc) and fisetin (a flavonoid) are examples of substances that may naturally protect your ACE2 receptors. Ivermectin works in this regard by binding to ACE2 receptors, preventing the spike protein from doing so.
Interleukin 6 (IL-6) is a proinflammatory cytokine that is expressed post-injection, and its levels increase in people with COVID-19. It’s for this reason that the World Health Organization recommends IL-6 inhibitors for people who are severely ill with COVID-19. Many natural IL-6 inhibitors, or anti-inflammatories, exist and may be useful for those seeking to detox from COVID-19 or COVID-19 injections:
Boswellia serrata (frankincense)
Dandelion leaf extract
Black cumin (Nigella sativa)
Krill oil and other fatty acids
Vitamin D3 (with vitamin K)
How to detox from Furin and Serine Protease
To gain entry into your cells, SARS-CoV-2 must first bind to an ACE2 or CD147 receptor on the cell. Next, the spike protein subunit must be proteolytically cleaved (cut). Without this protein cleavage, the virus would simply attach to the receptor and not get any further.
“The furin site is why the virus is so transmissible, and why it invades the heart, the brain and the blood vessels,” Dr. Steven Quay, a physician and scientist, explained at a GOP House Oversight and Reform Subcommittee on Select Coronavirus Crisis hearing.
The existence of a novel furin cleavage site on SARS-CoV-2, while other coronaviruses do not contain a single example of a furin cleavage site, is a significant reason why many believe SARS-CoV-2 was created through gain-of-function (GOF) research in a laboratory. Natural furin inhibitors, which prevent cleavage of the spike protein, can help you detox from furin and include:
Serine protease is another enzyme that’s “responsible for the proteolytic cleavage of the SARS-CoV-2 spike protein, enabling host cell fusion of the virus.” Inhibiting serine protease may therefore prevent spike protein activation and viral entry into cells. WCH compiled several natural serine protease inhibitors, which include:
Blue green algae
N-acetyl cysteine (NAC)
Time-restricted eating and healthy diet for all
In addition to the targeted substances mentioned above, WCH was wise to note that a healthy diet is the first step to a healthy immune system. Reducing your consumption of processed foods and other proinflammatory foods, including vegetable (seed) oils, is essential for an optimal immune response.
Time-restricted eating, which means condensing your meals into a six- to eight-hour window, is also beneficial. This will improve your health in a variety of ways, primarily by improving your mitochondrial health and metabolic flexibility. It can also increase autophagy, which helps your body clear out damaged cells. As noted by WCH:
“This method … is used to induce autophagy, which is essentially a recycling process that takes place in human cells, where cells degrade and recycle components. Autophagy is used by the body to eliminate damaged cell proteins and can destroy harmful viruses and bacteria post-infection.”
Another strategy to boost your health and longevity, and possibly to help detox spike protein, is regular sauna usage. As your body is subjected to reasonable amounts of heat stress, it gradually becomes acclimated to the heat, prompting a number of beneficial changes to occur in your body.
These adaptations include increased plasma volume and blood flow to your heart and muscles (which increase athletic endurance) along with increased muscle mass due to greater levels of heat-shock proteins and growth hormone. It’s a powerful detoxification method due to the sweating it promotes.
Top 10 spike protein detox essentials and the full guide
Below you can find WCH’s full guide of useful substances to detox from toxic spike proteins, including recommended doses, which you can confirm with your holistic health care practitioner. If you’re not sure where to start, the following 10 compounds are the “essentials” when it comes to spike protein detox. This is a good place to begin as you work out a more comprehensive health strategy:
Milk thistle extract
World Council for Health’s spike protein detox guide
Where to Get
Soil bacteria (avermectin)
0.4 mg/kg weekly for 4 weeks, then monthly *Check package instructions to determine if there are contraindications prior to use
200 mg weekly for 4 weeks *Check package instructions to determine if there are contraindications prior to use
Citrus fruits (e.g. oranges) and vegetables (broccoli, cauliflower, brussels sprouts)
Supplement: health food stores, pharmacies, dietary supplement stores, online
6-12 g daily (divided evenly between sodium ascorbate (several grams), liposomal vitamin C (3-6 g) & ascorbyl palmitate (1–3 g)
Prunella Vulgaris (commonly known as self-heal)
Supplement: health food stores, pharmacies, dietary supplement stores, online
7 ounces (207 ml) daily
Supplement: health food stores, pharmacies, dietary supplement stores, online
Consume tea 3 x daily (consume oil/resin that accumulates in the tea also)
Supplement: health food stores, pharmacies, dietary supplement stores, online
As per your practitioner’s or preparation instructions
In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.Keywords: COVID-19, fractalkine, endothelial cell adhesion molecules, D-dimer, coagulopathy
In December 2019, a severe public health event, manifested mainly with fever and respiratory tract symptoms, broke out in Wuhan, China, and quickly spread throughout the country and the world , which was named coronavirus disease 2019 (COVID-19) by the World Health Organization. As of 1 May 2020, more than 3 million cases have been confirmed, while more than 200 000 patients have died, and the number is continuing to increase.
COVID-19 causes a systemic inflammatory response, involving dysregulation and misexpression of many inflammatory cytokines . The recruitment and activation of inflammatory cells depend on the expression of many classes of inflammatory mediators, such as cytokines (interleukin [IL]-1, IL-6, and IL-18), chemokines (fractalkine [FKN]), and adhesion molecules (intercellular adhesion molecule 1 [ICAM-1)] and vascular cell adhesion molecule-1 [VCAM-1]) . Pathological evidence of venous thromboembolism, direct viral infection of the endothelial cells, and diffuse endothelial inflammations have been reported in recent studies [2, 3]. Therefore, it is of significance to investigate the expression of endothelial cell adhesion molecules in COVID-19.
Here, we collected clinical data and blood samples from confirmed COVID-19 patients in the Fourth People’s Hospital of Yiyang in Hunan, China, and performed enzyme-linked immunosorbent assays (ELISAs) to study the expression of inflammatory mediators and endothelial cell adhesion molecules in COVID-19 patients.Go to:
A retrospective study was conducted. From 1 February to 10 March 2020, 39 COVID-19 patients were recruited at the Infectious Disease Ward in the Fourth People’s Hospital of Yiyang, Hunan, China, and 32 uninfected participants were recruited from the physical examination center of Hunan Provincial People’s Hospital. All patients tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were hospitalized. Nine patients were diagnosed with severe pneumonia, while 30 had mild disease. Mild pneumonia was defined as positivity in quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests, with typical chest tomography imaging features of viral pneumonia , while severe pneumonia was defined as mild pneumonia plus 1 of the following criteria: (1) respiratory distress with a respiratory rate ≥ 30 times per minute;
(2) oxygen saturation ≤ 93% at rest; (3) oxygenation index ≤ 300 mmHg (1 mmHg = 0.133 kPa); (4) respiratory failure requiring ventilation; (5) refractory shock; and
(6) admission to the intensive care unit for other organ failure. All patients were given interferon-α2b (5 million units twice daily, atomization inhalation) and lopinavir plus ritonavir (500 mg twice daily, orally) as antiviral therapy. All patients with severe disease received preventive anticoagulant treatment with low-molecular-weight heparin (LMWH) 5000 IU/day by subcutaneous injection for 7 days. No patients died during the observation period.
The criteria for discharge were: (1) absence of fever for at least 3 days; (2) significant improvement in both lungs on chest computed tomography (CT); (3) clinical remission of respiratory symptoms; and (4) repeated negativity in RT-PCR tests of throat swab samples at least 24 hours apart.
Clinical data were measured at enrolment. The study was approved by the Medical Ethics Review Board of Hunan Provincial People’s Hospital (No. 2020-10). All study participants provided written informed consent.
Blood samples were collected at admission from each patient in a fasting state and repeated during the convalescence period for severe cases. Serum lipids, glucose, C-reaction protein (CRP), and D-dimer were determined by conventional laboratory methods. Blood samples of control subjects were also collected and tested. The obtained blood samples were placed in tubes containing EDTA and immediately centrifuged at 1500g and stored at −80°C.
Enzyme-Linked Immunosorbent Assay
Quantitative determination of IL-18, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), FKN, VCAM-1, ICAM-1, and vascular adhesion protein-1 (VAP-1) was performed using commercially available ELISA kits (BOSTER).
Categorical variables were reported as number and percentages, and significance was detected by χ2 or Fisher exact test. The continuous variables were compared using independent group t tests and described using mean and standard deviation if normally distributed, or compared using the Mann-Whitney U test and Kruskal-Wallis H test and described using median and interquartile range (IQR) value if not. Paired comparisons of the severe group were analyzed with the Nemenyi test. Statistical analysis was performed by SPSS version 19.0. Two-sided P values < .05 were considered statistically significant.
Patient and Public Involvement
In this retrospective study, no patients were directly involved in the study design, question proposal, or the outcome measurements. No patients were asked for input concerning interpretation or recording of the results.
Demographic information is shown in Table 1. Briefly, 20 patients were male, 19 patients were female, 16 controls were male, and 16 were female, and the median ages in the control, mild, and severe groups were 52, 49, and 54 years, respectively. Nine patients had severe disease, while 30 cases had mild disease. No significant differences were found between patients with mild disease and control participants in age, smoking, cardiovascular disease (CVD), autoimmune disease, low-density lipoprotein cholesterol (LDL-C), triglycerides, total cholesterol (CHO), glucose, and D-dimer. Significant differences in D-dimer were observed between the severe disease and control participants (median, 4.49 vs 0.34, respectively; P < .05), while no significant differences in age, smoking, CVD, autoimmune disease, and the levels of triglycerides, LDL-C, CHO, and glucose were observed. Significant differences in age (median, 54 vs 49; P < .05), triglycerides (median, 0.93 vs 1.29; P < .05), D-dimer (median, 4.49 vs 0.35; P < .05), and length of stay (mean, 16.6 vs 10.6; P < .05) were observed between patients with severe and mild disease, respectively, while no significant differences in smoking, CVD, autoimmune disease, and the levels of LDL-C, CHO, and glucose were observed.
Characteristics of Study Participants
Sex, male/female, n/n
Age, y, median (25, 75 percentile)a
50 (42, 57)
52 (44, 60)
49 (25, 55)
54 (47, 75)*
Current smoker, n (%)
Cardiovascular disease, n (%)
Autoimmune disease, n (%)
LDL-C, mmol/L, median (25, 75 percentile)a
1.81 (1.53, 2.17)
1.81 (1.45, 2.03)
1.81 (1.52, 2.34)
2.11 (1.58, 2.41)
Triglycerides, mmol/L, median (25, 75 percentile)a
Expression of Inflammatory Mediators and Endothelial Cell Adhesion Molecules in COVID-19 Patients and Uninfected Participants
The serum levels of the following were higher in patients with mild disease than in control participants: FKN (median, 880.1 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 3742.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 2866.1 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 16.81 vs 16.68 pg/mL; P = .41) (Figure 1A–D); CRP (median, 10.75 vs 1.59 mg/L; P < .01); IL-18 (median, 415.4 vs 276.5 pg/mL; P = .09); TNF-α (median, 257.1 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 46.00 vs 42.51 pg/mL; P = .50) (Supplementary Figure 1A–D). Of these, CRP, TNF-α, FKN, VCAM-1, and ICAM-1 were significantly elevated.
Expression of endothelial cell adhesion molecules in COVID-19 patients and uninfected participants, the horizontal lines represent median with interquartile range: (A) fractalkine; (B) vascular cell adhesion molecule-1 (VCAM-1); (C) intercellular adhesion molecule 1 (ICAM-1); and (D) vascular adhesion protein-1 (VAP-1). * P < .05; ** P < .01.
The serum levels of the following were significantly higher in patients with severe disease than in control participants: FKN (median, 1457.5 vs 684.6 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 891.4 pg/mL; P < .01); ICAM-1 (median, 4498.2 vs 1287.4 pg/mL; P < .01); VAP-1 (median, 28.80 vs 16.68 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 1.59 mg/L; P < .01); IL-18 (median, 670.7 vs 276.5 pg/mL; P < .01); TNF-α (median, 274.2 vs 242.9 pg/mL; P < .01); and IFN-γ (median, 76.50 vs 42.51 pg/mL; P < .01) (Supplementary Figure 1A–D).
The serum levels of the following were significantly higher in patients with severe disease than in patients with mild disease: FKN (median, 1457.5 vs 880.1 pg/mL; P < .01); VCAM-1 (median, 4991.3 vs 3742.3 pg/mL; P < .05); ICAM-1 (median, 4498.2 vs 2866.1 pg/mL; P < .05); VAP-1 (median, 28.80 vs 16.81 pg/mL; P < .01) (Figure 1A–D); CRP (median, 43.64 vs 10.75 mg/L; P < .01); IL-18 (median, 670.7 vs 415.4 pg/mL; P < .01); TNF-α (median, 274.2 vs 257.1 pg/mL; P < .05); and IFN-γ (median, 76.50 vs 46.00 pg/mL; P < .01) (Supplementary Figure 1A–D).
For severe cases, the serum levels of the following were lower in the convalescence phase than during the acute phase: FKN (median, 1028.2 vs 1457.5 pg/mL; P < .05); VCAM-1 (median, 3420.9 vs 4991.3 pg/mL; P < .01); ICAM-1 (median, 3046.9 vs 4498.2 pg/mL; P < .01); VAP-1 (median, 23.90 vs 28.80 pg/mL; P = .17) (Figure 1A–D); CRP (median, 10.20 vs 43.64 mg/L; P < .01); IL-18 (median, 514.6 vs 670.7 pg/mL; P < .01); TNF-α (median, 265.1 vs 274.2 pg/mL; P < .01); IFN-γ (median, 66.30 vs 76.50 pg/mL; P = .05) (Supplementary Figure 1A–D); and D-dimer (median, 0.45 vs 4.49; P < .01) (Supplementary Figure 2). Of these, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer were significantly lower.Go to:
Three novel findings were identified in our study. First, the endothelial cell adhesion markers FKN, VCAM-1, and ICAM-1 were elevated in COVID-19 patients. Second, the severity of COVID-19 was associated with the serum levels of CRP, IL-18, TNF-α, IFN-γ, FKN, VCAM-1, ICAM-1, and VAP-1. Third, recovery from severe COVID-19 was associated with reductions in serum CRP, IL-18, TNF-α, FKN, VCAM-1, ICAM-1, and D-dimer levels.
Endothelial activation is related to severe COVID-19, and antiphospholipid antibodies, von Willebrand factor, and factor VIII may play a role in coagulopathy . Endothelial cells express angiotensin-converting enzyme 2 (ACE2), the receptor for SARS-CoV-2 , and the interaction of SARS-CoV-2 and ACE2 possibly mediates endothelial activation. Endothelial cells are an essential component of the coagulation system and their integrity and functionality are critical to maintaining hemostasis, whereas endothelial cell activation or injury may result in platelet activation, thrombosis, and inflammation . Dysfunctional endothelial cells activated by proinflammatory cytokines may contribute to the pathogenesis of thrombosis by altering the expression of pro- and antithrombotic factors [8, 9].
In this cohort of COVID-19 patients, although apparent thrombosis formation was excluded by Doppler ultrasound in deep veins in the lower extremities and repeated chest CT scans, we found an interesting phenomenon in patients with severe disease, that is serum D-dimer levels were elevated during the acute phase and decreased significantly during the convalescence phase. As an indirect marker of coagulation activation, elevated D-dimer has been reported in several studies and confirmed to correlate with an increased likelihood of death in COVID-19 patients . We consider that the relationship between prethrombosis levels of D-dimer and thrombotic disease is likely partly attributable to subclinical clot formation.
Severe COVID-19 is commonly complicated by coagulopathy, while disseminated intravascular coagulation may contribute to most deaths . Anticoagulant treatment may decrease mortality due to coagulopathy . In patients with severe disease, serum FKN, ICAM-1, VCAM-1, and D-dimer levels declined significantly after antiviral and anticoagulant treatment. In addition to stimulating the immune system to suppress viral replication and clear pathogens, interferon-α also inhibits the inflammatory immune response that leads to histological damage . Hence, we speculate that the dynamic changes in these molecules resulted from the alleviation of endothelial cell injuries, the anti-inflammatory effect of medications, or recovery from COVID-19.
Limitations should be noted when interpreting the results of this study. First, the number of patients with severe disease was low, which may lead to statistical deviation. Second, due to tissue sample inaccessibility, the expression of endothelial activation molecules was not measured in tissues. Third, because we did not measure the direct biomarkers in the coagulation system, the specific disturbed pathways and mechanisms are still unknown. Fourth, due to the anti-inflammatory effect of interferon-α, the relationship between the anticoagulant effect of LMWH and the decreased expression of endothelial cell adhesion molecules in COVID-19 is still uncertain, and requires further study.
In conclusion, based on the results of this study, increased expression of endothelial cell adhesion molecules is related to COVID-19 and disease severity, and may contribute to coagulation dysfunction.
Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Acknowledgments. We sincerely thank clinicians at the Forth People’s Hospital of Yiyang, Hunan, China.
Financial support. This work was supported by the Key Research and Development Program of Hunan Province (grant number 2020SK3011).
Potential conflicts of interest. All authors: No reported conflicts of interests. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.Go to:
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause inflammatory lung disease, including clot formation and hyper-permeability of the lung vessels, resulting in edema and bleeding into the lung. Inflammation also affects other organs, mediated by the cytokine storm.
This inflammation is characterized by endothelial cell dysfunction in multiple organs. The cause of this endothelialopathy is unknown. It could be due to the direct infection of endothelial cells or an indirect effect of the cytokines.
Image Credit: Kateryna Kon/Shutterstock.com
Integrin binding by SARS-CoV-2
Unlike earlier coronaviruses pathogenic to humans, SARS-CoV-2 has a spike protein that is linked to host recognition and viral attachment via the angiotensin-converting enzyme 2 (ACE2) receptor. A unique three-residue RGD motif outside the ACE2 recognition site may allow the spike protein to bind to endothelial proteins called integrins, that bind the RGD group.
In fact, the major integrin on endothelial cells, called αVβ3, is able to bind to multiple RGD-binding ligands. It also engages multiple extracellular matrix proteins, such as fibrinogen, fibronectin, and vitronectin, via its binding pocket. These matrix proteins regulate cell adhesion, migration, and proliferation, as well as angiogenesis.
This mutation could thus enhance SARS-CoV-2 binding to the host cell and may be responsible for the high transmissibility of this virus compared to the earlier ones, while also allowing for multiple routes of entry for the virus and promoting its dissemination within the host by two receptors.
SARS-CoV-2 thus produces marked dysregulation of the endothelial barrier, causing it to lose its integrity and producing a hyper-permeable state. This leads to shock and the rapid spread of the virus to major organs.
Endothelial infection in COVID-19
Endothelial cells are key to several physiological processes including activation of immune cells, platelet aggregation and adhesion, leukocyte adhesion, and transmigration. They are also the target of many viruses, leading to multi-organ dysfunction.
Some studies have failed to show the growth of the virus within endothelial cells, which has been attributed to the lack of expression of the angiotensin-converting enzyme 2 (ACE2) receptor on these cells.
However, it may be argued that this is due to the intrinsic differences between the endothelial monolayer grown in vitro, vs the endothelial lining of the blood vessels that handle blood flowing under shear stress; the activation of the endothelial cells by the high volume of cytokines; and the tight contact with the epithelial cells of the lung capillaries.What is a Cytokine Storm?
Other researchers have reported that SARS-CoV-2 is found in association with the endothelial cell marker CD31 within the lungs, in infected mice and non-human primates (NHPs). Even more significantly, this finding has been identified in the lung tissue of people who died of severe COVID-19.
The viral proteins were also found in endothelial cells. Moreover, infected mice showed upregulated KRAS signaling pathways in lung tissue, known to mediate cellular activation and dysfunction. Experimental evidence shows that mouse endothelial cells are infected by SARS-CoV-2.
Though all endothelial cells express ACE2, all are not the targets of the virus. Instead, it requires the co-expression of other host proteases such as the transmembrane serine protease TMPRSS2, or cathepsins, that cleave the spike protein to its fusion conformation, allowing viral entry into the host cell via endocytosis.
Endothelial cell injury
Following the viral entry into the endothelial cell, it begins to translate its proteins, replicate itself, and may directly induce cell injury and apoptosis. Along with this, endothelial cells activate T cells, though less than other antigen-presenting cells do. In fact, endothelial cells activate only antigen-specific memory or effector T cells, not naïve lymphocytes.
In so doing, endothelial cells may promote the destruction of infected cells by presenting viral proteins to CD8 T cells. Moreover, endothelial cells in the microvasculature may cause memory or effector CD4 T cells to migrate through the endothelium. Antiviral cytokines including gamma-interferon (IFN-γ) may induce class I or II major histocompatibility complex (MHC) molecules, costimulatory molecules that are typically required for T cell activation to occur.
This means that the endothelial dysfunction caused by COVID-19 blocks lymphocyte activation via endothelial cells, causing an imbalance in the adaptive immune response.
The cytokine storm leads to a kind of overreach, causing further endothelial dysfunction. These cytokines include interleukin-6 (IL-6) that stimulates endothelial cell secretion of pro-inflammatory mediators and complement activation, thus further enhancing endothelial barrier breakdown.
Lymphocyte depletion often seen in COVID-19 could also be the result of the excessive inflammation induced by the endothelial cell injury. The reduced number of CD4 lymphocytes may cause an impaired response to the infection while also stimulating further inflammation. Thus, the hyper-inflammatory response in severe and critical COVID-19 could be due to endothelial cell infection and dysfunction.
Loss of endothelial barrier integrity
SARS-CoV-2 infection causes immune dysfunction as well as extensive endothelial injury, in addition to clotting defects and systemic microangiopathy. The poor disease outcome is mediated largely through the increased vascular permeability secondary to infection-related inflammation.
This hyper-permeability is associated with the leakage of both cellular and non-cellular components of the blood in the small blood vessels of the lung, causing the alveoli to become congested with liquid. The patient drowns in the fluid from the leaky blood vessels, which can endanger life by causing asphyxiation.
Simultaneously, the clotting cascades are dysregulated, causing microthrombi to form throughout the circulation, along with leukocyte infiltration. The endothelial cell dysfunction may cause further inflammation and leukocyte recruitment and adhesion.
Since endothelial cells express glycosaminoglycans and thrombomodulin on their cell surface, they inhibit the clotting cascade component, thrombin, as well as a protein inhibitor of tissue factor. Many relaxing factors such as nitric oxide (NO) and prostacyclin (PGI2) are also produced by these cells, thus blocking leukocyte and platelet adhesion and migration, smooth muscle proliferation, and exerting an anti-inflammatory, anti-apoptotic effect.
When the endothelial cells are injured by the viral invasion, they cease to exert their anticoagulant effect, leading to a thrombotic tendency that manifests as extensive microthrombi, hyaline membrane formation in the small arterioles of the lung, and diffuse alveolar injury.
Elevated D-dimer levels occur with this hypercoagulable state, causing poor outcomes and higher mortality with COVID-19. Multiple procoagulant mechanisms are at work, from the exposure of the tissue factor to clotting factors in the blood to the loss of endothelial integrity and thus activation of the intrinsic clotting pathway by the exposed matrix under the endothelial cell layer, to the devastating release of van Willebrand factor (vWF), due to endothelial dysfunction. This molecule acts to bridge platelets for aggregation and clot formation.
Infection of the endothelial cells could be associated with viral invasion of the adjacent tissues, that is, of the smooth muscle cells of the arteries and the cardiac myocytes.
Thus, SARS-CoV-2 infection of endothelial cells could be an underlying cause for the cardiovascular complications of COVID-19, including the end-stage multi-organ dysfunction. It is plausible that the endothelial cell apoptosis was seen in patients who have died of COVID-19, as well as the microthrombi scattered throughout the lung vascular bed along with right ventricular dysfunction, are associated with direct infection of the endothelial cells.
The binding of the spike protein to αVβ3 can be inhibited by the specific αVβ3-antagonist Cilengitide, an RGD tripeptide, that has a high affinity to this integrin and suppresses virus-endothelium binding at very low doses.
Other therapeutic strategies include serine protease inhibitors, renin-angiotensin-aldosterone system inhibitors, statins, heparin, corticosteroids, and IL-6 inhibitors, all of which act at least in part via stabilization and protection of endothelial integrity.
SARS-CoV-2, the pathogen, which is responsible for coronavirus disease 2019 (COVID-19), has caused unprecedented morbidity and mortality worldwide. Scientific and clinical evidence testifies about long-term COVID-19 effects that can affect many organ systems. Cellular damage, overproduction of proinflammatory cytokines and procoagulant abnormalities caused by SARS-CoV-2 infection may lead to these consequences. After suffering from COVID-19, a negative PCR test is only the beginning of a difficult path to full recovery. 61 % of patients will continue to have the signs of post-covid syndrome with the risk of developing serious COVID-19 health complications for a long time. Post-COVID syndrome is an underestimated large-scale problem that can lead to the collapse of the healthcare system in the nearest future.
The treatment and prevention of post-covid syndrome require integrated rather than organ or disease specific approaches and there is an urgent need to conduct a special research to establish the risk factors.
For this purpose, we studied the expression of markers of apoptosis (CD95) and intercellular adhesion (CD54) in healthy individuals and patients who underwent COVID-19, as well as the efficacy of the drug Mercureid for the treatment of post-covid syndrome.
The expression level of the apoptosis marker CD95 in patients who underwent COVID-19 is 1.7-2.5 times higher than the norm and the intercellular adhesion marker CD54 is 2.9-4.4 times higher. This fact indicates a persistent high level of dysfunctional immune response in the short term after recovery. The severity of the expression of the intercellular adhesion molecule (ICAM-1, CD54) shows the involvement of the endothelium of the vascular wall in the inflammatory process as one of the mechanisms of the pathogenesis of post-covid syndrome.
The use of Mercureid made it possible to reduce the overexpression of CD95 in 73.4 % of patients that led to the restoration of the number of CD4+/CD8+ T-cells, which are crucial in the restoration of functionally active antiviral and antitumor immunity of patients. Also, the use of Mercureid led to a normalization of ICAM-1 (CD54) levels in 75.8 % of patients.
The pharmacological properties of the new targeted immunotherapy drug Mercureid provide new therapeutic opportunities for the physician to influence a number of therapeutic targets, such as CD95, ICAM-1 (CD54), to reduce the risk of post-COVID complications.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) pandemic, which has resulted in global healthcare crises and strained health resources. As the population of patients recovering from COVID-19 grows, it is paramount to establish an understanding of the healthcare issues surrounding them. COVID-19 is now recognized as a multi-organ disease with a broad spectrum of manifestations. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged effects after acute COVID-19. Patient advocacy groups, many members of which identify themselves as long haulers, have helped contribute to the recognition of post-acute COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of the current literature on post-acute COVID-19, its pathophysiology and its organ-specific sequelae. Finally, we discuss relevant considerations for the multidisciplinary care of COVID-19 survivors and propose a framework for the identification of those at high risk for post-acute COVID-19 and their coordinated management through dedicated COVID-19 clinics.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused morbidity and mortality at an unprecedented scale globally1. Scientific and clinical evidence is evolving on the subacute and long-term effects of COVID-19, which can affect multiple organ systems2. Early reports suggest residual effects of SARS-CoV-2 infection, such as fatigue, dyspnea, chest pain, cognitive disturbances, arthralgia and decline in quality of life3,4,5. Cellular damage, a robust innate immune response with inflammatory cytokine production, and a pro-coagulant state induced by SARS-CoV-2 infection may contribute to these sequelae6,7,8. Survivors of previous coronavirus infections, including the SARS epidemic of 2003 and the Middle East respiratory syndrome (MERS) outbreak of 2012, have demonstrated a similar constellation of persistent symptoms, reinforcing concern for clinically significant sequelae of COVID-19 (refs. 9,10,11,12,13,14,15).
Systematic study of sequelae after recovery from acute COVID-19 is needed to develop an evidence-based multidisciplinary team approach for caring for these patients, and to inform research priorities. A comprehensive understanding of patient care needs beyond the acute phase will help in the development of infrastructure for COVID-19 clinics that will be equipped to provide integrated multispecialty care in the outpatient setting. While the definition of the post-acute COVID-19 timeline is evolving, it has been suggested to include persistence of symptoms or development of sequelae beyond 3 or 4 weeks from the onset of acute symptoms of COVID-19 (refs. 16,17), as replication-competent SARS-CoV-2 has not been isolated after 3 weeks18. For the purpose of this review, we defined post-acute COVID-19 as persistent symptoms and/or delayed or long-term complications of SARS-CoV-2 infection beyond 4 weeks from the onset of symptoms (Fig. 1). Based on recent literature, it is further divided into two categories: (1) subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19; and (2) chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses17,19. Herein, we summarize the epidemiology and organ-specific sequelae of post-acute COVID-19 and address management considerations for the interdisciplinary comprehensivecare of these patients in COVID-19 clinics
The COVID-19 outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global major concern. In this review, we addressed a theoretical model on immunopathogenesis associated with severe COVID-19, based on the current literature of SARS-CoV-2 and other epidemic pathogenic coronaviruses, such as SARS and MERS. Several studies have suggested that immune dysregulation and hyperinflammatory response induced by SARS-CoV-2 are more involved in disease severity than the virus itself.
Immune dysregulation due to COVID-19 is characterized by delayed and impaired interferon response, lymphocyte exhaustion and cytokine storm that ultimately lead to diffuse lung tissue damage and posterior thrombotic phenomena.
Considering there is a lack of clinical evidence provided by randomized clinical trials, the knowledge about SARS-CoV-2 disease pathogenesis and immune response is a cornerstone to develop rationale-based clinical therapeutic strategies. In this narrative review, the authors aimed to describe the immunopathogenesis of severe forms of COVID-19.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA-enveloped virus, is the causative agent of coronavirus disease 2019 (COVID-19), being first identified in Wuhan, China, in December 2019. Previously, other epidemic coronavirus such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and the middle-east respiratory syndrome coronavirus (MERS-CoV) in 2012, had serious impact on human health and warned the world about the possible reemergence of new pathogenic strains . Despite being a new virus, several common morpho-functional characteristics have been reported between SARS-CoV and the SARS-CoV-2, including the interaction of the viral spike (S) glycoprotein with the human angiotensin converting enzyme 2 (ACE2). These similarities may help understanding some pathophysiological mechanisms and pointing out possible therapeutic targets.
The first step for SARS-CoV-2 entry into the host cell is the interaction between the S glycoprotein and ACE2 on cell surface. Since the latter acts as a viral receptor, the virus will only infect ACE2 expressing cells, notably type II pneumocytes. These cells represent 83% of the ACE2-expressing cells in humans, but cells from other tissues and organs, such as heart, kidney, intestine and endothelium, can also express this receptor . A host type 2 transmembrane serine protease, TMPRSS2, facilitates virus entry by priming S glycoprotein. TMPRSS2 entails S protein in subunits S1/S2 and S2´, allowing viral and cellular membrane fusion driven by S2 subunit . Once inside the cell viral positive sense single strand RNA is translated into polyproteins that will form the replicase-transcriptase complex. This complex function as a viral factory producing new viral RNA and viral proteins for viral function and assembly . Considering these particularities, the infection first begins on upper respiratory tract mucosa and then reaches the lungs. The primary tissue damage is related to the direct viral cytopathic effects. At this stage, the virus has the potential to evade the immune system, where an inadequate innate immune response can occur, depending on the viral load and other unknown genetic factors. Subsequently, tissue damage is induced by additional mechanisms derived from a dysregulated adaptive immune response .
Although most of COVID-19 cases have a mild clinical course, up to 14% can evolve to a severe form, with respiratory rate ≥ 30/min, hypoxemia with pulse oxygen saturation ≤ 93%, partial pressure of arterial oxygen to fraction of inspired oxygen ratio < 300 and/or pulmonary infiltrates involving more than 50% of lung parenchyma within 24 to 48 h. Up to 5% of the cases can be critical, evolving with respiratory failure, septic shock and/or multiple organ dysfunction, presumably driven by a cytokine storm . Host characteristics, including aging (immunosenescence) and comorbidities (hypertension, diabetes mellitus, lung and heart diseases) may influence the course of the disease . The false paradox between inflammation and immunodeficiency is highlighted by the severe form of COVID-19. Thus, severe pneumonia caused by SARS-CoV-2 is marked by immune system dysfunction and hyperinflammation leading to acute respiratory distress syndrome (ARDS), macrophage activation, hypercytokinemia and coagulopathy .
Herein, we aim to review the factors related to the dysregulated immune response against the SARS-CoV-2, along with its relation with severe forms of COVID-19, namely ARDS and cytokine storm (CS).
When surveying the current literature on COVID-19, the “cytokine storm” is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, “forcing” many virus-infected host cells to decide to commit “suicidal” regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this “suicidal” cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses—as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.
When the first articles on severe and fatal outcomes of COVID-19 were published, researchers worldwide working in the field of damage-associated molecular patterns (DAMPs) thought spontaneously: this is the work of DAMPs! And the researchers were surprised that most authors focused on the pathogenetic role of the “cytokine storm” observed in patients developing viral pneumonia-induced acute respiratory distress syndrome (ARDS) without discussing the fundamental part of DAMPs in initiating cytokine production. However, quite admittedly, the dataset on the pathogenetic role of DAMPs in COVID-19 is still too poor to prove their vital pathogenetic role in this challenging disease. On the other hand, there is accumulating evidence indicating that DAMPs are involved in respiratory viral disorders (as in all infectious diseases), culminating in three recent reports on their detection in COVID-19 patients [1,2,3]. This should be reason enough for a short review.
DAMPs in infectious diseases at a glance
The danger/injury model in Immunology, proposed in 1994 [4, 5] and after that several times modified, argues that immune responses are driven by cell stress and tissue injury, including pathogen-caused stress and injury, rather than by the recognition of non-self molecules derived, for example, from pathogenic invaders. The core of this model refers to the generation and emission of DAMPs, that is, molecules that are generated, exposed, or emitted upon any stress, damage, or death of cells.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the virus that causes coronavirus disease 2019 (COVID-19), is associated with high mortality and hospitalization rates. However, many patients who are infected with SARS-CoV-2 remain asymptomatic or develop mild symptoms.
In a recent study published on the preprint server bioRxiv*, researchers focus on the relationship between the pre-existing airway neutrophils and SARS-CoV-2 infection to determine the impact that neutrophils have on COVID-19.
An overview of neutrophils
Neutrophils are the first and predominant immune cells that are recruited to the respiratory tract in response to viral infection. Upon their arrival, neutrophils release various inflammatory mediators in an effort to rapidly eliminate the pathogen from the infected area.
Neutrophils are capable of recognizing infectious sites as well as act as sites of infections which, together, leads to an acute inflammatory response. An uncontrolled massive inflammatory response, which is also known as the cytokine storm, has been documented in patients with severe COVID-19.
“Despite their importance in anti-viral immunity and response to viral pathogens, neutrophils have been somewhat overlooked for their role in the pathogenesis of SARS-CoV-2 infection.”
A preprint version of the study is available on the medRxiv* server, while the article undergoes peer review.
Since the beginning of the pandemic, it has become clear that men are often more affected by COVID-19, with a higher likelihood of severe illness and a greater chance of death.
The current study focused on assessing brain injury markers (BIM) within 48 hours of hospitalization and at three months later.
BIMs are recognized as being valid indicators of injury to nerve cells and astrocytes, in human immunodeficiency virus (HIV) infection, sepsis and cardiac arrest. The current study focused on six, namely, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), S100B, ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), Syndecan-1 and microtubule-associated protein 2 (MAP 2).
The scientists also examined levels of two markers of endothelial injury (Intercellular Adhesion Molecule 1, ICAM-1 and Vascular Cell Adhesion Molecule 1, VCAM-1) and of inflammation, in the form of cytokines or chemokines.
These were measured in hospitalized patients and in controls in a single hospital in Houston, Texas, USA. None of them had chronic lung, heart, neurological or psychiatric disease, cancer, or any disabling condition.
Increased markers of endothelial and brain injury
The researchers found that within 48 hours of hospitalization, that is, during the acute phase, patients had higher markers of brain injury like MAP2 and NSE than controls. The mean levels showed an increase of 60% to 145%, depending on the individual marker, relative to the controls.
Of these markers, MAP2 is a sign of dendritic injury, and was high at both acute and chronic time points. It has previously been shown to be high after traumatic brain injury and predicts long-term outcomes.
NSE is found in nerve cells and indicates damage. S100B is found in astrocytes and is high in traumatic brain injury and in strokes. Thus, this combination of BIMs shows combined nerve cell and astrocytic injury in COVID-19, worse in men than in women.
However, all markers had returned to normal at three months from hospitalization.
Markers of endothelial injury were also higher with acute infection, with the mean levels being two and three times higher than in controls, for ICAM1 and VCAM1, respectively. These were not assessed at three months.
The endothelial marker ICAM1 is released in response to IL-1b and TNFα. The effects are increased leukocyte adhesion, which reduces the barrier’s integrity and promotes leakage from the blood vessels.
Cytokines and chemokines were also much higher, in some cases, in acute infection, but others showed a decrease. Of 38 chemokines and cytokines evaluated, seven were high, while two were low. Again, these reverted to normal levels at three months.
TNFα is a potent inflammatory mediator. Its elevation in this context indicates that the vascular injury is probably inflammatory in origin and not due to viral injury.