COVID-19 and Cytokine Storm Syndrome
Approximately 5% of patients with COVID-19 develop a dysregulated cytokine response to the infection. This syndrome is called cytokine storm syndrome (CSS), and is associated with severe COVID-19 disease. Several assays can be helpful in detecting cytokine storm syndrome and organ dysfunction or damage caused by it. One assay, specifically IL-6, is thought to be the central regulator of the cytokine response and cytokine storm. Elevated IL-6 is associated with higher risk of progressing to severe disease or death in COVID-19 patients.
COVID-19 and cytokine storm syndrome. The COVID-19 pandemic has struck nearly every country in the world. Statistics change daily, but as of May 7th 2020, total confirmed COVID-19 infections have surpassed 3.8 million worldwide. And they continue to rise. Although this is a tremendous number, it represents only .05% of the total world population. For those affected, however, the virus can be deadly so far over 266 thousand deaths have been recorded. This represents approximately 17% of all cases that currently have a known outcome. The death count also rises daily and lags behind the infection rate by about 2 weeks. While the true mortality rate will not be determined until the pandemic has waned considerably and the majority of known cases have been resolved and recorded, the anticipated overall rate estimated in early March by the World Health Organization will be around 3.4%. While the disparity between the current apparent mortality rate of 17% shown here and the projected final mortality rate is large, it is important to keep in mind that the estimated rate was based primarily on the results from China, which had previous experience with the related SARS outbreak in 2003 and thus was able to employ erlian rapid containment and mitigation measures. The worldwide mortality rate is likely to decrease as more testing is conducted, and a larger prevalence of mild or asymptomatic infections becomes apparent. Development of new therapeutic options and the potential for a vaccine could also reduce the final mortality rate. Fortunately, 83% of the over 1.3 million individuals with known outcome have recovered at home or been discharged from the hospital. However, new infections are reported daily and the infection rate is still increasing in some areas. Although 98% of active cases are considered to be mild, 2% of current patients are in serious or critical condition. Currently the case rate has risen faster in the United States than in any other country worldwide, and more cases have been confirmed there than anywhere else. This is likely just the tip of the iceberg. It is difficult to know what the true case rate is without substantial testing as of May 7th no more than two point. 4% of the total US population has been tested according to information from Johns Hopkins University. This equates to 24 out of every 1000 people. Coronavirus disease 2019, better known as COVID-19, is caused by the SARS Cove, two coronavirus. It is closely related to the coronavirus is that caused the SARS outbreak in China in 2003, and the MERS outbreak in the Middle East in 2009. Although the current mortality figures suggest that it could be more deadly than SARS, it will likely not be as lethal as MERS. It is, however, far deadlier than annual influenza. One of the primary routes of infection is to inhale the virus when someone nearby coughs or sneezes. Transmission can also occur when secretions from an infected individual get transferred to their hands and left on a surface. If an individual touches that surface or the infected persons hand, the virus can adhere to their skin. If they then touch their nose, mouth or eyes, the virus can be transmitted to the mucous membranes. The virus is highly contagious. The transmissibility of a pathogen in a naive population is estimated by calculating the reproductive number, or are not. This value indicates the average number of people who will be infected by a single carrier in a naive population, that is, a population which has never been exposed to the pathogen. Are not greater than. One indicates that disease transmission is sustainable and can generate an epidemic. The higher the value, the more contagious the pathogen and the greater the risk of infections reaching epidemic levels. The reproductive number for COVID-19 is 3.28, which means that each infected person spreads the virus to approximately three others on average. As you can imagine, and can be seen in the statistics released daily, an at the beginning of this presentation, the number of infected individuals can increase very rapidly. At 3.28 the mean are not for COVID-19 is substantially higher than the reproductive numbers calculated for the 1918 Spanish influenza epidemic an for seasonal influenza. It is similar to the are not calculated for SARS and MERS, although the value can vary depending on the population analyzed. The reproductive number can be influenced by changing demographics and behaviors over the course of an epidemic. Especially if mitigating measures such as social distancing or adopted. It is possible that are not will increase once the true prevalence of the asymptomatic and mild cases has been determined. Some people are at higher risk of contracting COVID-19 and are also at higher risk of developing severe symptoms. People at high risk are the elderly. Individuals who are immunocompromised, such as cancer patients, patients with autoimmune diseases and transplant patients. And individuals with underlying medical issues, in particular those with diabetes. Hypertension. Chronic lung diseases such as asthma. And those with cardiovascular disease. At least 80% of those known to be infected with SARS Cove, two appear to Mount a typical immune response in a normal immune response when somatic cells are confronted with molecular patterns indicating an invasion or proximity of pathogen, they generate chemical alert signals to the immune system for help. In one of the earliest events in this process. Circulating monocytes arrive at the site of infection. Monocytes are a type of leukocyte which is a type of white blood cell. Monocytes ingest the detected pathogens and engulf them in a process called fragile cytosis The monocyte destroys the pathogen and proteins from the invader get extruded into the monocytes membrane. When this occurs, the monocyte is now referred to as an antigen presenting cell or APC. APC's sent out dozens of different chemical signal molecules called cytokines. Cytokines are usually small glycoproteins. In addition to proinflammatory cytokines such as interleukin 6, interleukin 8 and tumor necrosis factor Alpha. Anti inflammatory cytokines, such as interleukin 10 are released to regulate the cytokine response. The release cytokines recruit immature T cells to the APC. T cells are another type of leukocyte and are highly specific for the pathogen they respond to. This means that only the T cells that can recognize the proteins presented by the APC will become activated. Each type of cytokine invokes specific and nonspecific physiological effects. Proinflammatory effects of cytokines include temperature elevation, which can be local to the infection, like when you have a minor skin infection. Or it can be systemic in the form of a mild or substantial fever in COVID-19 fever can be very high and last for multiple days. Cytokines also cause inflammation of the vasculature, especially Kappel Aries. This results in mildly increased permeability of blood vessels, which enables movement of circulating immune cells, cytokines and other immune system elements such as complement, out of blood vessels, an into the infected tissue. This also causes fluid leakage into the affected area as a byproduct which causes localized swelling. Cytokines released by Apcs help T cells recruited to the infection site to mature and become activated so they can destroy the invading pathogens or the cells they're infecting. Activated T cells release more inflammatory cytokines into the infected site, which amplifies the cytokine cascade and recruits greater numbers of infection fighting cells to where they are needed. I'll 10 is also released from T cells to regulate the proinflammatory response. I'll six can also play an anti inflammatory regulatory role, but that will not be discussed in this presentation. Source Cove to can infect many different types of cells and tissues in the body. However, the respiratory system is the site most commonly affected. Most of the symptoms associated with COVID-19 are caused by the effect of the viral response in the alveoli. The sight of oxygen absorption and diffusion into the bloodstream. The source virus utilizes the ace two receptor to bind cells. The normal function of this receptor is to help to control blood pressure by breaking down angiotensin 2A protein that causes vasoconstriction. All the older cells and certain other types of cells are rich in ace two receptors. It is conjectured that individuals with hypertension have a much higher density of Ace two receptors on the alveolar epithelial cells and that individuals taking ace two inhibitors might have more ace two receptors than those people who are not taking this class of drugs. After contacting the ace two receptor membrane bound TMPRSS 2 Assyrian protease cleaves the trimeric binding region from the spike protein. Serum proteases have normal functions in the cell, but they are also used by other viruses, such as HIV, to help them gain entry to cells. Priming by TMPRSS 2 causes the Fusion peptide portion of the spike protein to undergo a confirmational change that allows it to attach to the host cell. Once the Fusion peptide has attached, the virus can come into closer proximity to the cell, allowing the viral and cell membranes to fuse so the virus can inject its RNA into the host cell. In the normal immune response, fluid accumulates in the alveoli as a result of increased vascular permeability. This and the destruction of infected tissues by the virus, cytotoxic T cells and natural killer cells, which are another type of immune cell, underlies localized inflammation that results in the characteristic symptoms of chest tightness and shortness of breath. Ask the disease takes its course. More cells become infected and damaged by the virus and more and more immune cells in cytokines. Enter the lungs, causing increasing inflammation and the accompanying symptoms. During the course of infection Accum Pensa Tori anti inflammatory cytokine response is initiated to help keep the immune response under control. Approximately 80% of individuals who have what is considered to be non severe or stage one disease recover without the need of hospitalization or anything more than over the counter medications. In these individuals, the immune response eventually outpaces viral replication and cellular destruction. As the infection resolves, Morcom, Pensa, Tori anti-inflammatory cytokines released to downregulate the inflammatory response. These messengers instruct cells to stop amplifying the cytokine cascade as the infection clears so that no more pathogen fighting cells are recruited and no more inflammatory cytokines are made. Fluid accumulation ceases and fluid is absorbed as appropriate. Tone is restored to Kappel Aries. Eventually immune cells disperse and inflammation resolves. One notable complication of COVID-19 is severe pneumonia, which occurs in about 20% of patients. One of the ways this can occur. Is if the immune system cannot fight the infection effectively. This can happen when viral replication outpaces the immune response. In addition to organs and other tissues, T cells are actively targeted by SARS Cove, two in much the same way that HIV targets and destroys T cells driving the patient to immune incompetence. These cells do not have ace two receptors. They do however have CD 147, which is a membrane bound protein complex that is essential for host recognition of other pathogens. The receptor also incorporates a tissue metalloproteinases which could be used by the virus to prime the spike protein for membrane Fusion. An entry of viral DNA, but this process is still poorly understood and studies are ongoing. To gain greater understanding. The viral membrane fuses with the T cell. After binding to the CD 147 receptor and injects its RNA into the cell. The virus then replicates until the cell bursts and dies. As he immune system begins to fail. Viral spread worsens, triggering a stronger cytokine response by undamaged immune cells. Greater immune cell proliferation and greater inflammation and fluid accumulation. As fluid and damage accumulate in the lungs, it becomes more and more difficult for the lungs to absorb oxygen and exchange it for carbon dioxide. As a result, the patient becomes increasingly hypoxic, which means their oxygen level is lower than optimum and increasingly hypercapnic, which means that there is more carbon dioxide in the blood that is optimal. Pneumonia is typically marked by a dry, unremitting cough. High fever and shortness of breath that results in the need for oxygen supplementations via nasal cannula or ventilator in more severe cases. Approximately 5% of patients with COVID-19 develop a dysregulated sided kind response to the infection. As in the normal response activated macrophages and T cells at the infection site along with circulating monocytes, released cytokines into the bloodstream to recruit more immune cells. Although multiple cytokines are released, the principle side akinde indicated inside a kind storm syndrome is IL 6. When side Akinde Storm syndrome develops, this response is greatly amplified. Recruited cells further amplify cytokine production. As circulating cytokines increase more and more, immune cells are recruited and perpetuate cytokine hyper production. Note that in this example, proinflammatory aisle 6 is emphasized, but other pro and anti inflammatory cytokines also elevate. Excessive cytokines cause Kappel Aries to become hyper permeable. Massive amounts of fluid began to leak into the cardiovascular system, stimulating the coagulations cascade. Micro thrombosis form and block. Kappel Aries. Over a century ago, Sir William Ostler, one of the four founders of Johns Hopkins Medical School and considered to be the father of modern medicine, made the observation that the body systemic response to inflammation caused more damage than the infection invoking it. In the case of COVID-19 pneumonia, severe pulmonary inflammation develops in response to the action of hyper amplified side accounts. Fluid leakage from hyper permeable Kappel Aries, in conjunction with a massive influx of macrophages and T cells fills the alveoli with a thick sticky fluid that disrupts oxygen. Carbon dioxide exchange, resulting in localized and systemic tissue, hypoxia and respiratory failure. Micro thrombosis can cause ischaemia in organs, especially the brain, lungs, heart, kidneys, liver and extremities. Excessive clotting subsequently depletes platelets and clotting factors, and can cause bleeding in organs and other tissues due to disseminated intravascular coagulations. Systemic inflammation can also cause acute liver and kidney injury, as well as myocarditis. Several assets can be helpful in detecting cytokine storm syndrome, an organ dysfunction or damage caused by it. Elevation and many proinflammatory and some anti inflammatory cytokines are the most direct indicators of inflammation, but not always the easiest to detect as circulating levels can be quite low and half life is frequently only a few hours. CR P is easier to detect, but it's a surrogate marker of inflammation. It elevates in response to I'll 6 so it is in general a later marker. But levels do not always correlate with file 6. Serum amyloid A is an early and sensitive marker of the acute phase inflammatory response and also appears to correlate with disease severity. As shown earlier, micro thrombosis often form in response to cytokine storm syndrome and coagulations markers, especially D dimer, have been shown to correlate with severity of cytokine storm. An mortality risk. Again, D dimer is a downstream marker and so would be expected to elevate later in the development of cytokine storm. Other assays shown here reflect various types of organ injury. Interleukin 6 is a small low molecular weight protein. It is released by several different types of cells and is a key mediator of inflammation in response to injury, infection, and neoplastic growth. I'll 6 serves many different functions, including but not limited to, stimulating B cell differentiation and proliferation. Promoting T cell maturation an cytotoxic T cell activity. And stimulation of acute phase immune response proteins by the liver. I'll 6X directly on several different white blood cell types. Several studies have now provided good evidence that cytokine storm syndrome is the driving factor behind the development of COVID-19 disease severity and many of its consequences, as exemplified here, by author statements from 2 recent review articles. Note that the first quote refers to Sadakane Storm syndrome as cytokine release syndrome, which is simply the same process by a different name. GAO, at all compared the haematological parameters of 43 adult patients diagnosed with sepsis. 28 patients were diagnosed with mild covin, 19 infection and 15 were classified as severe. This study determined that aisle six was elevated in the 15 COVID-19 patients who had severe disease. They found good differentiation between this group and those who had only mild disease, as can be seen by the minimal overlap between the lowest quartile with severe disease and the highest quartile of those with mild disease. Chow, at all, retrospectively evaluated a variety of biomarkers in 191 adult COVID-19 patients from Wuhan, China. 137 who survived and 54 who died in hospital. I'll 6 levels were observed to be higher in those who did not survive with only a small overlap between the interquartile ranges very early after disease onset. In addition. Levels and survivors remained low throughout the duration of the illness. While I'll six was higher and continued to rise throughout the disease course and those who did not survive. Similarly, data from a study by Lucing at all confirm that I'll 6 levels decrease as symptoms abate, and that patients with severe disease have higher. I'll 6 throughout the course of illness than patients with mild disease. During a 28 day. Harold at all evaluated 40 patients who were hospitalized with PCR confirmed covid for risk of progression to respiratory failure and the need for mechanical ventilation. A severe complication arising in a small but significant percentage of covid patients. 13 patients, 32.5% of the study group required ventilation. A statistically significant elevation in aisle six was observed in patients at first assessment who later required mechanical ventilation. The time to the need for ventilation range from one hour to 9 days after admission. The highest recorded level of I'll six before progressing to into Bashan was also found to be significantly higher in patients who progressed to the acute respiratory distress syndrome or a RDS. Note also that I'll 6 increased overall from first assessment in patients who progressed RDS, whereas the elevation was minimal in those who did not require mechanical ventilation. The authors concluded that although oil 6 levels were relatively low compared to levels often seen in patients with septic shock. I 06 greater than 80 picograms per mil was sufficient for predicting which patients were at high risk for progressing to RDS. Likewise Lu Tao at all showed the aisle 6 level could be correlated to imaging evidence of COVID-19 severity. Data were collected on 69 patients with symptoms of severe covin 19. Diagnosis was confirmed using PCR. Samples were collected at baseline and a followup cytokine profile was collected for 30 severe type patients after unspecified treatment. Some of the patient levels are shown in the graphs above, grouped by I'll. Six base level. Each line indicates a unique patient. The CT scans are from a single patient in each group. The authors observed that greater aisle 6 elevation was associated with evidence of increased severity in CT scans and decreased I'll 6 following treatment was positively correlated with improvement in CT images. In other studies, IO six was significantly greater in patients with severe disease than those who did not have severe disease. In addition, lower I'll six was associated with shorter time from diagnosis to cure and decreased. I'll six was associated with treatment effectiveness. Higher I'll six was associated with shorter time lapse from symptom onset to development of new Monia and high. I'll six was related to clinical manifestations of severity. Leading the investigators to the conclusion that the high level of I'll six was significantly related to the clinical manifestation of severe type patients. Don get all organized their data in such a way that it can be clearly seen that I'll six was over 7 picograms per meal in 97% of critically ill patients. In 62% of patients who had severe illness and in none of the patients who had only mild illness. I'll six was less than seven picograms per mil in 70% of patients with mild illness. In summary, cytokine storm syndrome in COVID-19 patients is caused by a dysregulated immune response to infection. Cytokine storm is associated with severe COVID-19 disease. I'll six is thought to be the central regulator of the cytokine response and cytokine storm. Elevated I'll six is associated with higher risk of progressing to severe disease or death in COVID-19 patients. Thank you for your attention. Siemens Healthineers hopes that you have found this video to be instructive.
SIEMENS .. SIEMENS The immune response in mild COVID-19 Tissue damage caused by CSS can be detected by T-Cells recognize protein remnants presented by the APC and T-CelIs recognize protein remnants presented by the APC and The normal immune response to SARS-CoV-2 T-CeIls recognize protein remnants presented by the APC and The virus infects alveolar cells Thank you! COVID-19 is a deadly and growing pandemic: COVID-19 is a deadly and growing pandemic COVID-19 is caused by the novel SARS-CoV-2 coronavirus and Symptoms are caused by alveolar inflammation and fluid Worsening pneumonia leads to severe symptoms What is Interleukin-6 (IL-6)? Cytokine response to severe viral infection is reflected in IL-6 Correlation between severity of COVID-19 pneumonia and IL-6 APC's send chemical signals to other immune cells COVID-19 is highly contagious and transmissible: CSS exacerbates pneumonia and damages other organs Severe COVID-19 and cytokine storm syndrome (CSS) SARS-CoV-2 infection of lung tissue is common COVID-19 is highly contagious a CSS can be lethal What is Interleukin-6 (IL -6)? Recruited cells amplify the cytokine response IL-6 levels IL-6 Levels and Respiratory Failure IL-6 elevation and subsequent decrease reflects COVID People at high risk of contracting COVID-19 How SARS-CoV-2 infects cells Monocytes detect and "eat" invading pathogens IL-6 elevation and decrease reflects COVID severity before and IL-6 is a sensitive indicator of CSS and developing CSS Kinetics of IL-6 in the peripheral blood of SARS-CoV-2 infected 19 is highly contagious are higher in COVID-19 patients who did not survive CoV-2 infects cells epidemic influenza COVID-19 in comparison to SARS, MERS, -19 is highly contagious Summary COVID-19 COVID- How SARS- Healthineers SIEMENS .. Global statistics as of May 7, 2020 Snd seasonal influenza severity before and after treatment and seasonal influenza after treatment: authors' observations and conclusions United States statistics as of May 7, 2020 levels observed in patients with COVID-19 infection Mean reproductive number (Ro) is 3.28 Mean reproductive number Ro) is 3.28 accumulation is related to the SARS and MERS viruses laboratory testing become activated patients is associated with disease severity Healthineers Low molecular-weight 1.5 15 1.0 Released by: Functions: Ta rgets: Targets: IL-6 at first assessment Maximal IL-6 before intubation ROC curve of maximal IL-6 Elevated test IL-6 <20 pg/mL IL-6 <20 pg/mL IL-6 420 pg/mL IL-6 20 pg/mL Infecated Indicates Infected 300 p -100 pg/mL 30-100 pg/mL 60 20 200 6.6 3,852,660 confirmed infections (total) fto T-cell Mechanical ventilation Mechanical ventilation Fluid 5.5 —France of severe type patients. The decrease of IL-6 was closely related Specificity 80 mmHg 60 mmHg 1.05 0.25 0 25 40 •c SARS-CoV-2 virus Stimulates acute -E 10 800% 300 400%0 10 100% 30 Severe disease Mild disease Myoglobin 80 200 300 values. 20 250 60 3020 40 Elevated IL-6 is associated with higher risk of progressing to severe disease or 10% mortality 34% mortality • termany Fibroblasts to treatment effectiveness, while the increase of IL-6 indicated Eosinophils 266,076 deaths phase C-reactive Alveolar Alveolus Alveolis "In addition, the maximal IL-6 level (cutoff 80 pg/ml) for each patient during disease predicted respiratory failure with IL-6 death in COVID-19 patients. Monocyte/macrophage activation Ferritin COVID-19: COVID-19 MERS: SARS: 1918 HINI 60 20% Coagulation cascade: clotting disease progression." Bronchus epithelial cell high accuracy (p=1.7•10-8, AUC=O.98)." protein - 45 mmHg Proinflammatory cytokine Siemens Healthineers cytokine assays, including IL-6, are not FDA cleared/approved in the U.S. Macrophages rophage 1,400,000 15 150 19 150 13 = 1.5-6.5 Alveolir Alveolis = 2-5 1 25 0 25 Ro=O.69-7.1 Ro=1.O9-7.5 Ro=1.O-7.5 Ro=O.69-7.1 1,317,121 recovered factors and thrombin A IL-IO Survivors Non-survivors Son-survivors Ammonia Kidney injury Liver injury 300 30 150 200 2020 30 10 40 1.0 2020). 20 40 4-6 7-9 13-15 10-12 216 20 150 900% 60% 80 T-cell Mean Ro=3.28 Mean Ro=3 Mean Ro=3.28 Mean 1.27 Mean 1.87 Mean 1.27 Severe disease Non-severe disease May 2020 Product availability may vary from country to country and is subject to varying regulatory Days from illness onset Creatinine "The risk of respiratory failure for patients with IL-6 levels of 80 pg/ml was 22 times higher compared to patients with A TNFa Days after reaching 10,000 cases Bastrophils Anti-inflammatory cytokine Proi-inflammatory cytokine Days after disease onset 2,269,463 currently infected patients Magnitude of cytokine response in serum: IFN-v, TNF, IL-6, IL-lß Infected Normal Severe Mild Cystatin C requirements. lower IL-6 levels." Lungs United Spain Italy UK Russia France Germany Turkey Brazil Iran Liu Y, et al. J Travel Med DOI:lO.1093/jtm/taaa021 (Accessed April 29, 2020). Liu Y, al. Travel Med DOI:10.1093/jtm/taaa021 (Accessed April 29, 2020). Wiersinga WJ, et al. Virulence McGonagle D, et al. Autoimmun Rev 2020:102537. (Accessed 4/15/2020) 48,030 (2% unresolved cases) in serious or critical condition Critical Mild Severe *Assay is not FDA cleared/approved for use in the U.S. Beamer U, et al. protein Sci Biggerstaff M, Infect Dis DOI: Please contact your local representative for availability. M, Infect Dis DOI: 10.1186/1471-2334-1,1-480 States Wiersinga WJ, et al. Virulence Maiumder MS, et al. PLOS Curr DOI: 10.1371/currents.outbreaks.98d2f8f3382d84f390736cd5f5fe133c. tlMMULlTE IL-6 assays are for research use only in the U.S. *Bars represent the median, and upper and lower quartile values. H, The Lancet. 2020. DOI: H, al. The 2020. DOI: H, al. The Lancet. 2020. DOI: accessed April 21, 2020). 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