studies emerging from China suggest that for many patients who die of Covid-19, it may be their own immune system, rather than the virus itself, that deals the fatal blow. This is called a cytokine storm.
The treating physician is often placed between a rock and a hard place. Corticosteroids can be powerfully broad immunosuppressive agents, and they are inexpensive and readily available throughout the world. However, it can be frightening for a physician to treat a severely ill, infected individual with such powerful and wide-ranging immune suppression.
Hypercytokinesemia (cytokine storm, cytokine cascade) is a potentially lethal reaction of the immune system, the essence of which lies in the uncontrolled and uncontrolled protective function of activation of immune cells by cytokines in the inflammation center and release by the latter of a new portion of cytokines, due to the direct connection between these processes. The vicious circle causes the destruction of the inflammation center tissues, at the same time the reaction spreads to the neighboring tissues and in the process of development becomes systematic, covering the whole organism.
It can lead to polyorgan failure.
Article Cytokine Storm Syndrome: Looking Toward the Precision Medicine Era
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Cytokine release syndrome (CRS) or cytokine storm syndrome (CSS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs.[3] It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies.[4][5] Severe cases have been called cytokine storms.[2] When occurring as a result of drug administration, it is also known as an infusion reaction.[1]
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In the 2019–20 coronavirus pandemic, a number of deaths due to COVID-19 have been attributable to cytokine release storms.[32][33][34]
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Prevention
Severe CRS caused by some drugs can be prevented by using lower doses, infusing slowly, and administering anti-histamines or corticosteroids before and during administration of the drug.[4] Additionally, blocking GM-CSF is being explored as prevention for CAR-T associated CRS, acute GVHD, and coronavirus disease 2019 (COVID-19) induced cytokine storm and ARDS.
In vitro assays have been developed to understand the risk that pre-clinical drug candidates might cause CRS and guide dosing for Phase I trials, and regulatory agencies expect to see results of such tests in investigational new drug applications.[2][20]
A modified chandler loop model can be used as a preclinical tool to assess infusion reactions.[21]
Management
Treatment for less severe CRS is supportive, addressing the symptoms like fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and antihypotensive agents to raise blood pressure. For moderate to severe CRS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgment must be used to avoid negating the effect of drugs intended to activate the immune system.[4]
Tocilizumab, an anti-IL6 monoclonal antibody, was FDA approved for steroid-refractory CRS based on retrospective case study data.[4][5] While anecdotal evidence suggests it may be efficacious in reducing CRS, no randomized prospective trial has provided direct evidence of IL-6R blockade reducing incidence or severity of CRS.
Lenzilumab, may also be effective at managing cytokine release by reducing activation of myeloid cells and decreasing the production of IL-1, IL-6, MCP-1, MIP-1, and IP-10.
Although frequently used to treat severe CRS in people with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.[15]
cytokine storm listen (SY-toh-kine …) A severe immune reaction in which the body releases too many cytokines into the blood too quickly.
https://www.cancer.gov/search/results
Flu-Like Symptoms and Cancer Treatment - Side Effects
Immunotherapy, including CAR-T cell therapy, and chemotherapy may cause flu-like side effects such as chills, diarrhea, fatigue, and fever. Some people may experience cytokine release syndrome (CRS). Learn what questions to ask your doctor and when to seek urgent medical care.
cytokine release syndrome listen (SY-toh-kine reh-LEES SIN-drome)A condition that may occur after treatment with some types of immunotherapy, such as monoclonal antibodies and CAR-T cells. Cytokine release syndrome is caused by a large, rapid release of cytokines into the blood from immune cells affected by the immunotherapy. Cytokines are immune substances that have many different actions in the body. Signs and symptoms of cytokine release syndrome include fever, nausea, headache, rash, rapid heartbeat, low blood pressure, and trouble breathing. Most patients have a mild reaction, but sometimes, the reaction may be severe or life threatening.
Journal for ImmunoTherapy of Cancer volume 6, Article number: 56 (2018) Cite this article
Abstract
During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.
Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction that is associated with chimeric antigen receptor (CAR)-T cell therapy, therapeutic antibodies, and haploidentical allogeneic transplantation. Immune effector cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome that can occur in some patients who are treated with immunotherapy and may or may not accompany CRS.
This topic will discuss the clinical presentation, diagnosis, and management of CRS.
Treatment of refractory B cell malignancies with CAR-T cell therapy and bispecific antibodies (eg, blinatumomab) is described separately. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Remission induction' and "Treatment of relapsed or refractory diffuse large B cell lymphoma", section on 'Treatment of later relapse/chemoresistance'.)
Clinical presentation, diagnosis, and management of macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) and related systemic inflammatory reaction syndromes are discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)
EPIDEMIOLOGY
CRS occurs in patients treated with various types of immunotherapy or haploidentical allogeneic hematopoietic cell transplantation (HCT). The incidence of CRS varies with the causative treatment, underlying malignancy, and because of different and evolving definitions of the syndrome.
Cytokine Release Syndrome (CRS) After Immunotherapy
What Is Cytokine Release Syndrome?
Cytokine release syndrome (CRS) is a collection of symptoms that can develop as a side effect of certain types of immunotherapy, especially those which involve T-cells. The syndrome occurs when immune cells are activated and release large amounts of cytokines into the body. Cytokines are small proteins that act as cell messengers to help direct the body’s immune response. However, high levels of cytokines may cause increased inflammation throughout the body. This can be harmful and interfere with a number of body functions. In severe cases, CRS can cause organ failure and even death.
CRS usually develops within 3-14 days after T cell based immunotherapy. It often begins with fever and flu-like symptoms but can worsen quickly and cause serious illness.
Management of CRS includes monitoring and supportive care to control symptoms. Some patients may need intensive care and medicines to lower the immune response (immunosuppressive drugs).
At-risk patients will be monitored for about a month after an immunotherapy infusion. Patients who develop symptoms usually improve within 1-2 weeks. Most patients do not have long-term problems from cytokine release syndrome.
Tocilizumab, also known as atlizumab, is an immunosuppressive drug, mainly for the treatment of rheumatoid arthritis (RA) and systemic juvenile idiopathic arthritis, a severe form of arthritis in children. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. It was developed by Hoffmann–La Roche and Chugai.[1]
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COVID-19
China's National Health Commission included the use of tocilizumab in guidelines to treat coronavirus disease 2019 (COVID-19) patients.[32] In March 2020, China approved tocilizumab for the treatment of inflammation in patients with the coronavirus SARS-CoV-2. As of March 2020, there is no evidence whether this treatment is effective.[33] Chinese health officials say that only 21 patients have been asked to use this medicine.[34]
On 11 March 2020, Italian physician Paolo Ascierto reported that tocilizumab appeared to be effective in three severe cases of COVID-19 in Italy.[35] On 14 March 2020, three of the six treated patients in Naples had shown signs of improvement prompting the Italian Pharmacological Agency (AIFA) to expand testing in five other hospitals.[36] Roche and the WHO are each launching separate trials for its use in severe COVID-19 cases.[37]
On 26 March 2020, Guglielmo Gianotti, executive director of surgery at the Cremona hospital said: "The only drug that we've seen that is showing the slightest bit of benefit to COVID-19 patients is the immunosuppressive drug Tocilizumab, which is mainly used for the treatment of rheumatoid arthritis. It's being trialled at the Pascale Cancer Institute in Naples with very encouraging results." [38]
https://en.wikipedia.org/wiki/Tocilizumab
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Hydroxychloroquine (HCQ), sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine.[2] Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda.[2] It is taken by mouth.[2] It is also being studied as an experimental treatment for coronavirus disease 2019 (COVID-19).[3][4]
Common side effects include vomiting, headache, changes in vision, and muscle weakness.[2] Severe side effects may include allergic reactions.[2] Although all risk cannot be excluded, it remains a treatment for rheumatic disease during pregnancy.[5] Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.[2]
Hydroxychloroquine was approved for medical use in the United States in 1955.[2] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] In 2017, it was the 128th-most-prescribed medication in the United States, with more than five million prescriptions.[7]
https://en.wikipedia.org/wiki/Hydroxychloroquine
During the current coronavirus epidemic, several cases of young patients in China and Italy with cytokine storm, whose immune system was "calmed" by a drug called tocilisumab, have already been described.
A classic example, described in Annals of Oncology: after only two doses, at eight-hour intervals, the patient's fever disappeared quickly, his oxygen level increased, and a chest scan showed that his lungs had cleared out, suggests that tocylisumab may be an effective antidote for coronavirus in some people.
Prior to COVID-19, tocylizumab was used to treat rheumatoid arthritis and some cancers: it mutes the activity of a specific cytokine called interleukin-6, which is associated with an overly intense immune response. Tocylizumab is now in clinical trials in China (where it has already been approved for treatment of serious cases) and the USA.
As a transmembrane protein, ACE2 serves as the main entry point into cells for some coronaviruses, including HCoV-NL63;[5] SARS-CoV (the virus that causes SARS);[16][17][18] and SARS-CoV-2[19] (the virus that causes COVID-19).[20][21][22]
This has led some to hypothesize that decreasing the levels of ACE2, in cells, might help in fighting the infection. On the other hand, ACE2 has been shown to have a protective effect against virus-induced lung injury by increasing the production of the vasodilator angiotensin 1–7.[23] Furthermore, according to studies conducted on mice, the interaction of the spike protein of the coronavirus with ACE2 induces a drop in the levels of ACE2 in cells through internalization and degradation of the protein and hence may contribute to lung damage.[23][24]
Both ACE inhibitors and angiotensin receptor blockers (ARBs) that are used to treat high blood pressure have been shown in rodent studies to upregulate ACE2 expression hence may affect the severity of coronavirus infections.[25][26] However, multiple professional societies and regulatory bodies have recommended continuing standard ACE inhibitor and ARB therapy.[27][28][29] A systematic review and meta-analysis published on July 11, 2012, found that "use of ACE inhibitors was associated with a significant 34% reduction in risk of pneumonia compared with controls." Moreover, "the risk of pneumonia was also reduced in patients treated with ACE inhibitors who were at higher risk of pneumonia, in particular those with stroke and heart failure. Use of ACE inhibitors was also associated with a reduction in pneumonia related mortality, although the results were less robust than for overall risk of pneumonia."[30]
ACE2 has been found to have an affinity for the S-glycoproteins of some coronaviruses, including SARS-CoV[4] and SARS-CoV-2[5][6][7], and thus is the point of virus penetration into the cell. Moreover, it is assumed that SARS-CoV-2 infection may suppress ACE2, leading to a toxic excess accumulation of angiotensin II, which causes acute respiratory distress syndrome and myocarditis[8][9].
A human recombinant soluble angiotensin converting enzyme 2 (hrsACE2) has been created, which is called APN01 and is already undergoing the second phase of clinical trials on the ability to treat pneumonia caused by SARS-CoV-2. APN01, simulating human ACE2, is supposed to be able to counteract the disease in two ways. First, the virus binds to soluble ACE2 / APN01 instead of ACE2 on the cellular surface, which means that the virus can no longer infect cells. Secondly, APN01, acting as APF2, reduces harmful inflammatory reactions in the lungs and other organs and protects them from damage[10][11].https://ru.wikipedia.org/wiki/%D0%90%D0%BD%D0%B3%D0%B8%D0%BE%D1%82%D0%B5%D0%BD%D0%B7%D0%B8%D0%BD%D0%BF%D1%80%D0%B5%D0%B2%D1%80%D0%B0%D1%89%D0%B0%D1%8E%D1%89%D0%B8%D0%B9_%D1%84%D0%B5%D1%80%D0%BC%D0%B5%D0%BD%D1%82_2
......
https://www.nature.com/articles/nm1267
A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury
IL-6-mediated endothelial cell contraction increases capillary permeability, causing interstitial pulmonary edema (imaging: ground-glass opacity), parenchymal infiltration & alveolar collapse (imaging: consolidations). Therefore, inhibiting IL-6 could possibly mitigate these severe complications. Preliminary research shows the effect of Tocilizumab on pulmonary edema (visible on imaging as decreasing ground-glass opacity). This research is far from perfect, however, and there are serious side effects of IL-6 inhibitors (such as increased risk of secondary infections). There are multiple studies (phase-3-trials) ongoing at the moment, but other than the results from Xu (2020), and anecdotal reports, there is no hard data yet.
Article Interleukin-6 Causes Endothelial Barrier Dysfunction via the...
Preprint Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis
Article Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-...
Article Tocilizumab treatment in COVID-19: A single center experience
Bradykinin (BK), formed by Kallikrein, also increases capillary permeability, and therefore contributes to pulmonary edema. BK-dependent pulmonary edema is resistant to corticosteroids (or adrenaline). ACE-2, next to its role in RAAS, also inactivates a BK-variant (that acts mostly on B1R in the lungs). Therefore, Ace-2 mitigates pulmonary edema. Covid-19 reduces ACE-2, thereby increasing BK, which subsequently increases pulmonary edema (linking the virus directly to pulmonary edema). Comorbidities (such as diabetes) also reduce ACE-2, thereby contributing to pulmonary edema. Blocking the B1R and B2R receptors (or the upstream Kallikrein-process) might mitigate severe complications. Icatibant is a selective B2R-inhibitor (Firazyr). There have been some preliminary good results using Icatibant on covid-19 patients. However, once again, there is no hard data yet (that I know of).
Preprint Kinins and Cytokines in COVID-19: A Comprehensive Pathophysi...
Article Attenuation of pulmonary ACE2 activity impairs inactivation ...
The complement-system activation possibly plays a role in this stage of the disease as well, and C5 blockade (with Eculizimab) might also help (studies are ongoing at the moment).
Preprint Highly pathogenic coronavirus N protein aggravates lung inju...
Article Will Complement Inhibition be the New Target in Treating COV...
C1-blockers not only downregulate the complement system, but also downregulate BK through inhibition up the upstream Kallikrein-process. I believe there are some preliminary good results using Ruconest on covid-19 patients. A clinical trial is ongoing at the moment.
Article C1-esterase inhibitor: An anti-inflammatory agent and its po...
Article The Influence of ACE Inhibition on C1-Inhibitor: A Biomarker...
So, there are lots of potential mitigating factors, and even though some preliminary studies have been done (with promising results), there is no hard data available (that I know of).
It would be interesting if some anti-hypertension meds might provide benefit in cytokine storm over the course of covid-19 infections. Would patients on any of them prior to & during covid-19 infection fare better than patients without any of them or similar after accounting for zinc status (altered zinc homeostasis portends poor outcomes).
Four meds follow that might because they have been found to be capable of supressing TNFα/(NF)-κB in studies though in doses higher than used to treat hypertension.
For instance, possibly carvedilol;
Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity [2003]
Olmesartan as used in the Marshall Paradigm (growing body of research supports the use of olmesartan as a part of a curative therapy for chronic disease).
https://mpkb.org/home/protocol
Science behind olmesartan (Benicar)
https://mpkb.org/home/protocol/olmesartan
And ARBs losartan & telmisartan;
Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting the MAPK and NF-κB pathways in B and T cells
A point of view from SPAIN in the management of Covid19 & use of steroids.
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My name is Angel Atienza, I am an internal medicine specialist and lead of the COVID area at the Hospital Doctor Peset in Valencia, Spain.
When the epidemic began we were horrified to see the severity of this disease. The patients developed respiratory failure, frequently in a very sudden way, with not much perceptible dyspnoea, and had to be transferred to the ICU for ventilatory support.
We have now learnt to manage this disease. As you know, the disease has two phases, first an infectious phase that lasts for a week after the onset of symptoms, and thereafter an inflammatory phase that starts around the seventh or eighth day, with the onset of lung infiltrates and biochemical derangements that are now well known.
It is not known why some patients develop this second inflammatory phase and others do not, what does seem clear is that the inflammatory phase is mediated by the activation of macrophages and the release of inflammatory mediators that disrupt the alveolo - capillary membrane, leading to respiratory distress.
In most hospital treatment protocols anti inflammatory therapy is reserved for those patients that progress to severe pneumonia.
In our hospital we have taken the opposite approach, we have defined a treatment protocol aiming to preempt the inflammatory changes.
We believe that the radiological changes that appear in chest imaging are not infectious in nature, but rather caused by the triggering of the inflammatory cascade. We should thus intervene early, before an anatomical injury of the alveolar membrane happens leading to respiratory distress.
In those patients that exhibit early radiological changes, we have started using a treatment protocol with steroids starting on the sixth day of symptoms and lasting to day 12, to dampen the inflammatory response and prevent the progression to ARDS.
We think that the treatment for COVID pneumonia is to start steroid treatment at the stage of mild pneumonia, particularly in febrile patients with biochemical disturbance, at the end of the first week.
We are using methylprednisolone at a dose of 80 mg per day, either as a single daily dose, or as 40 mg bd, and in some patients in whom we observe a satisfactory response we add a further antinflammatory agent such as tocilizumab or anakinra.
With this we are seeing very good results, a decreased need for admission to ICU, shorter hospital LOS and clinical and radiological responses that are nothing short of spectacular.
We believe that the WHO is mistaken in considering steroids contraindicated in patients with COVID 19; in following this, antiinflammatory therapy is delayed to a more severe stage when is is much less effective.
We are gathering data on this that we will soon share, but we feel duty bound to publicise this information without any further delay, and we encourage you to trial this treatment.
Patients are not being killed by the infection, they are being killed by the inflammatory response triggered by macrophage activation.
Please share this information and start using it, collect data and let´s beat the epidemic together.
EARLY ANTIINFLAMMATORY TREATMENT AND GOOD LUCK DEAR COLLEAGUES,
Many MABs are under study mainly focused on IL1, IL6 and TNF a. Recently we suggest a therapeutic repurposing of diacerein for COVID19 treatment. https://authors.elsevier.com/a/1bD4M15pGc1GGK