Can suppressing an out-of-control immune response treat COVID-19?

!-- webeditor: page title-- May 3, 2020 / -- There are many outstanding questions about COVID-19, one of which is how the virus, SARS-CoV-2, kills some patients without causing any symptoms in others.
researchers say clinical evidence and laboratory studies suggest that, for at least some severely ill patients, the main risk comes from an out-of-control immune response that can cause irreparable damage to tissue.
understanding the mechanisms behind this response may be key to finding treatments for these patients.
Dela Cruz, a lung physician at Yale University School of Medicine who studied COVID-19, said that when infected, the virus appears to replicate in patients, leading to disease and an inflammatory response from the immune system to intruders.
then, in patients with severe illnesses, "this inflammatory response can be too severe and excessive, causing many side effects in areas such as tissue damage and organ failure."
" photo source: This view is supported by early clinical reports that found elevated levels of inflammatory-related biomarkers, such as c-reactive proteins.
studies have shown that some patients with serious illnesses develop cytokine release syndrome, or cytokine storms, which means that their immune cells increase the secretion of inflammatory-driven cytokines to dangerously high levels.
for example, researchers in Guangzhou, China, reported in a preprint published in February that eight of the 11 patients with SEVERE respiratory distress syndrome had cytokine release syndrome, including fever, an increase in the number of CD4/CD8 T cells, and elevated levels of cytokine IL-6.
, a Study of 150 COVID-19 patients in Wuhan found that the level of IL-6 in patients who died was significantly higher than in patients who were later discharged from hospital.
authors believe that "cytokine storm syndrome" may be the cause of death from the disease.
" cytokine storm syndrome is a general name for a variety of "physiological phenomena" named by different types of doctors for different types of diseases," explains Randy Cron, a rheumatologist at the University of Alabama at Birmingham, who focuses his research on the phenomenon.
for example, when cytokine storms appear as a result of inflammatory diseases, it is called macrophage activation syndrome, and when cytokine storms originate from CAR T cells to treat leukemia, it is called cytokine release syndrome.
, the impact of cytokines can cause blood vessels to leak, allowing immune cells to enter the organ, potentially leading to organ failure.
cytokine storms can also cause blood clotting.
in influenza infections, cytokine storms are also associated with large amounts of glucose metabolism.
Cron wondered why some COVID-19 patients had cytokine storms while others did not, in part because of genetics.
His own past research has identified the genes that cause familial phage lymphocytosis, a rare autoimmune disease involving cytokine storms that occurs when a person inherits a copy of two mutations.
he said, in analyzing the patient's genes and studying cultured cells, his team found that if the cells were exposed to triggers such as infection, just one mutated copy could lead to macrophage activation syndrome.
he doesn't know of any current efforts to find the mutation in PATIENT-19 patients, but he expects such a study eventually.
extensive search for genetic variants associated with the severity of COVID-19 is already under way.
same time, doctors and researchers are trying to find a cure to stop cytokines from attacking.
may be tosijumal monoantigen, an antibody that binds to an IL-6 subject that inhibits the role of cytokines.
a recent case report in France found that two doses of tosijuba can significantly improve the symptoms of a COVID-19 patient.
currently, clinical trials of Tosiju monoantigen are being conducted in several countries.
possibility is anakinra, a treatment for rheumatoid arthritis and a disease known as neonatal multi-system inflammatory disease, which blocks the cytokine IL-1.
other drugs, anakinra is currently being tested as COVID-19 therapy in separate studies in Greece, Belgium and Italy.
Baricitinib is a drug used to treat rheumatoid arthritis, which blocks enzymes that cause cytokine release.
Baricitinib is another drug that plans to be tested multiple times.
clinicians try existing cytokine blocking drugs for COVID-19, other researchers are looking for potential targets that can stop cytokine storms before they begin, said dela Cruz, who fights the flame that causes cell deaths.
may be a process known as "coke death," a form of cell death that is usually caused by infection and stimulation of cytokines.
Akiko Iwasaki, an immunologist at Yale University who sometimes cooperates with Dela Cruz, said some studies have shown elevated levels of lactic acid dehydrogenase (LDH) in the blood of patients with COVID-19, suggesting that the core of the disease may be cell coke death.
LDH is a common enzyme in the body that converts lactic acid into acetone acid and releases it from cells in the case of cell coke death or tissue damage.
, she said, coke death may explain the elevated levels of IL-1 beta and IL-6 cytokines in severe cases.
said: "I'm just thinking that this inflammatory, intense death that's taking place in this person's body is triggering a chain of events downstream... This can lead to cytokine storms.
Kate Fitzgerald, an immunologist at the University of Massachusetts Medical Center who studied inflammatory small bodies, said apoptosis usually dies quietly without causing an immune response, unlike apoptosis, where the pathogen activates a protein complex called an inflammatory small body.
this activation triggers a series of events, including the release of IL-1 and other cytokines, as well as the formation of pores on the cell membrane, releasing "red flags" such as cytokines and LDH.
, the cells ruptured and died.
said: "It is thought that the death of this hot-deformed cell is particularly important for exposing the ecological position of bacteria in the cell.
"!--/ewebeditor:page--!--ewebeditor:page title"--Fitzgerald said that based on the clinical evidence she has seen, she believes it is highly likely that a problem with coke will help explain the serious COVID-19 case, but this has not been confirmed.
she points out that LDH appears to be a nonse specific marker of tissue damage, so it may not point to coke death itself.
but inflammatory small body activation has been detected when infected with other RNA viruses, such as influenza viruses, and overall, "I think there's a good reason to think that these pathfects may be out of order in this disease."
" other evidence of coke death that may point to severe cases of COVID-19 comes from previous studies of SARS-CoV,2, a close relative of SARS-CoV, the coronavirus that led to the SARS outbreak in 2003.
Two years ago, John Kehrl's team at the National Institute of Allergy and Infectious Diseases reported that a gene region called Open Reading Box 3a is critical to SARS-CoV's ability to kill mice, and that the protein it encodes triggers the assembly of NLRP3, an inflammatory small body, suggesting that the protein may induce coke death.
: His team is now studying the SARS-CoV-2 gene, including whether the protein in its open reading box 3a is the same as SARS-CoV.
'We would be surprised if it didn't do a lot of things like it did in SARS-CoV-2," he said.
but we obviously want to test it.
"There is currently a drug called parathion, which is thought to inhibit the formation of pores during coke death.
its approved use to curb alcohol abuse, it also appears in drug screening for the key SARS-CoV-2 protein and has been recommended for use in COVID-19 clinical trials.
addition, Fitzgerald noted that several companies have been developing inhibitors for the inflammatory small body NLRP3, with the goal of preventing abnormal coke death under other conditions, which she expects to be used in COVID-19.
when there is too much inflammatory media, it can lead to tissue damage, especially lung damage," she said.
, if you can reverse the condition of patients who are in the more serious stages of the disease, you can improve their prognosm.
() Reference: 1 Can Curbing Runaway Immune Responses Treat COVID-19? The definition and risks of Cytokine Release Syndrome-Like in 11 COVID-19-Infected critically ill patients: Diseases And Retrospective Analysiss 3" Pediatric macrophage activation syndrome, DNA Can Hold To Varying Severity of COVID-19.5 23 Found Studies for: Tocilizumab. Covid-19(6) Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related fely failure: a case report (7) Lactate dehydrogenase, a Risk Factor of Severe COVID-19 Patients (8) Detection of Pyroptosis by Measuring Released Lactate Dehydrogenase Activity (9) SARS-Coronavirus Open Frame Reading-3a drives multimodal necrotic death (10) NLRP3 resedors stoke. anti-!-- / ewebeditor: page.