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Replies to post #288782 on Innovation Pharmaceuticals Inc (IPIX)
03/30/20 10:21 PM
03/31/20 8:50 AM
Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality.
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Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p<0·001) and IL-6 (p<0·0001), suggesting that mortality might be due to virally driven hyperinflammation.
Up to 15% of the population
“Cytokines are inflammatory immunologic proteins that are there to fight off infections and ward off cancers,” Cron explained. “But when they’re out of control they can make you very ill.”
Symptoms include high fever, enlarged spleen, excessive bleeding, low counts of all types of blood cells (red, white and platelets) and, potentially, multiple organ failures.
Cron’s research has shown that cytokine storm syndrome is much more common than previously thought — as is the number of people at risk. Scientists seeking the cause of cytokine storm syndrome have focused their attention on the perforin pathway, the series of proteins that work together to deliver perforin. Perforin is a key weapon of the immune system’s cytotoxic T-cells and natural killer cells. They use it to punch holes in the walls of infected, cancerous or otherwise undesirable cells. Then they use these perforin channels to pour in toxic granzyme B, which induces the cells to self-destruct. Mutations in the genes responsible for “any one of the 10-plus proteins that get perforin to do what it does” are linked to a higher risk of cytokine storm syndrome, Cron said.
Some 10% to 15% of the population may carry these mutations, according to Cron’s calculations. Unlike infants, who tend to have two bad copies of one of the 10+ perforin-associated genes, these people have one mutated copy and one normal copy. “Generally, that’s enough to produce all the killing you need,” Cron said. “But if you get the wrong organism or the wrong inflammatory state it may push you over the edge.”
Two-phase immune responses induced by COVID-19 infection
Clinically, the immune responses induced by SARS-CoV-2 infection are two phased. During the incubation and non-severe stages, a specific adaptive immune response is required to eliminate the virus and to preclude disease progression to severe stages. Therefore, strategies to boost immune responses (anti-sera or pegylated IFNa) at this stage are certainly important. For the development of an endogenous protective immune response at the incubation and non-severe stages, the host should be in good general health and an appropriate genetic background (e.g. HLA) that elicits specific antiviral immunity. Genetic differences are well-known to contribute to individual variations in the immune response to pathogens. However, when a protective immune response is impaired, virus will propagate and massive destruction of the affected tissues will occur, especially in organs that have high ACE2 expression, such as intestine and kidney. The damaged cells induce innate inflammation in the lungs that is largely mediated by pro-inflammatory macrophages and granulocytes. Lung inflammation is the main cause of life-threatening respiratory disorders at the severe stage [4]. Therefore, good general health may not be advantageous for patients who have advanced to the severe stage: once severe lung damage occurs, efforts should be made to suppress inflammation and to manage the symptoms.
We speculated four potential mechanisms leading to lymphocyte deficiency. (1) The virus might directly infect lymphocytes, resulting in lymphocyte death. Lymphocytes express the coronavirus receptor ACE2 and may be a direct target of viruses. 9 (2) The virus might directly destroy lymphatic organs. Acute lymphocyte decline might be related to lymphocytic dysfunction, and the direct damage of novel coronavirus virus to organs such as thymus and spleen cannot be ruled out. This hypothesis needs to be confirmed by pathological dissection in the future. (3) Inflammatory cytokines continued to be disordered, perhaps leading to lymphocyte apoptosis. Basic researches confirmed that TNFa, IL-6 and other pro-inflammatory cytokines could induce lymphocyte deficiency 10. (4) Inhibition of lymphocytes by metabolic molecules produced by metabolic disorders, such as hyperlactic acidemia. The severe type of COVID-19 patients had elevated blood lactic acid levels, which might suppress the proliferation of lymphocytes 11. Multiple mechanisms mentioned above or beyond might work together to cause lymphopenia, and further research is needed.
