Demystifying Excess Immune Response in COVID-19 to Reposition an Orphan Drug for Down-Regulation of NF-κB: A Systematic Review.

The immunological findings from autopsies, biopsies, and various studies in COVID-19 patients show that the major cause of morbidity and mortality in COVID-19 is excess immune response resulting in hyper-inflammation. With the objective to review various mechanisms of excess immune response in adult COVID-19 patients, Pubmed was searched for free full articles not related to therapeutics or co-morbid sub-groups, published in English until 27.10.2020, irrespective of type of article, country, or region. Joanna Briggs Institute's design-specific checklists were used to assess the risk of bias. Out of 122 records screened for eligibility, 42 articles were included in the final review. The review found that eventually, most mechanisms result in cytokine excess and up-regulation of Nuclear Factor-κB (NF-κB) signaling as a common pathway of excess immune response. Molecules blocking NF-κB or targeting downstream effectors like Tumour Necrosis Factor α (TNFα) are either undergoing clinical trials or lack specificity and cause unwanted side effects. Neutralization of upstream histamine by histamine-conjugated normal human immunoglobulin has been demonstrated to inhibit the nuclear translocation of NF-κB, thereby preventing the release of pro-inflammatory cytokines Interleukin (IL) 1ß, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19.

The COVID-19 pandemic has caused a global health crisis, with no specific antiviral to treat the infection and the absence of a suitable vaccine to prevent it. While some individuals contracting the SARS-CoV-2 infection exhibit a well coordinated immune response and recover, others display a dysfunctional immune response leading to serious complications including ARDS, sepsis, MOF; associated with morbidity and mortality. Studies revealed that in patients with a dysfunctional immune response, there is a massive cytokine and chemokine release, referred to as the 'cytokine storm'. As a result, such patients exhibit higher levels of pro-inflammatory/modulatory cytokines and chemokines like TNFα, INFγ, IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCSF, HGF and chemokines CXCL8, MCP1, IP10, MIP1α and MIP1ß. Targeting this cytokine storm is a novel, promising treatment strategy to alleviate this excess influx of cytokines observed at the site of infection and their subsequent disastrous consequences. Natural immunosuppressant compounds, derived from plant sources like curcumin, luteolin, piperine, resveratrol are known to inhibit the production and release of pro-inflammatory cytokines and chemokines. This inhibitory effect is mediated by altering signal pathways like NF-κB, JAK/STAT, MAPK/ERK that are involved in the production and release of cytokines and chemokines. The use of these natural immunosuppressants as adjuvants to ameliorate the cytokine storm; in combination with antiviral agents and other treatment drugs currently in use presents a novel, synergistic approach for the treatment and effective cure of COVID-19. This review briefly describes the immunopathogenesis of the cytokine storm observed in SARS-CoV-2 infection and details some natural immunosuppressants that can be used as adjuvants in treating COVID-19 disease.