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

Abstract

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) 1β, TNF-α, and IL-6 and IL-10 in a safer manner. The authors recommend repositioning it in COVID-19.

Cytokine Overproduction and Immune System Dysregulation in alloHSCT and COVID-19 Patients

“…After that innate immunity receptors recognize viral RNA and proinflammatory cytokines are produced using the NFkappaB signaling pathway. Pyroptosis is seen and proinflammatory cytokines build up an inflammatory response ( 72 ). Then macrophages, monocytes and polymorphonuclear leukocyte are recruited and activated in the inflammatory environment and the next wave of cytokines surges.…”

The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19

“…Patients may remain asymptomatic or develop symptoms of varying severity [ 5 , 6 ]. In the resulting coronavirus disease 2019 (COVID-19), activation of the innate immunity, specific antibodies, and activated T cells represent basic defensive factors, while in more severe cases, lung injury progresses and leads to respiratory failure [ 5 , 7 ]. Severe lung injury in SARS-CoV-2 patients is considered the result of immune hyperreaction that involves both innate and adaptive immune responses [ 6 , 8 ].…”

Immunothrombosis in Acute Respiratory Dysfunction of COVID-19

“…Excessively secreted cytokines attract neutrophils, monocytes, and macrophages to the site of the insult, where they not only clear viral particles but also may cause organ failure (33). Importantly, these cytokines also activate immune cells, further increasing the production of cytokines.…”

“…Other immunological cells involved in SARS-CoV-2 infection include B cells, macrophages, T helper (Th) cells, neutrophils, and natural killer/cytotoxic T lymphocytes (CTLs) ( 21 , 30 – 32 ). Excessively secreted cytokines attract neutrophils, monocytes, and macrophages to the site of the insult, where they not only clear viral particles but also may cause organ failure ( 33 ). Importantly, these cytokines also activate immune cells, further increasing the production of cytokines.…”