Clinical Review

Short title: Treatment for severe COVID-19 pneumonia

Masato Hada, MD, Pharmacist

Hada Clinic, clinichada@cy.tnc.ne.jp

Corresponding author

Masato Hada, MD, Pharmacist (Medical Practitioner)

Hada Clinic, 1728-2 Oooka, Numazu City, Shizuoka Prefecture, Japan

Phone: +081559525779; FAX: +81559525779

E-mail address: clinichada@cy.tnc.ne.jp

Key words: proinflammatory cytokines, macrophages, SARS-CoV, thalidomide, celecoxib

Abbreviations used in this paper:

PAMP: pathogen-associated molecular pattern

PRRs: pattern-recognition receptors

TLR: Toll-like receptor

SARS: severe acute respiratory syndrome

MERS: Middle East respiratory syndrome

NF-κB: nuclear factor kappa B

IL: interleukin

TNF-α: tumor necrosis factor-α

TGF-β: Transforming growth factor-β

SARS-CoV: severe acute respiratory syndrome coronavirus

MERS-CoV: Middle East respiratory syndrome coronavirus

COVID-19: 2019 novel coronavirus

ACE2: angiotensin-converting enzyme 2

MyD88: myeloid differentiation factor 88

COX-2: cyclooxygenase-2

AMPK: AMP-activated protein kinase

VEGF: VEGF

bFGF: basic fibroblast growth factor

MCP-1: monocyte chemoattractant protein-1

iNOS: inducible nitric oxide synthase

Summary

Dysregulation of proinflammatory cytokines promotes immune-mediated injuries. Epithelial-cell proliferation and an increase in lung macrophages have both been associated with the 2003 SARS-CoV infection. Proinflammatory cytokines as well as lipopolysaccharide and pathogen-associated molecular patterns (PAMPs) promote macrophage transition which promotes ongoing inflammation. PAMPs are primarily sensed by Toll-like receptors and/or by angiotensin-converting enzyme 2; this interaction serves to activate NF-κB to promotes synthesis and secretion of proinflammatory cytokines. Activated immune cells secrete large amounts of specific proinflammatory cytokines including IL-1, IL-6, IL-8, TNF-α, and TGF-β1 which can promote severe lung injury. As such, immunomodulatory drugs alone may have an impact on the cytokine storm even without the addition of antiviral agents. The central transcription factor, NF-κB, induces angiogenesis during cancer progression; combinations of pharmacological agents, including thalidomide and celecoxib, show promising results in cancer treatment studies. This may be due to a low-level, chronic cytokine storm similar to that described for acute and chronic hepatitis as well as for cirrhosis and hepatoma. As previously described, I have used thalidomide, celecoxib, and low dose cytotoxic agents since 2000 for the successful treatment of a variety of cancers. This regimen is cited or introduced in leading medical journals. Thalidomide is an immunomodulatory agent that modulates the activities of NF-κB in combination with the cyclooxygenase-2 inhibitor, celecoxib. The combination of thalidomide and celecoxib might limit the inflammatory symptoms when used to treat severe COVID-19 pneumonia due to infection with SARS-CoV-2.