Archives of Academic Emergency Medicine. 2020; 8(1): e40

CO M M E N TA RY

Metronidazole; a Potential Novel Addition to the COVID-
19 Treatment Regimen
Reza Gharebaghi1,2, Fatemeh Heidary2,3∗, Mohammad Moradi2,4, Maryam Parvizi2,5

1. Kish International Campus, University of Tehran, Tehran, Iran.

2. International Virtual Ophthalmic Research Center (IVORC).

3. Taleghani Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

4. Department of Surgery, Iran University of Medical Sciences, Tehran, Iran.

5. Department of Pathology, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Received: March 2020; Accepted: March 2020; Published online: 30 March 2020

Abstract: Coronavirus disease 2019 or COVID-19 has rapidly emerged as a global pandemic. This viral infection involves
the upper respiratory tract and could lead to severe pneumonia with respiratory distress or even death. Cer-
tain studies have found higher initial plasma levels of most pro-inflammatory cytokines during the course of
the infection. In this context, both in vitro and in vivo studies have revealed that metronidazole could decrease
the levels of several cytokines, which are known to increase during the COVID-19 infection, including inter-
leukin (IL)8, IL6, IL1B, tumor necrosis factor (TNF)α, IL12, IL1α, and interferon (IFN)γ, as well as the levels of
C-reactive protein (CRP) and neutrophil count.
Furthermore, the drug could decrease neutrophil-generated reactive oxygen species during inflammation.
Metronidazole could counteract majority of the immunopathological manifestations of the COVID-19 infec-
tion. Therefore, studies with a large sample size are required to determine the efficacy of metronidazole in the
treatment of COVID-19 infection.

Keywords: Coronavirus disease; COVID-19; Metronidazole; Cytokines; Interleukins

Cite this article as: Gharebaghi R, Heidary F, Moradi M, Parvizi M. Metronidazole; a Potential Novel Addition to the COVID-19 Treatment

Regimen. Arch Acad Emerg Med. 2020; 8(1): e40.

1. Introduction

Coronavirus disease 2019 or COVID-19 has rapidly emerged

as a global pandemic since its first report in December 2019

in China (1, 2). The infection involves the upper respira-

tory tract and could lead to severe pneumonia with respira-

tory distress or even death (3). Currently, no specific treat-

ment is available, and most strategies are principally symp-

tomatic. Therefore, finding an effective and economical

treatment strategy is essential, particularly for those with life-

threatening infection (4). Here, we present evidence from the

literature of immunological manifestations of the COVID-19

infection and the potential effect of metronidazole in coun-

teracting majority of these immunopathological features.

∗Corresponding Author: Fatemeh Heidary; Head of Ophthalmology Division,
Taleghani Hospital, Padad, Ahvaz Jundishapur University of Medical Sciences,
Ahvaz, Iran. Email: drfatemehheidari@yahoo.com Office: +98-21-47627292

2. Immunopathological evidence of
COVID-19

Following an evaluation of 41 admitted patients with

laboratory-confirmed COVID-19 infection in Wuhan, China,

Huang et al. found higher initial plasma levels of most pro-

inflammatory cytokines, including interleukin (IL)1B, IL1RA,

IL7, IL8, IL9, IL10, basic fibroblast growth factor (FGF),

granulocyte-colony stimulating factor (GCSF), granulocyte-

macrophage colony-stimulating factor (GMCSF), interferon

(IFN)γ, IFN-γ inducible protein 10 (IP10), monocyte

chemoattractant protein 1 (MCP1), macrophage inflamma-

tory protein (MIP)1A, MIP1B, platelet-derived growth fac-

tor (PDGF), tumor necrosis factor (TNF)α, and vascular en-

dothelial growth factor (VEGF) in both intensive care unit

(ICU) and non-ICU patients than in the healthy subjects.

However, the plasma levels of IL5, IL12p70, IL15, Eotaxin,

and RANTES were similar. Further evaluation revealed

higher plasma levels of IL2, IL7, IL10, GCSF, IP10, MCP1,

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R. Gharebaghi et al. 2

MIP1A, and TNFα in ICU-admitted patients than in non-ICU

patients (5).

Chen et al., who retrospectively evaluated 99 patients with

laboratory-confirmed COVID-19 infection, reported lym-

phopenia in 35% of cases, as well as increased levels of neu-

trophils, IL6, erythrocyte sedimentation rate (ESR), and C-

reactive protein (CRP) in 35%, 52%, 85%, and 86% of cases,

respectively (6). However, whether the virus directly infects

the immune cells, including neutrophils and lymphocytes,

is yet to be established (7). Zhou et al. conducted a retro-

spective multicenter study of 191 patients with laboratory-

confirmed COVID-19 infection and reported elevated IL6 lev-

els and severe lymphopenia in non-survivors than in the sur-

vivors. Univariate analysis of the data revealed significant

associations of lymphopenia and elevated IL6 serum levels

with mortality (8).

3. Immunopharmacology of metronida-
zole

Metronidazole [1-(2-hydroxyethyl)-2-methyl-5- nitroimida-

zole] and related 5-nitroimidazoles are redox-active prodrugs

that act as biocidal agents via their interaction with a ni-

troreductase homolog (9). Both in vitro and in vivo studies

have revealed that metronidazole decreases the levels of sev-

eral cytokines, including IL8 (10-13), IL6 (10-15), IL1B (10-

15), TNFα (11-13, 15-17), IL12 (11, 13, 14), and IFNγ (11,

14, 16), as well as the levels of CRP (11, 12) and neutrophil

count (11, 17, 18). Interestingly, these parameters are shown

to increase during the COVID-19 infection (5-7). Moreover,

metronidazole could increase the number of circulatory lym-

phocytes (11, 17) and has lymphoproliferative properties,

suggestive of its immunopotentiating effect (11, 19). These

immunomodulatory effects of metronidazole have been dis-

cussed in detail in a previously published review by Shakir

et al. (11). Furthermore, this medication could decrease

neutrophil-generated reactive oxygen species during inflam-

mation (11, 20). Table 1 summarizes the effects of metron-

idazole on the immunopathological manifestations of the

COVID-19 infection.

Metronidazole, owing to its immunopharmacological behav-

ior, plays a pivotal role in several essential biological pro-

cesses. Based on the reported immunological manifestations

of COVID-19 infection, it could serve as a potential candidate

to counteract majority of the immunopathological features

of the disease. Therefore, clinical trials with a large sample

size are necessary to determine its efficacy in the treatment

of COVID-19 infection.

Table 1: Effects of metronidazole on immunopathological manifes-

tations of COVID-19 infection

COVID-19 Metronidazole
↑ IL8 (5) ↓ IL8 (10-13)
↑ IL6 (6, 8) ↓ IL6 (10-15)
↑ IL1B (5) ↓ IL1B (10-15)
↑ TNFα (5) ↓ TNFα (11-13, 15-17)
↑ CRP (6) ↓ CRP (11, 12)
↑ IL12 (21) ↓ IL12 (11, 13, 14)
↑ IFNγ (5) ↓ IFNγ (11, 14, 16)
↑ Neutrophils (5, 6) ↓ Neutrophils (11, 17, 18)
↓ Lymphocytes (5, 6, 8) ↑ Lymphocytes (11, 17),

lymphoproliferative proper-
ties (11, 19)

CRP: C-reactive protein; IFN: interferon; IL: interleukin;
TNF: tumor necrosis factor.

4. Declarations

4.1. Acknowledgements

Authors wish to thank the International Virtual Ophthalmic

Research Center (IVORC) for the continuous academic sup-

port.

4.2. Authors Contributions

RG, FH conceived the original idea. RG, FH, MM, and MP

designed the scenarios relevant to the idea and collected

the relevant manuscripts. They have performed acquisition,

analysis, and interpretation of data. RG, FH, MM, MP carried

out the evaluation on current evidences on the subject,

approved the final version that was submitted, revised it, and

drafted the manuscript. All authors are agree to be account-

able for all aspects of the work. RG, FH, MM, and MP met the

criteria of authorship based on the recommendations of the

International Committee of Medical Journal Editors.

Authors ORCIDs
Reza Gharebaghi: 0000-0002-4906-8597

Fatemeh Heidary: 0000-0002-6558-6132

Mohammad Moradi: 0000-0003-1560-7641

Maryam Parvizi: 0000-0003-2198-3520

4.3. Funding Support

This research resulted from an independent research without

financial support.

4.4. Conflict of Interest

The authors have declared that no competing interests exist.

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	Introduction
	Immunopathological evidence of COVID-19 
	Immunopharmacology of metronidazole
	Declarations
	References