Can colchicine curb COVID-19 related hyperinflammation?
Dear Editor,
In their paper, Chen et al. [1] reported signs of systemic inflammation and cytokine storm in a subset of patients who died from coronavirus disease 2019 (COVID-19). This phenomenon has been heavily debated, and the optimal treatment strategy is currently unknown.
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shares similarities with SARS, which was caused by SARS-CoV-1. Both SARS and COVID-19 can cause acute respiratory distress syndrome (ARDS) and multiorgan failure, which is thought to result from a combination of virus-induced cytopathic effects and a dysregulated hyperinflammatory state [2].
SARS-CoV-1 (and likely SARS-CoV-2) express proteins which attenuate the host antiviral type I interferon-response, which facilitates rapid viral replication and extensive virus-induced cytopathic effects in early stages of disease [2]. In a mice model of SARS, a delayed and persistent type I IFN-response was associated with a subsequent aberrant and dysregulated hyperinflammatory stage characterized by high levels of pro-inflammatory cytokines and chemokines and massive pulmonary infiltration of inflammatory monocytes/macrophages and neutrophils, culminating in severe lung injury [2]. Depletion of inflammatory monocytes/macrophages mitigated the lung damage [2], suggesting that dysregulated and counterproductive macrophage activation may be central to the pathophysiology of the hyperinflammatory stage.
NLRP3 inflammasomes are intracellular multiprotein complexes found in macrophages, which are assembled and activated in response to a number of cellular threats [3]. Activation of NLRP3 inflammasome triggers a series of events, in which pro-IL-1β and pro-IL-18 are cleaved into their active forms. The macrophage subsequently undergoes pyroptosis, which results in release of these newly formed pro-inflammatory cytokines [3]. SARS-CoV-1 has been shown to activate the NLRP3 inflammasome [4], and pyroptotic macrophages may contribute to the detrimental hyperinflammatory phenotype observed in a subset of critically ill COVID-19 patients [5].
Immunosuppressive strategies, including IL-1 and IL-6 inhibition, have been suggested for patients with COVID-19 and hyperinflammation [6]. In theory, this may be of benefit in carefully selected cases, after weighing the risk of impaired host antimicrobial defense and secondary bacterial infections. However, IL-1 and IL-6 inhibitors are expensive and not readily available worldwide. Hence, investigation of other potential strategies for mitigating the hyperinflammatory response is of interest. Colchicine is a cheap and readily available drug which inhibits polymerization of microtubules, thereby preventing chemotaxis and NLRP3 inflammasome assembly [7], both of which have theoretical therapeutic potential in the hyperinflammatory state. We encourage research evaluating the efficacy and safety of colchicine in mitigating the hyperinflammatory manifestation of COVID-19.
Jens Vikse, M.D.
Clinical Immunology Unit
Stavanger University Hospital
Gerd-Ragna Bloch Thorsens gate 8, 4068 Stavanger, Norway jens.vikse@sus.no
Guiseppe Lippi, M.D.
Section of Clinical Biochemistry
University of Verona
Via S. Francesco 22, 37129, Verona VR, Italy giuseppe.lippi@univr.it
Brandon Michael Henry, M.D.
Cardiac Intensive Care Unit
The Heart Institute, Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave., Cincinnati, OH, USA 45229 brandon.henry@cchmc.org
References
1 Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368. doi:10.1136/bmj.m1091
2 Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe 2016;19:181–93. doi:10.1016/j.chom.2016.01.007
3 Man SM, Karki R, Kanneganti T-D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61–75. doi:10.1111/imr.12534
4 Shi C-S, Nabar NR, Huang N-N, et al. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov 2019;5:101. doi:10.1038/s41420-019-0181-7
5 Fung S-Y, Yuen K-S, Ye Z-W, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558–70. doi:10.1080/22221751.2020.1736644
6 Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet 2020;395:1033–4. doi:10.1016/S0140-6736(20)30628-0
7 Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45:341–50. doi:10.1016/j.semarthrit.2015.06.013
Rapid Response:
Can colchicine curb COVID-19 related hyperinflammation?
Dear Editor,
In their paper, Chen et al. [1] reported signs of systemic inflammation and cytokine storm in a subset of patients who died from coronavirus disease 2019 (COVID-19). This phenomenon has been heavily debated, and the optimal treatment strategy is currently unknown.
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), shares similarities with SARS, which was caused by SARS-CoV-1. Both SARS and COVID-19 can cause acute respiratory distress syndrome (ARDS) and multiorgan failure, which is thought to result from a combination of virus-induced cytopathic effects and a dysregulated hyperinflammatory state [2].
SARS-CoV-1 (and likely SARS-CoV-2) express proteins which attenuate the host antiviral type I interferon-response, which facilitates rapid viral replication and extensive virus-induced cytopathic effects in early stages of disease [2]. In a mice model of SARS, a delayed and persistent type I IFN-response was associated with a subsequent aberrant and dysregulated hyperinflammatory stage characterized by high levels of pro-inflammatory cytokines and chemokines and massive pulmonary infiltration of inflammatory monocytes/macrophages and neutrophils, culminating in severe lung injury [2]. Depletion of inflammatory monocytes/macrophages mitigated the lung damage [2], suggesting that dysregulated and counterproductive macrophage activation may be central to the pathophysiology of the hyperinflammatory stage.
NLRP3 inflammasomes are intracellular multiprotein complexes found in macrophages, which are assembled and activated in response to a number of cellular threats [3]. Activation of NLRP3 inflammasome triggers a series of events, in which pro-IL-1β and pro-IL-18 are cleaved into their active forms. The macrophage subsequently undergoes pyroptosis, which results in release of these newly formed pro-inflammatory cytokines [3]. SARS-CoV-1 has been shown to activate the NLRP3 inflammasome [4], and pyroptotic macrophages may contribute to the detrimental hyperinflammatory phenotype observed in a subset of critically ill COVID-19 patients [5].
Immunosuppressive strategies, including IL-1 and IL-6 inhibition, have been suggested for patients with COVID-19 and hyperinflammation [6]. In theory, this may be of benefit in carefully selected cases, after weighing the risk of impaired host antimicrobial defense and secondary bacterial infections. However, IL-1 and IL-6 inhibitors are expensive and not readily available worldwide. Hence, investigation of other potential strategies for mitigating the hyperinflammatory response is of interest. Colchicine is a cheap and readily available drug which inhibits polymerization of microtubules, thereby preventing chemotaxis and NLRP3 inflammasome assembly [7], both of which have theoretical therapeutic potential in the hyperinflammatory state. We encourage research evaluating the efficacy and safety of colchicine in mitigating the hyperinflammatory manifestation of COVID-19.
Jens Vikse, M.D.
Clinical Immunology Unit
Stavanger University Hospital
Gerd-Ragna Bloch Thorsens gate 8, 4068 Stavanger, Norway
jens.vikse@sus.no
Guiseppe Lippi, M.D.
Section of Clinical Biochemistry
University of Verona
Via S. Francesco 22, 37129, Verona VR, Italy
giuseppe.lippi@univr.it
Brandon Michael Henry, M.D.
Cardiac Intensive Care Unit
The Heart Institute, Cincinnati Children’s Hospital Medical Center
3333 Burnet Ave., Cincinnati, OH, USA 45229
brandon.henry@cchmc.org
References
1 Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020;368. doi:10.1136/bmj.m1091
2 Channappanavar R, Fehr AR, Vijay R, et al. Dysregulated Type I Interferon and Inflammatory Monocyte-Macrophage Responses Cause Lethal Pneumonia in SARS-CoV-Infected Mice. Cell Host Microbe 2016;19:181–93. doi:10.1016/j.chom.2016.01.007
3 Man SM, Karki R, Kanneganti T-D. Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 2017;277:61–75. doi:10.1111/imr.12534
4 Shi C-S, Nabar NR, Huang N-N, et al. SARS-Coronavirus Open Reading Frame-8b triggers intracellular stress pathways and activates NLRP3 inflammasomes. Cell Death Discov 2019;5:101. doi:10.1038/s41420-019-0181-7
5 Fung S-Y, Yuen K-S, Ye Z-W, et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558–70. doi:10.1080/22221751.2020.1736644
6 Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet 2020;395:1033–4. doi:10.1016/S0140-6736(20)30628-0
7 Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum 2015;45:341–50. doi:10.1016/j.semarthrit.2015.06.013
Competing interests: No competing interests