Effect of Doxycycline on Cytokine Storm in COVID-19 Infection
Respiratory Infections and ARDS
The acute respiratory distress syndrome (ARDS) was described originally in 1967 by the late Dr. Thomas L. Petty and co-workers [i]. ARDS is a syndrome of acute respiratory failure which presents with progressive arterial hypoxemia and marked difficulty in breathing. Most patients may require endotracheal intubation and positive pressure ventilation.[ii]
The acute respiratory distress syndrome (ARDS), often a sequel of respiratory infections or acute lung injury causes 40% mortality in critically ill patients.[iii] Respiratory failure from ARDS is the leading cause of mortality in COVID-19 patients[iv]
Cytokine Storm & Interleukin 6 (IL-6) Interactions in COVID-19 Infections
Scientific evidence till date indicates that pro-inflammatory cytokines play a pivotal role in the pathophysiology of lung damage in patients affected by coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[v]. Patients affected by COVID-19 seem to be developing a fulminant and damaging immune reaction flared up & maintained by cytokines leading to alveolar infiltration by macrophages and monocytes[vi]
Predominant Burden of Interleukin-6 on COVID infection outcomes
Interleukin-6 (IL-6) has been cited as one of the critical mediators of inflammatory and immune response initiated by infection or injury. Increased levels of IL-6 have been identified in more than half of patients with COVID-19 as brought out in some published studies[vii]
It is noteworthy that levels of IL-6 seem to be associated with inflammatory response, respiratory failure, need for mechanical ventilation and/or intubation and mortality in COVID-19 patients[viii]
In a meta-analysis which included nine studies consisting of 1426 patients reporting on IL-6 and clinical outcomes in patients with COVID-19, the mean IL-6 levels were reported to be more than three times higher in patients with complicated COVID-19 as compared with those with the non-complicated disease, and levels of IL-6 were associated with increased risk of death [ix]
IL-6 levels at hospital admission seemed to be a good prognostic indicator for the combined endpoint progression to severe disease and/or in-hospital mortality, and it seemed to be a favorable marker of predicting negative clinical outcomes.5
Doxycycline – An Antimicrobial with IL6-Inhibiting Activity
Effect on IL-6 Pathway
Past documented experiences have taught us that intense proinflammatory state was central to the pathogenesis of dengue and hemorrhagic fever, which also led to cytokine storm. In such conditions, it is noteworthy that doxycycline reduced pro-inflammatory cytokines, including IL-6 and tumor necrosis factor (TNF)-α, in patients with dengue hemorrhagic fever, reducing the mortality rate to 46 % lower in the doxycycline-treated group as compared to the untreated standard care group [x]
Effect on SARS-CoV-2 papain-like protease
In addition to the interaction with IL-6 pathway, severe acute respiratory syndrome-related coronavirus (SARS-CoV) is known to be encompassing a papain-like protease that significantly triggers an Early Growth Response Protein 1 (EGR-1)– dependent activation of transforming growth factor-beta 1 (TGF- β1), resulting in upregulation of pro-fibrotic responses in vitro and in vivo in the lungs[xi] . Consistent with the emergence of such data, recent computational method studies have identified doxycycline among the drugs that could potentially be used to inhibit SARS-CoV-2 papain-like protease[xii]
Way Forward
With the a strong rationale for use of multimodal acting agents in serious or critically ill COVID-19 patients with predominant pulmonary involvement, and features overlapping with hyper inflammation, it may be useful to consider widely experienced drugs with IL-6 inhibitory properties as treatment options in clinical settings for COVID-19 infections, while we await more rigorous systematic evaluation through scientific studies. In the fight against highly transmissible and deadly SARS-CoV-2 causing COVID-19, such drugs like doxycycline can help save lives if used judiciously in appropriate clinical situations[xiii]
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Doxycycline, click HERE
References
[i] Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967; 2:319–23.
[ii] Michael A. Matthay et al, The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment, Annu Rev Pathol. 2011 February 28; 6: 147–163. doi:10.1146/annurev-pathol-011110-130158
[iii] Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005; 353:1685–93
[iv] Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 2020, doi:http://dx.doi.org/10.1007/s00134-020-05991-x.
[v] Elisa Grifoni , Alice Valoriani , Francesco Cei , Roberta Lamanna , Anna Maria Grazia Gelli , Benedetta Ciambotti , Vieri Vannucchi , Federico Moroni , Lorenzo Pelagatti , Roberto Tarquini , Giancarlo Landini , Simone Vanni , Luca Masotti , Interleukin-6 as prognosticator in patients with COVID-19, Journal of Infection (2020), doi: https://doi.org/10.1016/j.jinf.2020.06.008
[vi] Ye Q, Wang B, Mao J. The pathogenesis and treatment of the "Cytokine Storm" in COVID-19. J Infection 2020; 80: 607-13. doi 10.1016/j.jinf.2020.03.037.
[vii] Zhang ZL, Hou YL, Li DT, Li FZ. Laboratory findings of COVID-19: a systematic review and metaanalysis [published online ahead of print, 2020 May 23]. Scand J Clin Lab Invest. 2020;1‐7. doi:10.1080/00365513.2020.1768587
[viii] Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19 [published online ahead of print, 2020 May 18]. J Allergy Clin Immunol. 2020;10.1016/j.jaci.2020.05.008. doi:10.1016/j.jaci.2020.05.008
[ix] Aziz M, Fatima R, Assaly R. Elevated Interleukin-6, and Severe COVID-19: A Meta-Analysis J Med Virol. 2020;10.1002/jmv.25948. doi:10.1002/jmv.25948. Online ahead of print
[x] Fredeking T, Zavala-Castro J, Gonzalez-Martinez P, et al. Dengue patients treated with doxycycline showed lower mortality associated to a reduction in IL-6 and TNF Levels. Recent Pat Antiinfect Drug Discov 2015, doi:http://dx.doi. org/10.2174/1574891x10666150410153839
[xi] Li SW, Wang CY, Jou YJ, et al. SARS coronavirus papain-like protease induces Egr-1-dependent up-regulation of TGF-β1 via ROS/p38 MAPK/STAT3 pathway. Sci Rep 2016, doi:http://dx.doi.org/10.1038/srep25754.
[xii] Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and the discovery of potential drugs by computational methods. Acta Pharm Sin B 2020, doi:http://dx.doi.org/10.1016/j.apsb.2020.02.008
[xiii] Atal S, Fatima Z. IL-6 Inhibitors in the Treatment of Serious COVID-19: A Promising Therapy? [published online ahead of print, 2020 Jun 13]. Pharmaceut Med. 2020;1-9. doi:10.1007/s40290-020-00342-z
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