Therapeutic Management of Coronavirus Disease 2019 (COVID-19): A Systematic Review and Treatment Algorithm

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Rafat Zreiq
Najoua Haouas
Asma M. Khemakhem
Rawan M. Obeidat
Reem M. Ali
Asma Ayyed AL- Shammary
Bandar Alsaif
Fahad D. Algahtani


Coronavirus disease 2019 (COVID-19) is emerging contagious pneumonia due to the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It initially appeared in Wuhan China in December 2019 then rapidly spread worldwide and became a pandemic. For the time being, there is no specific therapeutic treatment for this disease. Herein, the "state-of-the-art" of treatment modalities was systematically reviewed and ultimately a practical therapeutic algorithm for the COVID-19 management was proposed. The systematic review was performed by using published articles retrieved from Science Direct, MEDLINE, and Scopus databases concerning this topic. Among 1060 articles collected from the different databases, 19 publications were studied in-depth and incorporated in this review. The most three frequently used medications for the treatment of COVID-19 was: the available anti-viral drugs (n= 9), the antimalarial hydroxychloroquine or chloroquine (n = 8), and the passive antibody transfer therapy (n = 2). Among all treatment modalities, antimalarial hydroxychloroquine ranked the highest cure rate. Therefore, this drug is considered as the first‐line of COVID-19 treatment. The second‐line treatment includes the lopinavir/ritonavir drugs combined with interferon β-1b and ribavirin. Finally, the third‐line treatments include the remdesivir drug and passive antibody transfer therapy. However, our review emphasis the urgent need for adequately designed randomized controlled trials, enabling a more significant comparison between the most used treatment modalities.

COVID-19, therapeutic management, treatment algorithm, Chloroquine, hydroxychloroquine.

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How to Cite
Zreiq, R., Haouas, N., Khemakhem, A. M., Obeidat, R. M., Ali, R. M., Shammary, A. A. A.-, Alsaif, B., & Algahtani, F. D. (2020). Therapeutic Management of Coronavirus Disease 2019 (COVID-19): A Systematic Review and Treatment Algorithm. Journal of Pharmaceutical Research International, 32(22), 119-134.
Systematic Review Article


World Health Organization. Coronavirus disease situation report-60; 2019.
Available: (2020).

Li Y. et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med; 2020. DOI:10.1016/j.medj.2020.04.001

Cao B. et al. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19. N. Engl. J. Med. 2020;382:1787–1799.

Wang Y. et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569–1578.

Antinori S. et al. Compassionate remdesivir treatment of severe Covid-19 pneumonia in intensive care unit (ICU) and Non-ICU patients: Clinical outcome and differences in post-treatment hospitalisation status. Pharmacol. Res. 2020;158.

Deng L. et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J. Infect. 2020;81:1–5.

Zhu Z. et al. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J. Infect. 2020;81:21–23.

Xu P. et al. Arbidol/IFN-α2b therapy for patients with corona virus disease 2019: a retrospective multicenter cohort study. Microbes Infect. 2020;22:200–205.

Lian N. et al. Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: a retrospective study. Clin. Microbiol. Infect. 2020;26:917–921.

Cao W. et al. High-Dose Intravenous Immunoglobulin as a Therapeutic Option for Deteriorating Patients With Coronavirus Disease. Open Forum Infectious Diseases; 2020. DOI:10.1093/ofid/ofaa102

Shen C. et al. Treatment of 5 Critically Ill Patients with COVID-19 with Convalescent Plasma. JAMA - J. Am. Med. Assoc. 2020;323:1582–1589.

Moher D. et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Rev. Esp. Nutr. Humana y Diet. 2015;20:148–160.

Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions The Cochrane Collaboration ®. (John Wiley & Sons Ltd); 2008.

Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. BioScience Trends 14, (International Advancement Center for Medicine and Health Research Co., Ltd); 2020.

Borba MGS. et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw. open 3, e208857; 2020.

Gautret P. et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: A pilot observational study. Travel Med. Infect. Dis. 2020;34.

Gautret P. et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int. J. Antimicrob. Agents. 2020;56.

Chorin E. et al. The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin. Nat. Med. 2020;26:807–812.

Mahévas M. et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: Observational comparative study using routine care data. BMJ. 2020;369.

Tang W. et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: Open label, randomised controlled trial. BMJ. 2020;369.

Million M. et al. Early treatment of COVID-19 patients with hydroxychloroquine and azithromycin: A retrospective analysis of 1061 cases in Marseille, France. Travel Med. Infect. Dis. 2020;35.

Hung IFN. et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395:1695–1704.

Werth VP. Principles of therapy of sin diseases" In ‘Goldman’s Cecil Medicine’. Elsevier; 2012.

Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today’s diseases? Lancet Infect. Dis. 2003;3:722–727.

Vincent MJ. et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol. J. 2005;2:69.

Savarino A. et al. Anti-HIV Effects of Chloroquine. JAIDS J. Acquir. Immune Defic. Syndr. 2004;35:223–232.

Wang M. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research. 2020;30:269–271.

Colson P, Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV-2. International Journal of Antimicrobial Agents. 2020;55.

Liu J. et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6.

Yao X. et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin. Infect. Dis. 2020;71.

Sheahan TP. et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci. Transl. Med. 2017;9.

Martinez MA. Compounds with therapeutic potential against novel respiratory coronavirus. Antimicrob. Agents Chemother. 2020;64.

Agostini ML. et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. MBio. 2018;9.

Brown AJ. et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase. Antiviral Res. 2019; 169.

Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Götte M. The antiviral compound remdesivir potently inhibits RNAdependent RNA polymerase from Middle East respiratory syndrome coronavirus. J. Biol. Chem. 2020;295:4773–4779.

Sheahan TP. et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat. Commun. 2020;11:1–14.

De Wit, E. et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc. Natl. Acad. Sci. U. S. A. 2020;117:6771–6776.

Holshue ML. et al. First case of 2019 novel coronavirus in the United States. N. Engl. J. Med. 2020;382:929–936.

Grein J. et al. Compassionate use of remdesivir for patients with severe Covid-19. N. Engl. J. Med. 2020;382:2327–2336.

Chandwani A, Shuter J. Lopinavir/ritonavir in the treatment of HIV-1 infection: A review. Ther. Clin. Risk Manag. 2008;4:1023–1033.

Kempf DJ. et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob. Agents Chemother. 1997;41:654–660.

De Wilde AH. et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob. Agents Chemother. 2014;58:4875–4884.

Chu CM. et al. Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings. Thorax. 2004;59:252–256.

Fuk-Woo Chan J. et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. J. Infect. Dis. 2015;212:1904–1913.

Choy KT. et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178.

Lim J. et al. Case of the index patient who caused tertiary transmission of coronavirus disease 2019 in Korea: The application of lopinavir/ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR. J. Korean Med. Sci. 2020;35.

Ierssel SV, Dauby N, Bottieau E. Interim clinical guidance for patients suspected of/confirmed with COVID-19 in Belgium. Unpublished; 2020.

Blaising J, Polyak SJ, Pécheur EI. Arbidol as a broad-spectrum antiviral: An update. Antiviral Res. 2014;107:84–94.

Du Q. et al. The antiviral activity of arbidol hydrochloride against herpes simplex virus type II (HSV-2) in a mouse model of vaginitis. Int. Immunopharmacol. 2019;68:58–67.

Khamitov RA et al. [Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures] - PubMed. Vopr Virusol. 2008;53:9–13.

Lin L, Li TS. Interpretation of ‘Guidelines for the Diagnosis and Treatment of Novel Coronavirus (2019-nCoV) Infection by the National Health Commission (Trial Version 5)’. Zhonghua Yi Xue Za Zhi 100, E001; 2020.

Lai ST. Treatment of severe acute respiratory syndrome. Eur. J. Clin. Microbiol. Infect. Dis. 2005;24:583–591.

Ivan FN Hung et al. Convalescent Plasma Treatment Reduced Mortality in Patients With Severe Pandemic Influenza A (H1N1) 2009 Virus Infection | Clinical Infectious Diseases | Oxford Academic. Clin. Infect. Dis. 2011;2:447–456.

Arabi Y. et al. Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol. Springerplus. 2015;4:1–8.

Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J. Neurol. 2008;255:3–6.

Wang JT. et al. Clinical Manifestations, Laboratory Findings, and Treatment Outcomes of SARS Patients. Emerg. Infect. Dis. 2004;10:818–824.

Arabi YM. et al. Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection. Ann. Intern. Med. 2014;160:389–397.