Reducing mortality from 2019-nCoV: host-directed therapies should be an option
Authors: Alimuddin Zumla, David S Hui, Esam I Azhar, Ziad A Memish, Markus Maeurer
Journal: The Lancet (2020)

The number of confirmed cases of the 2019 novel coronavirus (2019-nCoV) reported to WHO continues to rise worldwide.1WHONovel coronavirus (2019-nCoV) situation report - 14.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200203-sitrep-14-ncov.pdf?sfvrsn=f7347413_2Date: Feb 3, 2020Date accessed: February 3, 2020Google Scholar As with two other WHO Blueprint priority coronaviruses, SARS-CoV2Hui DSC Zumla A Severe acute respiratory syndrome: historical, epidemiologic, and clinical features.Infect Dis Clin North Am. 2019; 33: 869-889Summary Full Text Full Text PDF PubMed Scopus (376) Google Scholar and MERS-CoV,3Azhar EI Hui DSC Memish ZA Drosten C Zumla A The Middle East respiratory syndrome (MERS).Infect Dis Clin North Am. 2019; 33: 891-905Summary Full Text Full Text PDF PubMed Scopus (186) Google Scholar 2019-nCoV is lethal. As of Feb 3, 2020, 2019-nCoV has caused 362 deaths out of 17 391 confirmed cases reported to WHO.1WHONovel coronavirus (2019-nCoV) situation report - 14.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200203-sitrep-14-ncov.pdf?sfvrsn=f7347413_2Date: Feb 3, 2020Date accessed: February 3, 2020Google Scholar No specific anti-viral treatment exists. The mainstay of clinical management is largely symptomatic treatment, with organ support in intensive care for seriously ill patients. The unprecedented flurry of activity by WHO and other global public health bodies has mainly focused on preventing transmission, infection control measures, and screening of travellers. The development of vaccines has received immediate funding; however, as with SARS-CoV and MERS-CoV, support for developing treatments for 2019-nCoV that reduce mortality has not been forthcoming. There is an urgent need for focusing funding and scientific investments into advancing novel therapeutic interventions for coronavirus infections. All three coronaviruses induce excessive and aberrant non-effective host immune responses that are associated with severe lung pathology, leading to death.2Hui DSC Zumla A Severe acute respiratory syndrome: historical, epidemiologic, and clinical features.Infect Dis Clin North Am. 2019; 33: 869-889Summary Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 3Azhar EI Hui DSC Memish ZA Drosten C Zumla A The Middle East respiratory syndrome (MERS).Infect Dis Clin North Am. 2019; 33: 891-905Summary Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 4Huang C Wang Y Li X Clinical features of patients infected with 2019 coronavirus in Wuhan, China.Lancet. 2020; (published online Jan 24)https://doi.org/10.1016/S0140-6736(20)30183-5Summary Full Text Full Text PDF Scopus (32861) Google Scholar Similar to patients with SARS-CoV and MERS-CoV, some patients with 2019-nCoV develop acute respiratory distress syndrome (ARDS) with characteristic pulmonary ground glass changes on imaging. In most moribund patients, 2019-nCoV infection is also associated with a cytokine storm, which is characterised by increased plasma concentrations of interleukins 2, 7, and 10, granulocyte-colony stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1 alpha, and tumour necrosis factor α.2Hui DSC Zumla A Severe acute respiratory syndrome: historical, epidemiologic, and clinical features.Infect Dis Clin North Am. 2019; 33: 869-889Summary Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 3Azhar EI Hui DSC Memish ZA Drosten C Zumla A The Middle East respiratory syndrome (MERS).Infect Dis Clin North Am. 2019; 33: 891-905Summary Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 4Huang C Wang Y Li X Clinical features of patients infected with 2019 coronavirus in Wuhan, China.Lancet. 2020; (published online Jan 24)https://doi.org/10.1016/S0140-6736(20)30183-5Summary Full Text Full Text PDF Scopus (32861) Google Scholar, 5Li G Fan Y Lai Y et al.Coronavirus infections and immune responses.J Med Virol. 2020; (published online Jan 25.)DOI:10.1002/jmv.25685Crossref Scopus (1276) Google Scholar, 6Channappanavar R Perlman S Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology.Semin Immunopathol. 2017; 39: 529-539Crossref PubMed Scopus (1854) Google Scholar In those who survive intensive care, these aberrant and excessive immune responses lead to long-term lung damage and fibrosis, causing functional disability and reduced quality of life.7Batawi S Tarazan N Al-Raddadi R et al.Quality of life reported by survivors after hospitalization for Middle East respiratory syndrome (MERS).Health Qual Life Outcomes. 2019; 17: 101Crossref PubMed Scopus (100) Google Scholar, 8Ngai JC Ko FW Ng SS To KW Tong M Hui DS The long-term impact of severe acute respiratory syndrome on pulmonary function, exercise capacity and health status.Respirology. 2010; 15: 543-550Crossref PubMed Scopus (349) Google Scholar Specific drugs to treat 2019-nCoV will take several years to develop and evaluate. In the meantime, a range of existing host-directed therapies that have proven to be safe9Zumla A Chan JF Azhar EI Hui DS Yuen KY Coronaviruses - drug discovery and therapeutic options.Nat Rev Drug Discov. 2016; 15: 327-347Crossref PubMed Scopus (1273) Google Scholar, 10Beigel JH Nam HH Adams PL et al.Advances in respiratory virus therapeutics—a meeting report from the 6th ISIRV antiviral group conference.Antiviral Res. 2019; 167: 45-67Crossref PubMed Scopus (130) Google Scholar, 11Zumla A Azhar EI Arabi Y et al.Host-directed therapies for improving poor treatment outcomes associated with the Middle East respiratory syndrome coronavirus infections.Int J Infect Dis. 2015; 40: 71-74Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar could potentially be repurposed to treat 2019-nCoV infection. Several marketed drugs with excellent safety profiles such as metformin, glitazones, fibrates, sartans, and atorvastin, as well as nutrient supplements and biologics could reduce immunopathology, boost immune responses, and prevent or curb ARDS.9Zumla A Chan JF Azhar EI Hui DS Yuen KY Coronaviruses - drug discovery and therapeutic options.Nat Rev Drug Discov. 2016; 15: 327-347Crossref PubMed Scopus (1273) Google Scholar, 10Beigel JH Nam HH Adams PL et al.Advances in respiratory virus therapeutics—a meeting report from the 6th ISIRV antiviral group conference.Antiviral Res. 2019; 167: 45-67Crossref PubMed Scopus (130) Google Scholar, 11Zumla A Azhar EI Arabi Y et al.Host-directed therapies for improving poor treatment outcomes associated with the Middle East respiratory syndrome coronavirus infections.Int J Infect Dis. 2015; 40: 71-74Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar Zinc and other metal-containing formulations appear to have anti-viral activity,12Barnard DL Wong MH Bailey K et al.Effect of oral gavage treatment with ZnAL42 and other metallo-ion formulations on influenza A H5N1 and H1N1 virus infections in mice.Antivir Chem Chemother. 2007; 18: 125-132Crossref PubMed Scopus (20) Google Scholar are safe, cheap, and readily available. These formulations could be used as adjuncts to monotherapy or as combinational therapies with cyclosporine, lopinavir–ritonavir, interferon beta‑1b, ribavirin, remdesivir, monoclonal antibodies, and anti-viral peptides targeting 2019-nCoV.11Zumla A Azhar EI Arabi Y et al.Host-directed therapies for improving poor treatment outcomes associated with the Middle East respiratory syndrome coronavirus infections.Int J Infect Dis. 2015; 40: 71-74Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar Tocilizumab, a monoclonal antibody that targets the interleukin 6 receptor, has a good safety profile. Monoclonal and polyclonal antibodies to 2019-nCoV could be developed for post-exposure prophylaxis. Ongoing trials of cellular therapies for treatment of ARDS could be expanded to treatment of seriously ill patients with 2019-nCoV infection. Cellular therapy,13Horie S Gonzalez HE Laffey JG Masterson CH Cell therapy in acute respiratory distress syndrome.J Thorac Dis. 2018; 10: 5607-5620Crossref PubMed Scopus (42) Google Scholar using mesenchymal stromal cells from allogeneic donors, has been shown to reduce non-productive inflammation and affect tissue regeneration and is being evaluated in phase 1/2 trials in patients with ARDS (NCT02804945; NCT03608592). Infection with 2019-nCoV appears to be initially associated with an increased Th2 response,4Huang C Wang Y Li X Clinical features of patients infected with 2019 coronavirus in Wuhan, China.Lancet. 2020; (published online Jan 24)https://doi.org/10.1016/S0140-6736(20)30183-5Summary Full Text Full Text PDF Scopus (32861) Google Scholar which might reflect a physiological reaction to curb overt inflammatory responses, a clinical phenomenon that guided the optimal timing of interferon treatment in patients with sepsis, resulting in increased survival.14Davies R O'Dea K Gordon A Immune therapy in sepsis: are we ready to try again?.J Intensive Care Soc. 2018; 19: 326-344Crossref PubMed Scopus (49) Google Scholar Interleukin 17 blockade might benefit those patients who have a 2019-nCoV infection and increased plasma concentration of interleukin 17. The isolation and short-term expansion of anti-viral directed T cells has been proven to be a life-saving procedure in patients after autologous hematopoietic stem-cell transplantation with cytomegalovirus infection.15Lerias JR Paraschoudi G Silva I et al.Clinically relevant immune responses against cytomegalovirus: implications for precision medicine.Int J Mol Sci. 2019; 201986Crossref Scopus (6) Google Scholar Expansion of anti-2019-nCoV-specific T cells, as cellular drugs, could aid to prepare T-cell products for the adjunct treatment of patients with severe 2019-nCoV infection. Several unique opportunities to evaluate a range of treatment interventions at the peak of the SARS-CoV and MERS-CoV outbreaks were missed due to avoidable delays and subsequent decline of the numbers of cases, leaving numerous questions about coronavirus pathogenesis unanswered. Disappointingly, treatment trials registered for MERS-CoV are still not complete. As the 2019-nCoV continues to spread and evolve, and the numbers of deaths rise exponentially, advancing new therapeutic development becomes crucial to minimise the number of deaths from 2019-nCoV infection. We declare no competing interests. AZ is co-principal investigator of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET), funded by the European & Developing Countries Clinical Trials Partnership, supported under Horizon 2020, the EU's Framework Programme for Research and Innovation, and a National Institutes of Health Research senior investigator. MM is a member of the innate immunity advisory group of the Bill & Melinda Gates Foundation, and his work is funded by the Champalimaud Foundation.