Too much hype in trials of hydroxychloroquine in COVID-19
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Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data
Too much hype in trials of hydroxychloroquine in COVID-19
Dear Editor
There has been much public hype surrounding the use of hydroxychloroquine (HCQ) in COVID-19. The observational comparative study of Mahevas et al in 181 hypoxic patients with COVID-19 pneumonia suggests that when used later on the disease there appears to be no benefit on survival albeit with a relatively limited sample size [1]. This is perhaps not unsurprising given that HCQ primarily works upstream in COVID-19 by preventing viral entry into lung epithelium via ACE2 [2].
In the study of Mahevas et al 85% of patients already had evidence of cytokine mediated hyperinflammatory syndrome in terms of a C reactive protein (CRP) level more than 40mg/l on admission to hospital [1]. In this regard a CRP above 42mg/l at initial presentation is indicative of poor outcomes in COVID-19 [3]. By this stage of the disease it is probably too late for any impact of attenuated entry of SARS-CoV2 into type 2 pneumonocytes, especially when the inflammatory related lung tissue damage has already begun.
Although HCQ also inhibits production of interleukin-6 from T cells and monocytes [4], this putative downstream immunomodulatory effect clearly did not translate into improved outcomes. Indeed the results of Mahevas et al were similar to those of another observational study in 1376 patients with hypoxic severe COVID-19 in New York City, where there was no difference in the primary outcome of death or intubation compared to standard of care [5].
The NIHR RECOVERY randomised controlled trial is evaluating the use of HCQ as monotherapy in the first randomisation phase in large numbers of hospitalised patients with COVID-19. However for sick hypoxic patients with late stage COVID-19 disease the emerging data points to futility in regard to use of HCQ alone. Surely the time has now come to end the hype with regard to use of HCQ in severe COVID-19. Given the adaptive design of RECOVERY perhaps an interim analysis is now indicated to test if using HCQ on its own is pointless. We believe that for such patients perhaps a combined treatment regimen may be required comprising earlier use of antivirals such as remdesivir or interferon-beta-1b [6] together with later use of selective cytokine inhibition as either anti-IL6 [7] or anti-IL1 [8], in order to address both upstream and downstream disease pathways [9].
References
1. Mahévas M, Tran V-T, Roumier 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:m1844. doi: 10.1136/bmj.m1844
2. Yao X, Ye F, Zhang M, 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 doi: 10.1093/cid/ciaa237 [published Online First: 2020/03/10]
3. Liu F, Li L, Xu M, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020;127:104370. doi: 10.1016/j.jcv.2020.104370 [published Online First: 2020/04/29]
4. Sperber K, Quraishi H, Kalb TH, et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993;20(5):803-8. [published Online First: 1993/05/01]
5. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2012410
6. Hung IF-N, Lung K-C, Tso EY-K, 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. The Lancet doi: 10.1016/S0140-6736(20)31042-4
7. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences 2020:202005615. doi: 10.1073/pnas.2005615117
8. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology doi: 10.1016/S2665-9913(20)30127-2
9. Lipworth B, Chan R, Lipworth S, et al. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020 doi: 10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21]
Competing interests:
No competing interests
15 May 2020
Brian J Lipworth
Professor of Pulmonology
Dr Chris Kuo, Dr Rory Chan
Scottish Centre for Respiratory Research
Ninewells Hospital and Medical School, Dundee, Scotland, UK
Rapid Response:
Too much hype in trials of hydroxychloroquine in COVID-19
Dear Editor
There has been much public hype surrounding the use of hydroxychloroquine (HCQ) in COVID-19. The observational comparative study of Mahevas et al in 181 hypoxic patients with COVID-19 pneumonia suggests that when used later on the disease there appears to be no benefit on survival albeit with a relatively limited sample size [1]. This is perhaps not unsurprising given that HCQ primarily works upstream in COVID-19 by preventing viral entry into lung epithelium via ACE2 [2].
In the study of Mahevas et al 85% of patients already had evidence of cytokine mediated hyperinflammatory syndrome in terms of a C reactive protein (CRP) level more than 40mg/l on admission to hospital [1]. In this regard a CRP above 42mg/l at initial presentation is indicative of poor outcomes in COVID-19 [3]. By this stage of the disease it is probably too late for any impact of attenuated entry of SARS-CoV2 into type 2 pneumonocytes, especially when the inflammatory related lung tissue damage has already begun.
Although HCQ also inhibits production of interleukin-6 from T cells and monocytes [4], this putative downstream immunomodulatory effect clearly did not translate into improved outcomes. Indeed the results of Mahevas et al were similar to those of another observational study in 1376 patients with hypoxic severe COVID-19 in New York City, where there was no difference in the primary outcome of death or intubation compared to standard of care [5].
The NIHR RECOVERY randomised controlled trial is evaluating the use of HCQ as monotherapy in the first randomisation phase in large numbers of hospitalised patients with COVID-19. However for sick hypoxic patients with late stage COVID-19 disease the emerging data points to futility in regard to use of HCQ alone. Surely the time has now come to end the hype with regard to use of HCQ in severe COVID-19. Given the adaptive design of RECOVERY perhaps an interim analysis is now indicated to test if using HCQ on its own is pointless. We believe that for such patients perhaps a combined treatment regimen may be required comprising earlier use of antivirals such as remdesivir or interferon-beta-1b [6] together with later use of selective cytokine inhibition as either anti-IL6 [7] or anti-IL1 [8], in order to address both upstream and downstream disease pathways [9].
References
1. Mahévas M, Tran V-T, Roumier 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:m1844. doi: 10.1136/bmj.m1844
2. Yao X, Ye F, Zhang M, 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 doi: 10.1093/cid/ciaa237 [published Online First: 2020/03/10]
3. Liu F, Li L, Xu M, et al. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. J Clin Virol 2020;127:104370. doi: 10.1016/j.jcv.2020.104370 [published Online First: 2020/04/29]
4. Sperber K, Quraishi H, Kalb TH, et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol 1993;20(5):803-8. [published Online First: 1993/05/01]
5. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. New England Journal of Medicine 2020 doi: 10.1056/NEJMoa2012410
6. Hung IF-N, Lung K-C, Tso EY-K, 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. The Lancet doi: 10.1016/S0140-6736(20)31042-4
7. Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences 2020:202005615. doi: 10.1073/pnas.2005615117
8. Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology doi: 10.1016/S2665-9913(20)30127-2
9. Lipworth B, Chan R, Lipworth S, et al. Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020 doi: 10.1016/j.jaip.2020.04.014 [published Online First: 2020/04/21]
Competing interests: No competing interests