Combination upstream and downstream treatment modalities for RECOVERY from COVID-19
Dear Editor
Rapid and effective large scale recruitment into the NIHR RECOVERY trial is something we can be proud of as a nation. However the design of RECOVERY requires closer scrutiny bearing in mind that these were sick hospitalised patients with severe COVID-19 infection. In broad terms treatments may be divided into those which address the upstream disease pathway with antivirals or drugs which block viral host cell entry such as hydroxychloroquine; or the downstream pathway by modifying the adaptive cytokine cascade and associated hyper-inflammatory response [1]. In many respects COVID-19 presents in its later phase as a viral induced multi-organ autoimmune disease and hence strategies are required to selectively block the cytokine cascade. It is therefore somewhat naïve to believe that using monotherapy in the first randomised treatment arm of RECOVERY would be a successful strategy.
Somewhat late in the day a second randomisation arm has now been added to RECOVERY where the anti-IL 6 agent tocilizumab [2] or no additional treatment may be given concurrently within hours of the first arm in patients with evidence of hypoxia (SaO2<92%) and hyperiflammation (CRP >65mg/l), if and when their condition deteriorates. Unfortunately this will mean that it is not possible to assess the potential for any facilitation of response between the first and second randomisation arms due to simultaneous dosing regimens, for example, between hydroxychloroquine and tocilizumab, considering the former also inhibits IL6 production [3].
One also perhaps has to question the ethical aspects of a patient with severe deteriorating COVID-19 having a 10% overall chance of being randomised to standard of care in both the first and second arms. We believe a more cogent strategy would have been to add in a first randomisation arm comprising the combination of upstream and downstream treatments with hydroxychloroquine plus tocilizumab so that this could be compared head to head versus hydroxychloroquine alone to evaluate putative synergy [4]. As such we have reservations about the inherent design flaws in RECOVERY due to confounding carryover effects between the first and second randomisation arms, which in turn will obviate a proper evaluation of combination therapy for severe COVID-19.
1. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033-34. doi: 10.1016/S0140-6736(20)30628-0 [published Online First: 2020/03/21]
2. 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
3. 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]
4. 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
08 May 2020
Brian J Lipworth
Pulmonologist
Chris Kuo, Rory Chan
Scottish Centre for Respiratory Research, Ninewells Hospital and Medical School, Dundee
Rapid Response:
Combination upstream and downstream treatment modalities for RECOVERY from COVID-19
Dear Editor
Rapid and effective large scale recruitment into the NIHR RECOVERY trial is something we can be proud of as a nation. However the design of RECOVERY requires closer scrutiny bearing in mind that these were sick hospitalised patients with severe COVID-19 infection. In broad terms treatments may be divided into those which address the upstream disease pathway with antivirals or drugs which block viral host cell entry such as hydroxychloroquine; or the downstream pathway by modifying the adaptive cytokine cascade and associated hyper-inflammatory response [1]. In many respects COVID-19 presents in its later phase as a viral induced multi-organ autoimmune disease and hence strategies are required to selectively block the cytokine cascade. It is therefore somewhat naïve to believe that using monotherapy in the first randomised treatment arm of RECOVERY would be a successful strategy.
Somewhat late in the day a second randomisation arm has now been added to RECOVERY where the anti-IL 6 agent tocilizumab [2] or no additional treatment may be given concurrently within hours of the first arm in patients with evidence of hypoxia (SaO2<92%) and hyperiflammation (CRP >65mg/l), if and when their condition deteriorates. Unfortunately this will mean that it is not possible to assess the potential for any facilitation of response between the first and second randomisation arms due to simultaneous dosing regimens, for example, between hydroxychloroquine and tocilizumab, considering the former also inhibits IL6 production [3].
One also perhaps has to question the ethical aspects of a patient with severe deteriorating COVID-19 having a 10% overall chance of being randomised to standard of care in both the first and second arms. We believe a more cogent strategy would have been to add in a first randomisation arm comprising the combination of upstream and downstream treatments with hydroxychloroquine plus tocilizumab so that this could be compared head to head versus hydroxychloroquine alone to evaluate putative synergy [4]. As such we have reservations about the inherent design flaws in RECOVERY due to confounding carryover effects between the first and second randomisation arms, which in turn will obviate a proper evaluation of combination therapy for severe COVID-19.
1. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033-34. doi: 10.1016/S0140-6736(20)30628-0 [published Online First: 2020/03/21]
2. 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
3. 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]
4. 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