Re: RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials
Dear Editor,
As a junior doctor on a COVID-19 medical ward, it has been exciting to see the rapid progress of the RECOVERY trial, from patient recruitment to physician education and involvement. Our hospital was one of the first centres to introduce tocilizumab – an interleukin-6 (IL-6) receptor antibody – into its second randomisation arm for participants with progressive COVID-19. From my perspective as a junior doctor, the last few weeks have shown me how quick progress from bench to bedside can be made. I have experienced something like nothing before: a new condition that requires a new treatment.
Patients with COVID-19 on our ward often respond well to initial supportive therapy with oxygen, but then tend to go one of two ways: either steadily improving and recovering completely, or rapidly deteriorating (heralded by rising CRP, LDH, ferritin and D-dimer), requiring an escalation to HDU or ICU. Sadly, the outcome may be death for some.
It is evident that an uncontrollable hyper inflammatory response to the virus – a cytokine storm – is a crucial element in the pathogenesis of severe COVID-19 [1]. High numbers of pro-inflammatory cytokines recruit neutrophils and macrophages en masse into the lungs and other organs, driving tissue damage, hyper coagulation, systemic shock and multi-organ failure. This rise in inflammatory cytokines could also cause the exhaustion of T cell populations, driving the worsening lymphopenia seen in deteriorating patients [2].
It is also becoming increasingly apparent that IL-6, a multi-faceted immune messenger, is a central cytokine in this virus-induced storm. In the early days of the pandemic, researchers in Wuhan found that IL-6 serum levels significantly correlated with disease severity [3]. Now there is promising evidence that blocking the IL-6 receptor via neutralising antibodies may calm the cytokine storm and save lives. A clinical trial using tocilizumab in China found rapid improvement in fever and respiratory function in 21 patients with severe COVID-19 and all were discharged from hospital [4].
These encouraging initial results clearly need to be explored in a much larger randomised trial. This is why RECOVERY – at the time of writing the largest COVID-19 trial in the world – is so exciting. While we await its initial findings, let’s celebrate it for what it is: a scientific, medical and logistical achievement in a short period of time. From what I see in so many of our deteriorating patients, and from the emerging immunological research, drugs targeting IL-6 could well become important weapons against this global scourge. Like the name of the study, its findings will help us as we move to the recovery phase post COVID-19.
1. Chen, L., Liu, H.G., Liu, W., Liu, J., Liu, K., Shang, J., Deng, Y. and Wei, S., 2020. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Chinese journal of tuberculosis and respiratory diseases, 43, pp.E005-E005
2. Diao, B., Wang, C., Tan, Y., Chen, X., Liu, Y., Ning, L., Chen, L., Li, M., Liu, Y., Wang, G. and Yuan, Z., 2020. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Frontiers in Immunology, 11, p.827
3. Liu, F., Li, L., Xu, M., Wu, J., Luo, D., Zhu, Y., Li, B., Song, X. and Zhou, X., 2020. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. Journal of Clinical Virology, p.104370
4. Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., Li, X. and Zhang, X., 2020. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences
Competing interests:
No competing interests
18 May 2020
Monty Lyman
Senior House Officer
Dr Antoni Chan, Consultant Rheumatologist, Royal Berkshire Hospital
Royal Berkshire Hospital
Royal Berkshire Hospital, London Road, Reading, RG1 5AN
Rapid Response:
Re: RECOVERY trial: the UK covid-19 study resetting expectations for clinical trials
Dear Editor,
As a junior doctor on a COVID-19 medical ward, it has been exciting to see the rapid progress of the RECOVERY trial, from patient recruitment to physician education and involvement. Our hospital was one of the first centres to introduce tocilizumab – an interleukin-6 (IL-6) receptor antibody – into its second randomisation arm for participants with progressive COVID-19. From my perspective as a junior doctor, the last few weeks have shown me how quick progress from bench to bedside can be made. I have experienced something like nothing before: a new condition that requires a new treatment.
Patients with COVID-19 on our ward often respond well to initial supportive therapy with oxygen, but then tend to go one of two ways: either steadily improving and recovering completely, or rapidly deteriorating (heralded by rising CRP, LDH, ferritin and D-dimer), requiring an escalation to HDU or ICU. Sadly, the outcome may be death for some.
It is evident that an uncontrollable hyper inflammatory response to the virus – a cytokine storm – is a crucial element in the pathogenesis of severe COVID-19 [1]. High numbers of pro-inflammatory cytokines recruit neutrophils and macrophages en masse into the lungs and other organs, driving tissue damage, hyper coagulation, systemic shock and multi-organ failure. This rise in inflammatory cytokines could also cause the exhaustion of T cell populations, driving the worsening lymphopenia seen in deteriorating patients [2].
It is also becoming increasingly apparent that IL-6, a multi-faceted immune messenger, is a central cytokine in this virus-induced storm. In the early days of the pandemic, researchers in Wuhan found that IL-6 serum levels significantly correlated with disease severity [3]. Now there is promising evidence that blocking the IL-6 receptor via neutralising antibodies may calm the cytokine storm and save lives. A clinical trial using tocilizumab in China found rapid improvement in fever and respiratory function in 21 patients with severe COVID-19 and all were discharged from hospital [4].
These encouraging initial results clearly need to be explored in a much larger randomised trial. This is why RECOVERY – at the time of writing the largest COVID-19 trial in the world – is so exciting. While we await its initial findings, let’s celebrate it for what it is: a scientific, medical and logistical achievement in a short period of time. From what I see in so many of our deteriorating patients, and from the emerging immunological research, drugs targeting IL-6 could well become important weapons against this global scourge. Like the name of the study, its findings will help us as we move to the recovery phase post COVID-19.
1. Chen, L., Liu, H.G., Liu, W., Liu, J., Liu, K., Shang, J., Deng, Y. and Wei, S., 2020. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Chinese journal of tuberculosis and respiratory diseases, 43, pp.E005-E005
2. Diao, B., Wang, C., Tan, Y., Chen, X., Liu, Y., Ning, L., Chen, L., Li, M., Liu, Y., Wang, G. and Yuan, Z., 2020. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Frontiers in Immunology, 11, p.827
3. Liu, F., Li, L., Xu, M., Wu, J., Luo, D., Zhu, Y., Li, B., Song, X. and Zhou, X., 2020. Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19. Journal of Clinical Virology, p.104370
4. Xu, X., Han, M., Li, T., Sun, W., Wang, D., Fu, B., Zhou, Y., Zheng, X., Yang, Y., Li, X. and Zhang, X., 2020. Effective treatment of severe COVID-19 patients with tocilizumab. Proceedings of the National Academy of Sciences
Competing interests: No competing interests