Interview with Dr Juan Victor San-Martín López, a physician specialising in infectious diseases and a member of the task force coordinating responses to the leishmaniasis outbreak in 2011 and to COVID-19 at the Hospital Universitario de Fuenlabrada, Spain. He reports on his experience with tocilizumab use in COVID-19 patients.
What is the so-called cytokine storm? And why does it lead to such – often deadly – respiratory effects?
The ‘cytokine storm’, which is studied more in depth with the development of therapies based on CART or chimeric antigen receptor T cells (T cells genetically engineered to produce an artificial T-cell receptor for immunotherapy) since it is a characteristic side effect of this oncological treatment, leads to exceptionally high interleukin-6 (IL-6) levels, reflecting a brutal macrophage pro-inflammatory activity, which ends up producing lung damage very similar to that in COVID-19. This ‘oncological’ cytokine storm is treated with steroids and tocilizumab as first-line drugs, which led to their use in COVID-19.
However, despite the similarities, the COVID-19 cytokine storm also shows certain differences. The IL-6 figures found in severe COVID-19, although almost always high and related to mortality, are not as high as in the ‘classical cytokine storm’. From the information available so far, it seems that although IL-6 is important in the COVID-19 immune deregulation, the pro-inflammatory mechanism that produces tissue damage is more extensive than in the classical cytokine storm and therefore an intervention at various levels (for example, a combination of steroids and/or tocilizumab and/or anakinra) is probably more effective than cutting the inflammatory pathway at a single point.
Do you think all strategies against COVID-19 should focus on stopping the cytokine storm or on preventing it by using antivirals?
I think COVID-19 is an infectious disease and if we had a truly reliable antiviral the need for immunomodulators would probably be residual. The difficulties we have in treating COVID-19 only show the lack of an antiviral capable of stopping SARS-CoV-2 effectively. Remdesivir has not substantially modified the course of the disease, nor has it modified the evolution of the pandemic. If we had a working antiviral for SARS-CoV-2, we would be facing a potentially fatal but treatable respiratory disease, such as bacterial pneumococcal pneumonia, where current antibiotics are able to solve in a few days a disease that was fatal centuries ago. And we would only need to add immunomodulators in cases where treatment came late and the inflammatory storm was already triggered.
Is there any other way than a vaccine to strengthen the immune system to prevent this cytokine storm?
I don’t really see how. Assuming that in the short term there will be no effective antiviral, and while we wait for the vaccines to be ready and effective, we clinicians can only aim to detect as early as possible which patients are going to develop the COVID-19 inflammatory storm – or whatever we want to call it – in order to start anti-inflammatory/immunomodulatory treatments as soon as possible since these, to date, are the only ones shown to save lives. In my opinion, the challenge for clinicians is not to know whether steroids, tocilizumab or anakinra work, because in clinical practice we have observed that, in the right patients, they do. I think that trials which failed to demonstrate their benefit might have suffered from a design problem. Even more important than determining the dose, or whether one of those drugs is better than the other, or if a combination is possible, is to define who should receive them and when. In a disease with a clinical spectrum that varies between asymptomatic and severe respiratory distress with mechanical ventilation needs and > 50% mortality at this stage, finding early biomarkers for the cytokine storm to predict who is going to evolve for the worst would be key to intervening as soon as possible and avoiding treating those who do not need these drugs.
Where do you think should be the focus of research against the coronavirus?
The development of an antiviral. I see a wealth of news about potential vaccines, which obviously need to be investigated, but we primarily need antivirals for coronaviruses now. This is the third coronavirus to produce a health emergency in less than 20 years, and will probably not be the last. And clearly, a disease with an effective treatment can be managed in a much more relaxed way than otherwise.