Interview with Professor Cristina Mussini, Head of the Department of Infectious Diseases and Tropical Medicine at the University of Modena and Reggio Emilia in Italy and member of the European AIDS Clinical Society. She has been actively involved in various recent studies on the clinical use of tocilizumab in patients with COVID-19 pneumonia.
First a background question: what is tocilizumab?
Cristina Mussini: It is a monoclonal antibody of the IgG1 class, which is a specific ligand for the interleukin-6 (IL-6) receptor. So, it basically works by inhibiting the attachment of IL-6 to its receptor, and therefore, even though IL-6 circulating levels increase, they cannot further feed the cytokine storm, and the detrimental effects of this immune malfunction on respiratory function are hindered.
The first peer-reviewed articles on tocilizumab administration date from the spring; however, some were based on its use in China, where the pandemic had been ongoing for quite some time already. What led to tocilizumab administration in COVID-19-associated pneumonia patients during this initial stage?
Cristina Mussini: At the beginning of the pandemic, clinicians had to look for innovative and creative solutions. Since the cytokine storm is mostly driven by IL-6, and even though the idea of inhibiting a single molecule might seem far-fetched, there were reports of some rheumatoid diseases where just acting on tumor necrosis factor alpha (TNF-α) was enough to observe positive results, which supported the idea that tocilizumab could work.
On the other hand, since routine IL-6 analysis is not possible, and since there is no IL-6 threshold to inform clinical decisions, tocilizumab administration was based on clinical facts: a fast decaying respiratory function (PaO2/FiO2 ratio – partial pressure arterial oxygen and fraction of inspired oxygen – decreasing by 1/3 in one day or decreasing to 150 mmHg) and fever are both indicative of a cytokine storm, and mark the appropriate time for tocilizumab administration.
Most studies on tocilizumab use in severely affected COVID-19 patients have described the positive effects of this treatment, namely reduced mortality and a reduced need for mechanical ventilation. Why is the latter such an important outcome?
Cristina Mussini: Because it is directly linked to death. Some case series report up to an 80% death rate in mechanically ventilated COVID-19 patients. Basically, because these patients are at increased risk not only from COVID-19, but also from mechanical ventilation-associated pneumonia or other intensive care unit (ICU)-related infections. On the other hand, ventilation – if non-invasive – is important, not just placing patients in a prone position, but providing them with the oxygen they require to compensate the effects of the acute respiratory distress syndrome (ARDS).
In most studies, patients were already suffering severe COVID-19 pneumonia. What do you think would happen if patients were treated before reaching such disease stages?
Cristina Mussini: A randomised clinical study on 126 patients just published in JAMA tested earlier tocilizumab use in COVID-19 patients to try to avoid the cytokine storm, but without positive results. They observed no difference in clinical worsening between the patients receiving tocilizumab and those receiving only standard care. Therefore, it seems that tocilizumab administration time is critically restricted to compromised respiratory function, but ideally before intubation.
In your study you discuss the possibility of co-treatment with corticosteroids. What would such a treatment plan look like?
Cristina Mussini: According to the recent statement by the WHO, corticosteroids are to be administered to severe or critical COVID-19 patients, but in our protocol patients receive corticosteroids basically when they start receiving oxygen, whereas we initiate tocilizumab when respiratory function rapidly deteriorates. Therefore, I think that a sequential treatment, starting with corticosteroids and continuing with tocilizumab when corticosteroids fail or the patient condition worsens, might be the best way to go.
It would almost seem like tocilizumab can be the go-to drug for COVID-19 pneumonia, but what about side effects? Some authors report no side effects, others report – partial – immunodepression, and a recent analysis could not even conclude if there were side effects, nor identify them or assign them to the treatment …
Cristina Mussini: In our study, we had two cases of acute hepatitis with severe liver failure by Herpes Simplex virus 1. To prevent this from happening, we are now administering prophylactic preventative therapies to avoid viral replication in patients under corticosteroids and tocilizumab, and we are preparing a report precisely on this point.
In any case, given the severe disease stage at which tocilizumab is employed, even considering the possibility of side effects, it is a risk worth taking. However, prospective trial results would help clear up this point.
Another important question when talking about medication is dosage. Most published reports used 8mg/kg, whereas others used a flat dose of 400 mg: could that be the reason why they saw no side effects on immunity?
Cristina Mussini: Some clinicians/groups used a single dose, others two. When and how much tocilizumab to administer are the most important questions to be answered, but deciding on dosage sometimes depends on factors other than purely clinical ones (availability, price, etc.).
Also, one issue with getting comparable data is that running controlled randomised trials during an epidemic is difficult, not only because it would be unethical but also because patient selection would skew the data. The COVACTA trial (the first global, randomised, double-blind, placebo-controlled phase III study on tocilizumab use plus standard care on COVID-19) did not show significant results, probably because of patient selection, whereas EMPACTA the first global, phase III COVID-19 clinical trial to primarily enrol underrepresented minorities, with approximately 85% of its 389 patients coming from minority racial and ethnic groups, the populations heavily affected by the COVID-19 pandemic) did for similar reasons. You have to choose the right patient population: those suffering an important respiratory deterioration, but before undergoing intubation, since that is one of the main outcomes to avoid.
Which combination treatment do you think would be the most effective or which is the most promising while we wait for a vaccine to be ready? And speaking of vaccines, do you think it is reasonable to expect one to be ready in the next 6 months?
Cristina Mussini: I think that a protocol similar to ours is probably the most common: after corticosteroids, follow with immunomodulators (such as anakinra, the interleukin-1 (IL-1) receptor antagonist, or Jak inhibitors), which also aim to stop the cytokine storm and target the same signaling cascade as tocilizumab. However, new data are being released every day and even things we expected to work are shown to be useless, like for instance the results of the SOLIDARITY trial, which were an unpleasant surprise.
I really think that having a vaccine available in the next 6 months is hardly possible, because there are simply too many open questions: how long will protection last, for instance…? I think, in general, it is still very early to predict when things will go back to our pre-COVID times.