Immunosuppression for COVID-19

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We've learnt a lot about COVID-19 in a very short period of time and one thing that's clear is that it's not just another flu, and in particular, managing COVID-19 has brought up some unusual challenges, which are far from routine in an infection. One of these challenges, which has rightfully evoked an element of fear, is a hyperinflammatory state known by many names, including cytokine release syndrome, an often deadly state, which can emerge, even in young people, just as the embers are dying on the infection and the viral load is dropping. To combat inflammation we often evoke immunosuppression, but how does this sit in the context of an infective threat? And how do we find solutions rapidly, effectively, safely, and logically? I'm David Liew and today we've been joined by Senthuran Shivakumar, who is the clinical pharmacology registrar at the Austin Hospital in Melbourne, where I also work. And he's the first author on an editorial which addresses some of these issues about immunosuppression and COVID-19 and what repurposing means in this era. Sen, welcome to the program.

Thank you for having me David.

So, Sen, tell me a little bit about what repurposing means in a pandemic? Because I think for a lot of people, even if this is something which has been quite familiar to them, a concept which they’ve thought about, the idea of repurposing might be one that they're not necessarily familiar with.

Certainly yes, it is something that's become a bit more in the forefront of what we're doing in terms of research and endeavours and clinical encounters as we are faced with this COVID-19. As we all know, it's taken over the world and has put a lot of demand on our healthcare system and what we don't have a lot of time to work out is what effective therapies are available to us to treat this pandemic. And therefore, we fall back on medications that we've used in the past, and the reason we do that could be explained by the fact that the process of developing a new drug takes a lot of time, time which is precious in a pandemic. A normal clinical trial could take 12 to 16 years to develop an effective medication.

The benefits, as I mentioned, are not only from a time perspective, but also from other perspectives. We do have some knowledge about how these medicines work, in terms of mechanisms of action from previous studies. We also have some awareness about how these medications work in the body and safety profile is another thing we are aware of. And this knowledge can be very important in the situation where we have clinical uncertainty. This being said, there are some concerns, while these medications may have been effective in one indication, there's no necessarily guarantee that they may work in a COVID-19 pandemic and therefore they remain experimental. There have been examples where medications have been repurposed for different indications, for example, more recently sildenafil was used for treatment of erectile dysfunction, and now it's part of standard of care in pulmonary arterial hypertension. So, I guess we have done this before, but I guess what is different in this situation is that there is a time pressure on it.

So, that's an interesting example with sildenafil, where a similar mechanism of action is being adopted in different spheres, with the aim of effecting vasculature in different locations of the body. And so, is that similar to what we're seeing in COVID-19?

So, I suppose the differences are that the mechanisms of action have to match in some way, according to the disease process, for them to be paralleled. And I think that we are seeing a bit of evidence in the immunosuppression realms, where we are seeing an immuno phenomenon called cytokine release syndrome, which is an interesting phenomenon in the latter part of severe disease, which is associated with much mortality.

I gues, this gets to the heart of what your article is about, really, this seemingly contradictory idea that maybe in order to be able to defeat an infection and all of its consequences, that we might actually need to introduce ways to suppress the immune system. And that maybe not all the damage from an infection comes directly from the infection itself.

Yeah, it is quite a paradox, isn't it? That the use of immunosuppression is turning off the one system we're relying on to fight a virus. In many ways COVID-19 has two stages. If we look at it, the initial viral phase, where the virus replicates and causes damage and towards the latter stages, the immune response may take over. Now, it's important to understand that in COVID-19, around day 8 to 10, we sometimes see, in a subset of patients, not all, a rise in proinflammatory molecules, such as interleukin 6 and interleukin 1 and TNF alpha. And with this, there's a large recruitment of immune cells into the lungs. This results in lung damage and oedema, some of which causes some long-term fibrosis.

And what we would do in this situation is to suppress this immune reaction and prevent that damage. And the reason why this is interesting, in some ways, although devastating, is that it is comparable to other cytokine release syndromes we've seen in other clinical entities, such as rheumatic autoimmune diseases, as well as malignancies. In adults onset Still's disease we have a similar syndrome called macrophage activation syndrome. And in haematology we see CAR T-cell therapy and in that we have a cytokine release syndrome in that situation as well. And there are certain parallels we can draw upon and immunosuppression agents such as tocilizumab, which targets the interleukin 6 receptor, and steroids as well have been used in these situations to try and dampen the immune response in these hyperinflammatory states.

So, Sen, maybe I can ask what makes the hyperinflammatory state in COVID-19 any different to the hyperinflammatory state that one might get associated with any other type of infection, bacterial or viral infection?

It tends to occur in the later part of disease. It also has seemed to have more lung involvement and therefore once the lungs get involved, there's a high propensity for patients to end up requiring increased ventilatory support. I suppose, cytokine release syndromes in other entities have a more systemic involvement, but I suppose in COVID-19, it's more lung predominant and therefore is associated with a higher mortality. Immunosuppression has been the mainstay of treatment in most of these cytokine release syndromes. And they have been trailing the immunosuppressive agents in COVID-19 scenarios. Tocilizumab has not had any clear, large data from randomised control trials, but has had some promising results so far. Recently, the dexamethasone from the RECOVERY trial has had a preprint, releasing some of its evidence, and that has been acknowledged by the WHO. And what they've shown is that in the RECOVERY trial, the dexamethasone arm compared to standard of care, where they were giving dexamethasone at 6 mg for 10 days, reduced mortality in patients who were requiring oxygen, but not being ventilated. And the reduction in mortality was slightly higher in patients who were ventilated. Now, given this is a preprint and has not been peer-reviewed, I say it with some caution, but it sort of illustrates the point that dexamethasone and other immunosuppressives may have a role.

It's interesting that steroids in previous coronavirus outbreaks, such as SARS and MERS, had mixed results. While some said that they reduced in ventilation time, there was also the adverse effects such as fractures and psychosis that was noted. And there was also some suggestion that it may delay viral clearance. However, the clinical significance of this was not entirely clear. So, I guess, our past experience with these immunosuppressive agents is, we need to look at whether they're effective in this current situation, but also the longer term consequences of their use.

So, there's some good points there, Sen, and I think obviously that dexamethasone space is something to watch. And that's, I think, something that's been emerging in very recent times. Tell me a little bit more about some of the other immunosuppressive therapies that are targeting specific immune pathways.

Well, definitely tocilizumab, I guess, had had some interest. So far, there've been very small retrospective studies, which have shown some promise in terms of a reduction in time to clinical recovery, but these are all very small and not controlled randomised trials. There are some studies underway and hopefully results will come back to show us whether these are, in fact, effective in COVID-19. Other treatments that we could consider are medications such as anakinra, which target the interleukin 1 pathway. This has been used in macrophage activation syndrome in adults onset Still's disease. And this is another therapy that has been extensively researched, but however, results from large randomised control trials are still yet to come.

So, I guess you're talking about tocilizumab targeting the IL-6 pathway, anakinra targeting the IL-1 pathway, and IL-6 and IL-1 being part of this vicious reinforcing inflammatory cycle, which can potentially do the damage and cause mortality in COVID-19. I guess, this is the space which is of really great interest, just because this is where a lot of the death occurs, and this is what we're most scared about in COVID-19. Otherwise, will people who seem to be otherwise getting better, who might even be clearing the virus reasonably effectively, suddenly succumbing to this aggressive hyperinflammatory, reinforcing, snowballing type of state?

Yeah, certainly. I mean, they say the mortality rate associated with the ARDS is close to about 30% in some studies. And definitely, that a lot of the mortality is seen in the latter part of disease and this hyperimmune response definitely may be playing a part. And therefore, I guess, we have to have mechanisms to identify this early because it is quite a rapid and dynamic response.

Because, I guess, that raises a point, really, about where this belongs in terms of where in the course of COVID-19 this slots in? As much as we've talked about trying to dampen the hyperinflammatory state, there's a point earlier on, where there's a potential for risk here. So, I guess we've gone ... in risk, in terms of breaking down the immune system, which is actually fighting off the virus.

Definitely immunosuppression needs to be targeted at the right period of time in the disease process. This is mainly for patients who start to have high need for oxygen, requiring them to be hospitalised and requiring supplementary oxygen. That is the stage where, possibly, immunosuppression may prevent them from either going to ICU and requiring more invasive ventilation, and that is where we need to be targeted.

Well, Sen, that's been great. Thank you so much for joining us to talk a little bit about repurposing immunosuppressive medications in COVID-19. It's really a space that we're going to be watching in the future.

Thank you. It's been my pleasure.

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The views of the guests and the host on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew, stay safe and thanks for joining us once again, on the Australian Prescriber podcast.