Cytosorbents Corporation (CTSO) Earnings Call Transcript & Summary

Yes, hello, everybody, and a warm welcome here from our studio in Berlin. We just heard music from the Hamburg group, Roman Schuler. They have a little journey through the Harbor of Hamburg. But now we are here in Berlin and -- at the CytoSorbents' studio. And I want to welcome you all to our next International CytoSorbents Experts' Meeting, dealing with a topic, COVID-19. Yes. And I have the big, big pleasure to welcome a very renowned speakers and excellent experts. The first one is our chairman of today's event. This is Professor Manu Shankar-Hari from London. He is from the Department of Intensive Care Medicine in Guy's and St Thomas' Hospital and School of Immunology, King's College London. Hello, Manu.

Stefan, thank you so much. What a lovely meeting and a start to the meeting. Thank you. It's fantastic music. Thank you very much.

Yes. Thank you to have you here on board. And another thanks goes out to Chicago in the U.S. That's Professor Tae Song. He is a cardiac surgeon and leading the Lung Transplant Program and the ECMO program at the University of Chicago. Hello, Tae. Can you hear us?

Yes. Hi, Stefan. Very happy to be here.

Tae, nice to have you here. And yes, we are very keen to hear very soon your lecture. And the third expert in the round is my dear colleague, Professor Zsolt Molnar from the University Semmelweis in Budapest from the Department of Anesthesiology, and Zsolt is also our Senior Medical Director at CytoSorbents. So [Foreign Language] in Hungary.

Thanks a lot, Stefan, and a special thanks for the great music. I really enjoyed it. So I hope the lectures will be just as entertaining as the music. Thanks.

As I said, be prepared, yes? And there's last sound and then the last title, yes. And before I forget it and before I switch over to Manu to share here our event, let me give you some more information. First of all, we have, like in all the other events, we have 2 translators on board of our booth. This is one, Peggy is translating from English into German and Sydney from English into Spanish. So if you like to improve your language skills, please jump into the different language sessions, and you can also learn more about the different languages. So -- and the other thing I want to mention here is we have also great experts in our chat room. These are my dear colleagues, Dr. Teresa Klaus and Dr. Volker Humbert and Alex Bojan, and they will help you to answer many questions as possible. And of course, we also try to get many questions into our panel discussion later. So -- and with that, I really like to hand over to Manu now to introduce the first speaker. Manu?

Stefan, thank you, firstly, for the invitation and the wonderful organization of the seminar. The first speaker, you have already introduced, Dr. Tae Song, from Chicago, U.S.A., going to talk to us about the CTC multicenter registry. Thank you. Over to you.

Thank you for the introduction. Good afternoon. I will be giving a brief presentation on the preliminary results of the CytoSorb therapy in COVID-19, or CTC registry, which is a multicenter U.S. registry. These are my disclosures. In April of last year, the Food and Drug Administration of the United States issued an emergency use authorization. The EUA stipulated that CytoSorb devices could be used for patients 18 years or older with confirmed COVID-19 infection admitted to the ICU, with confirmed or imminent respiratory failure. Indications included early acute lung injury or early ARDS, or severe disease defined as dyspnea, tachypnea, hypoxia with saturation less than 93%, P/F ratio of less than 300 or significant lung infiltrates. Third indication was life-threatening disease defined as respiratory failure, septic shock and/or multi-organ system failure. So a broad range of indications, but basically, critical ill patients confirmed to have COVID-19 who are on ECMO were candidates for CytoSorb use under the EUA. The CTC registry was designed subsequent to this with the intent of enrolling multiple centers across the United States and create an observational registry for patients treated with CytoSorb under the EUA. The goal was to collect patient demographics, treatment characteristics and clinical outcomes on COVID-19 patients on ECMO treated with CytoSorb. After patient enrollment, data was collected in an electronic case report form. The primary outcome was ICU mortality. The initial participating centers included West Virginia University, University of Chicago, NYU, Medical College of Wisconsin and Franciscan Health, Indianapolis. Two additional centers have joined subsequent to this. Here is a table illustrating the demographics and baseline characteristics of the CTC registry cohorts. And as I referenced, the ELSO registry, ECMO ARDS cohort is also shown. There were 2 main differences. And as you can see, for U.S.-based registry, as expected compared to an international registry, there was a higher proportion of Caucasians. The second difference was interesting in that in the CTC registry, there were less patients who received conventional treatments listed below prior to initiation of ECMO. These are the treatment parameters and biomarkers that were analyzed. The duration of ECMO support was around 82 days. The time to therapy after initiation of ECMO was 2.5 days. The time to therapy after ICU admission was 1 week, and the total duration of ECMO support was 31.6 days. Biomarkers analyzed included CRP, ferritin and D-dimers. And as you can see, data was available for 19 to 22 patients and only included if we had both baseline and value at day 3. And for these levels, you can see that at day 3, after 72 hours of CytoSorb therapy, there may have been a slight reduction in the levels. This Kaplan-Meier curve shows our primary outcome of ICU mortality. At 30 days, mortality was 17.3% and at 90 days, 26.9%. As a reference, the reported mortality in the ELSO COVID-19 ECMO ARDS registry at 90 days is 50%. During the study period, there were no adverse reports -- events reported in any of the centers. This graphic depicts patient disposition from start of CytoSorb therapy up to day 90. And in a lot of cases, we did not have the final disposition, but it does show that there was a consistently higher rate of discharge from ICU compared to mortality throughout the study. Then we looked at the characteristics of survivors versus nonsurvivors. And as far as the baseline characteristics, you can see that there was no difference in any variable between survivors and nonsurvivors. As far as treatment characteristics, the most notable difference that we noted was that in the survivor group, the baseline D-dimer level had a trend toward being lower, with the mean at 2.3 versus 19.8 micrograms per mL in the nonsurvivor group. We performed a logistic regression on the D-dimer levels, and there was a borderline association between the baseline D-dimer level, with a 32% increase in the risk of mortality per 1 microgram per mL increase in the D-dimer level. So in conclusion, the CTC registry is the first reported multicenter experience with CytoSorb therapy in COVID-19 patients on ECMO. The CTC cohort was comparable to the international ELSO registry cohort. CytoSorb therapy in accordance with EUA criteria was used in all centers without any adverse events reported. CytoSorb in ECMO for patients in the ICU, survival was -- at 90 days was 73.1% compared to 50% in the ELSO registry. Elevated baseline D-dimer levels may suggest increased risk of death, and this is being reported in other COVID-19 studies as well. The CTC results suggest that CytoSorb therapy may be beneficial in critically ill COVID-19 patients, but further studies will be needed. We will continue to collect and analyze data in the CTC registry and also focus on additional clinical outcomes, including hemodynamics, lung recovery, duration of ECMO support. Thank you very much. I'd be happy to take any questions.

Thank you so much, Tae Song. And whilst we wait for some questions, can I start by asking, when you compare the ECMO group with the CytoSorb group, did you have -- did you match them in any way to try and understand why there is a difference between the 2 groups?

So Manu, thank you for a great question. And that's something that we have been thinking about a lot. But unfortunately, the registry design was such that we were not able to enroll a control arm. And I think that would have been very helpful. It's something that we are strongly considering moving forward. So this is an expanded case series of source and not a matched trial. But I do think putting in the context of other registry data, such as the ELSO, for example, I think the data nonetheless is useful.

Great. Are there any questions from the participants that we can ask?

Not yet, Manu, but maybe at the end in the panel discussion, we can.

Okay. Great.

Come back to that.

Fantastic. So let's move on to the next speaker. It's a friend and colleague of mine, Zsolt Molnar, who has done tremendous amount of work in the space -- intensive care space and published original research using CytoSorb. So Zsolt, over to you about the current studies and experiences. Thanks again for the lecture.

Well, thank you very much for the introduction. And it is my great pleasure to share with you my views on CytoSorb in COVID-19. So let's start with a bit of background. And the whole story revolves around the dysregulated immune response. And the common feature of all those diagnosis, you can see on this slide, that any one of these starting from trauma to sepsis, burns and whatever can provoke a host response that can become dysregulated. And during this process, pro inflammation overwhelms and inflammation. And this causes an imbalance between the 2 forces. And by using cytokine adsorption, you may just remove excessive amount of cytokines. And by doing that, you regain a balance. And it's important to know that it's not a privilege of the sepsis-related conditions, but in any pathogen or damage-associated insults and injuries can provoke this dysregulated immune response, including COVID-19. So what did we learn during the pandemic? This is a very important and nice article showing us that our immune system can defend us from the virus at several steps. Unfortunately, even those who are infected, about 80% of the infected population can -- in them the disease can go almost unnoticed. However, in the rest and in the most severe cases, this defense system fails to protect us. And in fact, the body can swing into an overwhelming host response, and that can result in a thing what we call cytokine storm, which can lead to the dysfunction of vital organs. Now even in this very early article, it was proposed by the authors, the mechanical removal of these circulating inflammatory mediators might be beneficial. And they go as far as stating that controlling the inflammatory response may be as important as targeting the virus itself. Well, however, it's not only inflammation, but also hypercoagulation, hypercoagulability, we have to take into account. And there are several papers coming from a year back and even recently, and they all conclude that they found high D-dimer levels in these patients. And in fact, and all these articles come to the same conclusion, that around 2-milligram per liter D-dimer level has -- with a count of this level, has a very high 90% area on the curve to predict hospital discharge and mortality. So in fact, hypercoagulation may play a very important role in the progress of the disease. And the main vital organ which the virus can attack and the process can damage is the lungs. So we know that the virus can inflict lung injury that again, it's a vicious circle, can trigger further inflammation. And the more severe the inflammation, the more severe the COVID-19 illness. And of course, with this, the risk of death is increasing. And this led to the discovery or the notion that there are 2 phenotypes of ARDS in this patient population. One that we have been very familiar with, those in whom capillary leak develops the heavy lung, the exudative ARDS patients. And those who develop thrombotic complications, which will impair the perfusion ventilation physiology, cause mismatch and then, via this process, cause hypoxemia in these patients. So CytoSorb, we all learned over the years that it can remove a wide variety of inflammatory mediators. And with -- by doing this, this early effect can help us, if we combine it with other extracorporeal-supported therapies like ECMO or renal replacement therapy, to put the lung at rest. And at this moment, the areas and thrombotic areas evolve into the same track that we want the injured lung to be at rest, allow time to heal. And the earlier we start the treatment, possibly the more time the lungs have to recover. Possibly these rationales led to key opinion leaders of intensive care medicine. But at the very early phase of the pandemic, they proposed that extracorporeal organ support therapies, including hemoadsorption, should be considered in the sickest patient population. This led to a further acknowledgment of the therapy. And the FDA and the DCGI granted emergency use application in COVID-19 patients in the United States for CytoSorb and hemoadsorption was included in several national guidelines and recommendations. And this led to more than 6,000, almost 7,000 treatments worldwide in more than 30 countries over the course of the pandemic. What clinical data have apart from the rationale and recommendations? Well, there are a lot of case series, and I have no time to dig into them. But more or less, they all conclude that they observe beneficial effects of CytoSorb therapy in the sickest COVID-19 patients in several conditions, different conditions. But this is one of the first case series coming from Iran, and 26 patients were treated with CytoSorb. And you can see that these inflammatory markers, procalcitonin, C-reactive protein, ferritin levels reduced significantly, lactate levels decreased and norepinephrine requirement also decreased before and after the course of the therapy. And oxygenation, as indicated by the change in the P/F ratio, also improved, and they concluded that the treatment seemed to be effective, feasible and well tolerated by the patients. This was one of the first case series, although just recently published coming from Wuhan and limited number of patients. But again, you can see that the trend is, before and after cytokine removal, improvement in hemodynamics, decreased lactate levels, increased improving oxygenation and reduced IL-6 levels. Regarding safety, we also found that there was no change in albumin, hemoglobin, white cell count, neither in platelets. So the treatment seems quite safe. So they concluded that it was well tolerated. And of course, further trials are warranted. This is very much in line what we found in Hungary. In a large district general hospital in one of the biggest COVID centers, 13 patients were treated with CytoSorb in severe respiratory failure. And this paper is under review, and we found that there was a decrease in norepinephrine requirement and improvement in the P/F ratio, so the treatment before and after treatment, it seemed to have a positive effect. And as far as safety is concerned, it is very similar to what the other groups found that there was no change in platelet count, so the treatment is indeed well tolerated and improved vasopressor need and improved oxygenation. This is one of the largest case series coming from Alharthy and coworkers. 50 patients treated with CytoSorb, COVID-19 patients, they had very high predicted mortality, around 70% based on the admission APACHE II score. And the observed mortality was much better, 30%. They compare survivors to nonsurvivors. And what you can see here that those patients who survived, they had improved P/F ratio, reduced SOFA score and reduction in IL-6 levels. And those patients who died eventually, then all these changes before and after treatment were not present. So this may be a signal that if you treat your patients for a few days and you see deterioration of all of these parameters, then possibilities should be regarded as nonresponders. They concluded that patients who needed CRRT and CytoSorb therapy after severe COVID-19 disease, they had positive signals, improvement in ARDS, septic shock and even hyperinflammation was attenuated. The only prospective randomized control study came from Germany, from Freiburg. And this was a study on 34 patients, randomized into 72-hour adsorp treatment versus controls. Their primary outcome was a reduction in IL-6 levels. You can see on the first graph that there was no change, but there was no difference between the 2 groups. There was a reduction in both groups, and the differences were not significant. And the secondary -- one of the secondary endpoint was survival. And in the control group, 76% of patients survived whilst in the CytoSorb-treated group, only 18% of patients survived. And they concluded that this is an alarming signal and cytokine adsorption should be considered carefully and only used within the domain of clinical trials. However, when we look at the results in detail, although they state that the randomization was successful. But when you look at the inflammatory marker levels, then they were higher, although not significant, but higher in the cytokine -- in the CytoSorb group and also, the D-dimer levels were more than doubled and significantly higher in that group as compared to controls. So a word of caution has to be said about the results. And my first warning is that there is some evidence there might be imbalance in the 2 groups, and especially the D-dimer levels, which are very high. These are quite alarming. And if you remember for my slide in which I discussed the cutoff value of D-dimer and its relationship to hospital discharge and mortality, and they recommended a cutoff level of 2-milligram per liter. Then taking into consideration these very high levels, 9 and 4.7, then it is highly likely that these patients, there's a risk -- high risk of dying with or without hemoadsorption because of the severe ventilation perfusion mismatch in these patients, which is also true not only in the lungs but also other vital organs. And if you take an even closer look to the Kaplan-Meier curve, the blue rectangle indicates the period during which patients received cytokine adsorption, 72 hours. And the Kaplan-Meier curve only starts to deviate after day 10. So something occurs much later than the -- substantially later than the cytokine adsorption therapy was completed, which is corresponding for this difference in mortality. Furthermore, their results are striking, remarkable, 76% survival in the control group. If you compare the data derived from these 17 patients to the ELSO registry, including thousands of patients who were treated with ECMO in COVID-19, then their mortality is 49%, several times worse than that reported in that paper. So we have to conclude that regarding mortality, it was severely underpowered to make any comment on mortality and their results, even in the control group and in the CytoSorb group as well, not consistent with previously published data. So to sum up the limitations on the CytoSorb trial, so we have to conclude that it was an unselected population. They included all-comers. The inclusion criteria wasn't that precisely defined. In fact, hyperinflammation was not included amongst the inclusion criteria. And the high D-dimer levels and also alarming and the medium baseline vasopressor, P/F ratio, fluid loss, all of that was worse -- a little bit worse than in the other group in the CytoSorb -- in the control group as compared to the CytoSorb group. So this may be responsible for the imbalance. And my last warning goes with this high D-dimer levels. Because if the patients have so high D-dimer levels, then this may mean that there is a clot burden and CytoSorb will not be able or any hemoadsorption device to treat clot burden. So these key imbalances highlight the limitations and give us a bit of caution to over-interpret the results of the small single center study. There was a retrospective prospective registry run in the United States 5 centers, patients treated for COVID-19 with ECMO and with CytoSorb. The results were demonstrated on the 40th Intensive Care Conference in Brussels 2 weeks ago, and we also submitted the paper, which is under review as we speak. Just a summary of the main results, that the mortality is a little bit better than even what was reported in the ELSO data, but definitely in line with the international standards. As I said, even a bit better. And when we compare survivors to nonsurvivors, survivors had a D-dimer level of around 2, whilst those who died, they had a very high D-dimer level. So the conclusion of this poster presentation was that CytoSorb in COVID-19 ECMO patients is associated with mortality that is comparable to international benchmarks. Elevated D-dimer levels appear to be associated with increased risk of mortality, which is, again, perfectly in line that have previously been published and CytoSorb was generally well tolerated. So to sum up, I use our article that we published recently before the CytoSorb trial actually. And we included in this review every published article, and we put them in this summary table. And we looked at 3 outcomes, improvement in hemodynamics, improvement in oxygenation and controlling the inflammatory response. So these outcomes were reported in the studies that were included. And you can see that most of those were interpreted as, yes, there was improvement in these outcomes. And based on that, we concluded that these are the indications in which we do recommend the consideration of hemoadsorption. Now as far as COVID-19 patients are concerned, of course, it's not a general adjuvant treatment for all COVID-19 patients, but only for a subset of patients. And those who are in vasoplegic shock and severe hypoxemia, in other words, severe organ dysfunction and in whom, and this is very important, the standard medical therapy fails to improve the clinical condition. So the take-home message of my presentation, to keep this mind in mind when you treat COVID-19 patients, that if you observe hyperinflammation based on elevated biomarker levels, then be on alert that your patient may benefit from cytokine removal, especially if organ dysfunction develops. If there is very high D-dimer level, then please be a bit more reluctant to start CytoSorb therapy because the clot burden will not be able to be solved by CytoSorb. So we do recommend to use CytoSorb when the D-dimer level is lower than 4 nanogram per milliliter. And when there is severe organ dysfunction, despite steroids, proning, so despite standard medical therapy, then consider CytoSorb treatment and consider it early, especially in patients who are on ECMO or on CRRT. And with this, I would like to thank you for your attention, and I'm open to any questions.

Zsolt, that's a fantastic summary. I think it looks like we are taking questions right at the end as part of the discussion. So perhaps will come back to the questions for you. Let's move on to the next talk, which is a prerecorded talk.

Yes. And the prerecorded talk comes from Manu Shankar-Hari. It's about multisystem inflammatory syndrome, a relatively rare indication, but maybe we see more of these indications in the near future, we don't know. But Manu will give us some insights into this indication. And I'm happy to discuss later on some of the burning questions with you, Manu.

Okay. Now on to the final talk of the session, which is the multisystem inflammatory syndrome in children or MIS-C or PIMS-TS. The reason why we are discussing this topic is that some elements of what we are seeing in SARS-CoV-2 in this third, fourth and the subsequent wave, we see younger patients are coming into hospital. And I think there may be similarities to what we have described in terms of MIS-C immunology. So when we think about MIS-C in children, the whole concept started with the 2 reports simultaneously, one from my hospital in the U.K., Guy's and St Thomas' Hospital, the Evelina Children's Hospital is the first report of what they call as hyperinflammatory shock in children during the COVID-19 pandemic. Around the same time, there was a region -- there was a report from Italy, where they talk about Kawasaki-like disease in SARS-CoV-2 epidemic in kids. And this was also followed by a report again from the much broader report from the U.K. led by Liz Whittaker and colleagues in [indiscernible] talking about the pediatric inflammatory syndrome. So I'm going to just talk a bit about our paper that was published in Nature Medicine. We essentially -- a big thanks to the group who worked hard on it, the idea to conception and write-up was 4 weeks. So it was at pandemic pace. And I think Mike Carter, Matt Fish and Aislinn Jennings are the 3 main people in the paper. We are talking about kids, 23 children, 3 different time points at admission, at peak disease and after recovery in the outpatients. The first point I want to kind of make to you is that MIS-C is very different from Kawasaki's disease. And there are a number of characteristics that makes them different. So MIS-C is in dark blue, and the Kawasaki disease is in light blue. And there are things in MIS-C that doesn't occur in Kawasaki's disease and -- for example, abdominal pain, diarrhea and vomiting, there's no data. Kids with MIS-C are older whereas Kawasaki's disease is a younger population. There are more respiratory and cardiac dysfunction in patients with MIS-C compared to those with Kawasaki's disease. I may touch upon the management later on, but I think initially, what we have done in these patients is to give corticosteroids, intravenous immunoglobulin and some immunomodulation with anti-IL-6 blockers such as tocilizumab. So there may be a role for the hemoadsorption that we heard from the previous speakers. The second point I want to make is that MIS-C patients have got SARS-CoV-2 infection 2 to 3 weeks before hospitalization. In other words, these are -- this is an immunological phenomenon that happens once the infection is better, but the patients are unwell because they got an immune response. And the characteristic features of this is reported in our paper, which is that these patients have got raised IgG, IgM for receptor binding domain of the spike protein and the spike protein itself. And what is interesting is that the nucleocapsid IgG is increased, IgM is not. And it's important to kind of remember that we are now going to see patients who are vaccinated either partially or completely. So some of these immunology will be different when you start to see second and subsequent waves of SARS-CoV-2 infection in younger patients. And the one common theme that you heard before and that's going to be repeated is that these kids have got evidence of organ injury and inflammation. So for example, these kids have got low platelet count that gradually get better. Their CRP is higher. Their ferritin is high. They got fibrinogen that is high and that gradually comes down. Their D-dimers are high that is suggesting activated clotting. These kids have got myocardial dysfunction. The troponin is high, NT-proBNP is high. The myocardium, especially when they're antibody-positive, the contractility is impaired. So the multisystem disease that you kind of have seen in adults are more or less replicated in these kids with PIMS-TS. And needless to say, given that we are talking about the cytokine adsorption therapy, kids with MIS-C and multisystem inflammatory disease have got very high levels of cytokines, in particular, IL-6, IL-10, interferon gamma and TNF-alpha and IL-8. So kids with MIS-C and similarly, multisystem disease, are associated with very high cytokines that may benefit from immunotherapy that you heard earlier. And the last point I want to make is about the immune cell. There is a completely altered, both innate and adaptive immune system, in particular, innate immune cells are activated, T cells are activated, but they are extremely lymphopenic. So that's a general cell count in these kids at different time points that I explained, and the C is the control, which are reagents [indiscernible]. What you see here are the neutrophil, the monocytes, the dendritic cells and the NK cells are relatively similar. What is different is the neutrophil CD64 MFI is very high, suggesting activation. Monocyte HLA-DR is impaired and this monocyte CD86 MFI is decreased. These 2 findings suggest that these kids have got impaired antigen presentation via monocytes. As I said earlier, there is pan T cell lymphopenia, CD4 T cells are decreased, CD8 T cells have decreased, gamma delta T cells have decreased, where regulatory T cells are decreased, which we didn't expect to see. And what is also apparent is that the CD4 MFI for HLA-DR is very high, and the gamma delta T cell MFI for HLA-DR is high, suggesting that the T cells are activated despite being depleted. And the B cell count, again, very similar, alongside the lymphopenia, you get the total B cell count decrease and the decrease in B cell count is differentially affecting the naive and the memory compartment, the memory B cells are more depleted compared to the naive B cells. So I said at the start that there are people have quite different treatment. And the next figure is essentially a summary of what happens when you treat these patients. Remember, when I started talking, look at figure A, we talked about 3 different time points, T1, T2 and T3. Now patients move from T1 to T2 and T3 as and they are different immunological states. Now look at figure 1B. Figure 1B talks about different types of immunotherapy. What you see here is that some patients got only intravenous immunoglobulin, some patients got intravenous immunoglobulin and corticosteroids, some patients got corticosteroids. What you see here is that patients who get IVIg and steroids more or less follow the same similar sort of path and the combination of IVIg plus steroids, with or without biologic, doesn't add too much, but it is small data. So we just need to kind of think a bit more here. And in my hospital, what we use is IVIg and steroids. As you heard from other speakers, there is value in thinking about hemoadsorption as a cytokine removal in this context. It's very difficult to get randomized control trials of this sort of intervention, but it's apparent that immunotherapy will help these kids. So to kind of summarize before we start our discussion, PIMS-TS is very distinct from Kawasaki's disease in that PIMS-TS patients are older -- or MIS-C patients are older. And they've got cardiovascular impairment and coronary artery aneurysms are much more of a feature compared to Kawasaki's disease. They are very different from toxic shock syndrome as well in terms of the rash, in terms of the mucosal involvement, in terms of GI symptoms. So very distinct disease, immunologically mediated phenomenon, probably multiple mechanisms, in particular, excessive systemic inflammation due to cytokine excess. So I'll leave you with that summary slide, and then we can now have a discussion around the topic. Thank you so much for listening to me.

Yes. Thank you, Manu. That was a great overview. Yes, the floor is now open for more discussion.

Fantastic. Thanks, Stefan. And thanks again to the previous speakers, Dr. Song and Dr. Molnar. Now I think there are a few questions that have been answered. I think I've got one question, probably, perhaps both you -- both Zsolt and Dr. Song can answer this. The question here is about should we use CytoSorb in patients with COVID-mediated ARDS, markedly elevated inflammatory markers and D-dimers more than 4. And their reasoning is that high inflammatory markers may be contributing to ARDS.

Tae, would you like to start?

Yes. I start with that one first. So I was actually talking with colleagues in [indiscernible] about this the other day. And just like ECMO, I think it works much better when it's used early. When the cytokine storm has already -- is in full-blown effect on the patient, that's usually too late. And when you start seeing these markers starting to go up soon after onset of disease or diagnosis, I think that's the time to use it. I always joke to my colleagues that if you know for sure you need ECMO, then that's too late. The patients should already be on ECMO. I think the same thing applies to CytoSorb. It should be -- if you know you need it, that's probably too late. It should have been started before the cytokine storm actually starts.

Great. Zsolt, do you want to add to that?

Yes. I mean, it is a very difficult and tough question to answer. And it is not that simple because in the question, there are only more or less 2 -- 3 conditions: ARDS, elevated inflammatory markers and the D-dimer. Now based on 3 things, it may not be enough for me to make a decision whether or not to start the therapy. So ARDS is not a definitive disease. I am really interested in what is the PEEP level, what is the FiO2, how desperate the situation is and whether there is hemodynamic instability or not. And putting all pieces of the puzzle together, I will make a decision. Regarding the D-dimer, I mean, there is a signal that the higher the D-dimer, it is really related to worst outcome. But to be honest, as a clinician at the patient's bedside, I may -- I would be just -- if I'm in doubt, I would possibly give one single treatment and see the effect. So if you think back on the Nassiri paper in which they found a very diverse trajectory in patients who survived versus those who did not survive. So if my -- if I start CytoSorb, and all the important clinical variables do not show any improvement up to 24 hours and the D-dimer is high, then this would give me a signal not to waste my resources because possibility is not going to help. But if I see an improvement clinically, and then it may be a false alarm. So these cutoff values doesn't mean that anybody who has a D-dimer of 4.5 should not be treated, and everybody who has a D-dimer of 3.9 should be treated. If you follow my -- so it is not -- at the bed side, I cannot really make a decision based on such sharp cutoffs, and I've been working with biomarkers for 20 years. So it's extremely difficult.

Great. So I think this probably leads on to the -- probably the next question that came up when you were speaking about the reduction in predictive mortality. Is that a good parameter is one of the questions that came up, so either one of you can answer that because both of you had mortality in your slides.

Yes. Let me start because, I mean, we've been writing -- manuscript has been submitted for publication on 1,500 patients treated with CytoSorb from the International CytoSorb Registry. And the primary outcome, which was defined by Professor Frank Brunkhorst's team in Jena, was -- because there was no control group, it was the actual mortality as compared to predicted mortality. And this is a very good question. And it is again difficult to answer. But in the registry, we didn't have anything else to compare the results to. And to be honest, when the registry was designed, that was 6 years -- 7 years ago. And we learned a lot since. So possibly, we would not design the registry this way, and we would not name the reduction in -- or the difference in actual mortality versus predicted mortality with all the knowledge that we gained, but it has been used. It is -- at least gives a signal, but this is not a very strong outcome I have to agree.

Great. Dr. Song, would you like to add anything to that point?

Just one thought. As we all kind of agree on, randomized controlled trials are going to be hard to do in extracorporeal circulation. And with that being said, this also, I think, is very closely related to mortality in ECMO, for example. If you have a mortality of -- a survival of 90%, then you're probably doing something wrong as is -- the opposite is true, too. If you have a mortality of 20%, that's probably wrong, too. So I think we do need to collect more data and gather evidence on whether or not the device actually helps. And then with that in mind, I think the patient selection will be key as far as how aggressive you are at using the device. If you use it too late, as we discussed, it's not going to help much, and we just need to have more information, I think.

Great. Manu, may I have a question, just following on the thoughts of Tae because Tae made a very important comment on selecting the right patient. And you, Manu, showed us a lot of biomarker -- a lot of inflammatory mediators that we do not regularly measure at the bedside. So on the long run, how do you see this? Will -- do we need to do such a detailed evaluation of immune parameters and the mediators and markers, put them in context or artificial intelligence will help us or defining phenotypes, allocating the right patient, personalized medicines? So I'm sure you understand what I'm getting at.

Is that a question to me or Zsolt?

Yes, please. Yes, yes, yes.

Okay. So...

Yes, there is another interesting question in the chat.

Okay. I'll come back.

Related to start, yes, so there's someone who's asking why should we not use it before ECMO.

Sorry. Okay. So I'll answer that quickly, Zsolt, once we take the questions. So I think it's important to probably think about the host response to infection. And if we think that the host response biomarkers to cytokines are in the causal pathway to the outcome and an intervention can modify that, then perhaps I think we should think about using that intervention. And both of your talks highlight the fact that there is an association between the excessive cytokines and organ dysfunction, therefore, you are kind of highlighting that population as the one to target. My kind of challenge, I think, for all of us is to try and figure out what is the right time point at which you need an additional intervention, such as CytoSorb. And that timing is the issue as opposed to the intervention per se. So hopefully, that kind of starts to answer your question. I just want to kind of -- Stefan has kind of gently pointed us to this question, which is COVID -- fourth wave of COVID is affecting the younger population under 18 years old, would you recommend CytoSorb to be used? Would either one of you want to take that question, guys? Or anybody else in the panel?

Yes. I think Zsolt can answer that.

Yes. Okay. Zsolt?

I mean, why not? It's -- cases have been reported, so CytoSorb has been used in younger population, but we will see. And I'm not a physician who is dealing with the population younger than 18 years anyway. So possibly, I'm not the right person to answer that. But as far as I can see, Teresa is typing an answer right now.

Great.

I remember also 2 cases with multisystem inflammatory syndrome where patients were younger than 18 and could be successfully treated with CytoSorb. There's one case report out from Barcelona group from Ricard Ferrer's group and one from Gabriella Bottari in Italy and Rome. So one can read about the details in these publications, yes?

Yes. Thanks, Stefan. I will put the link of those publications in the chat. Perhaps, I think this is a question that followed up from Tae Song's point, which is -- Jim is asking a question. In these ICU patients with ARDS, why wouldn't CytoSorb be added earlier as a treatment prior to ECMO rather than just being added to ECMO?

Thanks, Manu. So yes, as I mentioned, I think starting this early in the course is key. And by the time patients are on ECMO, oftentimes it is later in the course. So I agree that it makes sense to find a way to try to use therapy such as cyto adsorption earlier. And I've been discussing with our medical ICU colleagues as well about this. And we, in the U.S., are somewhat behind as far as the widespread use of cyto adsorption therapy. There are centers that are starting to use the CytoSorb filter on CRT devices. So I agree that if you're thinking about this, CRT would be a very viable way of doing -- initiating this therapy early.

So I think somebody needs to translate the next set of questions for me. I don't understand the question. Something about 24 or 48 hours on septic shock is what I understand, but can someone translate that for us, please? Whilst that is happening. Can I just come back to you, Tae, just to kind of give us a bit more idea of what you mean by early? And how has the EUA helped you achieve that goal of getting the CytoSorb therapy early in the U.S.?

Well, it hasn't only helped. It's the indication that allowed us to start using the device really before it was used on a trial basis. And I think with early evidence of a cytokine storm being a strong component of the pathology of COVID-19, the FDA released several EUAs for several different therapies. And I keep saying early, but I honestly don't know when that is or when too late is necessarily. But should we start it the day they're diagnosed? Probably not. A lot of patients recover without such aggressive interventions. Should we wait a month until they've been on ECMO for a month and lungs start becoming fibrotic? I think that's too late. So I think sometime in between. And again, this is something why, as you stressed, finding out the right timing is important, and we need more data for that.

Great. I think I managed to translate the question. The question probably is best answered by Zsolt. The question they're asking is, could you use CytoSorb within the first 24 to 48 hours of septic shock? How long would you use it for? How many sessions would you give? And would you measure cytokines beforehand?

Yes. I would -- I'd rather start CytoSorb therapy within 24 hours, but I usually, in my practice, I used to start it earlier, so 6 to 12 hours and -- or even earlier. But it depends. We had a case after cardiac surgery, came out from theater, on VA ECMO, a young lady on multiple catecholamine support in really dire straits. We started her on CytoSorb during the night and by the morning, she regained hemodynamic stability. So we did not wait for 6 hours. We waited basically 0 hours. As soon as she came out from the theater, the lines were already in and we started CytoSorb. And sometimes, we allow a bit more time and we had a CytoSorb session here. I'm on a conference -- a national conference here in Hungary. And this is a question always comes up that when should we start. And at the moment, I cannot really give an advice. Apart from CytoSorb, if you know the article, this can be useful, which evaluates the dynamic of the most important parameters like the noradrenaline and so on within a few hours' time. But what we need is really close observation of the patients, especially by those who are experienced. So we need well-devoted, well-trained, experienced intensivist at the patient's bedside at the moment to make this very important decision. At the moment, it cannot be protocolized, at least in my view.

Great. I think the related question from the state -- from Manuel Vilas, which is essentially, would you use any other inflammatory biomarkers or interleukin-6 levels to start CytoSorb therapy? That's very important clinical point, right? So...

Yes. Well, Manuel, I'm a PCT guy, a procalcitonin man, and I've been researching that for 20 years. And I like biomarkers not for deciding whether or not to start adjuvant therapy, including CytoSorb in my patients. Now I follow the clinical picture. So if -- based on the clinical picture, which is severe hemodynamic instability, not responding to therapies, severe respiratory failure, high lactate level, medium lactate levels. And then I think that the patient benefits from this, I start CytoSorb. I measure cytokines. And -- but the only thing I use it for that if they are elevated, it gives me some kind of comfort that my assessment might be correct. But I did not start the therapy because procalcitonin or IL-6 or any other CRP, whatever, is high. I always started based on the clinical picture.

Great. So it also kind of leads me to 2 additional questions in the chat, which is about core interventions. Can you give it alongside immunoglobulins? And can you give it alongside tocilizumab? And would it be okay to use CytoSorb in pregnant patients? So 3 questions. So people can -- I think these are all very relevant, clinically useful questions. So perhaps, Zsolt, to start off with and maybe Tae can join in there.

We treated pregnant patients, no problems. So going backwards, what was the previous question?

Tocilizumab and IVIg?

Yes, you can use it with tocilizumab. You can use it with immunoglobulins because it does not remove it. It's going to put up the price, but it is, again, a difficult question at the bedside, but theoretically, by all means, because you are targeting the -- we are supporting the immune system from 2 different angles.

Yes. I think those are clinically interesting question that came to my mind as you were speaking, which is in COVID-19, if there is a -- if you're critically ill and you get heparin, there is probably a greater risk or lack of benefit with heparin therapy. Whereas in -- before they are critically ill and the ward patients, there is probably a benefit. And given that this intervention may need anticoagulation, what's your advice around dealing with that interaction?

Tae?

Yes, sure. I can go first. So again, our experience has been exclusively with ECMO, and therefore, the majority of patients are anticoagulated. Now that being said, because of some evidence showing that these patients are quite hypercoagulable, we use bivalirudin most of the time in these patients, which cannot be used with CytoSorb. So for the duration of CytoSorb therapy, we use heparin and then switch back to bivalirudin. Whether or not that helps with anything, I don't know. But -- and then the -- what was the other question, I'm sorry?

No, that was the only question. The other question that just come up is, again, patient indication. So can -- are there any contraindications for patients within the -- with vaccinated within the last month? So I would have said no, but...

Now we here do finish other therapies, conventional therapies first before moving on to CytoSorb therapy. So remdesivir or convalescent plasma, what have you, we generally do like to complete that course fairly quickly and then move on to CytoSorb.

Looks like a lot of people are interested in using it. So there is another question about antibiotics and CytoSorb. Will it affect the antibiotic concentrations presumably is a question. So?

Yes. A paper was published recently, which is an in vivo experimental model measuring a lot of antibiotics. And by and large, we can say that apart from a few antibiotics, the treatment is quite safe. However, we still recommend to use -- if you have doubts, use therapeutic drug monitoring. Because at the moment, we don't have satisfactory human data to give straightforward the instructions. But this is a very nice paper published recently on that topic.

And we've used it on a couple of transplant patients, heart and lung transplant patients, and it does not seem to have a significant effect on immunosuppressants either, as far as we can tell.

Great. Well, that's very interesting, Tae. Did you measure it really before and after?

Some of the levels we measured such as calcineurin inhibitors and things like that, but yes, you can...

Okay.

Great. I think we're probably coming towards the end of the -- our session. We're probably, in fact, 5 minutes overrun. So shall I hand it back to Stefan to wrap this up? Other than -- I just want to thank the speakers again and the wonderful participants who have made this discussion very interesting and for CytoSorb -- the company to organizing such an important topic as a webinar. Back to you, Stefan. Thank you again for the invitation.

Yes. Thank you, Manu. Thank you, Zsolt. Thank you, Tae, for this wonderful International Experts Meeting. As you could feel, there are a lot of questions still. But on the other side, we also have some answers already, and that is important. So we could hear about the great results from the CTC registry and from the other publications by Zsolt. So I think there is still a lot to do and to, yes, discover. But on the other side, we are -- we always have to remind that this disease is new for everyone, and we all can learn and have to learn. And we, of course, hope that the next wave were not as big as the last ones here, especially in Europe. But we have to be prepared for that. And our -- I think our expert meeting was doing a great job. And I thank also to the team, to the CytoSorbents team in the background, to Teresa, Volker, Alex. I thank you a lot for all your input. And thanks to the -- to all the participants from more than 20 countries, I have to say. So we had roughly 200 people here in the world that is excellent, of course, and it speaks for itself, yes. And yes, with that, I really like to tell you a little bit about our next events. We will have a symposium at the ESICM Congress, dealing with different topics on the 5th of October. And then on the 28th of October, we will have a hybrid meeting. We will, again, invite all the international users to Berlin, of course, not everyone will make it. But on the 28th of October, please save this date, we will have our next great international users' meeting. And on the 13th of November, we will have our German-speaking users' meeting in Hamburg. So if you can save these dates already, that would be fantastic. And yes, with that, I'd like to thank you again, wish you a good time, stay healthy. And if you like, stay with us a little bit longer so you can hear for another time a song by Roman Schuler and his trio. And yes, I wish you all the best, take care and goodbye and hope to see you soon.