| 1 | CTSI-CN | Dr. Srinivasalu: Immunomodulation and Cytokine Profiling in MIS C | 84 | 3 | 2 | 45.8 | positive | 18:15 | Hello, everyone. I would like to thank the organizers for giving me this opportunity to speak at this symposium. I have no disclosures that are relevant to this talk. Listed are the objectives I aimed to cover in today's talk, basically to describe this as a hyper-inflammatory state, temporarily associated with SARS-CoV-2. I'm going to summarize the distinct immune dysregulation in MISI. Discuss the lessons learned from cytokine profiling. Discuss the existing clinical guidelines for immunomodulation in MISI and describe the immunomodulation algorithm that we use at children's national. Before we start talking about MISI, it's important to understand that the terminology to define MISI is different based on the region. The UK has a slightly different definition from that from CDC and that from the WHO. In the UK, it is called the PIMSTS that stands for pediatric inflammatory multisystem syndrome, temporarily associated with SARS-CoV-2. MISI is a rare condition affecting two in 200,000 individuals less than 21 years of age. This is a pictorial diagram that the CDC came out with, which is current as of May 3rd, as you can see, the distribution of MISI is not uniform. The underpinning of the clinical manifestations of MISI is hyper-inflammation with a subset of patients presenting with features of Kawasaki disease, another subset presenting with cardiovascular shock, and patients also presenting with GI or CNS manifestations. In essence, patients may have several of these four laughing symptoms. With this background, let's talk about cytokine profiling in this condition. Dr. Levin in his New England Journal editorial eloquently described our understanding of MISI as a blind man trying to describe an elephant. The group at CHAP was able to demonstrate that the inflammation in MISI is distinct from that scene in severe COVID-19 infection in children. In panel A, what they did was they generated a heat map of the most differentially expressed cytokines, specifically the interpronged gamma, IL-6, IL-8, IL-10 and TNF alpha. And they were able to demonstrate they were different signatures in MISI patients compared to severe COVID infections. They then tried to use the cytokine profile as a five-dimensional vector. They could not find a difference between severe MISI, severe COVID infection and MISI. However, the sum of IL-10 and TNF alpha was able to differentiate between severe COVID infection and MISI in their cohort. There is a distinction in the plasma proteins between MISI and Kawasaki disease as is described in this principle component analysis where the gray dots represent the MISI patients and the pink dots represent the Kawasaki patients. The proteins that were notably different were IL-6, IL-17A and CX-L-10 with IL-17A, with most of these being increased in Kawasaki patients. Serum cytokine levels in MISI patients show an elevation of IL-6 and IL-10. There is also elevation of soluble IL-2 receptor IL-18 and CX-L-9. Although they in comparison to a historic macrophage activation syndrome cohort, the response was less robust. This heat map depicts the multiplex cytokine analysis in patients with MISI were compared to healthy people, people with COVID infection both in the pediatric age group and in the adult age group. I am supervised hierarchical clustering. They notice that the MISI patients cluster together. There is a very high signal for IL-6. And as you can see in the principle component analysis here, the solid yellow circles represented by MISI separate out nicely and during convalescence they shift their cluster. The MISI circulating in-un profile was marked by cytokines and chemokines that recruit NK cells and T cells from the circulation and modulate their functions such as CCL-9, CX-L-10 and CDCP-1. Additionally mediators of neutrophil and monocyte chemo-taxes and differentiation and activity were also elevated in MISI patients. It is also interesting to note that there is a stark upregulation of PDL-1 which is an anti-inflammatory cytokine reflecting a host driven compensatory response to the inflammation. The cytokines potentiating mucusyl immunity were also prominently elevated in MISI patients, specifically those related to T cell helper functions such as IL-17-A and mucusyl chemo-taxes such as the CCL-20 and the CCL-28. They were also able to demonstrate that most of these proteins returned to normal levels in convalescence. What we saw in the children's cohort was something similar to what has been noted in the published cohorts. We separated our cohorts into three different ones. The patients who were labeled as MISI confirmed, satisfied the CDC definition of MISI and had either a positive SARS-CoV-2 antibody or PCR. The MISI probable cohort satisfied the clinical definition for MISI but had negative antibody and PCR and the negative controls were initially worked up for MISI but then subsequently were noted to have an alternate diagnosis. As you can see here, the blue circles representing the MISI patients separate out nicely compared to the MISI probable and the negative controls. We were further able to demonstrate an elevated level of IL-10, IL-6 and also soluble IL-2 receptor in our cohort. Now shown in the diagram here were sub phenotype analysis that did not show a difference in the cytokine expression between patients who had a Kawasaki phenotype versus those who did not. We did notice that patients who were ICU bound and who had SARS-CoV-2 PCR positivity tended to have elevated levels of IL-6 and IL-10 compared to those who were not. We also noted that patients who had reduced cardiac function had elevated IL-6 levels. Solubil IL-2 and IL-2 levels were elevated in ICU patients and TNF-Alpha was elevated in patients who were SARS-CoV-2 PCR positivity. We saw that IL-17 levels were higher in patients who did not have cardiac abnormalities. In summary, MISI-L-6 is a distinct immune response from that of acute COVID-19 infection and Kawasaki disease. The sum of IL-10 and TNF-Alpha differentiates between MISI and severe COVID-19 infection. The cytokine's term seen in MISI is less robust than seen in macrophage activation syndrome due to other conditions such as systemic JIA. The cytokine profiling indicates myeloid cell pymotaxis and eucosal inflammation and there is normalization of cytokine elevation during convalescence. Now we'll shift gears and talk about immunomodulation in MISI. The American College of Immodology came up with guidelines for management of MISI in the summer of 2020. This guideline has gone through two iterations. The highlight of the guideline regarding immunomodulation specifically is a stepwise progression. The guidelines recommend that all hospitalizations receive IVIG-2 gram per kilo. A second dose of IVIG is generally not recommended. Glucocorticoids at a dose of 1 to 2 milligram per kilo per day is recommended as an urgent treatment. In patients who have a sub-optimal response to these steps, the next step is pulse dose steroids which is 10 to 30 milligram per kilo per day. Hydro-Sanachylera defined as more than 4 milligram per kilo per day either IV or subcutaneously is reserved for refractory MISI patients. They recommend immunomodulation to be being slowly over 2 to 3 weeks to prevent rebound phenomena. The two guidelines that was developed by a delphi consensus process slightly differs from the ACR guidelines in that they divide in the patients into two phenotypes. Kawasaki and non-Kawasaki. The Kawasaki phenotype patients are treated with IVIG-2 gram per kilo. They do recommend a second dose of IVIG in those who have incomplete response. Metal predisolone in pulse dose range that is 10 to 30 milligram per kilo for 3 days is recommended as a second line agent and influx map is recommended as a third line agent. For those with non-specific phenotype, meaning non-Kawasaki-like phenotype, the guideline for first line and second line remains the same. However, they leave the choice with third line up to the treating position. The delphi survey respondents had echo poised between the choice between influx map and Akira and tostlyzumap. It is to be noted that this delphi process informed the treatment groups for the UK recovery trial, which is the first randomized control trial looking at treatment for MISI globally. This study from France was able to retrospectively compare patient outcomes in those who are treated with a combination of IVIG and metal predisolone with those who are treated with IVIG alone. They were able to demonstrate that patients who were treated with the combination of IVIG and metal predisolone, failed much better in terms of treatment failure when compared to those who are treated with IVIG alone. Along the same lines, several of the secondary outcomes such as second line treatment, hemodynamic support, left ventricular ejection fraction, and also duration of the Q state was favourable in the IVIG and metal predisolone group. Several biologics are being used in MISI and Akira is considered a good choice due to experience in treatment of systemic JIA, macrophage, activation syndrome, Kawasaki disease. Akira has also been used in sexist trials and has also been used in adult COVID-19 infection. It has a sharp half-life that enables early treatment in sick patients, even when other infectious ecologies have not been completely ruled out. Elevated IL-6 have been consistently seen in COVID-19 and MISI and IL-6 also has a role in hip-ractor Kawasaki disease. However, IL-6 invaders should be used with caution because of their long duration of action. TNF-Alpha is also elevated in COVID-19 and MISI and influx-Mab also has a role in treatment of repraper Kawasaki. Along the same lines as two-cellus-Mab, use of influx-Mab must also be carefully weighed because the duration of action is longer and we need to make sure that other infectious etologies have been ruled out. There is a role potential role for the JAK-STAT inhibition as well as there have been more studies that have been looking into how the JAK-STAT pathway is involved with COVID-19. University of California at San Diego has recently launched a multi-center trial looking at compared to effectiveness between influx-Mab, anaquira and methyl-bremous lomb. This and the UK recovery trial will perhaps inform the optimal choice of biologics in this disease process. I'm showing you this chart to illustrate the timeline of MISI at our center in relation to when MISI was reported and the various studies published. The first case at Children's National was diagnosed on April 27 of 2020 and on the same time the UK PQ Alert came out. Within a matter of weeks, Children's National was able to put together a multi-disciplinary MISI task force with representation from various specialties. We were able to establish our treatment algorithm by the 20th of May before the ACR guidelines came out. Having a standardized method for evaluation and management of MISI patients has served as well. Two days we have treated around 150 patients with MISI. We have had only one patient require ECMO. We have had one bounce back and no mortality. This is an overview of the immunomodulation algorithm that we use at Children's. Don't worry, I don't expect you to read the small font here. I'm going to go through the highlights of the immunomodulation pathway that we use here. We treat all our patients with IVIG-2 gram per kilo regardless of their Kawasaki phenotype. And we use anaquira as a second-line agent at a dose of 6 to 10 milligram per kilo per day. The dose is generally given IV, divided Q6 hours. In the presence of renal injury, we renaly dose the medication dose and give it twice daily. The maximum dose of anaquira that we use is 600 milligram per day. The renal schedule is generally coming down by 2 milligram per kilo per day on every day or every other day basis based on the patient's clinical picture. As an institution, we decided to use anaquira as a second-line agent versus corticosteroids, partly due to our experience as a center with viral myocarditis. This decision was also informed by systematic meta-analysis and carcorder review of viral myocarditis that did not support routine use of corticosteroids. Early on in the pandemic, we did not know how much of a cardiac burden this disease process would have. So we chose to opt for corticosteroids only as a third-line agent. We reserved the other biologics such as Tosilusumab, influx-Mab or jacketuitars for renal refractory cases. In summary, I've described the ACR and UK guidelines that provide a framework for management of missing. In most cases, IVIG is used as a first-line agent. Corticosteroids are recommended as abjunct therapy in both of these guidelines. Today, I've shared with you our experience using anachina as a second-line agent. Option of using such as T-OX-Pain agent is attractive, although cast and availability may preclude wide usage of this regimen. Other centers have preferentially used either Tosilusumab or influx-Mab. We need comparative effectiveness trials such as the ones that are starting to help inform which immunomodulation is ideal. We have a lot more to learn about this condition and I would like to be with some additional questions to ponder. Do we, is there now time to refine the case definition for missing? Are the hospitalized missing patients only the tip of the iceberg? Do patients with missing have an inherent defect in their innate immune system? Do all patients with missing need IVIG? What is the appropriate dose and duration of corticosteroid treatment? What is the role of biologics? If so, which one is better? Will we continue to see missing post-pandemic? And finally, now that the vaccination trials are ongoing for younger kids, is it safe for missing patients to get COVID-19 vaccine? Hopefully we'll get answers to these questions in the coming days. These are my references. I would like to acknowledge the MISI task force and also my colleagues' division of immunology without whom all this work would not have been possible. Thank you for your attention. I would be happy to take questions during the panel discussion. Thank you so much, Dr. Strenovassoly. I have to say I'm sorry I lost the connection and didn't have the honor of introducing her but as you can see we selected her because she's been an absolutely integral person on our own. She's been an integral person on our multidisciplinary task force for this whole year. She's really been integral in coming up with the diagnostic and particularly the immunomodulatory regimens and she sits on national groups so that we get both her local expertise as well as the national data. So really thank you so much, Hema, for fabulous talk and we'll certainly have questions for you. Many of which you already post to have us ponder between the next speaker and the session. So thank you. | ↗ |