Immune Dysregulation: What is it, and what is it NOT?

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Summary

In a comprehensive virtual symposium by the Children's Hospital of Philadelphia, Dr. Edward Behrens delves into the complexities of immune dysregulation, explaining what it is and what it is not. Highlighting the importance of a multidisciplinary approach, Dr. Behrens discusses how immune dysregulation affects various organ systems and the difficulty in diagnosing these conditions due to their diverse presentations. He stresses the importance of recognizing immune dysfunction symptoms for effective referral and treatment. The symposium also touched upon advances in targeted therapies and genetic testing in understanding immune dysregulation, providing valuable insights for healthcare professionals.

Highlights

Dr. Edward Behrens led a deep dive into what immune dysregulation is and what it isn't 🤓.
Cytokine storm syndromes are heightened examples of immune dysregulation, demonstrating severe inflammatory responses if untreated 🔥🚑.
Genetic testing helps in diagnosing complex immune conditions by identifying potential defects and suggesting specific therapies 🧬💡.
The symposium emphasized the importance of a team approach, breaking down traditional medical silos for better patient care 🤝.
Healthcare professionals are urged to stay informed and collaborate for improved management of immune disorders 🔄📈.

Key Takeaways

Immune dysregulation involves complex interactions of the immune system, affecting multiple organs and presenting diverse symptoms 🌐.
A multidisciplinary approach is crucial for diagnosing and managing immune dysregulation 😷🔍.
Advances in genetic testing are vital for identifying the underlying causes and finding targeted therapies for immune dysregulation 🧬🔬.
Recognizing symptoms of immune dysfunction is key for timely referral and treatment 🕒📋.
Not all multi-organ symptoms are due to immune dysregulation; proper evaluation is necessary to determine the correct cause ❌🆚✅.

Overview

The Children's Hospital of Philadelphia hosted an insightful virtual symposium on immune dysregulation led by Dr. Edward Behrens. The session highlighted the complexities surrounding immune dysregulation syndromes, outlining both classical cases and the challenges of diagnosing unclear syndromes that don't fit traditional medical silos.

Dr. Behrens emphasized the need for a multidisciplinary approach when treating immune dysregulation. He explained the interplay between different immune functions, using cytokine storm syndromes as an example, to illustrate how immune dysregulation can lead to severe systemic inflammation if not identified and treated promptly.

The presentation also shed light on the advances in genetic testing, which play a critical role in diagnosing and identifying potential targeted therapies for immune dysregulation. Dr. Behrens encouraged consistent interdisciplinary communication to achieve accurate diagnoses and effective patient care. The symposium concluded with a call for healthcare providers to be vigilant in recognizing symptoms of immune dysfunction for timely intervention.

Chapters

00:00 - 03:00: Introduction and Speaker Introduction The chapter titled 'Introduction and Speaker Introduction' begins with a welcome message to the attendees of a virtual symposium focusing on immune dysregulation. Attendees are informed about logistical details, including a survey link at the end and the process for claiming CME credit.
03:00 - 09:00: Dr. Edward Barrons: Educational and Research Background The chapter begins with housekeeping information about a survey related to the lecture, urging attendees to complete it by Friday, November 6th, while encouraging questions via the Q&A section. Subsequently, the introduction of Dr. Edward Barrons is highlighted, marking the beginning of a detailed discussion on his educational and research background. The program manager for immune dysregulation takes the stage to introduce Dr. Barrons to the audience, preparing the ground for an in-depth exploration of his contributions and expertise in the field.
09:00 - 13:00: Immune Dysregulation: Overview and Challenges The chapter 'Immune Dysregulation: Overview and Challenges' begins with a brief introduction to the professional journey of a medical expert who specializes in immunology and pediatric rheumatology. The narrator details their academic and professional background, highlighting undergraduate studies in biology at Johns Hopkins University followed by medical training at the University of Pennsylvania. During medical school, they were awarded the prestigious Howard Hughes Medical Institute's Medical Student Research Fellowship, allowing them to gain valuable experience under the guidance of Dr. Phillip Cohen. Following medical school, they completed a pediatrics residency and a pediatric rheumatology fellowship at the Children's Hospital of Philadelphia. The narrative sets the stage for discussing the complexities and challenges associated with immune dysregulation.
13:00 - 19:00: Multidisciplinary Approach to Immune Dysregulation The chapter titled 'Multidisciplinary Approach to Immune Dysregulation' discusses the career of a researcher who completed postdoctoral fellowships with Stefania Gallucci and Gary Koretsky. In 2009, the researcher joined the faculty of the Division of Rheumatology at CHOP as an assistant professor. The researcher's interests are focused on understanding and treating cytokine storm syndromes, which include conditions like hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS).
19:00 - 28:00: Cytokine Storm Syndromes: Pathogenesis and Treatment This chapter discusses cytokine storm syndromes, particularly focusing on their pathogenesis and treatment. Despite available therapies, these conditions have a high mortality rate of about 50%. The chapter highlights current research progress, including a novel murine model of macrophage activation syndrome (MAS) developed by ED, which is pivotal for dissecting the immunologic mediators of the disease. Additionally, ED is exploring new mediators of hemophagocytic lymphohistiocytosis (HLH) and working towards developing new immune interventions.
28:00 - 33:00: Genetic Syndromes and Autoimmune Cytopenias The chapter focuses on the recognition and treatment of genetic syndromes associated with autoimmune cytopenias. Dr. Ed Behrens, recognized by prestigious organizations such as the American College of Rheumatology and the Arthritis Foundation, is highlighted for his contributions in this field. He is a founding member of the International MAS Study Group and is known for his international lectures on MAS (Macrophage Activation Syndrome) and HLH (Hemophagocytic Lymphohistiocytosis).
33:00 - 41:00: Importance of Understanding Fundamental Immune Defects This chapter focuses on understanding what immune disregulation entails and what it does not. The speaker discusses the complexity of the concept, noting that perceptions may differ based on one's training and perspective. Initially, the aim was to help generalists identify immune disregulation correctly.
41:00 - 47:00: Challenges in Diagnosing and Treating Unknown Syndromes The chapter discusses the challenges faced in diagnosing and treating unknown syndromes. The speaker notes a significant interest from sub-specialists in various disciplines, highlighting an inclusive approach to cater to a diverse audience. The session aims to offer something valuable for everyone involved and promises to explore topics of interest in depth during the Q&A section. The chapter sets the stage to delve into the conception and understanding of these unknown syndromes.
47:00 - 57:00: Advanced Diagnostics in Immunology This chapter, titled 'Advanced Diagnostics in Immunology', explores the topic of immune dysregulation. It discusses common conditions handled at an immune dysregulation clinic and emphasizes the benefits of a multidisciplinary approach to diagnosis. The chapter also clarifies misconceptions about what immune dysregulation is not, often based on alternate diagnoses observed when cases are referred to the clinic.
57:00 - 73:00: When it is Not Immune Dysregulation The transcript discusses the common misconception of attributing health issues to immune dysregulation and emphasizes the importance of identifying other potential causes of patient symptoms.
73:00 - 84:00: Case Studies in Immune Dysregulation This chapter titled 'Case Studies in Immune Dysregulation' discusses the various manifestations when the immune system malfunctions. The myriad of symptoms can include skin rashes, fevers, joint pain, bleeding issues due to malfunctioning platelets, respiratory problems, liver issues, and recurring infections. Each symptom highlights the diverse ways in which immune dysregulation can present itself.
84:00 - 94:00: Key Recommendations for Multidisciplinary Care The transcript discusses the complex nature of diagnosing conditions that present with diverse and confusing symptoms. It highlights the challenges posed by immune dysregulation, which can lead to the body fighting off pathogens ineffectively, and sometimes even targeting its own tissues, as seen in autoimmune disorders. The key recommendation emphasizes the importance of taking a step back to look for a unifying cause amidst the myriad symptoms, suggesting a multidisciplinary approach to address the underlying immune dysregulation issue effectively.
94:00 - 109:00: Long-term Surveillance and Treatment Decisions This chapter discusses the challenges of diagnosing certain medical conditions due to their varied and unpredictable symptoms. It highlights the difficulty in identifying whether these symptoms are caused by issues with the immune system. Traditionally, medicine has approached such complexities by categorizing symptoms and conditions into separate "silos."
109:00 - 120:00: Conclusion, Questions, and Opportunities for Collaboration The chapter discusses how medicine categorizes and names different states or conditions of the immune system. It mentions autoimmunity as a loss of tolerance and autoinflammation as a loss of control of immune effector functions without the necessity of a loss of tolerance. Additionally, lymphoproliferation is mentioned, though the transcript cuts off before its definition is complete.

Immune Dysregulation: What is it, and what is it NOT? Transcription

00:00 - 00:30 welcome everybody we are gonna go ahead and get started thank you so much for joining today's virtual symposium immune dysregulation what is it and what is it not a few housekeeping items first off everybody attending will get a link to a survey at the end of this event those claiming cme credit please complete that survey so your certificate can be auto emailed to you
00:30 - 01:00 the survey will remain open until close of business on friday november 6th but we urge you all to complete it as soon as possible secondly please post questions as you have them in the q a section on the right of your screen we'll be getting to these questions at the end of the lecture but we encourage you to ask them throughout the presentation thank you all again so much for attending and now our program manager for immune dysregulation is going to introduce today's speaker thank you dr edward barrons received his
01:00 - 01:30 medic undergraduate training at the johns hopkins university where he majored in biology i then attended medical school at the university of pennsylvania where he received the prestigious howard hughes medical institute's medical student research fellowship to train in the laboratory of dr phillip cohen after medical school ed then completed a pediatrics residency and pediatric rheumatology fellowship at the children's hospital of philadelphia he performed two
01:30 - 02:00 postdoctoral fellowships in the laboratories of stefania gallucci and gary koretsky after which he joined the faculty of the division of rheumatology at chop as an assistant professor in 2009 ed's research interest is the pathogenesis and treatment of cytokine storm syndromes including the hemophagocytic is syndromes hemophagocytic histiocytosis hlh and macrophage activation syndrome mas these are uniquely
02:00 - 02:30 pediatric immunologic conditions that result in severe systemic inflammation and death if unrecognized and untreated despite current therapies mortality remains high for these conditions hovering around 50 percent of patients ed has developed a novel murine model of mas that has allowed the careful immunologic dissection of the mediators of disease more recently ed has begun to work on novel mediators of hlh and is developing a new immune
02:30 - 03:00 modulating therapy to treat this disease his work has been recognized with many awards from the american college of rheumatology the histocyte society and the arthritis foundation he is the founding member of the international mas study group and has given lectures internationally on mas and hlh so without further ado please join me in welcoming dr ed behrens hey thanks for that introduction um
03:00 - 03:30 and we're going to talk today about uh what immune disregulation is and what it isn't and and this was a somewhat tough um um lecture to to put together uh because i think everyone's conception of what this is and isn't might be different depending on how you trained and some sort of from what perspective you're coming from um and when we were first putting together these slides you know we were thinking about the generalist um trying to identify immune disregulation um and referring to
03:30 - 04:00 subspecialty care uh and as we noticed that there was a lot of interest from sub-specialists of various disciplines i've tried to include a little bit of everything uh for everybody so hopefully hopefully everybody will find something of interest a lecture and certainly i think in in the q a section we can we can certainly dig deeper into the into the things that um that are of interest to the attendees today so we're going to go over sort of how we conceive of
04:00 - 04:30 immune dysregulation you know what we think it actually is some of the common conditions that we consider in our immune dysregulation clinic here at chop talk a little bit about the benefits of the multidisciplinary approach to these diseases diagnostics that we use spend a little bit of time on what it is not um and in in many ways you know what what i've come up for with what it is not is based upon the alternate diagnoses that we see in clinic when cases are referred to us and we say well
04:30 - 05:00 your problem isn't immune this regulation but there's really something else going on um and then talk about um what one should do if you have a case that you think is immune to regulation where should that patient be referred what's the most effective way to get care all right so i think the the the philosophically you know this idea of immune disregulation really speaks to the fact that the immune system um touches everything right so you have a whole bunch of different effector arms of the immune system t cells and b cells and antibodies and
05:00 - 05:30 neutrophils and so on and those elements patrol and interact with every tissue every surface of the body so the potential for the ways in which you can present when the immune system goes awry are almost limitless you can look like a rash you can have fever you can have joint pain you can have bleeding because your platelets don't work maybe it affects your lungs and you have shortness of breath maybe it's affecting your liver maybe you're just having recurrent infections
05:30 - 06:00 because you can't fight off the pathogens that are attacking you sometimes it presents with autoimmune features so you make antibodies against um self tissues maybe you're just presenting with malaise you know and all these things are sort of running together and it's a very confusing picture and um when one takes a step back and tries to find a unifying cause for all these sort of diverse features that a patient might be presenting with um you you realize that there's a fundamental immune dysregulation problem
06:00 - 06:30 going on and that makes it difficult to diagnose because it can present with a whole host of different features sometimes you have some and sometimes you don't have others sometimes you have all of them um and you don't always necessarily have the immediate clue as to what your handle is in terms of what's wrong with the immune system or if there's anything wrong with the immune system as driving that diverse array of symptoms now the way that medicine philosophically has dealt with this in the past is putting things in the silos right i
06:30 - 07:00 mean that's that's medicine is very good at that find a box put something in that box so we can do that by naming different immune states or immune conditions and so that's what's on the left hand side here so we can talk about autoimmunity which is loss of tolerance we can talk about auto inflammation which is a a loss of control of immune effector functions but without um without any um necessary loss of tolerance lympho proliferation which is an
07:00 - 07:30 expansion of immune cells giving you big lymph nodes in a big spleen immunodeficiency atp pyroneoplastic syndrome cytokine storm right so we would box things up on the basis of how we thought about what was the most what was the problem of the immune system that was most gone wrong and then perhaps you know sort of even older than those ideas are sort of all of the ologies you know oh you've got a rheumatologic condition you just see a rheumatologist you've got an oncologic condition you need to go see an oncologist so on and
07:30 - 08:00 so forth and that only works as well as you have only one problem that that sub-specialist is trained in and i think what has um become more and more apparent is that there are some things that that overlap now there are things that really remain crystal clear right like lupus is always going to be best cared for by rheumatoid if you have skid you're going to be cared for by an immunologist if you have leukemia clearly you need a cancer doctor right so this isn't to say that all things need
08:00 - 08:30 this this big multi-disciplinary approach but there are definitely things where there are overlaps where you can bring in expertise from different sub-specialists that can contribute to the care of a patient in a way that you just can't get from being boxed into these traditional silos so for instance you know there are many patients that have common variable immune deficiencies so they suffer from infections they need ivig for ig replacement so all of the sort of standard of care
08:30 - 09:00 that goes into doing that but because many of these cvid patients also have autoimmune cytopenias perhaps they might benefit from the care of a hematologist to help with that or they might benefit from the care of a rheumatologist who can use certain kinds of immunomodulatory medicines to get rid of the autoimmune portion of the things while the immunologist is treating the immunodeficient portion of the thing um we're recognizing monogenic autoinflammatory diseases that show as one of their signs
09:00 - 09:30 lymphocliferation so the oncologist gets called to think about malignancy but the rheumatologist gets called to think about the autoinflammatory disease um and again just sort of drawing from sort of recent cases you know that we've had um erlichiosis as an infectious pathogen causing a fulminant hlh like cytokine storm right so you clearly needed an infectious disease doctor to help you with the management the diagnosis and management of eliciosis but perhaps you would benefit from a rheumatologist or an oncologist that can
09:30 - 10:00 help manage your cytokine storm the other kinds of issues we run into is what happens when you have multiple organ systems involved right so who owns it who is the quarterback uh taking care of the the leading the patient care team when both the brain and the gut are involved in the immune disease you know we've had many examples of and you can name any two organs you want brain and gut lung and liver um you know uh joints and skin um you know who who
10:00 - 10:30 owns it when you have or sometimes there's three or four organs involved who owns it when there are multiple organs involved that's where the the ology system breaks down because you need more than one subspecialist who owns it when for instance the lung is a target organ but the treatment is going to be a bone marrow transplant so you clearly need a pulmonologist to diagnose and monitor and manage the pulmonary aspects of the disease but the fundamental therapy is going to be something that's best handled by an oncologist so there are lots of reasons why a
10:30 - 11:00 multi-disciplinary approach to immune patients makes sense and and and trying to sort of break out of our old silos by creating essentially a new one immune dysregulation um i think is helpful and having a clinic then that brings together all these different expertises around immune dysregulation and all the things that could possibly happen um is is sort of a you know an emerging paradigm for caring for these complex patients
11:00 - 11:30 so you know maybe taking you know as you heard from my sort of introductory bio taking a a condition that's sort of near and dear to my heart to acidic and storm syndromes and thinking about them for a little bit you can again appreciate this spectrum right so cytokine storm is basically when the immune system goes completely haywire uh produces copious amounts of cytokines um arming effector functions all throughout the body you again get multi-organ failure often results in death if not rapidly recognized and treated and there are
11:30 - 12:00 lots of ways of trying to break down what causes that process what's driving that so one way is thinking about what are environmental factors versus what are host factors that are driving the disease and so in the case of environmental factors well just about anybody on this uh on this blue jeans call would end up getting sepsis if you had gram-negative rods in your blood right that doesn't require anything more than a particular environmental trigger on the flip side if any of us were to be completely deficient for perforin we would get hlh
12:00 - 12:30 um and doesn't really require a a whole uh a huge uh environmental trigger to set it off and then there are a whole host of things that are in between macrophage activation syndrome immunodeficiency associated steadicam storms malignancy or ebv associated set against storms to varying degrees of environment and host that contributes to setting off the immune system and doing something incorrectly and so already you're getting a sense that as we're thinking about cytokine storms we're going to need oncologists and rheumatologists and
12:30 - 13:00 infectious disease doctors um and and likely many others in terms of both diagnosis and treating the various things that can go on with the patients and you can see how the different treatments might differ depending on what the trigger is and what types of physicians might be getting involved to pick it apart you know a little bit more closely we often talk about these big buckets of hlh and mas and so in hlh or fhl familial hlh these are genetic mutations that result
13:00 - 13:30 in the loss of perforin or perform function and disease usually presents in the first year of life in contrast macrophage activation syndrome is what is often used to call the same thing when it happens after a rheumatologic condition like systemic juvenile idiopathic arthritis or after infections or malignancies and and having these main buckets have allowed us to kind of tease apart the immunology a little bit and understand the immunology and that's where i think you know in the modern era this gets exciting because
13:30 - 14:00 if we can understand these fundamental immune mechanisms we can then develop targeted approaches to treating patients so i think hlh is a great example of this and so it's worth spending maybe a little bit time thinking about it as we said it's a monogenic defect in cytotoxic granule exocytosis so if you're you're missing perforin so your set of toxic granules can't kill because they're missing the effector molecule that's important for punching holes in the target cells or you're missing any one of a number of these genes that's important for taking the perforin
14:00 - 14:30 and excreting it out to the target cell to kill the target cell so effectively patients with hlh don't have a working performant axis well what does that do to an immune response so from mice we've been able to learn by using peripheral knockout mice what actually goes on in an immune response when you're missing preference the normal immune response you take some virus in the case of mice we use this conical sort of model pathogen lcmv the lcmv infects the mouse it gets in
14:30 - 15:00 inside of an antigen presenting cell that antigen presenting cell presents to a cdt cell and that cdta cell gets excited by the lcmv antigen and the cdt cell will do what cdt cells normally do they'll make interference gamma and that interferon gamma as an effector cytokine gets the apc even more excited so it's an even better antigen presented to the cdat cell so the cetl gets even more excited and it makes interfering gamma once again and so you have a feed forward loop and normally what breaks that feed forward loop is the cd8t cell itself
15:00 - 15:30 and it does this by shooting out perforin and killing the apc you take away the stimulation the cdt cell can now calm down because it's no longer being stimulated and the immune response terminates but if you're missing perforin because you're a knockout mouse or you're a human that's missing the gene for perforin you can no longer kill that antigen presenting cell that signal continues and continues and continues the c8t cell proliferates you make an excessive amount of interference gamma and that's what drives the pathology in both the mice and the human
15:30 - 16:00 and the reason why all this work has been important is because we now an fda approved medication that blocks interference gamma that's indicated for the treatment of fhl and so it's really a great example of where going after the fundamental immunology reveals therapeutic targets those that are pretty targets can be developed into drugs and then those drugs end up actually working for the disease and in hand um and um and so we're able therefore to treat our patients better
16:00 - 16:30 and they can benefit from um you know from the fact we actually can now recognize um and go after their their pathologic target of course life's not that simple right so these things aren't always um 100 clean or pure right now we know for sure that this does translate from mice to humans we can look at gene transcripts and we can show that indeed if you look at patients with hlh you can see an up regulation of an interferon gamma
16:30 - 17:00 signature that's not present in control patients but if you look at the cytokines that hlh patients are making the spectrum as well of cytokines is well beyond interferon gamma and so it turns out that it's not always true that shutting down the interferon gamma is able to turn off the disease process and that's not always true in mice and unfortunately it's not always true in humans and so of course then the search for additional targets needs to be made um to try to figure out well in these patients aren't responding interfering
17:00 - 17:30 gamma blockade are there other medicines that they can respond to and so some of the work that we've done you know in our own laboratory has revealed um another uh important signaler for hlh and that comes from the tissue damage itself that happens during the hlh process that releases another cytokine called il33 that is another way to turn on both cd4 and cd8 t cells to make them make more interfering gamma and so there's this additional loop that involves il33 that we've been able to show in in mice
17:30 - 18:00 models is an important uh mediator of hlh as well and if you neutralize and block alpha 33 you can also cure the mice and you can also cure the mice in an interfering gamma independent way so that il33 covers other immune effector functions besides what i'm showing on this slide and of course il-33 is now getting some recognition during the pandemic times as this is one of the molecules that did show some initial benefits um in treating coca-19 patients
18:00 - 18:30 and trying to quiet the hyperinflation of covet 19. so you know we can learn about these other targets again by doing um um you know this this mouse research and i think that sort of broadens the spectrum then of a the types of things that we might be interested in trying to diagnose in hlh because you might want to measure interfering gamma but you also might want to measure alpha 33 and b the types of therapeutic options we might have to treat patients whereas some people might be great candidates for aisle uh for interfering gamma blockade others might
18:30 - 19:00 be better candidates for al 33 blockade others might be better candidates for il-1 blockade so and so forth the picture is is equally as complex and growing in the case of multi-lineage cytopedia disorders right so when i was a resident you know we talked about itp and then you know if it got really complicated maybe you talked about evan syndrome so you had more than one lineage down and that was like the extent of our sophistication in thinking about
19:00 - 19:30 autoimmune cytopenias and with the advent of um of of you know modern uh genomic and genetic analysis we've been now able to recognize a number of genetic syndromes that are associated with autoimmune um cytopenias and as we do a much more sort of careful job in phenotyping some of our other immune syndromes we're realizing that you can have autoimmune cytopenias as well as for
19:30 - 20:00 instance immunodeficiency like cvid and so all these overlaps then begin to heal themselves and so this is again one sort of complicated figure to try to put things into buckets you can think about immune dysregulation and hemophagocytic and lymphoproliferative syndromes associated with cytopenias you can think about antibody in cellular mediated um um cytopenias you can think about bone marrow failure syndromes you can think about myelo-suppressive
20:00 - 20:30 syndromes and you know even in these buckets there's overlap and so the world of autoimmune cytopenia has rapidly expanded beyond the hematologist you know it's not enough now to just be the hematologist and say you have evidence syndrome because your platelets and your hemoglobin are down but you need to think about well do you have evan syndrome because you have cvid associated with it or could i be missing one of these other conditions on the slide and so again this sort of intersection of the disciplines arises
20:30 - 21:00 um in and broadens the way in which we think about how our patients are presenting so sort of taking alps as a canonical example alps are genetic you know traditionally genetic defects in fast mediated cellular death so you get a lymphocliferation because the lymphocytes don't die from fast uh dependent pathways and the disease as you can see in the slide is associated with a host of different things autoimmune manifestations malignancies and so again you know
21:00 - 21:30 you're going to want a multi-disciplinary team taking care of your apps patients to be able to screen for all the things that can go wrong with them and to think about the different types of medicines that might be or therapies that might be used to try and mitigate some of those problems in much like i was driving at for hlh in the modern era it is very worthwhile trying to figure out what the fundamental defect is because when you can figure out the fundamental defect you can associate uh off-the-shelf therapy with it okay so
21:30 - 22:00 for instance if your defect is in um um uh antibody or b cell um development and you have cvid treating that with b cell directed therapies like ivig and rituximab helps if your defect is a rasopaphy and therefore you have a problem with map kinase signaling there's a multitude of map kinase inhibitors available that you can use to shut that off if you have a defect in the pi3 kinase pathway you can treat with a pi3 kinase
22:00 - 22:30 inhibitor if you have a defect in um regulating this molecule ctla4 you can give back ctla4 in the form of a betacept if you have a defect in a signaling molecule the il-6 pathway you can use an il-6 blocking molecule to try and revert that and so getting at these fundamental causes of the immune disregulation syndrome even when they can present with a whole host of different um um pathologies and organs involved and
22:30 - 23:00 so you know if you look at some of the diagnoses on this slide you know lupus can affect almost any organ we talked about the different things that that that alps can affect um and so even with these divergent clinical presentations that really you can get with almost any of these diseases understanding the molecular defect leads you to pick a particular therapy um and and that um can improve patient outcomes so again getting a sort of multiple list
23:00 - 23:30 discipline a multi-disciplinary team together but a team that has an immunologic orientation to try and go after these fundamental causes often leads to being able to select rational therapy to treat the disease process sometimes we don't even know what the patient has i know you've got immune dysregulation i just don't know what it is right so you often will see patients that are clearly affected their immune systems are clearly not working correctly and
23:30 - 24:00 you can tell that on the basis of functional studies and yet they don't fit a known syndrome and that's where um you know the the again the modern era of genomics has uh often come to the rescue so being able to no longer have to take five years to do positional cloning of some candidate gene to only find out that i'm wrong and that wasn't actually the causative gene but instead look at every gene in the body through whole exome and now even whole genome studies has allowed us to much more rapidly help
24:00 - 24:30 uh patients that sort of fit into this n of one unknown uh category it's still not easy to do right it's still not easy to do i think you still need a good paired clinical and research team and again that's where these multidisciplinary immune disregulation clinics come uh really come into their own um but because the technology is now within reach of you know uh uh most large research institutions or or not even large but even you know
24:30 - 25:00 um uh i would say most academic centers in the u.s you know you can order a whole exome now clinically um it's no longer the purview of lar of places like the nih um but when you start to do that you need to know what are you going to do with that information that you're getting and that's where having the the the multi-disciplinary research team and clinical team uh really comes into play so why do we do this multidisciplinary thing well the first
25:00 - 25:30 is that every specialist that's needed gets involved nobody really sort of falls through the cracks so if i can get together in one room the pulmonologist the hepatologist and the rheumatologist then everybody gets to see you you're not missing out on one important organ that um that is going to be crucial for your care the diagnosis happens faster because the physicians are all together we're all in the same room we all get to talk to each other as we're seeing the patients uh and putting all those brains together um is certainly better than everybody
25:30 - 26:00 operating in a silo and then you know maybe if you're lucky the letter gets to you and you get to read what the other guy thought um so so being together and and working as a team um expedites the way in which all the different sub-specialists contribute to the care um the other thing is that we can sort of synergize between our recommendations to try and reduce polypharmacy and side effects by saying well i might have this choice of these three drugs for my thing and you have a choice of those two
26:00 - 26:30 interventions for your thing oh but these two things are the same they they overlap why don't we pick that one particular drug it'll get your thing and my thing at the same time um and so we can come up with a much more refined and um i think um targeted approach by uh by leveraging everybody's expertise and then finally i think communication both between physicians but also between the patient their physicians uh is is is much easier when there's a single point of contact you don't need
26:30 - 27:00 to know who to call if you're the patient if you have problem x do i need to call my rheumatologist or my oncologist and you end up calling everybody and then you end up getting different opinions or different things on different opinions on different days if you know i just need to call the immune regulation clinic and i've got my single point of contact for that you know you're going to get the right answer from the right docs without having to worry about having to to reach out and and sort of get the whisper down the lane of oh no it's not me you need to call this guy oh no it's
27:00 - 27:30 not me need to call this one um so i think it's a better experience with the docs and for the patients when we can um do this in a multidisciplinary way all right so what does it mean this regulation look like so so this in some ways you know this slide is obvious in other ways it's not right um at the end of the day immunous regulation has to have some objective evidence of abnormal immune function something's got to be wrong with the immune system or you don't want to suspect immune dysregulation now that
27:30 - 28:00 can come from labs right that can come from having an elevated separator crp so documented evidence of systemic inflammation it could come from abnormal immunoglobulins so if you're hypogammaglobulinemic something's wrong with the immune system maybe it comes from objective documentation of having high fevers uh with no known source but in one way or another you're getting objective evidence of abnormal immune function from from labs the other way that you might come to this is objective evidence that there's
28:00 - 28:30 inflammation of a target organ so maybe there's a rash or maybe there is a hepatitis that you can see or maybe there's a lymphadenopathy so that um you're palpating big lymph nodes or maybe you're seeing cytopedias so that the bone marrow seems to be targeted but one way or the other there is something that is connecting you to say yes my patient has a complex array of symptoms but there's something associated with an
28:30 - 29:00 immune problem uh that might be driving those symptoms um because the the trap is that you can have a lot of ways in which you can have these complex multi-organ uh syndromes like i've been describing and have nothing wrong with your immune system in which case the last place you want your patient to go is an immune regulation clinic because we can't help the patient that doesn't have um an immune problem at the source of their multi-organ multidisciplinary disease
29:00 - 29:30 the other thing that often tips you off is that there's sort of more dysfunction than the expected right and i think you know one of the way one of the one of the things that i was struck by when we first started doing this was when our hematologists were saying you know we've got all these evan syndromes patients and everyone you know hematology is comfortable with evan syndrome that's that's what they do but boy they've got evan syndrome and then these other weird things like this patient has a rash that i can never figure out or you know they're complaining to me that my my
29:30 - 30:00 joints hurt and you know i'm not a rheumatologist i don't know how to examine a joint um but they clearly have evans syndrome you know could it do could those things be related so that there's more than it's more than just evan syndrome there's something else going on and i would say that more generally this comes in one of two ways you can either have a more dense loss of function or gain a function than you might otherwise expect right like a complete absence of a cell an inch like if you have absolutely no cd8 t cells just as an example i'm
30:00 - 30:30 making something up clearly that's something really wrong right that's not just run-of-the-mill whatever that there's something there must be something fundamentally wrong with the immune system that's causing you to not have any cd8s or to not have any igg at all or to have too much igg right so gain a function um when there's you know or autonomous activity of of a of a of an immune function so that you know um you're you're always you're you're
30:30 - 31:00 your il1 is too high because you're always making too much il1 so you've got some autonomous activity of the inflammasome that's making you make too much il1 that often will make you suspect an immune dysregulation the other thing that makes you disrespect it is when you have two sort of disparate immune functions that aren't working so you make auto antibodies you've got a loss of tolerance but you have a poor vaccine response you can't actually respond to an exogenous challenge so when you see those two things
31:00 - 31:30 together you think you mean dysregulation or too much th2 directed inflammation a very atopic patient but also increased infections that that are well beyond what you might expect for for instance the skin breakdown of eczema maybe you have too many pneumonians that i can't explain on the basis of the th2 inflammation so when you have two disparate immune functions that are off that often also leads you to benefit and then we get to you know i wrote down advanced diagnostics and i'll admit that depending on your subspecialty and who's
31:30 - 32:00 on this symposium some of these may be more or less advanced to you but i think one of the things that we are benefiting from is an explosion of uh different ways by which we can assess different immune effector functions now the key to it is that we need to make sure that the labs that we're using are being done in a way that are reproducible and are um um you know validated against normal controls and so
32:00 - 32:30 trying to use cloud clear validated assays that are being performed in cap inspected labs i think is critically important it's not always possible sometimes you will use research-based assays to try and get an answer for what you're looking for but as much as we can trying to use validated um certified laboratories is important one of the things we suffer from is that a lot of the labs don't have normal ranges for children depending on what assay you're looking at and so i think you know that's something that our community needs to begin to
32:30 - 33:00 work on which is understanding what normal ranges uh are for some of these measurements in the pediatric population and i think the third bullet point is probably the most crucial so interpreting the labs in the context of the entire presentation is always going to be required particularly because of the second bullet point if you don't know what's normal then you need to at least and be able to interpret the lab values in the context of your patient's disease presentation and the types of diagnoses that you're considering and so
33:00 - 33:30 again this is where the multidisciplinary specialized team comes into play in helping to understand what the diagnostics are actually trying to tell us so measuring cytokines is um is uh is certainly of a lot of use in a number of different conditions because we know that certain immune dysregulation syndromes are associated with um abnormalities in in particular cytokines and not in others um it also allows you to determine the qualitative nature of the inflammation present in your patient when you don't
33:30 - 34:00 have a predetermined set of cytokines you're looking for to make a diagnosis if you can at least say well the th1 axis is elevated so i'm seeing lots of interfering gamma i'm seeing lots of il-12 versus the th2 axis is elevated ooh there's lots of il-13 or il-4 present at least drives you to different qualitative immune processes um rather than just saying oh your sun rate's up you must be inflamed so the cytokine panel does help
34:00 - 34:30 figure out what qualitative aspects of the immune system are dysregulated and often we can find cytokine panel um patterns that lead us to specific diseases one of the problems with advanced diagnostics is turnaround time so often you know you get an a an answer but you get your answer back days later and if you have a critically ill patient in front of you that can be very difficult to have those data in an actionable time frame to actually make a decision
34:30 - 35:00 um you know one of the ways that at chop we've dealt with this is a we've we've rolled out our own cytokine panel that we can turn around in 24 hours so if we have a critically ill patient i can know what their cytokines are um you know usually by the next morning in order to make a decision within the uh a time frame that's actually actionable and i think as we get more and more of the these assays we'll look to having more and more of the mindset of these are critical lab values we need them performed in a critical turnaround time there are a number of sort of single set of kind of essays even for getting the
35:00 - 35:30 panel that let you probe dysfunction in particular pathways some of the examples i gave here are il-18 and cyber l2 receptor and so like if you're looking for one of the so-called il-18 apathys nlrc4 being the canonical one but there are other diseases of il-18 you can look for elevated il-18 um in a single assay similarly you can use fibro-l2 receptor to look for essentially what is activation of lymphocytes that has been associated with a number of different diseases including hlh
35:30 - 36:00 and then finally there are diagnostics that don't ask about the cytokine itself but ask about whether the patient is is experiencing the downstream effects of that cytokine are they functionally are they functionally elevated for that particular cytokine so for instance interferon gamma is a great example where sometimes the interfering gamma is present and is active but it's in the tissues and not in the blood so trying to measure interfering gamma from the blood doesn't help you
36:00 - 36:30 but yet i can tell that the patient is overdriven for interfering gamma function if their cxcl9 levels are elevated because that's a protein that is driven or that is made by interfering gamma's activity so sometimes measuring not the cytokine itself but the biomarker of the cytokine function um is is more informative similarly for type one interferons we can measure the interfering gamma gene or sorry the interferon gene signature to let me know that this patient has an interferonopathy or an or a
36:30 - 37:00 an elevation or a increase of the interferon alpha axis and so measuring not only the cytokines themselves but the labs that lead us to be able to assess their function becomes important um flow cytometry is a crucial tool in trying to understand immune disregulation it allows us to do a couple things it allows us to assess both cell number but it also allows us to assess activation status so i can not only say you have too few
37:00 - 37:30 or too many b cells but if i have a a flow cytometry panel that measures mhc class 2 levels on b cells i can say that not only are those b cells increased in number but they're activated they're they're turned on um you can look at city 45 ra ro for instance is an example of do i have naive versus memory lymphocytes and so you can assess not just number but activation and that's always that's important because number doesn't always equate to function there are many patients that
37:30 - 38:00 have a normal number of cd4 t cells but those cd4 t cells are doing something they shouldn't be doing they're either activated or they're not acquiring memory status so on and so forth um again this will be where you want to have somebody on your team who has expertise in understanding what all the different markers and combination of markers mean um for immune function you can profile the humeral response so you can ask questions about amount of antibodies
38:00 - 38:30 i'll use the type of anybody being made and the specificity of the antibodies that are being made so we can use diphtheria and tetanus to look at protein specificities we can use pneumococcal responses to look at carbohydrate specificities and once again either too much or too little can be the sign of a problem so you have a patient that can make uh protein specificities but not carbohydrate specificities that lead you down into specific antibody deficiency and other defects that prevent you from making um t-independent b-cell responses
38:30 - 39:00 um and and so on and so forth and once again you know the answer isn't always in the serum uh sometimes you have to worry about either tissue bound antibody or the surface in the globulin patterns on b cells and so like for instance igg4 related disease is another sort of immune dysregulation syndrome often the igg4 will be completely normal in the serum but if you can get a piece of tissue that's affected you can see that the
39:00 - 39:30 plasma cells are all uniformly igg4 positive in the tissue so um you know considering not just what's going on in the serum or the plasma but remembering that we need to look in the tissues sometimes where the organs are being infected is important and then finally genetics um you know has really sort of revolutionized this and there are lots of ways of approaching this i mean you know the genetics of amino regulation quite frankly could be an hour-long talk right there um if your phenotype is specific enough we
39:30 - 40:00 will start with targeted panels so if we know we're thinking about things in the autoinflammatory category we can do an autoinflammatory gene panel um if we suspect a genetic cause but the phenotype does not suspect a particular panel that's where the whole exome becomes important and these are really much easier interpreted if you can do the trio so if you have both mother and father to allow you to look for de novo genes to allow you to look for autosomal recessive genes um having having that trio becomes crucial and
40:00 - 40:30 really being able to interpret the whole exome and then finally deletion duplication studies uh become important in the workup of unknown variants because uh it may be that if the exome detects a particular variant that might be pathogenic what exomes are not so good at are looking for deletions for instance so you might have a pathogenic variant that is accompanied by a deletion on the other chromosome um following up your sequencing um assays with
40:30 - 41:00 uh dell dupe assays uh to look for copy number variation uh becomes critically important the the sort of the bugaboo of all this is the variance of unknown significance and you almost always get one one variant of unknown significance in your study um and sometimes these are critically important sometimes these are actually the answer right these are genetic variants um that have not yet been associated with a particular disease
41:00 - 41:30 but uh you know are present in the patient and are either like de novo therefore not in either parent and therefore of interest or have such a slow to non-existent allelic frequency in the normal population that you suspect that maybe the variant is important but there's not enough information in literature to say ah that's the causal variant or not these really require significant expertise to interp interpret you need to have people that know the gene function you need to have
41:30 - 42:00 people that understand the physiology to comment whether these are important to pursue or not and they often will require a research level validation you know expressing the variance seeing whether the variant results in protein instability and therefore differences in protein levels seeing whether the variant has normal protein levels but abnormal function um and and they can require you know a significant amount of work but again when you have a a a dedicated team to immune this regulation that includes not
42:00 - 42:30 just the clinical side but the research side you're able to leverage this and and often actually find causal variants that often again suggest rational targeted therapies because if you can know the gene you can often picked an off-the-shelf drug that that addresses that genetic dysfunction all right so when is it not immune to regulation and i would say the biggest thing that comes to us is that the patients may have multi-organ or you know sort of vague symptoms and
42:30 - 43:00 it often takes the form of things like fatigue or musculoskeletal pain or brain fog or you know changes in behavior or just you know oh this is a diagnostic challenge i can't figure out what's going on but there isn't one of these things we just mentioned that is clearly pointing to yes the immune system isn't working right in some way or the other so you know brain fog and fatigue but no fevers said rate is normal crp is normal so on and so forth and you know i would say that the immune
43:00 - 43:30 system is not the best poker player usually when it's driving something that is severe enough to cause a multi-organ problem it reveals itself we might not understand what's going on we may not understand what the fundamental defect is but usually there's something wrong either your set rate is high or your igg is low or i can measure some component of the immune system that tells me yes there is an immune problem that explains all these other symptoms
43:30 - 44:00 you know inflammation um is is not necessarily a subtle thing you know it is the immune system is turned on and you get heat and you get swelling and you get redness because these blood vessels are dilating and you're seeing inflammation you can have different flavors of inflammation you can have different t cells that are activated you could have compliment driving inflammation you're going to need cytokines inflammation inflammation could be systemic or it could be local but inevitably you can find it if it's
44:00 - 44:30 systemic you'll find it in a crp or a sudden rate if it's local when you biopsy that that that that organ you'll see inflammatory cells in that organ pain as a complaint doesn't always equal inflammation right so pain often people say oh man you know my knee is really inflamed today it's hurting me so bad but that doesn't necessarily mean the knee is inflamed if i took a baseball bat and smashed your knee it would hurt but it's not necessarily inflamed it's just injured it's traumatized
44:30 - 45:00 um and likewise there are lots of ways you can get pain that have nothing to do with immune activation so what is it when it's not immune dysregulation and i would say the number one diagnosis that we see in the immune dysregulation clinic when it's not immune to regulation is amplified musculoskeletal pain syndrome it's a central sensitization the pain that results from a combination of altered neurovascular dynamics and psychosocial stressors and the treatment has nothing to do with modulating the immune system it has to do with physical therapy and stress
45:00 - 45:30 management and and there's an entirely other multi-disciplinary clinic in chop that handles these patients and can do quite well with them and treat them um but it's not immune disregulation and the clue is these patients have normal labs they have normal radiologic studies they have normal uh biopsies if they've had biopsies there's no evidence for inflammation despite the fact that they have these multidisciplinary multi-organ complaints and that's not you know they're not going to be helped by our clinic when we
45:30 - 46:00 can make the diagnosis and move them to the right clinic that's great but even better would be to to direct them to the right physicians in the first place so amps is really an umbrella diagnosis for a whole host of different conditions that go by a million different names that's not important really what's important is that at the end of the day they're all diseases of central sensitization and amplification of the neural signaling that that elicits pain hypersensitivity so under normal neural function you get
46:00 - 46:30 pain because the nocia scepters receive some stimulus that causes them to fire and drives a pain signal that goes to your brain likewise if you're tickled with a light feather a different set of nerves fires and signals this as being light touch and in amps the wires get crossed so that these toxic stimuli produce an increased pain response called hyperalgesia but now the tickle from the feather also crosses over into the pain nerves and gives you
46:30 - 47:00 allodynia where it's experiencing pain to a stimulus that otherwise shouldn't cause you pain and that produces hyperaesthesia and as an example this is you know what a child draws as their symptoms um um in the midst of a amplified pain flare and you can see all the places that the child is hurting and all the different kinds of pain that they have um you know and and it's it's quite severe um and it would appear at first blush to
47:00 - 47:30 affect all sorts of different places and organs and functions of this patient that might make one think that maybe there is an immune dysregulation syndrome involved but when you measure a new look the immune system is normal and therefore it can't be immune to regulation syndrome it really belongs in in an amplified pain clinic the other thing that we often see are these sort of diagnostic challenges multisystem complaints happening in the absence of an immune etiology but not amplified pain so connective tissue disease is one example you might have genetic mutations
47:30 - 48:00 of collagens or elastin genes and although like sort of in the older textbook textbooks people connect connective tissue disease to rheumatic disease that's not really the case these are really genetic diseases these are these are diseases that belong in the geneticist clinic um and things like ehlers-danlos or marfan syndrome um where you can have multiple organs involved but it's not a fundamental inflammatory process and then metabolic
48:00 - 48:30 or mitochondrial disease these can be tricky because they can have some immune overlap sometimes having a metabolic or mitochondrial problem does actually cause the immune system to be activated but at its fundamental basis it's not an immune dysregulation problem um it's a problem of metabolic dysfunction um and if if you uh attack that fundamental issue that's how you can make the disease get better um and so you know again it's not a problem when patients with these conditions come to our immune regulation
48:30 - 49:00 clinic we often are able to identify where they need to go but with respect to sort of the referring physicians um if we can take the initial steps to decide yes i see immune activation or no i don't often you might get somebody to their correct clinic faster rather than referring somebody to immune to regulation um um when it's fundamentally not that in the first place the other main thing that i would say is that this doesn't supersede sort of the classic silos of immune disease a
49:00 - 49:30 patient with lupus needs a rheumatologist yes it might be multi-organ but at the end of the day it's going to get taken care of much more efficiently much more rapidly if you send that patient to a rheumatologist if you have a cancer go see the the oncologist you don't need you know me or the pulmonologist or what have you the first thing you need is to get and go and see an oncologist and they can direct the team you know if you have specific antibody deficiency that's managed by an immunology you don't necessarily need a an entire immediate regulation team to
49:30 - 50:00 take care of that so these this isn't the sort of supersede or replace these sort of classic silos of immune disease but rather to catch everybody else that fits between those cracks that doesn't fit into one of those diagnosis all right i think we can end with just a couple of examples a couple of keys presentations and then we can take some questions so as an example of an immune disregulation condition this was a 26 year old that nine months prior to presentation developed a nephrotic syndrome and at the time was found to be evb viremic but his
50:00 - 50:30 you know the the physicians taking care of him didn't sort of put those two things together and just said well that's curious you're just kind of sick from your nephrotic syndrome um and and treating them as such nine months later presents with pancytopenia high ferritin big liver and spleen and elevated soluble2 receptor um his outside hospital diagnosed him with ebv hlh because he remained ebv viremic and started him on a protocol for ebv hlh however um um uh they they consulted with our team and we
50:30 - 51:00 asked for a few labs and what we realized very quickly is that this isn't just your run-of-the-mill ebv hlh that this was a profound b-cell dysfunction um because the patient had no b cells in the peripheral blood and that was prior to rituximab um so the patient was given a b cell depleting therapy even though the patient mdb cells to begin with and on top of that when we looked at the original bone marrow um that was done months and months earlier we realized there were no b cell precursors in that bone marrow
51:00 - 51:30 so once we recognized that this was actually a b cell a b cell immune dysfunction syndrome the patient was transferred to chop and we do take care of the the the young adult population as well with this because they're often we find that there are not um colleagues in the adult side that have this much expertise um we realized that the uh the ebv had uh had an altered tropism rather than infecting the b cells which weren't
51:30 - 52:00 present was actually infecting the nk and t cells which is a pattern that we see uh in chronic active ebv infections we did a whole exome sequencing and found a um a variant of unknown significance that we believed to be the causal genetic variant um which suggested that bone marrow transplant was the appropriate therapy um and so we were able to successfully get this patient to a bone marrow transplant so this is an example of a patient that had lots of different organs nephrotic syndrome kidney big liver and spleen lympho proliferation hlh looking
52:00 - 52:30 condition with the high ferritin ebv viremia but when one takes a closer look in profiling the immune system you can see that there's a very specific compartment that was abnormal in the b cells genetic analysis brings a causative gene um and then we're able to sort of get the patient definitive therapy in the form of a bone marrow another example um was a 20 year old with what had been called called sarcoidosis by the primary team for many years lesions that had
52:30 - 53:00 granulomatous inflammation and was treated with a tnf alpha inhibitor that was mostly affecting skin and lungs however eventually was found to become a hypogammaglobulinemic that required ivig replacement and then neurological disease in the form of headache and dizziness and ataxia and an abnormal mri at the same time developed a significant thrombocytopenias now again we've got lots of multiple organs this granulomatous disease it's also associated with a cvid this is clearly
53:00 - 53:30 the mean dysregulation um um syndrome we did hold up some sequencing and could not find a variant here that uh that we thought would be of interest but because the description of the disease sounded so much like ctla 4 deficiency on a research basis we stained her cells for ctla4 and basically there was a complete loss of ctla4 we've not identified the genetic defect yet that is driving that but given that presentation and given that um immune finding
53:30 - 54:00 treated as if this were a ctla 4 deficient patient with steroids in a bad acept um and has ultimately resulted in a resolution of her symptoms so um those are just sort of a couple examples of how you kind of get to an immune dysregulation uh a phenotype multi-organ clear elements of the immune system that are dysregulated or dysfunctional um we may not know the disease in the first you know at first blush but going through the work up doing all
54:00 - 54:30 the advanced diagnostics lets us get to a more specific immune diagnosis that often suggests a definitive therapy so when do we refer for immune disregulation when there's objective evidence of immune activation right so i think there needs to be something some reason why you expect the immune system it's not enough to just have fatigue malaise and um and and and you know nothing else that would suggest the immune system there needs to be at least something that suggests the
54:30 - 55:00 immune system i think patients that have multi-system involvement benefit from our approach and then there should not be some otherwise clearly defined syndrome for which referral to a traditional subspecialist would be warranted right so if your question was does my patient have lupus refer straight to the rheumatologist don't refer to the immune dysregulation if your question is does my patient have leukemia refer to the oncologist don't refer to the immune dysregulation clinic but when it's clearly none of those things to you
55:00 - 55:30 but yet you have this complex multi-system presentation and at least one piece of evidence that makes you think immune activation that's the perfect patient for an immune regulation workup so i'm going to stop here and turn it over to my colleagues on the national provider engagement team who can explain you know how we might be able to help um no matter where you are in the country um in order to uh get patients with immunities regulation and other uh conditions um evaluations at shop so
55:30 - 56:00 i'm to turn it over to zach thank you so much dr behrens for the fantastic lecture um so we'll get the q a in one moment we just wanted to um close with sort of two slides about uh how we can keep the conversation going and opportunities to continue collaborating um as you can see here and you know we will share some of these resources chop does post many if not all of our evidence-based clinical pathways to our
56:00 - 56:30 website so we would encourage folks to go and look there uh there's several pathways that um ed and the team have actually collaborated on uh during covet uh that have have been published here uh we're also gonna be hosting a lot more virtual education so if you're interested in signing up for additional uh cme lectures we'd encourage you to go browse what we have coming up we have some exciting lectures uh planned over the next uh six to eight months and ed can you go to the next slide and
56:30 - 57:00 you know just looking at the registration list you know we're thrilled that we've helped to you know share this message with institutions that cover across 27 different countries on today's lecture and here at the united states we have 29 different states represented so we would love to keep this dialogue going with you you know whether that would be getting in touch about a patient if you're looking for more information you'd like to arrange some follow-up education within your own institution or
57:00 - 57:30 need support on on a referral we do have specific teams that can help you so whether you're here in our local area for our national partners or international partners some of the information you can see here is sort of how to stay in touch and how to keep the conversation going and i think we can now shift to question and answers in the view that you can see there is a question answer button we would encourage you to put your questions in and we will start
57:30 - 58:00 going through them in the time that remains right so i see some questions coming through the first one that we have is ed if somebody wanted to or if a group of providers wanted to improve multi-disciplinary care for these particular types of patients at their hospital are there two or three key recommendations that you would give on how to get started yeah so you know i think um uh just
58:00 - 58:30 having been through the process myself uh it requires i guess a couple of key things i think to get started the first is that you know it you really gotta have uh truly interested parties uh from each of the sub-specialties you wanna pull in um you know and i think you know kind of the core group maybe is rheumatology immunology um oncology um and and if you can identify just one person that has says that yeah this is what i
58:30 - 59:00 want to take on this is this is what i want to do get that team together and then that's where you start you begin to think about okay can we create a clinic where we will see patients together what kind of pathways and standardization of care do we want to have for our institution the way it sort of started here at shop is we wanted to standardize the way we treated hlh and it was just that one specific question it wasn't really anything bigger or broader that like we were talking about today but just how can we do better for hlh at chop and we were getting we got a couple of different sub-specialists from each of
59:00 - 59:30 the different sub-species involved and we just worked on pathways for hlh and then we said you know what we could do this even bigger and better and broader for other patient um um problems as well so i think it really comes down to having the right people that are truly interested in in the process and are going to be effective partners um and then and then you build from there great with respect to looking for the smoke when there's fire what guidance can you offer for testing for various
59:30 - 60:00 aspects of immune dysfunction so um uh there's it's often um it's often they're often not like sometimes it's completely random right like like i'm always amazed at how like what can go wrong will go wrong but i would say it's often related functions right so a patient with autoimmunity um so uh you know is making some auto antibody to
60:00 - 60:30 whatever um but you're like oh that that this is there's something odd about it this feels weird this doesn't feel just like my run-of-the-mill autoimmune cytopenia is a classic example but you can like autoimmune hepatitis uh you know pick your pick the organ that's being affected searching for imminent efficient defects on the human immune side then becomes sort of interesting right like so measuring vaccine responses measuring immunoglobulin levels um you know some you know sometimes you might not think to do it if you already
60:30 - 61:00 well my patient already already has an anti you know smooth muscle antibodies so it's it's just autoimmune hepatitis until you realize that it's not just autoimmune hepatitis hepatitis being accompanied by hypogam and a poor vaccine response and that's when it becomes something more right um you know so uh you can imagine on you know the t cell side you know patient who is having recurrent viral infections or something and then you know you look for t cell function and realize that there is a defect in t cell maturation
61:00 - 61:30 or t cell numbers or something so i think this where the smoke there's fire kind of thing is this is to say you know it's interesting what you find when you start thinking more broadly right so if you find that there's something wrong with one aspect of the immune system work up all the other pieces that go along with that aspect of the immune system because you might find dysfunction that you didn't recognize in other spots did you have the opportunity to look at il-33 blockade with and without
61:30 - 62:00 ifng blockade and pre-clinical models so in pre-clinical models uh it works beautifully um so if you give al-33 blockade to hlh mice um they're they're basically cured um um as well as if they're cured from an inferior gamma blockade and then if we tweak the system in various ways to make it where interference gamma blockade no longer works for various reasons our 33 blockade still works even in those scenarios so
62:00 - 62:30 actually we're really um we were really bullish on il-33 blockade on the basis of preclinical models for hlh um at the time i tried to pitch this to a couple of pharmaceutical companies that had il-33 products for patients because it's more of a th2 directing cytokine they're very interested in developing it for asthma uh and they did not want to jeopardize their asthma programs by using it in patients where there's a high mortality rate like hlh and so i
62:30 - 63:00 could not convince any pharma to um to try and look at il-33 blockade in patients of course um once cobit 19 came along um everyone sort of changed their mind and i think they began using it in those scenarios and there was at least some preliminary data that was interesting uh we'll need to see where it plays out but you know i think that i'll 33 blockade is viable because there are antibodies that have already passed phase one and phase two trials um and so the question is again i think getting a willing partner that would be
63:00 - 63:30 interested in actually looking in human disease populations and see whether that would be a viable way forward how do you deal with a vus in immunological genes um so you know um it goes to a couple of stages i guess of triage so um um if there's a vus in the clinical report um you know first thing we'll do is we'll
63:30 - 64:00 look at the gene does the gene make sense you know could we could it be a viable story for what's going on in the patient does the variant make sense is the variant predicted to be pathogenic by using things like sift and and polyphene and other algorithms to say um you know um oh yeah that's an amino acid change that would cause a problem what's the allelic frequency in the general population by looking at tools like nomad um if it sort of reaches the bar to
64:00 - 64:30 where you know is of interest because of those things then we um try to see whether there are there's anyone anybody already on campus or that we know that we could collaborate with that's already working on that gene that might be interested in looking at that variance and if we can at that point in time establish that the variant is doing something meaningful that's how we can sort of move it on the other way that we get vus is that what we try to do on a research basis um and so most of the patients that we
64:30 - 65:00 see get consented onto our protocol if you have a clinically negative exome we'll try to get those data and actually do a exome board research review again to look for variants that don't make the cut for a clinical call because they're they're not you know validated variants enough that people feel comfortable reporting out as a clinical um um uh possible hits but on a research basis you often will find genes that become of interest that you can then take through the same process right and if you can get it
65:00 - 65:30 to the lab and at least show that your variant causes a problem in protein stability protein levels um or that the variant causes a defect in rna levels um you know that's often the easiest first clue it becomes harder when protein and rna is normal and then you've got to try and show function but you often are able to not often but sometimes you are able to show that function is abnormal and if you can do that then it becomes sort of worthy of moving it on to the next stages but i mean i think this is
65:30 - 66:00 the biggest problem of our times right like all the vus's you're convinced that this patient has got something something genetic you know and how do we how do we rapidly move from a vus to something that's a little bit more of a known significance i think is the problem of our times um and you know um there are people that are working on sort of high throughput ways of doing this but i think that that's going to be you know um some years away before we can just sort of chuck a variant into sort of a large screen and say oh yeah
66:00 - 66:30 that's real or that's not real for a patient with known or suspected immune dysregulation syndrome do you have a standard surveillance protocol to assess for possible other autoimmune conditions affecting other organ systems or is this symptom driven i i would say it's a little bit of each i mean i think um i think it's it's very it's certainly symptom driven um but i think you know like this is where honestly this is where the
66:30 - 67:00 multi-disciplinary thing is so awesome because number one i'm like a million times better doctor now than i was even like two years ago before i started doing this because i just learned so much from my colleagues and what you learn is how we all do a slightly different review of systems how we all do a slightly different hpi and how we all do a slightly different physical exam and i would say in many ways like that makes our surveillance much more powerful because our hematologist on the team is going to ask different questions than i do
67:00 - 67:30 and i'm going to ask different questions an immunologist does who's going to ask different questions than the infectious disease doctor does and by the time you finish with all of those hpis and reviewer systems you've done a pretty good surveillance and you'll be shocked by what you dig up right like things symptoms or questions that i don't i just wouldn't have asked um that somebody else asks and then all and then the patient answers in the positive and then you work that up and that's sort of how we do the surveillance so i think part of the way we do effective surveillance is by having this very
67:30 - 68:00 multidisciplinary approach to these patients essentially assuming nothing right assuming nothing you need to see all these different people because who knows what's actually going on and if i don't ask the right questions i'm not going to find it so so that that i would say is the strongest part of our surveillance is the multidisciplinary aspect sometimes it takes one to two months to get genetic testing results would you start empirical treatment if phenotype is not typical to any certain mutation
68:00 - 68:30 um that's a very patient specific question and i think we probably do different things for different patients um but but we do we do sometimes end up having to do empiric treatment because the patient is sick enough because you know um the symptoms are severe enough you know and often what we try to do is i think as you're sort of suggesting um try to draw parallel for what it looks like the most clinically
68:30 - 69:00 and say well this feels like a periodic fever syndrome and it feels fmf-like so we're going to try some culture scene we do sometimes do that um we prefer to try and get as much data as we can before we make the um the decision to start empirical therapy that often will come in the form of more functional immune testing that comes back quicker so certainly you know i might want to know what your cytokines look like what your cell populations look like so i at least can have a sense of what targets i'm going after um but there are times when you have to start in pure therapy before you get
69:00 - 69:30 your genetic testing back um i think it just it depends on each individual situation are there any translational lessons from the immune dysregulation work that has helped with cobid um so you know i think um in the in the beginning of it all you know there was a lot of excitement about this being a hyper-inflammatory disease and a cytokine storm and you know people are trying to selizumab and people are trying aisle one blockade
69:30 - 70:00 and you know the larger still studies studies have sort of um um tampened uh tampered and or dampened enthusiasm for some of that stuff i suspect if we could find the right subpopulations um the right to write directed therapies would work for the right code patients but i think the place where it really helped us in particular to be prepared was for the miss c um um presentation um in children um so when that was sort of first hitting
70:00 - 70:30 the scene um you know our team was was was ready and prepared uh to think about how the intersection between the immune system and coping infections might cause problems for patients um and we were immediately able to jump on it and leverage some of the things that that we've already been doing for other amino regulation patients like cytokine panels like um like other types of immune assays to help us a make the diagnosis more specifically
70:30 - 71:00 and be again think about what kinds of therapies that um that uh we would want to use and so you know even even in infections right there's an immune response that's part of the infectious presentation and so i would argue that even even in infectious disease problems um having the immune disregulation approaches can be helpful both diagnostically and therapeutically great i think that that's it on the question so and any final remarks before i close this
71:00 - 71:30 out no just to say thank everybody for uh for uh tuning in i'm i'm flattered that you all wanted to come and hear the talk today and um you know as was pointed out if you guys have other um other questions specific patients you want to discuss you know there's that that contact information there please feel free to reach out our team is happy to collaborate with with anybody and everybody just a final reminder please fill out your post event surveys before friday november 6th if you have any questions following this
71:30 - 72:00 event or would like to access the link to the recording send us a note and we would be happy to connect you to the resources that are needed from you and your team thanks so much again for attending take care