Mast cell activation disorder with Dr. Anne Maitland

[Music] hi everyone good evening thank you so much for joining us um our apologies we're getting started a little bit later this evening but we're so excited to have Dr maand with us to talk about Mass Cell Activation disorder this evening um we're going to go ahead and get started with the webinar so good evening and welcome to tonight's webinar this evening we are joined by Dr Anne maand who will be discussing Mass Cell Activation disorder as a co-occurring addition condition with primary imun

o deficiency my name is Emma Mertens and I'm the program manager of Community Health at the immune deficiency foundation on behalf of the foundation we thank you so much for tuning in tonight's webinar is is one of many virtual education opportunities available in our 2023 programmatic lineup we recognize that through the provision of timely comprehensive and accessible information we can improve the diagnosis treatment and quality of life of people affected by primary immuno deficiency we appre

ciate you being a part of this journey before we get started um I would like to point out a few Tech pointers to keep in mind for tonight's program this evening we are using the zoom webinar feature and attendees should be able to see the slides and hear our presenter and host speak attendees will not be able to activate their video camera or their microphone there will be the opportunity for questions after the presentation you are welcome to submit any questions you have for Dr matland as you

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Pharmaceuticals and now I am so pleased to introduce our presenter for this evening Dr Anne Maitland is an Allergy and Immunology specialist with the metrodora Institute whose focus is treating complex chronic conditions from a multi-disciplinary approach prior to joining metrodora Dr maitlin served as the medical director of comprehensive Allergy and Immunology in New York an assistant professor of medicine allergy and clinical Immunology at The Icon school of medicine at Mount Si Dr maand is

one of the country's top experts in immune mediated disorders including MK Cell Activation we're thrilled to have her join us this evening welcome Dr maand good evening everyone and thank you for that wonderful introduction and invitation um considering Charlotte Cunningham reyolds is one of my mentors I've been very fortunate to have wonderful exposures to how the immune system is misbehaving in our modern era so let me see if I can start perfect so we're going to talk about massol activation u

h and how this leads to Adent release of chemical mediators in the setting of individuals that have more than likely undiagnosed immuno deficiency syndromes uh this are my conflicts of interest I'm a consultant and on the speaker Bureau for blueprint medicines I've uh authored authored uh books for disjointed transforming ERS download syndrome and National Academy of Sciences engineering and Medicine heritable disorders of connective tissue all volunteer efforts on my part um and so we're going

to talk about Mass activation in health um and then the recognition of mass activation in common disorders uh noting that within the past 10 years one out of 50 Americans have treated for anaphylaxis and the latest report from the CDC is one out of three Americans have one positive allergy test but what's really interesting in many ways mass cells are acting kind of like the engine light on your car saying something's wrong underneath whether you're hiving coughing having brain fog or joint issu

es and trying to understand why the mass cells are misbehaving is what me to understand that individuals with IMO deficiency it is a hypersensitivity disorder that pointed me the way of them having an unidentified primary imuno deficiency so just a brief history of mass cells um they were first identified interestingly enough in frogs in the mid- 1800s and you can see there were lots of different things that were identified regarding mass cells and Allergy but really we didn't know what these ce

lls did until 1989 oops and I actually entered medical school in 1989 and at that time this was the first a report that actually gave allergists ammunition to say what we're seeing when we're skin testing individuals or challenging them with either Airborne or Foods is actually a biological basis and that led to the relationship between mass cells and uh one form of allergy in form of allergen driven Mass Cell Activation disease but for the next 20 years um basically because of this observation

in 1989 most allergy techology Specialists have a tendency to and actually most medical professionals have a tendency to focus on the roles of mass cells and IG mediated disease and it's hard to think about the fact that mass cells might be able to release these chemicals inappropriately especially in the context of imuno deficiency so when I first learned about mass cells literally what I was taught is anybody's presenting with nasal congestion rashes headaches Gest intestinal upset um neurocog

nitive impairment fatigue or brain fog um I was taught to allergy test so you can either do skin testing like you see with this gentleman's arms or you can actually order uh several different types of allergen specific IG through commercial lab tests Quest lab core Mayo um and that can give you an idea of at least one way mass cells might be misbehaving and if somebody was still reacting um but allergy testing was completely negative whether skin testing or through uh blood testing we were taugh

t to look for a very rare disease called systemic mastocytosis which affects maybe one out of 32,000 Americans and to the left is one gentleman that um I had the pleasure of participating in his care when I was training in Boston and to the right was little boy who came to me when he was about two years old who was actually born with a form of mastocytosis called cutaneous mastocytosis erary Pigmentosa and I have to tell you only within the past few years do we have actually rigorous uh diagnost

ic criteria to lead to this indication of this clonal Mass cell disease so essentially over the past 25 years um when it comes to education about mass cells it was two to three Medical School lectures nothing in residency training medical specialty training especially in allergy IM anology just focused on allergy testing or identifying systemic mass of cytosis um and essentially that's where most of the education for mass cells kind of halted except for maybe about 10 years ago so what started t

o happen is a lot of patients as well as practitioners were identifying that mass cells can release these chemicals inappropriately for reasons other than going through the allergy receptor the IG receptor um or through having a broken uh receptor in the form of systemic mass of cytosis and I just want to go through how I came to think about uh the possibility of other syndromes especially imuno deficiency syndromes that may be contribut to mass cell disease such as recurrent hives a recurrent a

sthma exacerbations susceptibility to anaphylaxis or food intolerances that had nothing to do with having a positive allergy test either through skin testing or through blood testing or not unable to identify any form of a clonal massal disease like systemic Moc cytosis so let's start off with quote unquote skin allergies which when you hear the term allergies it's allergen-driven massal activation dis disease but that's a mouthful so it's easier just to say that this is allergen driven skin dis

ease or skin allergies and again we have a tendency if someone is having recurrent Rich itchy itchy red hives um or swelling we'll do environmental testing for pollen mold animal dander components of dust or we'll do food allergy testing and again it's very easy most allergists will prefer the upper panel but any practitioner can order the blood tests um but understand that I can go out right now and test 100 people for for instance IG to peanut I'll get 100 people who have I'll get 15 of those

individuals that were tested that will have a positive test and only five of the 15 will say I actually can't eat peanuts so having a positive test is not guarantee that you're actually symptomatic from um that antibod that is running around it's no different than we see individuals who run around with auto antibodies such as Ana it's around but it's not really causing problems so so in addition to learning about allergy testing we also learned that there are a lot of different non-allergic trig

gers and that's actually how most allergists thought about um skin Mass activation disease or ticar and angiodema is well do I find allergies or not and so in addition to um doing allergy testing and if that was uninformative or not really giving us an idea why this person keep on suffering with recurrent itchy rash I would tell them 15 20 years ago I'm going to go doing I'll do some testing I hope I don't find anything because typically it means that you have another serious chronic condition w

hether you might have a chronic infection like hepatitis you might have IMO deficiency like you you're lacking complement or antibodies you might have an autoimmune thyroid disease like Graves disease or Hashimoto I've actually identified at least two individuals who had um had a form of lympho of disease or cancer um simply because they kept kept on having an itchy rash so in many ways again if your skin is acting up allergy testing is uninformative it's it's important to kind of dig a little b

it more but you want to make the person comfortable with medications that actually have a very good safety profile such as hist blockers or Lucine blockers um and interestingly enough the panel on the lower right is a young lady who actually has a physical trigger of mass Cell Activation chemicals in the skin um and this is someone who actually has cold induc ortic care and Through the Years there's been several uh physical triggers that are known to cause people to have uh increased chemical re

lease typically can be in the skin it can be in the Airways in the form of nasal congestion or asthma exacerbations some people people even have neurocognitive changes or or cluster headaches due to physical changes like some people can actually predict a change in the climate because their joints hurt or they might end up having a migraine because they're or are more brain fog simply because there's a change in the climate or they look up at the sun this is a physical trigger meaning there's so

mething about the nerves that don't like that change in the environment that the mass cells then release these chemicals and let you know something is wrong that the body doesn't like I wanted to show you that over the past I would say 10 years we're starting to get more information about other receptors that are responsible for causing massels to inappropriately release these chemicals this is a paper that was done about eight or n years ago showing that this is an autosomal dominant rare disea

se and that uh family members would have a mutation in a stimulatory receptor on mass cells that would cause them to release and have hives and potentially even uh anaphylaxis due to vibration um and so here you have a nerve perception of of a change that the body is thought to be in danger and then the mass cells then release those chemicals because it's a false alarm just want to give you an idea what mass cells look like because we kind of think about it in an abstract sense but mass cells ag

ain are found in lots of different animals and are found in every part of our body and essentially they have a job to do um and in my opinion have been mispred as as dangerous cells but literally what they're trying to do is let you know that something's come into you that they think are dangerous they're trying to contain it and sometimes they're going to call on help so resting Mass cell looks it's just usually isolated and sitting by themselves as opposed to a mass cell that's been triggered

to releases chemicals they start to spread out you start to see particulate matter in the area so it goes to show you that mass cells have the ability to release some very potent chemicals not only just histamine but enzymes that can modify connective tissue it has heprin or platet activating Factor so you can clot or bleed it has the ability to call in other cells that have very potent chemicals like ES and neutrophils if you're in a riverbed and you're having a worm that's kind of boring into

your foot the massel is there to try to contain that parasite and then call it an eosinophil if it's a bacteria that you breathe into your nose and the massel detects the bacteria the massel will release chemicals such as enzymes uh to kind of fight off that that bacterial infection and at the same time calling nutrifil so in many ways massels are kind of like the first responder uh trying try to identify what has changed in the environment that seems to be causing tissue injury can I contain th

e danger or do I need extra help in order to eliminate the danger and then after the harm is contained mass cells play a key role in uh tissue repair and and um uh healing I wanted to also show you that mass cells are also very involved uh in asthma exacerbations and this is an article by uh Sally welzel who's been very involved with asthma for throughout the years and she wanted to point out that there are plenty of allergic and non-allergic triggers that can cause someone to have respiratory d

istress this focuses in the lower airway but I can say for the same thing for the upper Airway you have internal changes like increase of estrogen and progesterone or dropping off of cortisol that may cause you to have increased nasal congestion or or lower airway uh congestion developed you have exercise which is a physical trigger you have susceptibility to infections including viral viral or bacterial and especially with the the Corona virus that we've been dealing with for the past several y

ears and then you have environmental um chemicals whether indoor or outdoor pollution that can cause tissue injury and because there's tissue injury mass cells will be called into action hopefully they're able to recognize an appropriate Target and then potentially call in help depending on what the danger is perceived and this is just emphasizing the fact that mass cells up or work upfront detect injury try to contain the injury call an appropriate help in the form of loosening up the blood ves

sels so there's leakage of not only cells but proteins such as compliment and antibodies and then try to contain the danger and then what happens if this keeps on happening you end up with scarring or remodeling of the tissue because the danger never goes away or the mass cell is has lost tolerance and continues to recruit in more inflammation because it perceives that there's a danger going on and then the last uh hypersensitivity disorder that I want to talk about is anaphylaxis and um I just

want to redefine Anais it basically talks about the fact that you had a point of entry of some substance or some change that your body didn't like and it ended up to be a whole body wide reaction and in many ways anaphylaxis I often treat like earthquakes you can have a 1.2 for instance somebody gets an allergy shot in their arm and then they start to excuse me clear their their throat like I just did or they start to have tingling in their hands or feet then you have a much more severe form of

this hypers sensitivity events such that you start to drop your blood pressure you start vomiting you start to have respiratory distress and that's a much more serious form of anop flais and unfortunately literally this was considered a rare disease when I first entered medical school and 30 years later this is now considered one out of 50 Americans have been treated for anaphylaxis and the triggers can be anything from susceptibility to infections to chemicals that you're taking to control auto

immune diseases antibiotics uh Foods unfortunately we're seeing individuals that are just more sensitive to our modern world and the manifestation is in the form of hypers sensitivity disorders such as mass activation disease and this is one I just wanted to emphasize the different things that we can see happen when mass cells start releasing chemicals very potent chemicals inappropriately you can have lip swelling like you see on this child you can have these migrating hives you can have gastro

intestinal distress or respiratory distress some people even describe an impending sense of Doom where they can't think clearly and so it all depends on where the mass cells have detected danger quote unquote and then start releasing chemicals that change the blood flow start altering the local environment and then potentially calling other cells that can cause a much more systemwide impact and again I just wanted to show you that this is an article from the New England Journal of Medicine back

in 1991 and in this they said this was a rare event and now like I said we have patients who have to carry two epipens children that have to have epipens at school and at home simply because the mass cells have lost tolerance to our surrounding environment and now are releasing chemicals inappropriately even in the setting of potentially having lacking other proteins or cells in the immune system and the mass cells seem to be stepping in uh as backup um I often compare mass cells participating i

n a infectious process as a like a police officer who shows up to a fire it's lovely that the police officer is there and may be able to try to offer some assistance but does not have the skills to actually put out the fire in many ways if you have an imuno deficiency like you're lacking an antibody that can recognize bacteria or viruses or you're lacking component in your in your lymphocytes will not stand down their job as a first responder is to back up uh whatever danger and try to contain i

t to their best of ability and once that danger is under control the massels will stand down so um one important receptor that I learned about just a few years ago um and I'm just going to call it the merg receptor for short but this is important to know if you have an imuno deficiency and you have a tendency to have problems with anesthetic agents uh when having a procedure or an operation where there's certain medications that are used for uh treating certain antibiotic uh certain infections s

uch as Vancomycin it is the mg receptor that is responsible um for uh causing the sensitivity to fluoroquinolones certain anesthetic agents use during op operative procedures um and there's a variability in this receptor it doesn't happen to everyone but it seems that whatever as we better understand how this receptor is different from person to person we may have a better idea of preventing individuals from having hypers sensitivity or massal activation events in the setting of procedures or be

ing treated for certain infections uh such as vomisin for for for instance Clum defal colitis infections um I just wanted to show you the different antibiotics and agents that are known to tickle this merg receptor and if you have a tendency to have hypers sensitivity reactions you should have an action plan that you can take to the provider whether it's an anesthesiologist or a surgeon or a dentist um or a radiologist who wants to do a procedure there should be a protocol to avoid certain agent

s that may cause that mg receptor to cause mass cells to release chemicals and also to consider using alternative agents because when it comes to mass cell disease an ounce of prevention meaning avoidance of things that might cause you to feel unwell during a procedure or a treatment for another process uh is much better to use agents that are less likely to tickle tickle the mass cells and I can say the same thing for opioid receptors that are on mass cells as well so if you have a chronic pain

syndrome it's important to identify uh an analgesic agents that have a less likely to cause Mass cels to release chemicals because now the mass cells are going to irritate the nerves and the nerves are already irritated that's why you're taking payment medication in the first place so in many ways if you're having a chronic condition it's really important to understand whether or not your mass cells are doing their job or they're doing it inappropriately um there's no getting rid of mass cells

unless you have a clonal massel disease such as systemic Mass cytosis the idea is to understand your mass cells are releasing these chemicals causing you to have chronic issues whether it's in your nose or your lungs or your skin or your gut or your bladder uh or your brain um and then if you can identify why the mass cells are misbehaving you can then have better tailored Therapeutics to help you feel better um and I just wanted to point out that when we talk about anaphylaxis we always seem to

link mass cells to anaphylaxis but this is an article by Mariana castels who points out that not only mass cells are responsible for causing anaphylactic events but basophils which is the bloodborne cousin of mass cells we have individuals that are receiving chemotherapeutic agents for cancer for instance or or or arthritic conditions and massels don't have anything to do with this this is a t- cell maccrage monoy issue so again it's really important to understand there are individuals that hav

e mass activation disease but don't have anaphylaxis they're individuals that have anaphylaxis that don't have mass activation disease and I know this sounds like alphabet soup but it's really important to understand that your immune system has overlapping uh compensatory mechanisms to protect you from the sea of things that come at you every time you breathe every time you swallow every time you put something on your skin your body has to deem safe or not safe and if it's not safe the massels a

nd other cell populations have the tendency to go after this inappropriately and cause tissue damage as a bystander on trying to quote unquote help you so I would say about 2010 2011 this is after I had been in private practice with a multi specialty group um if if I remember correctly uh one of the practice managers at Mount sa asked me if I had placed 50,000 tests on individuals in the past year and I said that's probably so but in the setting of doing so much allergy testing that's when I sta

rted discovered that individuals were having reactions in allergy testing nor systemic mass of cytosis was explaining it and so in 2011 the World Health Organization Mass cell disease uh committee decided to put forth a different definition to understand if someone is having allergic hypers sensitivity like reactions is it the mass cells and then if you decide that it's the mass cells you need to figure out is this broken mass cells that are causing this or is there something driving the mass ce

lls to inappropriately release these chemicals so this was uh put forth on our National Journal just a few years ago where the simp it's a it's a it's a simple formula believe it or not to see whether or not quote unquote your mass cells are breaking bad but it's do you have signs or symptoms of mass cells misbehaving in at least two organ systems so are you having nasal congestion and headache disorders are you having skin reactions and gastrointestinal upset you just need two otherwise you're

talking about an isolated massell disease or possibly another process now after you've identified the fact that you have at least two organ systems that are impacted in order to secure the doses diagnosis of mass Activation Syndrome um you want to know do you can you detect any substances that point to the mass cells as the culprit uh in this recurrent or chronic hypers sensitivity issue and then lastly if you use medications that know that tell the massels to be quiet and don't secrete these th

ese these substances or you give it up with medications that actually block the action of these cells of these chemicals that get released by activated mass cells such as histamine blockers or Luc TR antagonists then the diagnosis of massel Activation Syndrome a subset of massel activation disorders is appropriate to go into more details here it is different signs or symptoms of isolated Mass activation disorders massel activation disorder of the skin you're hiving your itching your flushing mas

sel activation disease in the joints you're having swelling or or recurrent uh joint pain or loss of function in the urinary tract I can tell you in the United Kingdom they diagnose individuals that have intitial ctis or or bladder pain syndrome simply by biopsying the the bladder wall and seeing whether or not it's chalk full of activated mass cells what does massel activation disease look like in the gastrointestinal tract you're having bloating alternating diarrhea and constipation you're hav

ing malnutrition or you're losing weight or recurrent reflux or heartburn uh what if it's affecting your heart or your blood vessels you have you know we have people who have sudden rates of of arhythmia where they'll have chest pain or low blood pressure what does it look like if your mass cells are misbehaving in your brain or your spinal cord you can have pain syndromes neurocognitive impairment um also known as brain fog you can have recurrent headache disorders and then you have the upper A

irway which never gets any attention but Mass cell disease of the nose and the back of the throat nasal con gestion recurrent postnasal drip itch itchiness or fullness in the ears or the eyes this is all mass cells releasing chemicals that are impacting your upper Airway and possibly your um eyes as well so if you check off two of those things next question is you know did you try any of these over-the-counter medications and did it give you some relief such as you know plenty of over-the-counte

r histamine blockers such as Loratadine Fexofenadine or H2 blockers typically used for heartburn but also very effective for individuals that have mass activation disease such as photine or or sadine you have mass cell stabilizers such as kapin which is readily available interestingly enough over the counter as an eye drop and then you have some prescription medications such as chromin um or amalm which is an injectable anti-ig molecule that is able to help individuals that have recurrent uh tic

aria or persistent asthma with an allergic component and so now you have a good story your your signs and symptoms here are things that you've tried in the past that seem to give you some modest temporary relief what data do you have and I think this is probably the most controversial um unfortunately we live in a Health Care System where data precedes your story um so it's really important to try to identify a practitioner who who allows you to be seen and heard regarding the the medical Odysse

y that you've been dealing with up to this point in time and I have to tell you I've identified at least more than a few individuals that have IMO deficiency syndrome simply because they're presenting with symptoms that are depicted in the cartoon on the left so with those stories it's important to understand these are the markers that are associated with mass Cel Activation Syndrome Mass cels release lots of different chemicals but if you want to worry if you want to focus on the component of c

ausing hypers sensitivity issues so then we can then identify better therapies for you you want to see a recurrent uh trip tase that's elevated or goes up and comes back down you have surrogate markers such as elevated methylhistamine prostaglandins uh in the urine but the the the the gold standard for diagnosing misbehaving mass cells is the tissue there are some massel progenitor cells in the blood but the majority of mass cells are found in the tissue and you need to look into the tissue skin

biopsy if you undergone an endoscopy and a colonoscopy by a gastrologist you want to stain that tissue for uh stains that will light up the mass cells because if you don't ask you won't see them um and then instead of just counting them you want to say are they overactivated um are they upregulating activation markers all the time because having a massol chronically activated is kind of like a police officer who just got out of a firefight and didn't put their gun back in the holster because th

ey're just so revved up you don't want to see cd25 elevated on mass cells in it sight of active inflammation um which un unless there was a reason there's some type of injury that that mass cell is trying to address so you secure the diagnosis of masso Activation Syndrome you have two signs and symptoms impacting two organ systems you get better with medications that either Target the mass cells or chemical mediators such as histamine um or lucr that are released by the mass cells and you have t

est results such as an elevated trip tase or a elevated 24-hour urine collection for the proin or methylhistamine metabolites then you want to find out why are your mass cells misbehaving are you a fortunate one that has gotten the genetic Lottery luck of having a broken Mass cell such as in systemic mass of cytosis or monoclonal massal Activation Syndrome these are individuals that seem to have a clonal massell problem but haven't met the full criteria for Mass cytosis um but I have to tell you

the majority of patients that come through my practice if I'm able to identify dysfunctional Mass cell compartments it's likely due to the fact that the massels are being driven to release those chemicals by other processes the one we're most familiar with is you know allergen driven massel disease you have positive allergy tests to Foods medications stinging insects latex but there are other things that can cause massels to release those uh chemicals inappropriately because there are other rec

eptors that the mass cells use to kind of do surveillance of the tissue to see is everything copacetic and quiet and at peace or is there some type of danger or impending danger that's coming to that tissue that will cause damage Mass cel's job again is I use the receptors to see what's going on in the surrounding environment I'm seeing whether or not I can detect tissue injury and then determine what is doing the injurious event and then after that can I contain it with these other chemicals uh

such like tryptase and Chimas or do I need to call and help by releasing chemicals that will call in eosinophils and neutrophils depending on what I'm seeing you also we're also starting to appreciate the the regular cross talk between the nerves so the fact that um several individuals suffer from inducible physical ertic areas for instance such as individuals that have uh recurrent cold induced hives uh or they they look up they look up at the Sun and they start to sneeze or they're eyes water

or you have someone who goes into um uh goes into uh cold water and comes out and that causes them to Hive so there there's miscommunication between the somat centry neural network and the mass cells that raises that D danger signal and then the mass cells will release chemicals and then like any other cell in the body the mass cells can be a victim of an autoimmune process U this was identified over two decades ago where people who had their serum taken from one part of their body injected int

o the other and it caused a hive and wheel to develop and that's called chronic immune or dearia but can be impacting other organ systems as well so you have the diagnosis you may have figured out what is causing the mass cells to inappropriately releasing those chemicals let's move over to what kind of therapies are available oh I didn't want to bring up uh this identification so this was put forth by Dr lions and Milner when uh Dr Milner who was uh at uh a major division at the niid uh they we

re looking for the genetic basis for um allergies and what they found was they found individuals families uh that would have an elevated level of this enzyme that's only found in Mass CS called tryptase and what was really interesting it was a autosomal dominant process and it was found to be associated with massal activation disease connective tissue changes reminiscent of hypermobile air download syndrome or hypermobile Spectrum Disorder as well as autonomic dysfunction such as pots so again i

t points to this communication between the mass cells and the nerves in the connective tissue and one one of the the communicators between the nerves and the massels I'd like to point out that has really gained Traction in the neurology world is the uh medic ations that Target uh cgrp uh so you have a lot of these migraine medications that are now being routinely used that interrupt the communication between the mass cells and nerves in order to get their migraine headaches under control but as

I said before I learned about allergies or SE allerg driven masso activation disease where for some reason you've developed an IG that was normally used to recognize parasites uh with our forefathers mothers living in areas where parasite burdens were High um and then this this antibody now recognizes harmless substances like Airborne pollen or milk or a stinging insect and then you have a release of all these different chemicals I just wanted to point out there are lots of other receptors on th

e mass cells that can cause chemical release and this is also to emphasize that sometimes it's not just the massel or basophil that's participating in these hypers sensitivity reactions you have cross talk between other cell populations and I have to tell you in the few years that I've been in uh my private practice trying to evaluate whether or not people have massol Activation Syndrome uh it we've identified over 24 patients that have idiopathic city4 lymphocytopenia coming in for an evaluatio

n of possible Mass activation disease we've identified compliment deficiencies we've identified antibody deficiencies again this is how mass cells kind of see the world uh in their micro environment whether they've been assigned to the brain or to the gut or to the skin and depending on the detection of danger and then the detection of a potential entity that's causing that danger the mass cells will release those chemicals and unfortunately we've seen an huge increase uh in the amount of mass C

ell Activation disease especially secondary Mass Cell Activation disease and I'm going to try to in a few slides I'll talk about some of the data that we've seen regarding the role of identifying individuals with primary immune deficiency because they were presenting with more classic uh allergic like disease so I wanted to point out mass cells have a major job to do they sit right below this area of any organ system that's exposed to the environment so you're talking about the skin and the Lini

ngs of the gastrointestinal tract respiratory tract ental tract and they're also uniquely situated right next to blood vessels and nerves and what they do is have the ability to detect danger that comes in they'll release chemicals to try to contain that danger and then call in help and the way they release the granules sometimes it's local but sometimes those granules actually go into the lymphatic system travel up to lymph nodes and then call in help and I just want to point out all the differ

ent types of receptors that mass cells have I originally learned that they had the FC receptor and the K kit receptors so this is the one that's involved in systemic mass of cytosis this is the one that's involved with allerg driven Mass cell disease whether not again pollen or food for instance or medications but you can see there are compliment receptors The tolac receptors this is a a receptor that we think it might be involved in the recogniz recognition of viruses including uh one that caus

es covid we have opioid receptors so some individuals when their mass cells are stressed and you add a pain medication not only will the pain medication not give you any relief it may actually cause you to have a hypers sensitivity reaction and aggravate your illness we have platelet activating Factor we have this Factor this receptor that can recognize certain antibiotics so if you have IM deficiency and you have a tendency to have hypers sensitivity reactions certain medications that you need

to avoid here's for when it comes to women going in or out of their menstrual cycle or whether they're pregnant this can also alter the ability for mass cells to release their chemicals inappropriately uh and then you have this cross talk between other cell populations you have indirect conversation between B cells uh based on on their production or lack of production of IGG and IG for instance or IGA and then you also have communication between T cells as well so when individuals come through m

y practice I have a tendency to um and usually most patients have had a long medical Odyssey uh of recurrent illness uh involving multiorgan systems so I have a 15 page questionnaire that people fill out and then I start reviewing what has been done a lot of individuals have already had allergy testing and that was not informative um they have in we have people who've undergone endoscopies and colonoscopies but not have has not tested for the presence of um mass cells um being um malformed or cl

ustered or overactivated we have individuals that have undergone evaluations by rheumatologists and neurologists looking for auto antibodies um but Auto antibodies are kind of like mug shots for the mass cell um and sometimes you'll make a mug shot uh with nuclear antigen which is found in lots of cells or rid factor or your thyroid or um uh channels on your neurons and so and we also know that individuals that have imuno deficiency interestingly enough are at increased risk for developing autoi

mmune disease so we try to screen for all the different ways mass cells can misbehave and one that I've been uh intimately involved with in the past decade is the role of connective tissue disease heritable disorders of connective tissue leading to um Mass cell dysfunction and uh to the right is a questionnaire where you can actually detect someone who has a connective tissue disorder like ERS danlo syndrome simply by answering yes to five of these conditions that you may have been experiencing

within the past six months or so so once you've identified someone that has massal Activation Syndrome or massal activation dis disease um and you've identified why uh such that they have for instance positive allergy tests or they're dealing with recurrent infections or they have an imuno deficiency depending on what is tickling the mass cells to Mis to release those chemicals inappropriately you then can tailor the therapies based on the positive testing um so for individuals that have um alle

rgen specific IG uh such as pollen or food or medications or stinging insects um you can do allergen desensitization and avoidance measures uh you can use medications such as histamine blockade lucat blockade tricyclic agents which were used to be used very frequently by by psychiatrists um for mood disorders but interestingly enough allergists use it for ticaria SL hives gastrologists use it for quote unquote itable bowel syndrome and neurologists use it for migraine so it's interesting that th

is uh tricycle agents that have the ability to work on the first second and third hist receptors have found a home in other uh clinical Specialties you have kopin and chromin which has the ability to stabilize mass cells from releasing those chemicals inappropriately during degranulation events such as anaphylaxis uh and then you also have biologic such as amalis map for infections depending on what you identify you want to use appropriate antimicrobials and you might actually have to use someth

ing to reduce any hypersensitivity immune responses such as cortical steroid or Luc or triagonist to kind of modify that overactive immune response to an infectious agent uh you have individuals that have developed Auto antibodies or Auto reactive uh lymphocytes and so you have anti-inflammatory agents including imunoglobulin and then for individuals that have primary imuno deficiency you have the use of prophylactic antibiotics I have several patients who for instance have recurrent hives and w

ere found to have selective IGA deficiency and then actually putting them on aiyin uh three times a week uh helped get their erary under control and then we also have other anti-inflammatory agents that are available uh classically used in higher doses for individuals that have transplant or or certain cancers but in lower doses that have been shown to be effective uh in reducing recurrent massell disease in different organ systems just as much as people um have the vocabulary of massel activati

on disease mass cells can be masquerading other conditions and so it's really important this is kind of like The Unsung fourth criteria for trying to understand whether or not massel disease is driving the symptoms or is is coming in from another process so it's really important and uh to the left are different medications that can be used for individuals that have mass activation disease I don't want to park somebody on medications if there are other things that are going on and I have to tell

you in the past few years we've identified a lot lot of individuals that have connective tissue issues or have um imuno deficiency simply because they're having recurrent ticaria not well-controlled asthma neuros psychiatric issues actually there's a growing body of information uh in the Psychiatry World showing that immune disregulation in even in the setting of secondary Mass activation diseases associated with developmental disorders such as ADHD uh and mood disorders such as anxiet in depres

sion so this is again emphasizing that the unfor unspoken forth criteria is to make sure that you're not missing any of these other conditions that can look like massal activation disease and I wanted to show you that um having one form of mass activation disease does not exclude you from another and this was actually an interesting article that was in the allergology literature U where they asking a question or giving a review about about anaphylaxis and mass activation disease is it stinging a

naphylaxis mastocytosis or something else and the punchline is this was a gentleman who had a history of of Venom allergy and that's path demonic to allergist if they hear somebody has anapilis to stinging insect and we can't find any IG um and he was found to have an elevated tryptase of 14 and so um but reactions kept on happening and so he was actually diagnosed with systemic Mass cytosis he also was diagnosed with the the hereditary alpat tremia so he has two uh primary mcel diseases but he

also was diagnosed with Alpha gal meat allergy and he was also diagnosed with environmental allergies as well the stinging insect allergies so IG was detected to cats and it was also detected to Yellow Jackets so this gentleman is looking at several different forms of therapies including immunotherapy for the stinging insects um he sh should avoid uh meat because we have no treatments other than using some of the biologics to keep the massels under control um he was on antihistamines and tricy a

gents because he had this clonal massel disease including systemic mastocytosis and Hyper Alpha tremia so just because you secure one diagnosis of wide mass cells misbehaving should not prevent you from looking for other reasons that might cause those mass cells to inappropriately release these chemicals um I want to and this was reiterated by Matthew Hamilton who's very active in the massel world out of bream women's unfortunately when it comes to massel Activation Syndrome it's not very easy t

o get a trip tase uh unlike unlike if you go into the emergency department God forbid that you're having a heart attack we have lots of different ways for looking to see whether or not your heart is misbehaving we need more data and testing validated test to identify whether or not somebody's masss are misbehaving but just because we're still trying to elucidate uh why the mass cells are misbehaving or maybe contributing to an a patient's individual illnesses it's important to maintain every eff

ort to continue pursuing uh the possibility of of underlying undiagnosed imuno deficiency for instance and then also um uh tailor the therapies based on what might be causing your mass cells to misbehave and I want to emphasize that there are different criteria for massal Activation Syndrome out there this is uh from a different group that proposed consensus to they they prefer to Le lean into an overdiagnosis of mass Activation Syndrome and although it's relatively safe to park people on medica

tions like histamine blockers or lucr antagonist if it's going to prevent you from pursuing other other other diagnoses that might be causing the mass cells to misbehave like someone who has an undiagnosed cervical spine injury or somebody who has an undiagnosed imuno deficiency you know if you stop at antihistamines that give them modest relief but not get at the fact that they might have common variable imune deficiency which I have identified in several patients or idiopathic CD4 lymphocytope

nia or a complement deficiency such as Manos binding lectin deficiency which has been Associated if you have Manos binding lectin deficiency and imuno deficiency you're at increased risk for requiring gammaglobulin replacement to keep your symptoms under control and prevent you from getting ill from major infectious events so why do people come for an allergology evaluation it's like I got Ma I got mcast and my response is maybe but just because I say maybe doesn't mean I don't think any I don't

think nothing is going on or this is all contrived it's just that it takes time to kind of peel back all the layers because for the most part patients as we know with primary immuno deficiency can have an undiagnosed no IMO deficiency 6 to 12 years after initial onset of symptoms I could say the same thing for masso Activation Syndrome which is a subset of massal activation disease um and I wanted to use uh this 10 warning signs for primary immun deficiency because this is what both patients an

d doctors need to be aware it's not acceptable for you to have a pneumonia every year it's not acceptable for you to have four recurrent sinus infections in a year or not get better when put on prolong courses of antibiotics um or for you to have sepsis or an abscess or if you have a family member interestingly enough who's already being treated for imuno deficiency getting a good story will lead you to appropriate testing and the appropriate testing will lead to tailored therapies based on what

diagnosis you're able to secure to give you guidance now this is the questionnaire that I'm and I'm happy to provide this but this is the questionnaire that I have patients fill out before I see them and just again remember the first criteria do you have mass cells misbehaving in least two organ systems and if I see if they check two of these organ systems I know that I need to think a little bit more deeply about the fact that their massels are misbehaving and then once I find out that their m

assels are misbehaving it's important to identify why those massels are misbehaving do you have some Rogue broken mass cells such as systemic mastocytosis or hyper alpha tremia or do you have other process that's driving the mass cells in misbehave like do you have pots uh do you have an imuno deficiency do you have an autoimmune disorder um it's important to try to understand why the mass cells which are educated in the tissue that guard the tissue in the form of surveillance with the different

markers that the mass cells in many ways are trying to compensate especially in individuals that imuno deficiency they might be compensating for those missing components that are important to contain the plethora of of micro microbiota some of them are friendly some of them are not and some of them are squatters and it's the squatters that have a tendency to keep on causing injury uh in our GI lining or our respiratory tract that might be recruiting mass cells and other components of the immune

system and contributing to Chronic injury uh and inflammation in affected organ systems so this was an article that came out uh just a few years ago doctor I think I'm suffering from mcast again this is just a reminder of the checklist to try to consider whether you have massal activation disease even if you already have a diagnosis of imuno deficiency do you still have signs or symptoms of not walk controlled nasal congestion gastrointestinal distress brain fog uh and actually we're starting t

o see a role of the immune system even in the form of an the inate immune system such as mass cells and contributing to on Co do you get better with medications that Target the mass cell compartment and then what data do you have to support it so I wanted to kind of just briefly go into some of the observations that we have reported uh in the private practices that I've worked in um and some of that led it that led me to even think about autoimmune imuno deficiencies and people who were thinking

that they were having allergies or mass activation disease this is a paper showing that individuals that have selective IG deficiency or increase risk for chronic ticaria and also autoimmune diseases and then uh 10 warning signs of primary immune deficiency which we just reviewed uh they're showing that if you have allergies for instance or allerg driven massel disease that's it's as though your mass cells are so preoccupied with Innocent uh substances like pollen or animal dander that they com

pletely ignore the bacteria that's hiding in the tonsils or sitting in the gastrointestinal lighting waiting for an opportunity to get in so in some ways having an allend driven massel disease can make you susceptible U or cause you to have a imuno deficient uh condition um and this is a paper from uh David Khan who is the past president for the American College of asthma allergy immunology and he's saying okay we have individuals that have refractory ticaria or refractory asthma it's interestin

g enough that uh one of the agents that's used for rosant chronic Ed ticaria which is basically massel activation disease of the skin is imunoglobulin so if amalis doesn't work imunoglobulin has been used successfully and also again prophylactic antibiotics uh this is a paper that I had uh done with uh two uh two lovely individuals in my practice Isabelle Brock and Walter pette um uh where we did a retrospective analysis of all comers uh claiming that they had massal activation issues and what w

e found interestingly enough this is 9 over 980 patients came through my practice 46% had evidence of single organ involvement of massel dysfunction but what was even more concerning is 21% had evidence of massal activation disease and imuno deficiency so one out of five had some evidence of a deficiency in the antibody compartment everything from common variable imuno deficiency to normal imog globulins but poor protection against bacteria such as streptococus pneumonia hemophilus influenza as

well as IGG subclass deficiencies and this is simply by by taking a really good history and then doing a appropriate testing looking at total imunoglobulin levels looking at what protection you have against misles m rebell streptococus pneumoni hemophilus influenza just an extra step that then led to better therapies for these patients um this is a very busy slide but I just wanted to show you that uh this was a study that I had done almost six or seven years ago where we identified individuals

that lacked a protein called Manos sping lectin which is part of the compliment system and compliment hasn't gotten much attention until lately but it's interesting to think that this part this part of your system can not only predispose you to infections it can also predispose you to ongoing tissue damage because you're not clearing away the injured tissue and that in turn leads to autoimmune development and so these are 25 patients who had Manos spining lectin uh levels lower than detectable a

nd they were they were plagued with neuros psychiatric symptoms gastrointestinal distress lower respiratory symptoms and skin symptoms as well so when you think about Mass activation disease and these are the various on the right these are the various syndromes that are associated with mass cell dysfunction ritis or rhinosinusitis in the upper Airway asthma the lower airway you have hypers sensitivity gastroenteritis sometimes referred to as irritable bowel syndrome until you identify something

other than idiopathic that might be causing gastrointestinal stress Interstitial cystitis ticaria andema flushing neurocognitive impairment in the form of headache disorders or brain fog and pain syndromes that's what most of us have learned what mass cells can do but I want to take you back to the fact that not a single human lacks mass cells mass cells are found in lots of different organisms they have the capacity to do lots of different things not only tissue defense but tissue repair and th

ey have an intimate relationship with the connective tissue the blood vessels and the nerves they all talk to each other trying to figure out whether or not this is a safe environment for the body or or not and the the mass cells are equipped with different receptors to find out whether this is active or not and they also um uh have a plethora of chemicals to to activate other uh immune cells uh change blood flow um recr in cells direct antimicrobial or anti-parasitic effects and then also can c

ause tissue remodeling so in many ways I I consider having a mass cell disease in most of the patients that I've CED it's kind of like what you find on your car you know something's wrong you need to go looking that's what I find with ticaria that's what I find with asthma that's what I find with gastrointestinal distress and neurocognitive impairment and it's important again to realize that mass cells can misbehave in any organ system it's important to figure out whether or not they're driving

most of the symptoms or they're reacting to another process uh again this is the criteria and I just want to be a reminder uh I don't have to tell the individuals that that are attending this this conference that we underestimate how many individuals are impacted by primary immun deficiency Jordan orange who now heads uh the department of pediatrics at at Children's Hospital of New York um has estimated that one out of 1200 individuals have some form of imuno deficiency whether we're talking iss

ues with the epithelium the inate immune system or the Adaptive immune system and with that I will round up with just gratitude I'm grateful for Ida for inviting me for this I've had the pleasure of of patients telling me stories that kind of just lifted all the misinformation or at least the helped round out the foundation that I had when I was training um and as in private practice I have phenomenal colleagues that I've had the pleasure of of working with I have to uh tip my hat to the massive

cytosis Society ER dler Society disom National and kir sering f f cingal milia foundation and this is my contact information at Mount siai um and the building here is metrodora uh in Salt Lake City um where we are trying to make new inroads uh in a collaborative environment to try to tackle complex diseases including individuals that have imuno deficiency in com War Rec connective tissue as well as uh massell disease all right thank you so much Dr maitlin that was incredible um and I have to sa

y every time someone would submit a question your next slide would address the question so um excellent presentation thank you so much um all right everybody so um I know everyone's eager to get into the Q&A so we're gonna transition to that next um a friendly reminder that if you would like to ask anything to please please enter your question in the Q&A box um Dr Maitland we're going to skip around a little bit um just based on some of the questions being answered on some slides and then some t

hat I feel apply to more folks in the audience so um and I also want to let everyone know we do have a large number of folks on the call which is great um but that does mean that we may not get to every single person's question um we want to be considerate of Dr matlin's time she is with us after hours so we're going to work through as many Q a um questions as we can and we appreciate your patience all right Dr Menin first question um so this individual asks um they have shared that they have au

toimmune chronic ticaria and serum histamine that is too high to measure um they've undergone uh testing for mastocytosis which was negative and they're taking zir which has been helping their symptoms however their serum histamine remains above the top of the Test's ability to register their actual value um what are your thoughts on that individual situation so we've identified several individuals that have an expansion of a different te- cell population called Gamma Delta T cells that seem to

be associated with persistent histamine elevation and Gamma Delta T cells are very interesting and if you don't look for those cells you won't identify them so that would be my one situation I would identify and then also it's important to scream for other disorders that can contribute to that especially if it's in the setting of again undiagnosed imuno deficiency can do that as well um and then we also find individuals that may have cervical spine issues uh the Vegas talks directly to the mass

cell compartment um and if there's any issues with neck pain um or or Central Central Nervous System issues that can also cause the Vegas to um be uh disarmed uh which will then allow the fight ORF flight response to keep persisting um so I I would say that further evaluation needs to be uh employed um I would see whether or not there's an expansion of these Gamma Delta T cells I would evaluate for peral and central nervous system issues as well thank you Dr matland all right next question this

individual asks is it possible to have chronic idop pathic urticaria and mass Cell Activation Syndrome concurrently or are they mutually exclusive they overlap you can have ticara for reasons other than than mass cells but so far it sounds like you have at least one secondary Mass cell disease in that you've have Auto antibodies that have not only the ability to recognize mass cells they also have the ability to recognize basophils so you can have so you have two two cell populations that are be

ing tickled um so so so it overlaps and that mass cells are definitely involved but understand some of the receptors that are in basophils also are found on mass cells and Ma mass cells and Basils have the largest collection of histamine uh uh in the human body so I I it's overlapped it overlaps but um I would just I would say you have an IM you have an immediate hypers sensitivity disorder in the setting of having another immune system Drive the mass cells to release those chemicals thank you a

ll right next question is anaphylaxis required for a mass Cell Activation Syndrome diagnosis absolutely not literally it's two organ systems so if you have anaxes by definition that's multi-organ system involvement but we have individuals that have M have an Anais and mass cells are not involved and then we also have individuals that have mass Activation Syndrome and anapilis is not on the table so I I either way it just tells me your ma your your immune system is an overdrive inappropriately an

d you need to figure out why your mass cells are misbehaving or why you're susceptible to Anil axis thank you next question what evidence is there for associating Mass cell Activation Syndrome as a source or Ed idiology of brain fog or migraine great question so um there was a great paper that just came out of briam and women's it was a joint effort and again I emphasized joint effort between allergy immunology and neurology and they show that if you have a pre-existing neurological issue right

you if you have mass cells that are are are suceptible to being Twitchy for whatever reasons releasing histamine and other factors that loosen up the blood vessels will drop your blood pressure and can EXA and can ex and actually even drop the blood pressure in the cerebral vasculature and that will exacerbate your brain POG we also know we also know that mass cells the more they're activated the closer they move to the nerves and the mass and and the blood vessels and so the more you tickle the

mass cells it's kind of like you keep on calling 911 and the police keep on coming and after a while they might just just station you right there um that's what seems to be happening also there is direct communication between the mass cells and the nerves so for instance you have these new migraine medications you have to forgive me I don't know their their generic names but Elli is one a jov is another that's those are all anti-cgrp antagonists and cgrp directly communicates between the nerves

and the mass cells so here you have a medication that targets a chemical from the nerves that keeps the massels quiet thank you all right our next question um I think this is one that probably a lot of folks have on their mind what are the best lab tests to get to identify Mass cell issues so I usually um when a patient first comes to my office I want to see serum trip taste um 24hour urine collections for methylhistamine and prostaglandins total serum IG level um I go ahead and also if they've

had endoscopy or colonoscopy I I'd like to see that path the pathology there and a lot of people get those and that's easy enough allergy testing either skin testing or through blood testing as as well um I go ahead uh if if if you've checked off anything regarding the screening test for imuno deficiency I'll go ahead and do a screening test for uh imunoglobulin deficiencies uh lymphocyte deficiencies and complement deficiencies as well so um so the first set of tests are your massels misbehavi

ng the second set of tests are why they might be misbehaving and so that's where I would normally start first great answer all right next question um we actually had a webinar on this topic last month so I think it's also top of mind for folks um Can Mass Cell Activation problems cause interstitial lung lung problems mass cells will respond to any danger but the issue is the the medications that are typically recommended for like anaphylaxis and ticaria really is focusing on a different pathway

than what be participating in intial lung disease um so you're really talking about tissue Remodeling and so a lot of people think about mass cells and tissue defense but tissue remodeling so mass cells had the ability to release vef and Incans and cyto kindes um and growth fact factors and if those growth factors are not released in a coordinated fashion or are continually being released along with enzymes that can modify the tissue then using histamine blockade is going to be useless um using

lucat Trine antagonist are going to be useless So you you're going to have to start moving into um going after the cells and the chemicals that are known to be more common in interstial lung disease I'll give you an example of another as not wellc controlled asthma is associated with tissue Remodeling and using histamine blockers and all the medications I talked about regarding allergen driven massel disease or physical triggers of massel disease are going to be useless they might give you some

symptomatic relief but it won't stop the remodeling in the tissue the ones that have been shown to stop the remodeling in the tissue Target some of the sodin and chemokines that get released by the mass cells right so so there's massel activation disease can be a over it can be an immediate hypersensitivity issue can be a tissue modeling issue right but that's going to require a different set of testing to understand what part of the mass cells are misbehaving is this too much of a growth factor

too little of a growth factor too much of an enzyme and understand the enzymes that mass cells have have the ability to deactivate like Venom anytime you have you ever have a chance to like look into honey badgers and mass cells honey badgers actually have trip taste that can deactivate the Venom of snakes that they attack so you don't want those you don't want those enzymes out there unless you really need them it's kind of like the police officer you don't want the police officer to pull the

gun out to take the cat out in the tree right because you know so you don't you don't want those enzymes out there you don't want Hein out there you don't want plet activating factor out there unless you really need it like puncture wound infection you know cancer cell you want that's why you want it out there all right thank you um all right next question so these are some individuals sharing kind of their current situations um this individual asks I was on IGG replacement for seven years um I

identified Mass Cell Activation syndrome and my body was rejecting many foods as well as medications including Cubit is it possible for mass cells to react to plasma infusions yes uh and the reason why is um when you use and this is the issue with with subcutaneous preparations period there there are stabilizers in there um that may be problematic and also when you think about gamma globulin replacement um you have to think about how they obtain it so it's 20 of your closest neighbors then it go

es under goes filtration radiation um just let her know um radiation um and detergent and so so and different different companies have different production processes for making their products so I find that intravenous is a lot better tolerated than subcutaneous um but a lot of insurance companies prefer subut because it's cheaper to administer to you so if you're having a problem with a gaml globulin product you either have to think about how you're administering it or whether you need to consi

der a different preparation or maybe you need to move away from subcutaneous and go to Ivy thank you so much all right next question um this one's about food allergies this individual says I have many food triggers that cause allergic symptoms including angioedema or anaphylaxis but no detectable IG do you know if this is a common scenario Yes actually um there are receptors other than IG that they receptors on mass cells other than ones that recognize IG so we know that mases have compliment re

ceptors so they can respond to compliment um they can respond to IGG um you know so we have individuals I've had one patient anaphx to vaccine years ago it was pumac numax and actually I was so worried about her I only gave her a quarter of her dose and she still had a minor reaction and so um I I I think it's important to kind of take a step back and understand that masses are not a one Pony right um they have it's kind of like that police officer that's in your neighborhood do you really want

him to only determine whether or not somebody is a perpetrator because they have a mug shot right they should be able to have a sense like you know common sense that person with the gun or the person with the hatchet or if somebody's down on the ground you know you want them to be able to assess danger and that's what mass cells that's their job their job is to assess assess danger contain it call in help and then once the danger is contained help with tissue remodeling lots of different recepto

rs we have women who go in or out of their menstrual cycle ending up with worse hives and worse asthma that's an estrogen progesterone issue on the mass cells we have individuals that can't tolerate certain medications that's a mg receptor issue um and then I have to tell you I'm I'm I I I'm surprised that I was able to identify so many different imuno deficiencies simply because people were having food intolerances medication intolerances um air quality issues causing them to have respiratory d

istress and it and a lot of them their IG was like undetectable a matter of fact they're now starting to look into IG deficiency which we don't talk much about because we don't live near the Amazon and have to worry about parasites but um I I would lean into the Goldilocks role for most of the things that are in our body we don't want too little and we don't want too much thank you so much all right next question um this individual asks for those of us with autoimmunity allergies and high norrin

e in pots could the norepinephrine be fueling the Mast Cell problems actually epinephrine has a tendency to keep mass cells quiet um I'd be more concerned about why that was happening and so again you want to make sure that there not other processes going on so pots is a general description that just tells me your nerves or misbehaving there's something there's an imbalance between the rest and digest part and the fire to flight part and you can either have too little rest and digest or too much

fire to flight or both at the same time it's kind of like hitting the brake and the accelerator of your car at the same time that only describes what's going on it doesn't tell me why it's happening so did you develop Auto antibodies against your your your neuronal tissue um do you have cervical spine issues or occult tether cord issues or do you have an undiagnosed connective tissue issue there's so many different things that can and and that can be happening and unfortunately because our soci

ety our Health Care system is so siloed people have a tendency to be camped into one diagnosis and one clinical specialty and I had to tell you for instance Mass Activation Syndrome the first clinical um cohort was a joint effort between gastroenterology and um allergology and gastroenterology um uh this was an IBS clinic and people were parked in that IBS clinic for five to seven years until they got the diagnosis of mass Activation Syndrome so I I I would say that better things need to be addr

essed certainly thank you um all right next question we have time for just a couple more Dr Matlin if you're okay with that yep I think I have a I'm getting a call from a patient I might have to handle a couple more and I have to then go back to no problem just when when you need to go just let me know and we'll we'll wrap things up we we really appreciate it um okay we'll do maybe two more um and if you need to go just let me know all right um this next question if PS aren't diagnosed and treat

ed until later in life after Decades of frequent infections is that person more likely to develop autoimmunity and mass cell disease due to foundational immune disregulation from their untreated PID so untreated PID means there's more susceptibility to tissue injury the more you have tissue injury the more you're going to have normal tissue broken normal tissue out there which your immune system can recognize so especially when it comes to P you know um antibody PS um we find that the red blood

cells in the platelets end up to be a major Target um we see autoimmune disease that happen and thyroid disease that happens as well so the more you have tissue injury the more likely you're going to start hurting uh direct tissue and by the way those antibodies that recognize you know your thyroid the the business and recognizes mass cells so so and the same thing the same thing for autoimmune disease um there's been a lot of work showing that mass cells May either contribute to the initiation

of loss of Tolerance in autoimmune disease or perpetuated so so again I think it's all about balance and you you want to use your your your police force when you need it um you don't want the SWAT team being called in in when you don't you don't want eosinophils running around I mean they have the ability to to release um eosinophil derived neurotoxin so um I don't want trip taste out there unless I really need it like if I get a cut I want trip taste out there if but if I'm just sitting there y

ou know reading a book and chomping on an Apple no I don't want it out there so so it it really it's all about tolerance but but not well controlled having an IMO deficiency tells me you're at increased risk for having not only bad bacteria sit there but squatters and and typically the respiratory tract and the GI tract are the major targets in that respect um and so that's why we need to intervene early I'm deal I'm working with a family right now that the two two two of the children one child

was I diagnosed early with autoimmune en sephtis and was put on gammaglobulin the other child had um had evidence of recurrent sinus infections before the age of five and never got gammaglobulin until he was a teenager and now he's much more susceptible to autoimmune disease M he has it and I'm going to and here's the thing it's not just autoimmune disease it's autoinflammatory syndromes also they get unmasked when you have ongoing tissue dis disease ounce of prevention it's much better to preve

nt the fire than to try to put it out certainly all right do you have time for one more okay awesome thank you so much Dr Matlin all right I think this is a good time with that last question um have the PID patients you have treated that also have mass cell disorders have more difficulty tolerating IVIG or subq than patients without a mass cell disorder if yes what is the best way to partner with their immunologist to find a treatment that a sensitive Mass cell patient can tolerate so we we have

a tendency to onboard gaml globulin slowly so we'll typically do a quarter dose twice IV I I have to tell you I'm not I don't lean into subcube very often I really I I prefer having a nurse monitor you um who's knowledgeable in this space as opposed to you you know what are we going to start doing now colonoscopies and aisle five of Walmart I mean it's crazy um so not to prge Wal walart um that being said we have a protocol where we onboard it very slowly I I even do that with old there we we g

o alisma we go very slowly so you know typically I do a quarter dose and we do prehydration and um premedication before and after we use specialized tubing we usually go for the expensive tubing uh that's PVC and dhp free uh and and uh then we work you up to every 3 to six weeks depending on how how you're responding to the initial management then once you're stable we'll start expanding the dose expanding the time between episodes but onboarding slow and steady wins the race I think that's a gr

eat approach well thank you so much Dr maitlin that is going to wrap up our Q&A this evening we are so appreciative of your time and your extremely thorough presentation and taking the time to answer everyone's questions um it was a pleasure having you join us this evening thank you so much thank you for the invitation everybody stay well and Happy Thanksgiving thank you so much you too right now all right everybody so we just have a couple more slides to get through um and then we will wrap thi

ngs up this evening um all right so again a huge thank you to Dr maitlin for her time this evening and thank you everyone for your participation and engagement in the Q&A um we really had some great questions and we appreciate you submitting them if your question was not addressed during our program go online and submit your question to ask IDF visit primary immune.to resource Navigator will personally connect with you to answer your question or direct you to appropriate resources you can also c

heck out our Resource Center report services and YouTube page to find more videos and educational materials as we head into the holiday season we have a few events left to close out the year and we hope to see you at one of our upcoming programs our final webinar of the year will take place on December 6th and we will be discussing CO's impact on the pi community and our teen holiday hangout will take place the following week on December 12th visit primary immune.to register and learn more regis

tration is open for our 2024 Pi conference which will be hosted in person at the Sheridan Grand Riverwalk Chicago from June 20th to 22nd 2024 visit primary immune.to to register today and scholarships are open for the conference and are available to individuals who have been diagnosed with a pi visit the conference landing page to apply by January 5th 2024 and you can also email events primary immune.to our wonderful sponsors for their generous support of our programming this evening and thank y

ou everyone for your participation this evening a huge thank you again to Dr maitlin for her time um on behalf of the foundation we wish everyone a healthy and safe Thanksgiving next week take care and have a great rest of your [Music] evening