Dr. Ari Fried - Mast Cell Disorders and Perioperative Care

have you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you nice Welcome to Combined Grand Rounds. Our speaker this morning is Dr. Ari Fried. It's my great pleasure to introduce him today. He's an instructor in Pediatrics at Harvard Medical School and attending within the Division of Allergy and Immunology here at Boston Children's Hospital. He's originally from Germany, which is where he studied and received his medical degree, and then did his pediatric residency at the University of Iowa. And subsequently came here to Boston Children's where he did his fellowship in Allergy and Immunology. And where he has been on staff since then. One of his clinical interests is Master Tytosis. And he has spoken this topic at a national level. He has worked to create the Pediatric Master Tytosis referral program. He was PI for an investigational drug for pediatric Master Tytosis and has helped develop the guidelines for perioperative management of these patients here at the hospital. So this is the topic that he'll be speaking on to us today. Please join me in welcoming him. Thank you. Thank you. Thank you. Thank you. So thank you for asking me to speak here today to you. This is a topic you probably don't hear that much about. Usually, I was asked to speak about Master Tytosis and implications that having such a disorder may have on perioperative care. And some of you may have encountered patients with this disease. I just may wonder how does it relevant to your specialty? Let me start with trying to illustrate possible significance by presenting a case. Let's see. So this is a male infant seeing a children's hospital several years back. He presented a birth with widespread hyperpigmented indivated lesions, plexus. These would often become erotaminous, adaminous, and would form blisters. You see, it's quite prominent skin disease with these larger indivated nodules covering most of his body. He had a skin biopsy done that identified cells consistent with mass cells and positive mass cells, staining. Also staining that showed that these cells were likely aberrant mass cells as seen in Master Tytosis. So the diagnosis of cutaneous Master Tytosis was made. He had a lot of problems with flushing irritability on a daily basis. Triggers included exposure to heat and eating. He was hospitalized twice at three and four months for eagerness episodes where he would develop unaphylaxis-like symptoms, including one, at least one episode of respiratory distress requiring I am epinephrine. So he was treated symptomatically with any histamine sprung with dilators, topical treatments, and then had a circumcision revision done under the Journal of anesthesia at seven months. Standard regimen was used, including nitrous opsy, seval fluorine, cysatracurium, my dazzle, and was premedicated with benedrol. And then, unfortunately, had a severe and diffuse listering event following a procedure, recovered well from this, but then later, at the sites where he had these large bulae developed hypertrophic scars on trunk and legs. So this is the boy, several years later, you see some of the legions have already healed, but you see this hypertrophic scars, the celoid that these legions are not really that active anymore, but certainly there are cosmetic issues at this point. He is now doing quite well, he's mostly asymptomatic, has occasionally itching, no major events anymore for several years in terms of, you know, degenerational lymphylaxis. He has an undermarked blood counts, nor organometalline. He's treated with antihistamine and occasionally use of steroids and he has a very good prognosis. These are basal theorem triptase levels, so not you're an acute episode, but at baseline. This is a, this year, triptase is a reflection of mass sub burden, it's a good surrogate marker in the blood, and the reference range is less than 11.4, and you see here elevated levels when he was an infant, and then gradually decline here, and now he has had normal levels, and no rise for many years. So, let me talk a little about mastocytosis. Sound elusive disease, it's characterized by excessive mast and accumulation in one or several tissues. It's known now to be due to colonel expansion of mast cells, due to mutation in the gene encoding receptor tyrosine kind is C-Kit or Kit. The prototypic mutation is a gain of function, point mutation, where valence is substituted for a sparring acid, D816B. Most common disease is seen in adults, but we also find this one in Kits. Here you see crystal structure of a Kit, C-Kit, so the natural ligand is stem cell factor, upon its minding, there's phospholation of cellplasmic residues, and then signal and cascade has started, results in activation of transcription factors. These are essential for cell growth. And so, the mutated version is considered if you activate without interacting with ligand, and as a result, you see expansion, accumulation of mast cells in tissues. Now, for a long time, it was thought that these mutations are only found in adults, and in about nine years ago, a French group showed that they were actually found also in most cases of contains mast cell tyrosine lesional skin, you see here, 42% of these cases had X1-17 mutation, and other patients in a large number had other mutations, other variants in different axons. There were a few patients with wild type, Kit, where we don't know the reason for their mast cell tyrosis. But despite this similarity, you think, in a genotype, it's quite interesting. It seems that adult and pediatric mast cell tyrosine different entities in terms of their biologic behavior and clinical presentation. So when you look at the adult onset disease, it's almost always systemic. So all patients will undergo boromel biopsy because it's a systemic until, you know, through mother-wise. Whereas pediatric cases are mainly cutaneous, there are rare systemic forms, there's a small overlap between these two, but they're quite different for reasons we don't well understand. So the estimated prevalence in US is about 1 in 10,000, two thirds of patients with mast cell tyrosis have childhood disease. Most of them, large majority have somatic mutations, as sporadic or rare familial cases. Disease onset is usually for childhood disease within the first two years. If it's after age two, it has less feral outcome, more likely to persist. So this is a panagnomatic sign, the rear sign that you can elicit on lesional skin if you stroke it or decay it and form some, usually redness around it within minutes. It's present in most kids with kidneys, mast cell tyrosis and found in all subtypes, but it's not uniformly present. And it's also less easily producedable in lesions that already have excessive for some time and are slowly involuting. So there are different mast cell tyrosis subtypes. I'll show you some examples in a bit and of the most common cutaneous version. And then there's a rare pediatric onciss systemic disease which I'll talk about too. So here you have a common variant, mast cell tyoma which is on these larger, well-sircom-scribed placts with a nodular center. They develop early in life and like most of the other lesions, but they're probably earliest to develop. They would often form blisters. There are, so they have a very good prognosis. Most patients are generally asymptomatic, but actually physical stimulation of these lesions can not only cause local symptoms, but can cause systemic symptoms such as bronchospasal and flushing hives, generalized hives, has been described. Here are some, you see that them coming in different shapes and sizes, different degrees of pigmentation. Now this is another variant. This is the macropapular form of Cranis mastatosis or Ticaria pigmentosa, UP. This is a child with quite widespread disease, but it can be only a few of these smaller, light brown to dark brown, reddish, macros and papils. They usually occur in kind of semantic distribution. Here's another child with extensive skin disease. So in these cases you'd say it's pretty easily appreciable. But there are cases where it's not that easily seen and they're maybe mistaken for being freckles and they're only noted once when they start to swallow. So there are other forms, nodular forms here. Lots of different shapes. There are the plaque variant with more flat, lighter lesions. And you can see if there's activation, there can be extensive wheeling and these kits are often times quite uncomfortable reaching when they have episodes. So vesicles and bula can occur in about 30% of these kits. You see quite impressive findings. They can be seen in all variants. They usually occur within the first two years of life and they often times would heal fortunately without any scarring. Now there's a severe form that's diffused between this mass-setosis where you see infiltration, almost all the skin with a sheet like infiltration and lots of nodular lesions within the skin. Because of their heavy mass, so burden, these patients are particularly prone to developing systemic symptoms early on. But their prognosis is quite good if they're taking care of properly, these would usually resolve over time completely. There can be kind of a leather-like skin appearance here. It's a pretty rare form. It's about one to 3% of cases with the exchange mass-setosis that we'll have this time. So the natural history of this disease is spontaneous resolution in large majority, 80-90% of kits. Some will have persistence into adulthood and some will develop systemic mass-setosis. We don't really have good markers right now to determine who these kits are. All of these variants can present with both local symptoms but also systemic symptoms. The extent of skin involvement does not always correlate with symptoms which symptoms they have. The classic forms that usually most severe in acetatology in the first one and a half years of life. So you see symptoms in the skin, you talk about blistering, flushing, itching, redness, GI symptoms such as bowel pain, cramping, diarrhea. They're often as very irritable when they have your generalization episodes. They sometimes have systemic symptoms, such as hypertension and bronchospasm, syncopy, full-anifal axis, GI bleed. Older children will complain of headaches, muscle-scalopane fatigue when they have episodes. And the triggers are quite variable. We'll talk about that in a second. So there is a rare systemic variant of this. Oftentimes these patients have the adult type mutation in progenitors so you can actually detect it in the blood. It's easy to testable. The majority have UP legions. It's actually the scenic one on of childhood mass-setosis is having the characteristic skin stigma out of it. So if you have a child, not even all that teenager, but if you have a younger child without the classic skin lesions, they don't have mass-setosis, which I think is good to remember. So the ones with systemic variants that have more common mediator symptoms, are rare forms of aggressive disease, progression into a mass-selocemia, and mass-setosis within associated with an allergic disorder, another hyponometric disorder. So this is a set of twins that I saw here. One is a garlic twins. They presented an infancy with classic UP legions, lots of GI symptoms, diarrhea, cramp your abdominal pain, and they had quite elevated serum triptains levels both. The bone fibosy confirmed early on since the stank mass-setosis. Interesting in these cases is they both have found to have a somatic mutation. So it's a familial disease in their case, but it didn't have a germline mutation. And it's quite puzzling, you don't even know why. Here you see some abnormal morphology of mass-synosinobomero of these patients. Now this is not a case. This is a girl with early on to advance to stank mass-setosis. She had the market, Hepatomegalae, spinoe-megalae infiltration of mass cells into these organs early on. She was quite miserable, always uncomfortable itching. Had marketly elevated serum triptase levels up to about 200. Bone marrow aspirate here shows numerous mass cells well differentiated. She has an unusual subtype of all differentiated stank mass-setosis. And here, that we treated her, following a compassionate use protocol with the tires and kindness inhibitor and mitestarring. And you see, so she was much less dramatic on therapy and the triptase levels came down from 180 to about 60. Unfortunately, there was only transient. And as we stopped, we had to stop therapy at some point and the triptase rose back up. Briefly, I want to just mention a couple of things here in diagnosis of these patients. Oftentimes, we can diagnose them just with a physical exam and getting a barrier sign positive. If there's suspicion for extensive systemic disease, sometimes we get basal serum triptase levels and other markers in the blood and only rarely in kids, bone marrow biopsy is indicated. So there are specific certain laboratory features like high triptase levels, organometalline lymphinopathy or other clinical features are being met. Now, how does it treat it? We try to identify and avoid potential triggers, local control with topical treatments. You try to target mediator symptoms with mainly anti-histaments and then we prescribe a penneffinodinjectus to families and patients. Only rarely we need to use cytoreductive therapy or thyroid is kind of an inhibitor treatment. What are the triggers? They can be quite variable. And so really on top of list, our physical stimuli, he exposure, he had cold, water, air, friction, pressure, sunlight, emotional factors can play a role. So emotional stress, anxiety can cause exacerbations and then that can cause more anxiety and so it's kind of a vicious cycle there. Certain drugs have been implicated as triggers and then there are other triggers such as hemoptera, stings if you have a sensitivity to these dental procedures, vaccines, surgery, simple infections. Now, when you go on a master's-centrosis website, as a parent, you'll see a list of all of these and you think they apply all to your child. So oftentimes they come with charts with, you know, where all of these are listed and lots of drugs are listed as allergies based on that, based on the possibility of being a trigger, not because they're an established trigger. So it wants to be aware of that too. Now, I briefly wanna just take a few words about mass-collectivation syndrome, which is a little bit of confusing terminology. It was coined some time to, some experts to try to identify and be able to, you know, treat patients better that presented with master-mediator symptoms but did not have monoclonal disease and no allergies. So there's three patient groups that will fall on their category according to these, you know, experts that made this diagnosis. There's the ones that have allergic symptoms, the ones that have monoclonal disease and the ones where there's no identified genetic lesion but they still have recurrent anaphylaxis. We don't know why. So now you see this term often synonymous so you're used for the third group, only the ones who have idiopathic mass-collectivation syndrome. So not mass-collectivation syndrome but no allergies identified but still have symptoms. And to meet the diagnosis, to make the diagnosis, you have to meet, you know, stringent criteria that includes recurrent symptoms of, you know, severe mass-collectivation such as anaphylaxis with different systems being involved at least too. A documented increase in mass-mediator levels mainly triptase for other mediators that can be measured at baseline and during the episode and then clinical improvement with intermediary therapy. So unfortunately, these criteria have been, you know, broadly widened or you're definitely broadened by some publications in the medical literature and also, you know, lay press information to include a lot of symptoms that are not really likely due to, you know, mass cells. That includes an isolated form of combination fatigue, fibromyalgia type symptoms, chronic ill appearance, headache, anxiety, mood disturbance, tinnitus, et cetera. You see where this is going. So there are a lot of patients that identify with this diagnosis based on this literature that's available, particularly on the internet, who don't truly have a problem with mass cells. And if you go back and, you know, try to apply these criteria, many of these wouldn't meet them. So that's maybe as much as I would say about mass activation syndrome in this contact for the scope of the talk. Now getting to the operating room. So we have a patient group that's where there's a generally increased unaffilated access risk, not just only limited to the operating room. Then there are agents used in anesthesia and preoperatively that are implicated as being mass and activators. And there are case reports or cases that are present, you know, described of severe, sometimes fatal adverse events for unaffilated access that includes cardiovascular, cardiovascular arrests, mostly described in adults with systemic disease, but also in children. No fatal reports in children though. So one has to consider that the lifetime risk for adults with mass cathosis, developing an unaffilated access is quite high, 20 to 40%. That's about 100 to 1000 times higher than the general population. In children, the risk is estimated to be somewhere between one and 10%, and that maybe even over estimated because a lot of cases that are benign and may not be reported of child, the contains mass cathosis. In children, the unaffilated access risk is increased if you have elevated basal serum, triptase levels and the high extent density of skin disease. So the proposed or possible mechanisms there are that having an activated in-kit mutation will lead to an hyperactive mass of phenotype. So there's likely a decreased threshold for de-gradulation, for developing an unaffilated access. And then you have the clonal disease, where there's a high number of effector cells, and that can amplify symptoms. What are triggers for unaffilated access in adults? It's really oftentimes common opera stings. To an extent that if you have an adult or an adolescent where you have a severe insect-thing reaction, you oftentimes wanna check if they have a thangmousis atosis, at least get a serum, triptase level. There are other triggers less frequent in children, it's most often idiopathic, then food, medications and insect things can also be an issue less frequently. And oftentimes systemic severe reactions are in-kits associated with these acute bulls skin eruptions. Whether it's just a food-dustinic. Well, so you can have a concomit, allergies are common, mass ofosis is rare. So if you have both, there is a likelihood that you could have more severe food reactions that are generally food-duralogenic, seen in the general population as well. And I've seen, I know all of cases where a girl, with a cashew allergy, pretty low, IGE levels detected in the blood and had severe anaphylaxis, protracted anaphylaxis, leading apodrip ICU care. And it's quite interesting because one could possibly that having lots of mass cells around, it would bind up some of the IGE and so the blood test could be falsely low. And that was probably the case for her. She ended up having systemic disease. So she was maybe not the typical in that case of mass as well. Now, let me just review a few case in literature. So this is an adult case report, 43 year old man, with no prior anaphylaxis history under Van General anesthesia for fracture fixation. He received proper full fentanyl, nitrous oxide, isoflorene. And after he got IV morphine, he developed hypotension, tachycardia, eventually cardiac arrest. He did not have any ultecaria or angedema reported. He was successfully resuscitated but never regained consciousness and died four weeks later in the ICU. Now, the operating team did not know that he had a 15 year history, prior history of flushing, maclopapular rash, and was diagnosed by dermatologist with having cutaneous mass as a dosage. Postmortem, they found mass aggregates in the bone marrow liver, lymph nodes, skin, and elevated transcription phase levels. There is one single case report of cardiac arrest in a seven months old child in the male infant, was described to have bullies, cutaneous mass fatosis, probably diffused cutaneous mass fatosis for neurosurgery. Anesthesia, he received civil flora, anti-opental, so fentanyl, and 60 minutes after induction developed on a fullactic shock with cardiac arrest. He was resuscitated with full recovery. Interestingly, he had a previous anesthesia that included civil flora and sulfentanyl without any complications. And subsequently, he had an anesthesia of 140 minutes with civil flora and alphentanyl a month later, tolerated that without any complications. So there's another case report, more recent one from this year, two-year-old girl and they went post-year sexual anorectoplasty, received mydazolam fentanyl, lidocaine, proper fall, post-op, was put on a dexcateoprofen, a continuous infusion, developed bronchospasal acne, hypertension, and then was found to have an edemotus bullies lesion on her shoulder. She did quite well after treatment, and then the exam showed a well-circumstriped 1.5 times 1 centimeter yellow-brown patch with positive air sign. So she had a solitary coutaneous mastatoma. She had normal basal serum triplase levels. So that would be a lesion that's not that commonly known or seen to cause systemic symptoms, but it can. There are some case serious, this isn't all the one from the 80s, reported 15 kids with coutaneous disease, received 29 transceza procedures. Only two of them were premedicated with any estimates. There were no severe life threatening as soon as reported. Two children had some skin flare-ups after getting coding. Another study from the NIH, Melody Carter reported 22 patients with different forms of pediatric mastatosis, including severe variants, who underwent 29 procedures under general anesthesia. They received routine anesthetic management, and then stayed on their regular medications per operatively, and there were no major adverse events reported. Two patients developed flushing, two nausea and vomiting. One patient with a few coutaneous disease developed an iteration of a heel after a six-hour procedure. There's another more recent, a most complete series of Spanish group that looked at adults and kids. There's six hundred and seventy-six procedures looked at adults. Only 10% of these, about 60, are actually general anesthesia, but they observed three episodes of anaphylaxis in their group. In kids, 50 cases were looked at retrospectively, half of them were general anesthesia. There was one episode of anaphylaxis. Now, they felt that they had limited data to look at, but they thought that there was a low anaphylaxis risk if prophylactic and immediately medications were given prior, mainly including any histamins. So, now, there are many drugs used per operatively that are known to have been veto properties of mastat activation. For example, muscle vaccines after a meaver coriom, I know to do that in some IV anesthetic agent, allegesics. For most of the carly use agent, there's really no evidence that they would use complications in patient mastatosis. Caught in many to be exercised with using morphine coating and some end sets. Lightly safe per operative drugs are benzodiazepines, local anesthetics, IV hypnotics, halogenated gas, and alleges are known to not cause mastat activation. And the carly use neuromuscular blocking agents are quite safe. Maybe with preference of cis-atrocurriums, sexinolocalling, but that is really based on their in vitro properties, not because of any evidence that other ones can't be used. And neuroopiweights, alphaentinol, femeninol, remyventinol, syphinol, should be safe. Now, what about corin morphine end sets? They are well-known mastol-medi-activators. There is one lethal idiosyncratic reaction to petroloc. It was an actodil episode described by group on the NIH. It was actually never reported. But one may need to be careful with this particular one. These drugs are not per se contraindicated in patient mastatosis. They give an incremental doses in higher risk patients. Zellaminophen is safe. And then clearly obtaining a history prior, if that establishes that our proven was tolerated before, then it can be used again. What about skates testing pre-op? That question sometimes comes up. One has to know that the risk of having an IgE-mediate drug algae is not per se increased in this population. Also, we know that for most drugs, there is no standardized skin testing available. So it's really unclear or poor predictive value for most of these tests. Also, testing is quite dramatic for younger kids. There's a series of tests that kids have to go through skin-pre-test, intradermal tests. So generally, skin testing for this patient group is not recommended unless there is a concern for a specific drug algae. And even then, the value of it has to be questioned. What about pre-medication? So really, there's a lack of data to strongly support it. But most experts recommend using any estimates pre-operatively and would continue using their routine anti-media therapies that patients are on, if possible, throughout the prior operative phase. And additional preventative medications you may want to consider for higher risk patients. And I would classify them as having previous medial release symptoms during a procedure, history of ophthalaxis or severe skin disease or high serum chiptase levels. So what I usually recommend is for standard risk patients give Benadryl one hour prior to procedure and for rare high risk patients consider adding, you know, predisone, predisolone, ethylpred, not really based on much evidence because there is no available strong evidence. It's a little bit extrapolated from other clinical scenarios for like radio-contrast media reaction prevention prevention of undefalaxes for non-messagellospatients. It's also important to note that there are other decaronylation triggers, such as temperature, dramatic temperature changes, infusion of cold solutions, strong or friction-tutistio, and then as you talk about emotional stress and anxiety, it should be avoided possible. And in some cases you want to consider preoperative sedation for anxiolytics. So I would summarize perioperative strategy as pre-procedure verification of an exact diagnosis. For reasons that I mentioned, you want to get a good history of a previous drug reactions and drug tolerance, establishing individual treatment plans so you can make an informed choice on which agents you want to use. Continue routine medication that these patients are on if possible, address anxiety if needed with drugs, and then consider pre-treatment based on assessment of a risk for the patient, try to control environmental triggers and anticipate adverse effects and be ready to treat these promptly if they were to occur. I will conclude here with pediatric mastatoosis being most often have been nine self-limited conditions. There are rare pediatric cases with either extensive skin disease or systemic disease. Some of them have disease that resembles adults, mastatoosis. Even if it's a self-limited condition for most patients there, are likely at risk for complications, including anaphylaxis, some with design, it be nine forms that maybe only a low risk. There's lack of knowledge in the medical community about this topic, and that void is sometimes filled with wrong information or outdated information propagated through the internet. As a result, thereof anesthesia risk is often times overstated. Generally anesthesia and therapeutic procedures are well-tolerated in this patient population, and the risk for the individual patient may be further decreased by being aware of this disease, knowing potential serious adverse, offensive, may occur, control of triggers, and having treatment readily available. I acknowledge Stephen Gallas, who provided some of the pictures shown here, Choi Makin, who was previously at the Brigham, who referred me some of the interesting, unusual pediatric mastatoosis cases. I thank the audience for how I didn't bore you too much, and we're ready for questions. Well, that was a beautiful review of a rare condition that is obviously frightening. I've only seen this once in the pair of upsetting and nobody knew it was going on. I'm fascinated by the fact that this understanding of the mutation and the mechanism, if something is genetic and that pathway is stimulated, why does it get better as a child gets older? Why isn't it a lifelong problem? Why does it resolve? They're only symptomatic in infants. It's positive. You're quite interesting to find out. And the second thing I caught your eye when you showed the two twins, I assumed there's identical twins that had a condition. I have two twins with the somatic mutation, the same mutation, of another condition that affects widespread areas of the skin. It's a rare vascular malformation called Blue River Blood Nevis Syndrome. We've now done mutational analysis and proven that their mutation must have happened very early, and that it's a clonal and therefore benign metastases. I don't know if you think there's the same thing. Are there other twin cases here? There are not many twin cases like this, but that is a suspicion. Probably at an early mionic level, the mutation occurred. Another hypothesis would be that there's some other mutation, somebody else that predisposes them to develop these mutations, I don't know. But it's certainly puzzling, and we don't really have a conclusion answer to that. I'm sure the clinical diagnosis is much more interesting to the anesthesiologist because it looks really frightening to me. Thank you for your talk. As I was listening to you, I confess I was hoping I was going to hear you advancing exciting research on immune modulation. As you know, in the ICU and as you rightly outlined, the evidence for how we should treat this remains the same as we did three decades ago. It hits me in steroids and will squeeze your blood vessels and will hang on with up an effort. What we've noticed in the ICU is that our oncology colleagues appear to be opening the window to how we're going to be treating shock in a very short period of time, not only because CAR-T is inducing a new kind of shock, but a better understanding of shock, but we're also giving immune modulators to mitigate the cytokine release syndrome. So I confess I was hoping that you were going to tell us about some exciting checkpoint inhibitor or some insight into why the mast cell is so potent as a systemic disorder. So I'm not going to hang this all on you, but is there anything out there that points the way to something more sophisticated than antihistamines and steroids? I was focusing mostly on this specific disorder. And clearly once the research advances there, it will likely be used for this more rare patients. But clearly we have many more patients who will have mastocytosis to the allergic trigger and these immune modulators will probably first be used for them. But I really can't elaborate that much on that issue. And certainly there's no data out there regarding these patients, but maybe there would be a good group of patients who study particularly once such agents are available. Thank you. Other questions, comments? Can you? Thank you. You suggest the continuation of immune modulation in patients who are already receiving such medications. If you anticipate non-urgent surgery in someone who has significant disease but is not on those agents, should they be instituted prior to an elective procedure? Well, in such cases they may be fine with just using an antihistamine one hour prior. But that's a good question. There are some patients who are completely asymptomatic and I would not necessarily put them on a regimen additional to that. Because the fact that there are asymptomatic probably leads to the assumption that there may not be having lesions that are easily triggerable. So I don't know if that answers your question. Others? If not, thank you for educating us about this really frightening topic and maybe three decades from now, Jeff will get his answer. Thank you.