Mast Cell Activation Syndrome (MCAS) & Covid-19 Coronavirus Update



Dr. Lawrence Afrin MCAS Coronavirus Update

COVID-19 STATEMENT FROM DR. LAWRENCE AFRIN ON MCAS & CORONAVIRUS


May 1, 2020

Dr. Lawrence Afrin on the Treatment of Covid-19 to Patients Who Have Mast Cell Activation Disease (MCAS)

I was requested by another group of (Covid-19-focused) professionals to provide recommendations for treatment of Covid-19 patients who have mast cell disease. 


Thousands continue to die world-wide every day from this virus, and if even a few of them can be saved by applying the information in this posting (which I hope will be read by professionals world-wide) that's obviously quite important. 

To the "Covid-19 Professional" Community: My previous posting on Dr. Tania Dempsey’s Facebook page explained why I suspect MCAD/MCAS patients are at higher risk for developing more severe courses of Covid-19 illness (and I'd like to add at this point the caveat to that posting that a *well-controlled* MCAD/MCAS patient might reasonably be expected to have less risk for developing a severe course of Covid-19 illness than a less-well-controlled MCAD/MCAS patient). The follow-up question to that posting which has been posed now is as follows: "If a patient does have mast cell disease, which specific medicines would be most likely to bring that component under control the fastest?  MCAS patients tend to react poorly to new medications, so having an expert comment on the safest route would be priceless.  I would also be interested in hearing what they think as to whether certain medications (especially IV) usually used for MCAS patients in anaphylaxis or cytokine storm would be helpful to give crashing Covid-19 patients in general." My own opinions on these matters are as follows (and let's be clear that everything I'm writing here is an *opinion* (based on what little I know about mast cell biology and pathobiology and what my clinical experience with MCAD has been across several thousand patients (almost all with MCAS) in these last dozen years) because there simply are not yet any data on which to base a *fact*-driven response, i.e., there have been no studies yet of Covid-19 in a population of patients known to have MCAD of any form): 1. First of all, I think it is an incorrect assumption, or at least a "misunderstanding," that "MCAS patients tend to react poorly to new medications."  I think most MCAD patients (referring here to mast cell activation disease, encompassing the small population with the rare disease of mastocytosis in one form or another together with the quite large population with the quite prevalent disease of MCAS of one variant or another (perhaps up to 17% of the general population per available epidemiologic research (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076241) -- yes, think about that figure for a moment and the implications if the truth of the matter is "anywhere close" to that figure)) *tolerate* most new medication products they try fairly well (*response* rates and degrees, of course, are an entirely separate issue).  Yes, in my experience there is no question that MCAD patients "more commonly" (as compared to patients without MCAD) demonstrate intolerance of, or adverse reactivity to, medication products they are newly trying, though there has not yet been any research to quantify and otherwise characterize the extent of this difference between the MCAD and non-MCAD populations.  Nevertheless, that statement is a far cry from a statement that "MCAD/MCAS patients tend to react poorly to new medications," suggesting/implying (at least in my mind) that the majority of MCAD patients adversely react to the majority of the medication products they try -- and that definitely (again, based on my experience extending across several thousand MCAS patients now in the last dozen years) is *not* the case. 2. It sounds from the question which was posed as if treating physicians are interested in learning about a "cocktail" of medications (targeted either at mast cells themselves and/or at various mast cell mediators) which they can simultaneous (or near simultaneously) start in a Covid-19-infected patient to "rescue" the patient or otherwise favorably modulate the course of the disease.  I think this aspect to the question offers an important opportunity to note that *in general* it's almost always a much smarter (and, in the end, much more time- and cost-efficient!) approach to start an MCAD patient on just *one* new medication product at a time for the obvious reason that if two or more changes are made in an MCAD patient's regimen around the same time and then the patient gets either better or worse, nobody will have the slightest idea which change (or which combination of changes) actually resulted in the improvement or worsening, and -- again, speaking from experience -- it not uncommonly is a holy mess to sort out the matter at that point, resulting in the end with more time and money having been spent on the affair (and potentially more morbidity incurred, too) than if just one change had been made at a time.  That "general rule" having been said, it must be acknowledged that patients are being "taken down" by Covid-19 frightfully quickly (not uncommonly within days to even mere hours), and in that setting one obviously just doesn't have the luxury of the time needed to make one change at a time.  Thus, while it is acknowledged that MCAD patients "more commonly" react adversely to new medication products than do patients without MCAD, and thus also acknowledged that the simultaneous (or near-simultaneous) addition of multiple new products to an MCAD patient's regimen probably significantly escalates (compared to initiating just one new product at a time) the likelihood of seeing an adverse reaction, and thus also acknowledged that such a development may make it very difficult to know how best to further adjust the patient's medication regimen, nevertheless the acuity of Covid-19 illness probably makes simultaneous changes to an MCAD patient's regimen "acceptable" and perhaps even "preferred" so as to maximize the chances of gaining sufficient (and sufficiently timely) control over the inappropriately exuberant mast cell activation which might be at the heart of (or at least a "major component of") the "hyperinflammation" or "cytokine storm" being seen at the heart of the more serious cases of Covid-19 illness.  We're all just trying to do the best we can with the very limited understanding we presently have of the virus -- and of MCAD. 3. With the exception of mast-cell-neoplasia-targeting treatments in advanced cases of mastocytosis, most or even all of the treatments needed in MCAD are targeted at the chronic inappropriate constitutive and reactive *activation* of the patient's dysfunctional mast cells, i.e., the inappropriate production and release of various subsets of the menagerie of more than 1,000 mediators known to be produced by mast cells.  Though it is frustrating that the state of the science in this area remains so immature that there does not yet exist even a single method for reliably predicting which drug(s) will best control which aspects of the disease in which particular MCAD patients, we are fortunate that there already exists a quite sizable array of drugs which have already been shown (with varying degrees of evidence, of course) to modulate mast cell activation or mitigate the actions of released mast cell mediators in various MCAD patients.  Thus, the challenge in treating any given MCAD patient is not at all a matter of finding "a" (or "the") drug which will help the patient but rather a matter of determining the *sequence* by which one will proceed through trials of these many treatments which have been found helpful in various (but certainly not all) patients.  Again, lacking any guiding science in the matter, such sequencing usually is unique to each patient, guided principally by the individual patient's symptoms together with the treating clinician's experiences which obviously bias him/her toward or against various treatments.  That all having been said, MCAD treatment most commonly (by far) begins with initiation of histamine H1 and H2 receptor antagonists for the simple reason that some combination of "H1/H2 blocking" actually does seem to bring clinically significant benefits to the majority of MCAD patients (again, the research has not been done to be able to clearly quantify this observation), and H1 and H2 blockers are cheap and long-term safe.  (Come back another time for a discussion as to the misinterpretations of the studies in the last few years which have found "associations" between chronic antihistamine use and dementia.)  Again, we generally prefer to take MCAD patients through a rotating series of trials ("one change at a time") of the several different non-sedating H1 blockers (obviously preferred over the sedating H1 blockers to treat a disease in which fatigue is one of the most common complaints) to find which specific such drug serves the individual patient the best (in my experience, most MCAD patients who do the diligence of these trials indeed find one particular such drug -- though a different such drug in each patient -- which clearly serves them better than the other drugs in this class), followed by similar trials of the H2 blockers "piled on top" of ongoing use of the already discovered optimal H1 blocker.  However, in the setting of a Covid-19-infected MCAD patient who is exhibiting the "hyperinflammation" of Covid-19 illness, it probably makes sense to simultaneously (or near-simultaneously) initiate both H1 and H2 blockers.  And in Covid-19-infected MCAD patients, I actually think the sedating H1 blockers (principally, diphenhydramine) might have an advantage over the non-sedating H1 blockers, for the simple reason that the hyperinflammation of Covid-19 illness seems to extend to all organ systems in the body, including the central nervous system, and by their very chemistry, the non-sedating H1 blockers cannot penetrate through an intact blood-brain barrier (BBB).  (Yes, one can argue that a BBB made "leaky" by inflammation -- a known phenomenon -- might permit passage of the non-sedating H1 blockers, but there is no inexpensive, safe, non-invasive, widely available testing to determine the extent of such leakage in the "typical" patient, so we need to operate on the assumption that penetration through the BBB by the drugs which ordinarily cannot penetrate through the BBB will be "clinically insignificant.")  Furthermore, the ability to administer medications via IV is important in severe Covid-19-infected patients, and for all practical purposes, the *only* H1 blocker (sedating or non-sedating) which is available IV in the U.S. is diphenhydramine (better known, at least in the U.S., as brand-name Benadryl, though certainly a great many generic formulations are available, too).  (Note that diphenhydramine is not available in every country, so dimenhydraminate is another sedating H1 blocker available in IV form which can be considered in such countries.)  There's just one problem with diphenhydramine: you would have a hard time finding another H1 blocker with a half-life in the human body that's shorter than that of diphenhydramine.  Diphenhydramine has a half-life in humans of only about one hour.  So I know doctors are used to ordering Benadryl to be given at a "maximum" of roughly 25-50 mg every 6 hours or so, but there are plenty of (more severely afflicted) diphenhydramine-experienced MCAD patients for whom significantly higher doses and/or significantly greater frequencies are appropriate and sometimes even necessary.  In fact, there even is a tiny, most unfortunate fraction of MCAD patients who are essentially *constantly* (and I do mean 24-by-7) in an anaphylactoid state (if not frankly anaphylactic), and in some of those patients, it has been my experience that nothing less than a continuous diphenhydramine infusion (CDI) can get them out of that state, as I've briefly published (https://ashpublications.org/blood/article/126/23/5194/94347/Utility-of-Continuous-Diphenhydramine-Infusion-in).  Note, again, the propensity of MCAD patients to react to excipients in their medication products.  I have now seen hundreds of MCAD patients who have reported to me an intolerance of diphenhydramine in one formulation or another, and so far in my experience, every single one of those intolerances has proven, on further investigation, to be excipient-driven intolerance, not drug-driven intolerance (i.e., reactivity by the dysfunctional mast cells against some excipient, not again the drug itself).  I actually have not found a single patient yet who truly has been intolerant of diphenhydramine.  As such, if a patient is reacting to IV diphenhydramine, consider strongly the possibility that the patient is being administered standard preservative-laden IV diphenhydramine rather than (more expensive, less widely available) preservative-free IV diphenhydramine -- but the latter should be available to any physician who specifically orders a preservative-free formulation.  There was a bad shortage of IV diphenhydramine (especially preservative-free IV diphenhydramine) in 2019, but that shortage seems to have largely passed.  With regard to H2 blocking, at least here in the U.S., thanks to the FDA's recall of ranitidine (listen up, FDA: contrary to your statement at the time of the recall, experience across my thousands of patients shows that the various H2 blockers are *not* functionally equivalent to one another *in MCAD patients*, and there is *zero* evidence that the billions of doses of ranitidine given to hundreds of millions of patients world-wide in the last 40 years have caused increased rates of *any* cancer in the ranitidine-using population!), we are left with famotidine, nizatidine, and cimetidine as the only remaining H2 blockers, and I have been hearing lately that all three of them are in short supply, especially since famotidine (to which many ranitidine users had turned upon the FDA's recall of ranitidine) recently surfaced as another potential treatment for Covid-19 (ostensibly targeted, based solely on computational modeling rather than in vitro demonstration, at the virus's papain-like protease needed for viral replication, but how do we know the principal route of benefit isn't via blocking of the activating mast-cell-surface H2 receptors instead?  And ask yourself *why* the Chinese peasants who survived Covid-19 better with famotidine than the wealthy Chinese who used PPIs had all of that "GERD" in the first place -- but it's a topic for another day as to the extent of MCAS that's long been getting misdiagnosed as "GERD" and similar labels).  So, bottom line, starting a less severely ill Covid-19/MCAD patient on a twice-daily H1/H2 blocker regimen such as cetirizine (or another non-sedating H1 blocker such as loratadine, fexofenadine, levocetirizine, or desloratadine) (or, in Europe, Canada, and elsewhere, additional choices of rupatadine, bilastine, ebastine, etc.) together with an H2 blocker such as famotidine, nizatidine, or cimetidine (or, where it's still wisely available, ranitidine) would be quite reasonable.  This twice-daily regimen could even be increased to thrice-daily, presuming the patient is able to tolerate any mucosal dryness or other anticholinergic toxicities which might come with that frequency of dosing.  The actual dose to be used at each dosing would be at least the "standard" dose for the drug in question (e.g., 10 mg for loratadine or cetirizine or rupatadine or ebastine, 5 mg for levocetirizine or desloratadine, 90 or 180 mg for fexofenadine, 20 mg for bilastine), and it would not be unreasonable, either, to consider dosing twice as high as the "standard" dose for any of these drugs.  The same approach (re: "standard" or "twice-standard" dosing, twice- or thrice-daily) would be taken for the H2 blocker, too.  And for the more severely ill Covid-19/MCAD patient, these drugs could be administered via the feeding tube which presumably is placed soon after the patient is intubated, or a regimen of IV diphenhydramine every 6-12 hours together with an IV H2 blocker every 6-12 hours can be considered, and if the patient is especially sick, I personally wouldn't have any trouble whatsoever in starting the patient on CDI (probably starting at just 5 mg/hr in these mostly diphenhydramine-naive patients but escalating as needed and tolerated, to a max of 15 mg/hr; I've never seen doses > 15 mg/hr help, and somewhere in the 17-20 mg/hr range assorted toxicities inescapably begin emerging). 4. Benzodiazepines address not only inhibitory benzo receptors on the neurons but also inhibitory benzo receptors on the mast cells (it's a topic for another day as to what fraction of the "idiopathic anxiety/panic attack" population frequenting emergency rooms and psychiatrists' offices have unrecognized MCAS), and I wouldn't hesitate to start a moderately ill Covid-19/MCAD patient on regular (at least bid-tid, perhaps even qid) dosing of a benzodiazepine (oral or IV; dosing typically is equivalent between the two routes).  Lorazepam or clonazepam could be started at 0.25-1 mg, and I probably would not push any individual dosing past 2-3 mg; diazepam dosings could be started at 5-10 mg, probably not to be pushed past 20 mg.  There's evidence that flunitrazepam has much better affinity than the other commercially available benzodiazepines for the benzo receptor on the mast cell, so in Europe and other (non-U.S.) places where that benzo remains available, flunitrazepam 1 mg bid-qid, with or without additional lorazepam or clonazepam at 0.5 mg, would be quite reasonable to try on a bid-qid basis (in addition to the H1 and H2 blockers, of course). 5. Cromolyn is a useful drug in inhibiting mast cell activation in many patients, but its chemistry is such that it is absorbed very poorly from whatever surface to which it is applied.  Therefore, oral cromolyn is a very reasonable intervention to try to control dysfunctional, excessively activated mast cells in the gastrointestinal tract, but that cromolyn will not be absorbed (to any significant extent), will not be absorbed, and will not come to inhibit mast cells anywhere else in the body.  Therefore, in addition to trying oral cromolyn (100-200 mg bid-qid, preferably 30 minutes before meals and at bedtime), one can also try nasal spray cromolyn (1-2 sprays in each nostril bid-qid) or nebulized cromolyn (20 mg bid-qid), and there also is eyedrop cromolyn to try to control the conjunctivitis ("pink eye") which is being reported in many Covid-19 cases. 6. Ketotifen is a useful drug in inhibiting (mostly inflammatory aspects of) mast cell activation in some MCAD patients.  Oral ketotifen (typical dosing 1-4 mg bid-tid) is easily, cheaply (even over-the-counterly) available in every country on the planet -- except the U.S., where it is available in oral formulations only by either importing it from a foreign pharmacy or by obtaining it from a compounding pharmacy.  The only formulation of ketotifen which is commercially available within the U.S. is eyedrop ketotifen, which also is a reasonable intervention to try for Covid-19 "pink-eye." 7. Non-steroidal anti-inflammatory drugs (NSAIDs such as aspirin and ibuprofen) are helpful in many MCAD patients but also trigger (via unclear mechanism) reactions in a minority of such patients (and I'm talking about a real drug reaction (of flaring of mast cell activation), not an issue of excipient reactivity).  So I would be hesitant to start an NSAID, in the context of a Covid-19 crisis, in an MCAD patient not previously known to be tolerant of NSAIDs.  But if the patient has -- like most people in the world -- previously taken an NSAID and tolerated it OK, then I think such a drug would be quite reasonable to start in a hyperinflamed Covid-19/MCAD patient, and the only question would then be *which* NSAID.  We typically prefer aspirin for NSAID treatment of MCAD patients because it irreversibly inhibits both the COX-1 and COX-2 enzymes and because it has a long half-life, but in the context of Covid-19, where so many troubles with bleeding are being seen, a longer half-life and irreversible COX inhibition may not be such great features, so simple, cheap ibuprofen (400-800 mg, preferably with food bid-qid) probably would be reasonable for patients still taking oral medications, and ketorolac (e.g., 30-60 mg bid-qid) probably would be reasonable for patients requiring IV treatment.  Renal function of course needs to be watched in patients on extended courses of high-dose NSAIDs. 8. "High-dose" vitamin C has been shown to reduce the production and release of histamine from mast cells.  Ideal dosing is unclear (and I'm aware that dosing being explored in sepsis protocols is far higher), but I typically shoot in my patients for the range of 500-1000 mg bid, preferably with an extended-release formulation.  Of course, in a patient with severe Covid-19 illness, IV vitamin C can be used at least as well as (and may even be preferable to) oral vitamin C. 9. Via disengagement of the mast-cell-surface vitamin D receptors, vitamin D deficiency has been shown in vitro and in animal models to increase mast cell production/release of various inflammatory mediators.  As such, vitamin D supplementation in the range of 4000-8000 IU once-daily would be reasonable. 10. Flavonoids such as luteolin and quercetin, when tried at reasonable doses, are fairly non-toxic and sometimes can be quite helpful in MCAD patients.  Luteolin dosing is typically 100-200 mg bid-tid with meals; quercetin dosing is typically 500-1000 mg bid-qid.  There are several nuances to optimal selection of these products, and the reader is referred to a very recent publication on the subject by a master in the field at https://www.ncbi.nlm.nih.gov/pubmed/32339387. 11. Mast cells can produce significant quantities of leukotrienes, yet another potential axis of inflammation in MCAD.  Leukotriene receptor blocking with montelukast 10 mg doses or zafirlukast 20 mg doses would be quite reasonable to try, though I have found that twice-daily dosing of these blockers usually brings much more benefit than once-daily dosing in MCAD patients who actually are responsive to these drugs.  Risks for toxicities, especially neuropsychiatric, increase somewhat with higher dosing of montelukast, but with appropriate education of the patient, I still think it's perfectly reasonable to try any MCAD patient on montelukast 10 mg bid, and in my experience the vast majority of montelukast-responsive MCAS patients tolerate such dosing quite well.  Zafirlukast requires liver function test monitoring (e.g., monthly in the first quarter, then quarterly).  As with the H1 blockers, H2 blockers, and benzodiazepines, failure to respond to one drug in this class doesn't say *anything* about likelihood to respond or not respond to any other drug in this class.  Whether a leukotriene receptor blocker helps or not, the (far more expensive) leukotriene synthesis inhibitor zileuton (600 mg bid-qid, and later on, extended-release 1200 mg bid) would be reasonable to try. 12. Cannabinoids can help in some MCAD patients, presumably via engaging the cannabinoid receptors which are present not only on neurons but also on mast cells.  Anti-inflammatory cannabidiol (CBD) of course is to be preferred over "high"-inducing tetrahydrocannabinol (THC).  Thanks in significant part to U.S. federal constraints on cannabinoid research, effective dosing of CBD is quite unclear, and I've had patients report benefits at doses ranging from as little as 5 mg once- or twice-daily to as high as 125 mg once- or twice-daily.  Some patients find even more benefit with smaller doses taken more frequently. 13. At least some of the JAK1 inhibitors (e.g., tofacitinib per my published report (https://www.ncbi.nlm.nih.gov/pubmed/28382662); ruxolitinib per my anecdotal observations; and probably baricitinib and upadacitinib, too) appear helpful in at least some MCAD patients.  Furthermore, ruxolitinib is fairly well established now as quite helpful in the hyperinflammatory states of hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), and there have been rumblings in the community of professionals dealing with Covid-19 as to whether either of these entities might be playing a significant role in more severely ill Covid-19 patients, and some of these drugs now are in clinical trials in Covid-19 patients.  Despite their black-box warnings, these drugs tend to be well tolerated at recommended doses.  From the remarkable acute turnarounds I've seen in some chronically hyperinflamed MCAS patients, I wouldn't hesitate to try a severely ill Covid-19/MCAD patient on a JAK1 inhibitor, probably tofacitinib or ruxolitinib to start with.  Tofacitinib would be initially dosed at the standard 5 mg bid, but it has a short half-life of only about 3 hours, so if the drug appears well tolerated in the first 1-2 days, I'd probably rapidly switch a severely ill Covid-19/MCAD patient at that point to the extended-release product at standard dosing of 11 mg once-daily.  Ruxolitinib could be started at a standard dose of 20-25 mg bid, adjusted downward (to as low as 5-10 mg qd-bid) if thrombocytopenia is present. 14.  And as if the JAK1 inhibitors aren't expensive enough, we finally get to the KIT inhibitors such as imatinib, which also work very well in some MCAS patients.  Although imatinib is almost never helpful in mastocytosis due to the imatinib-resistant KIT-D816V mutation at the heart of most cases of that disease, MCAS patients almost never bear that mutation and imatinib has a chance of helping such patients, as it fits perfectly into the ATP-binding (i.e., activating) pocket in the intracellular domain of KIT and thus prevents ATP from binding and activating KIT once KIT's extracellular domain has been engaged by KIT's natural ligand stem cell factor (SCF).  I typically start imatinib in an MCAS patient at 100 mg once-daily, escalating to 200 mg once-daily after 4-7 days if it's being tolerated OK but not yet showing benefit.  In my experience across a few hundred MCAD patients tried on this drug, pushing the dose beyond 200 mg per day rarely provides greater benefit, and -- just as one could say about any of the other drugs -- if benefit is not seen after 2-4 weeks, then it should be stopped.  Imatinib at such low doses typically is well tolerated, so a patient who clearly is adversely reacting to a low dose of an imatinib formulation probably is reacting to an excipient rather than to the drug, and, if desired, just in case the offending excipient is in the coating of the tablet rather than its core, the coatings on the various tablet formulations of imatinib, which in a dry intact imatinib tablet is unremovable by design, usually can be removed by dunking the tablet in water for 3-5 seconds, then fishing it out and (at that point fairly easily) stripping the coating.  Other KIT inhibitors (e.g., sunitinib, dasatinib) very occasionally benefit MCAD patients (e.g.,https://www.ncbi.nlm.nih.gov/pubmed/26072665), but the response rates are so low, and toxicities are seen so commonly, with these drugs that they're probably not worth talking about in this present Covid-19-centered discussion.  (Contact me directly if dosing guidance for use of sunitinib or dasatinib in MCAD is desired.)  Some of the new KIT inhibitors either approved for mastocytosis or being investigated for mastocytosis (e.g., midostaurin, avapritinib, masitinib, etc.) theoretically have potential to also help in MCAS, but only a very few MCAS patients have been tried so far on (somewhat-difficult-to-tolerate) midostaurin, and I have not yet seen a single MCAS patient who has meaningfully responded to this drug.  For all intents and purposes at the present time, if a KIT inhibitor is going to be tried, it's just going to be imatinib. 15. There has been much reporting of late about significant abnormalities in the coagulation system in Covid-19 patients, including excessive clotting and excessive bleeding (both of which MCAD is capable of driving either directly or indirectly via an assortment of mechanisms).  Mast cells are warehouses of heparin, and mast cell activation commonly drives "unusual" bleeding -- far more commonly *localized* where the mast cell activation is taking place rather than systemic/disseminated -- both by inappropriate release of heparin and induction of fibrinolysis by non-heparin-dependent mechanisms, so if excessive bleeding is seen in a Covid-19/MCAD patient, then if mast-cell-targeted treatments (e.g., H1/H2 blockers and benzodiazepines) don't provide sufficient acute benefit, fibrinolytic inhibitors (tranexamic acid or aminocaproic acid, 250-1000 mg bid-qid) would be reasonable to try.  It's unclear if the heparin antidote protamine might help; I'm not aware of any cases in which protamine has been tried for bleeding from excessive mast cell heparin release.  If excessive thrombosis is seen, then "anti-inflammatory" and anti-thrombotic treatments of course need to be considered, but since MCAD can (again, in my experience) easily drive the development of autoimmune disease of any type, a careful check for anti-phospholipid antibodies (which, if found, raise therapeutic possibilities of immunosuppressants, rituximab, gamma globulin supplementation, and plasmapheresis) is warranted in any MCAD patient who develops thrombosis. 16. There also has been a good bit of reporting of late of the renal damage in Covid-19 patients.  And, yes, mast cells are present in the kidneys and throughout the urinary tract just like they're present in every other tissue/organ/system in the body.  I consider pentosan to be sort of the "cromolyn of the urinary tract," and I wouldn't hesitate to add pentosan (100 mg bid-tid) to the regimen of any Covid-19/MCAD patient who's having "mysterious" renal, ureteral, cystic, or urethral issues which are not responding to other MCAD-targeted treatments.  Note that chronic use of pentosan requires liver function test monitoring (e.g., monthly in the first quarter, then quarterly). 17. I am aware there have been reports of non-virally-targeted antibiotics (e.g., azithromycin, ivermectin, etc.) possibly helping to ameliorate the course of Covid-19 infection -- despite no such drugs ever having been shown to bear any virucidal properties.  (Ivermectin is an interesting drug in this potpourri of antibiotic drugs, as it has recently been shown by at least one laboratory to have virucidal properties *in vitro* against Covid-19, but independent studies (albeit just by computational simulation thus far) suggest the tissue concentrations of ivermectin likely necessary to achieve this effect *in vivo* probably are well beyond what is achievable with what is thought to be maximal safe dosing for this drug.)  I am loath to recommend antibiotics which do not have demonstrated in vivo Covid-19-virucidal properties to be used as treatment intended to be virucidal against Covid-19; such recommendations just make no sense.  That said, I think it bears note that *many* antibiotics (e.g., the macrolide family (erythromycin, azithromycin, clarithromycin, etc.), the tetracycline family (doxycycline, minocycline, etc.), clindamycin, clofazimine, dapsone, metronidazole, rifampicin, the anti-malarials, ivermectin, levamisole, etc.) have anti-inflammatory properties utterly independent of their microbicidal (i.e., "antibiotic") properties.  Many physicians are unaware of these effects, and even those who are generally aware of such properties often underappreciate the potency of these properties in some inflammatory scenarios in some patients.  As such, analogous to how one can use "anti-inflammatories" other than traditional NSAIDs (e.g., ketotifen, cannabidiol, flavonoids, leukotriene blockers, JAK1 inhibitors) to try to settle the hyperinflammation of severe Covid-19 illness, I also wouldn't have any problem whatsoever with adding any of these anti-inflammatory "antibiotics" (preferably, of course, those which tend to be better tolerated, e.g., azithromycin, doxycycline) to the regimen of a severely afflicted Covid-19 patient (regardless of whether MCAD is present or not), though doctors prescribing such drugs probably ought to be transparent with their patients (and patients' families) that such drugs are not expected to have any virucidal effects and are not being given for any other antibiotic effects and instead are being used for their anti-inflammatory properties (whether targeted against MCAD-driven inflammation or against inflammation driven by any other cellular source).  Of course, if an antibiotic is *also* being used to treat proven or suspected non-Covid-19 infection (perhaps arising superficially/consequentially to a Covid-19-driven hyperinflammatory state), that's obviously perfectly fine, too, but if no infection (other than Covid-19) is clearly present, then I think we need to be cautious about the justifications we present to our patients about why we might be treating them with "antibiotics" of various sorts. 18. Finally -- and I'm a bit hesitant to bring this up due to the controversy surrounding the subject -- hydroxychloroquine has been found helpful in some MCAD patients (https://www.ncbi.nlm.nih.gov/pubmed/30004016).  But it should go without saying that use of this drug should be closely monitored. There are plenty of other drugs, too, which have been found helpful in various MCAD patients (e.g., see discussions of such at open-access https://www.ncbi.nlm.nih.gov/pubmed/27132234 and open-access chapter 6 at https://novapublishers.com/shop/mast-cells-phenotypic-features-biological-functions-and-role-in-immunity/), but I think initiation of at least twice-daily dosing of an H1 blocker and an H2 blocker at a bare minimum, "plus/minus" a benzodiazepine, cromolyn by one or more routes, ketotifen, leukotriene blocking, a flavonoid, vitamins C and D, CBD, and/or (in tolerant patients) an NSAID would be a very reasonable "cocktail" to start in a Covid-19-infected patient with known (or at least "strongly suspected" MCAD).  Note the "and/or" in that last sentence, i.e., I am not saying that a Covid-19/MCAD patient should necessarily be started on *all* of those treatments, but rather "some appropriate selection" of MCAD-targeted treatments beyond a core H1/H2/benzo regimen.  Anti-inflammatory antibiotics could be considered, too (with appropriate monitoring for the particular antibiotics (e.g., hydroxychloroquine) warranting such), though I usually don't think of such drugs as anywhere close to "first-line" drugs in treating MCAD.  Tofacitinib and/or imatinib would be reasonable to start in the patients who don't respond to the above and are still "heading downhill," though I suspect ruxolitinib and baricitinib would be good alternatives if a trial of a JAK1 inhibitor is desired and tofacitinib is not readily available.  The IL-6 inhibitor tocilizumab (yes, it's yet another topic for another day as to what portion of the "systemic inflammatory response syndrome" (SIRS) and "chronic inflammatory response syndrome" (CIRS) populations probably have MCAS at the roots of those diseases) seems quite reasonable to try in the Covid-19 patient who's at death's door regardless of whether the patient is thought to have MCAD or not.  (Note mast cells certainly produce plenty of IL-6.)  The IL-1 inhibitors (e.g., anakinra, canakinumab) might be reasonable "Hail Mary" drugs to try, too.  (Again, note mast cells produce plenty of IL-1.)  Another interesting drug to try would be the anti-IL-4/IL-13 monoclonal antibody dupilumab, as IL-13 is a key route for driving mast cell activation, and I've begun seeing a wider spectrum of benefit in my MCAD patients given this drug than in just the psoriasis/eczema at which this drug is primarily targeted.  (Yes, it's a topic for another day as to what fraction of the eczema and psoriasis populations have MCAS at the roots of those diseases.)  At least on a theoretical basis, one even wonders if the calcitonin-gene-related-peptide (CGRP) inhibitors (both the injectable long-half-life monoclonal antibodies such as erenumab, fremazenumab, and galcanezumab and the short-half-life small molecule ubrogepant) might be helpful, as the mast-cell-surface CGRP receptor is another route for mast cell activation/degranulation, though so far the CGRP inhibitors have not shown much benefit for MCAS-type symptoms beyond the migraine headaches they primarily target.  (Yes, it's a topic for another day as to what fraction of the refractory migraine headache population has MCAS at the root of that disease.)  I do not have much expectation that the anti-IgE monoclonal antibody omalizumab (Xolair) would be of much help in Covid-19/MCAD. And even though the question at hand is mast-cell-focused, I feel it's pertinent to again note (as first mentioned in my posting two weeks ago at my partner's Facebook page athttps://www.facebook.com/taniadempseymd/photos/a.1619874344943319/2538033749794036/?type=3&theater) that it's possible that what's going on in the terminal phases of severe Covid-19 illness is a *macrophage* activation syndrome (MAS) which is being triggered either directly by the virus and/or by exacerbated MCAD, and as such, treatments targeting MAS would be reasonable to try, too.  I'll note that the JAK1 inhibitor ruxolitinib is already fairly well established as a treatment for MAS (and the similar hyperinflammatory disease hemophagocytic lymphohistiocytosis (HLH)), but overall I'll save a discussion of treatment for MAS for another day since the question presently at hand is mast-cell-focused. Above all, it must be kept in mind that MCAS is an extraordinarily heterogeneous disease (at mutational, mediator expression, and clinical levels) which warrants extraordinarily individualized treatment decisions.  Yes -- and especially so in a crisis where there's just not a whole lot of time available to think about individual cases -- everybody just wants an easy-to-memorize protocol or cocktail, but MCAD just isn't simple or easy like that.  If MCAD were a simple problem, it would have been figured out a long time ago.  The only problems left to be solved are the complicated ones. In closing, again, it's critically important to understand and appreciate that mast cells produce and release more than a thousand mediators.  They are not merely the mediators of some allergic reactions and the bags of histamine and tryptase and we were all taught in training, and they have *enormous* potential, *especially* when functioning abnormally, to drive inflammatory problems, allergic-type problems, and, on longer time scales, even aberrancies in growth/development in any tissues (i.e., dystrophisms, fortunately almost always benign (e.g., cysts, fibrosis, vascular anomalies, etc. etc. etc.)).  Note, too, that it's *inflammation*, far more so than allergic-type phenomena or dystrophisms, which is the "universal constant," the sine qua non of MCAD/MCAS.  Take a *careful*, life-long history from the patient if at all possible (note "previously healthy" patients may actually not have been so healthy once you start diving into the weeds of it all, and you're probably going to have to re-train yourself all over again how to take a really thorough review of systems, as MCAD patients typically long ago stopped reporting their symptoms (from having learned that all manners of investigations and empiric therapies never accomplished anything, so they just "learned to live with it" and stopped complaining), and instead you're going to have to *extract* from them the problems they've long had, but if you can somehow manage to just give them the *time*, show them that you're *listening*, and let them *tell their story*, you'll be amazed all over again, just like you were in medical school, as to what you'll learn about your patient), and pay attention to the possibility that MCAD (far more likely MCAS than mastocytosis) might be the root issue in any of your patients with a plethora of chronic multisystem inflammatory +/- allergic +/- dystrophic troubles, and when you start diagnosing it (preferably with appropriate testing rather than just a "clinical diagnosis") and you start treating it, you soon will be astounded as to the wide range of improvements which can be gained from drugs you never before would have thought could bring such benefits. With the caveat that new data are emerging almost every day and I thus reserve the right to change my opinions based on emerging data, the above are my thoughts as of today on MCAD-targeted drugs and strategies which would be reasonable to try in a Covid-19/MCAD patient.  I should note, too, that I have discussed all of the above with my associate Dr. Tania Dempsey here at Armonk Integrative Medicine, and she fully concurs with all of these opinions, too.


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Please note, this page will serve as an updated resource on COVID-19 and MCAS. We will post the Facebook posts we have shared on this page as well.


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May 7, 2020


Myself and Dr. Tania Dempsey, together with more than 40 other practitioners from all over the globe who have considerable experience with diagnosing and managing mast cell activation syndrome (MCAS), have now published in the peer-reviewed medical journal "Diagnosis" a major new article comparing the different approaches being used by different authorities in diagnosing MCAS. The new article asserts that the diagnostic criteria previously advocated by Dr. Gerhard Molderings at the University of Bonn and a small group of collaborators should now be seen as a much more widely (indeed, literally globally) accepted "consensus-2" proposal for diagnostic criteria, i.e., a new alternative to the first "consensus" (or "consensus-1") diagnostic criteria which have long proven problematic in a number of respects.


Now, patients whose illnesses "clinically fit" with MCAS but who could not meet diagnostic criteria under the problematic "consensus-1" criteria (and thus could not access treatment for the MCAS they likely have) finally have a new, globally accepted path to potentially achieve diagnosis -- and thus effective treatment.

This is an incredibly important development for the millions of patients world-wide who likely have MCAS but haven't been diagnosed yet. When the only "consensus" diagnostic criteria that consensus-adherent doctors had available for making the diagnosis of MCAS were the "consensus-1" criteria, only about 1% of the patients who truly have the disease were getting diagnosed by those criteria.

The consensus-2 criteria now provide global consensus criteria (and a consensus declaration made by a much larger group of authors than the group which developed consensus-1, at that) which will help the other 99% get diagnosed. And given that achieving a definitive diagnosis (per published, widely accepted criteria) is a critical step toward accessing the *treatment* needed for somebody to get better, the new consensus-2 criteria will be of enormous benefit to a vastly greater number of patients than could previously benefit via the consensus-1 criteria.

The article's webpage at the publisher's website also can be reached via the federal government's "PubMed" medical literature index at

https://www.ncbi.nlm.nih.gov/pubmed/32324159


Diagnosis of mast cell activation syndrome: a global "consensus-2"



-Dr. Lawrence Afrin


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CORONAVIRUS AND THE CYTOKINE STORM

"Nobody who knows me or my writings will be surprised to learn I have been suspecting for some time now that the "hyperinflammation" (a.k.a. the "cytokine storm") which unfortunately seems to be the principal feature in the later stages of those with Covid-19 infection who suffer more serious courses of the illness might be arising -- perhaps not in all in such patients, but in "at least some" to "perhaps many" -- either directly or indirectly due to a mast cell activation syndrome (MCAS) which, more likely than not, was already present long before the infection came along.


I feel it's important to add as a sidebar at this point that I know it's been presented as "mysterious" that many Covid infected patients have been described as "previously healthy" and yet still are getting so ridiculously sick from this virus, but I've learned the hard way that many MCAS patients, too, have been described (indeed, often even have long taken to describing themselves) as "healthy" and that such a descriptor often belies the assortment of symptoms the patient in truth has long been having but has learned to tolerate/dismiss/ignore (or even self-treat) for various reasons we can all easily imagine, so you'll have to pardon me for wondering how accurate these descriptions of "previously healthy" actually are. 


I would imagine that the doctors in the emergency rooms and in the hospitals, who are being overwhelmed taking care of these very sick patients simply don't have the time to delve much into the patient's history, extracting reports of symptoms the patient in truth has long been experiencing but also long ago stopped reporting/volunteering after learning that, for various reasons, such complaints were going to get the patient nowhere. Instead, the doctors just take it as gospel from the patient's chart, or even from the patient himself/herself, that he/she was "previously healthy" and move on to attending to higher priority matters. And thus, without a full backstory on the patient, it gets assumed by at least the doctor, and again sometimes even the patient, too, that the patient indeed was "previously healthy" when the truth is a good bit otherwise. See a few dozen patients with MCAS (let alone a few thousand, as I have) and you'll soon learn to question much of what's previously been assumed and written about a given patient who's now being suspected of having MCAS. Maybe most of what was said previously was accurate/correct -- and maybe parts of it were not and instead were just reported or recorded at the time as they were as a convenient shortcut when the doctor and/or the patient is pressed for time.)


At the same time, though, it must be acknowledged that there are certain aspects to the hyperinflammation of Covid-19 illness which are not well explained -- at least, not *directly* explained well -- by abnormal activation of the patient's *mast cells* (i.e., MCAS, not even severe MCAS) and instead are better explained by what ordinarily is a *much* rarer hyperinflammatory phenomenon called macrophage activation syndrome (MAS) -- though it's certainly not necessarily the case that it's an "either/or" situation with a severely ill Covid-infected patient having "either MCAS *or* MAS" and instead it's easily possible (pure conjecture at this point on my part, but nevertheless easily *possible*) that there is some curious aspect of the interaction between the Covid-19 virus and mast cells (normal or abnormal) which sparks the end-stage MAS. There even are aspects to the Covid hyperinflammatory syndrome which are not well explained by MCAS or MAS and *may* be due to yet other mechanisms.


So, yes, it's *possible* -- especially so given present best estimates of the substantial prevalence of MCAS -- that (almost always previously unrecognized/undiagnosed/untreated/uncontrolled) MCAS, by being "triggered" by the virus to "flare" to a more activated state, *might* be a key factor in the "inappropriate" progression of Covid-19 infection from a mild-moderate illness to a severe illness, and it's *possible* that MAS, too, might either emerge on its own or as an additional complication of flaring of MCAS. But let's get real here: at present these are merely hypotheses, without a single shred of *actual research findings* to support them. There's just been no research at all -- none, zero, zilch, nada -- into the interactions of the Covid-19 virus with MCAS. Importantly, note I am *not* saying that we don't know whether Covid-19 causes mast cell activation. Of course the Covid-19 virus causes mast cell activation. There's already at least one peer-reviewed published paper on that, but even without a published paper on that, we'd already know this to be a fact because we've *long* known that mast cells *normally* react to infections (including viral infections) of all types. That's what mast cells are *supposed* to do. So, the issue isn't *whether* mast cells are reacting to this virus. Rather, the issue is whether the mast cells in the individual patient's body are reacting *normally/appropriately* to this virus. And *maybe* the patient's *normal* mast cells indeed are reacting *normally* to this virus -- and *maybe* it's the case that it's just the (again, likely previously unrecognized/undiagnosed/untreated/uncontrolled) *abnormal* mast cells in an MCAS patient which are reacting *abnormally* to this virus. But, again, these are just interesting hypotheses, and it's going to need hard research to sort it all out -- though nobody who knows how little appreciation of mast cell activation disease (especially MCAS and its prevalence) there presently is in the medical profession at large will be surprised if such research doesn't get done for a long time to come (if ever). And if it gets done, this (challenging!) research almost certainly will get done at the major academic medical centers which have the sophisticated biomedical research resources needed to do this sort of work.


Finally, the question about whether imatinib might be helpful in Covid-19 infection might as well be expanded to a much more generic question as to whether *any* drug which has been shown helpful in at least some MCAS patients (and, for that matter, in MAS patients) might be helpful, at least at some point, in (at least some) Covid-infected patients with known or suspected MCAS. (Note that -- at least here in the U.S. -- imatinib is an extraordinarily expensive drug, and there's simply no way (yet) to know whether far less expensive drugs might serve the patient just as well as imatinib.) Again, though, we just don't have the research to know the answer to this question of therapeutic utility (vis-a-vis Covid infection) with regard to *any* of the drugs already found helpful in various MCAS or MAS patients. Yes, a few such drugs actually are being tested in Covid-19 clinical trials right now (and you can bet your bottom dollar that the researchers running those studies are not looking to see whether the subjects in those studies have MCAS), but the bottom line is that it's way too early right now to know with any meaningful degree of confidence which of these drugs (if any!) can be meaningfully helpful in Covid-infected patients with known or suspected MCAS (or any other Covid-infected patients, either, for that matter). 


All I can tell people with interests in such matters is "Stay tuned..." And since this posting certainly isn't the place to go giving specific medical recommendations for individual patients, all I can say with regard to treatment of any patient with known or suspected MCAS who also unfortunately contracts a Covid-19 infection is that that treatment probably ought to "take into consideration" the patient's MCAS, but *specific*, *personalized* recommendations must be, well, *personalized* to the individual patient. 


Anybody who knows MCAS even a little bit knows how differently the disease behaves in different MCAS patients; treatments which make sense to try in one patient might well be pointless (or even harmful!) in another. As always, if the local doctors attending to a patient with known or suspected MCAS would like to informally consult Dr. Dempsey or me regarding potential approaches to managing MCAS in the context of a Covid-19 infection, we will be happy to try to assist, and we merely request that the local doctor should *directly* reach out to us at our main office number (914-730-7390) to initiate a dialog. 


MCAS itself -- let alone MCAS in the context of a Covid-19 infection -- is just far too complicated for us to try to have a technical medical discussion about it with the local doctor *via the patient*. It just won't work. There has to be *direct* doctor-to-doctor dialog, and for various reasons, it doesn't even work for the local doctor to ask the patient to ask us to call back to the local doctor. The local doctor himself/herself needs to *directly* reach out to us, and we make ourselves readily available to our colleagues who do so, to try to provide what assistance we can in the best spirit of professional collaboration."


-Dr. Lawrence Afrin

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If I go to the hospital, how will I explain to the doctors that I have immune issues, like MCAS, and will the doctors understand how to address it? What should I tell them? 

In this age where the vast majority of the world's doctors have never even heard of MCAS let alone have any meaningful degree of familiarity with it, all one can do is inform the doctor that one has long had a chronic condition in which one's mast cells are excessively activated, causing a wide, multisystem range of inflammatory and allergic/reactive-type problems -- and thus that it's easily possible that the inflammatory reaction to the COVID-19 virus in that person's body may be even more heightened than a usual inflammatory reaction to a virus. (Importantly, note that this is a different concept than how *susceptible* one is to contracting an infection with the virus. An MCAS patient's *susceptibility* may be no significantly different than anybody else's susceptibility -- the virus is remarkably infective/contagious, no matter what type of patient one is talking about -- but an MCAS patient might be at higher risk for suffering an abnormally greater inflammatory *reaction* to the virus than anybody else's reaction.) 


Plus, there of course may be risks in some (certainly not all) MCAS patients for reacting to some of the medication products which the patient's doctors may try to use to help control some of the symptoms (of the infection and of the body's inflammatory reaction to the infection). Thus, a courteous caution (by the patient or a family member or attendant) to the patient's doctors that if "unusually exuberant," and "difficult-to-control," inflammation is seen in the MCAS patient who has contracted a COVID-19 infection, then the doctors should *quickly* consider trials in the patient of medications aimed at suppressing mast cell activation, such as both H1 and H2 antihistamines, leukotriene inhibitors (such as montelukast or zafirlukast or zileuton), cromolyn (especially nebulized cromolyn if respiratory issues become significant), non-steroidal anti-inflammatory drugs (NSAIDs, unless the patient has previously demonstrated intolerance of such drugs), other types of anti-inflammatories (such as ketotifen and quercetin and luteolin and cannabidiol, among others), vitamin C (and possibly also vitamin D), benzodiazepines, and other mast-cell-targeting drugs. 


In severe cases, certain very expensive anti-inflammatory drugs, such as JAK inhibitors and interleukin-6 antagonists and interleukin-1 antagonists, might be reasonable to try, too. Furthermore, although *ordinarily* a cautious approach to such medication trials ("one by one") is highly recommended in MCAS patients (because of (1) the challenges in identifying the particular culprit if multiple medications are started at the same time and the patient has a reaction, and (2) the risks in many MCAS patients in reacting to the excipients in medication products), in the setting of a rapidly worsening COVID-19 infection there just won't be the time for such caution and it will be OK to try initiating multiple such treatments (for example, H1 and H2 blockers and cromolyn and montelukast or zafirlukast or zileuton) all around, or at, the same time. Yes, if the patient then unfortunately demonstrates an adverse reaction to such a new cocktail, it will become quite a challenge to identify which component of the cocktail is causing the trouble, but, again, in the setting of a rapidly worsening COVID-19 infection, there often just won't be sufficient time to permit introduction of new medication products into a patient's regimen one by one.


If the patient is having trouble which the patient or close ones recognize, through the greater experience they have had with the patient than the patient's doctors at the time might have had, as more likely to be heightened symptoms of mast cell activation (MCAS) than any other process and yet the patient's present doctors do not appear to be giving serious consideration to the potentially important role that mast cell activation might be playing in the patient's total picture of illness at that time, then it would be very reasonable to ask the patient's doctors (again, courteously; there's just nothing productive that's ever going to be accomplished by getting hostile with any doctor, and such an approach could easily wind up being *counter* productive) for an urgent consultation with an immunologist, as there is some chance that immunologists (or allergists/immunologists) might be more familiar with MCAS than other types of doctors.

As is the case in general for MCAS patients, guidance for MCAS management in COVID-19-infected MCAS patients will need to be provided on an individualized basis. We are happy to speak with the other emergency room medical physicians attending to any of our patients at this time who may be infected with COVID-19; all they need do is contact us. 


Although we have to prioritize care for our established patients, we are happy to speak with other health care providers (doctors or otherwise, even if they are attending to patients who are not established with our own practice) who would like to understand more about mast cell activation disorders such as MCAS (for example, if they need urgent counsel on how to treat a COVID-19-infected patient who appears to be suffering severe inflammation from mast cell activation syndrome).



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