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January 2017

Flame

A few days ago, while I was walking my dog, I thought I saw my best friend’s father. He died two and a half years ago after a series of complicated health issues. I had known him for 25 years.

After not seeing him, I started thinking about the last time I saw him. It took me a while to remember when exactly that was. I thought of events we both attended, weddings, birthdays, and backyard fires on summer nights.

The last time I saw him wasn’t at an event. A few weeks before he died, I visited his daughter and walked upstairs to say hi to him and his wife before I left. It was painfully ordinary and completely unremarkable. Just another autumn day, only noteworthy in retrospect. I had no way of knowing that it was the last time I would see him.

I find myself wondering lately if today will be the last time I do something, some small thing that formed the rich backdrop of my life. I also find myself wondering how many things I did for the last time without realizing it. It’s so easy to do, such a slippery slope. One day, you’re tired and you want a break. Not a forever break, just a short break. So you decide that you won’t do these things today. Letting things go for one day is fine. And so you do. You let it go. You put it down and you never pick it back up again.

When was the last time I didn’t have abdominal pain? When I felt healthy? What were those days like? What did I feel? What animated the world around me? I can’t remember. Years from now, when I look back, I won’t remember this moment either, or the meaning of these words. I won’t even remember writing them. How can any of this matter so much when I won’t even remember?

Every patient has a line where they stand their ground to not lose anything else. Every patient decides that this position must be held for as long as possible and that once this line is crossed, you can never go back. This is how I feel about eating. This is my line. It’s not that I can’t live with a feeding tube or on IV nutrition. It’s not that I find either of these options particularly repulsive. I just want to be able to eat. Such a simple, primal thing.

I have always felt that I have this little light inside of me, really deep, beneath all the swollen and damaged places. It has been dimming for years now. I have been cupping my hands around this tiny flame to keep it alive. But I can’t keep out the wind forever. I am only one person. And I am so, so tired.

I am afraid that I am approaching the last of the days when I can eat. I am afraid that this little light will wink out and nothing will replace it.

Skinny

My body is my adversary. I hardly remember a time when that was not the case. Even before I got sick, I struggled to make my body do the things I wanted it to. You can only do that so much before you begin to resent these shells we live in.

I was a small child, very small. I wasn’t four feet tall until eighth grade. That year, I grew a foot, and never again. Throughout elementary school, people commented on how small I was and how little I weighed. I was limber and very nimble; together with my lack of height, these characteristics gave me the body of a gymnast. I did splits and back handsprings and aerial cartwheels in my living room and backyard. I threw tricks during recess. I weighed so little that very little strength was required.

In seventh grade, I acquired the body of a woman overnight. I took ballet classes at that point in a small brown building around the corner from my house. One day, I caught my reflexion in the wall mirrors. I was rounder, with thick legs, breasts and a forming hourglass figure. I was still short but I wasn’t small.

I lamented the loss of my tiny frame but I wasn’t overly concerned with toning or losing weight. I walked a lot and was active if not athletic. In 2000, I started getting a three month birth control injection. In the months that I followed, I gained 26 lbs. I went from being thicker to being fat.

I was very unhappy with my body throughout college and grad school. I worked more than full time and carried a full course load. I picked up better eating habits when I got an apartment but I didn’t have time to exercise.

In 2007, I woke up in the middle of the night and while walking across my living room carpet to the bathroom, I realized my ass was jiggling. It actually stunned me awake. The next morning, I signed up to walk the Breast Cancer 3-day, 60 miles in three days, largely for the fitness aspect of the event. For the next six months, I walked increasing distances 3-4 days a week and did short workouts on the other days. I didn’t change my diet at all except for not drinking coke. I lost 25 lbs and gained a lot of muscle.

The summer of 2007 stands out for me as a time when I was happy with my body. I was still bigger than I wanted to be, but I was actively losing weight and felt much stronger and more able. I went backpacking in Scandinavia and was on strenuous mountain hikes without trouble. I took up rock climbing. I completed the 3-day and continued with the training schedule. Over the next three years, I would walk four more 3-days.

In 2009, I lost most of my hearing. I ended up on high dose oral steroids for a few weeks and quickly gained 20 lbs. My face was squishy and I was swollen everywhere and nothing fit anymore. At the same time, my disease was also accelerating. I still walked and tried to make time for yoga class but I was in a lot of pain and often too exhausted to work out. I gained more weight. And more.

By 2012, I weighed about 165 lbs. I started doing advanced yoga several times a week and was able to lose 10 lbs in about nine months. The following year, I had my colostomy placed and lost 10 more lbs. I was stably 145 lbs until the end of 2013 when I started high dose steroids again along with several other meds known to cause fluid retention and weight gain. I gained 30 lbs in six weeks and then gained a little more. My abdomen was so swollen that I looked nine months pregnant. I had to wear maternity clothes to accommodate my belly.

Decreasing steroids took off some weight but I was still much bigger than I wanted to be. In 2015, I had another GI surgery. I again lost 10 lbs almost immediately. Following the surgery, I was able to do a reconditioning program before I returned to work in order to build up my stamina and physical tolerance for exercise. I was less inflamed than before the surgery and reacting less. I was able to address several smaller concerns that had been on the back burner like vitamin D levels. Together, these changes allowed me to recondition effectively. I could exercise again, making it easier to manage my fitness. (For those interested, I describe my reconditioning program here.)

Over the next 18 months, I lost another 10 lbs. I found long, flat muscles in places I never expected to see. Even as I cursed my body for having this disease, I was happier with how it looked. I had to buy new clothes because even my smallest clothes, saved from previous years, were too big.

Last fall, I started dropping weight, much faster than I should have been. At the same time, I was having fevers, night sweats, and a slew of other symptoms I have written about. I countered the weight loss by eating more but I eventually developed gastroparesis and started throwing everything up. I am now getting some of my calories through 2L of IV fluids daily. I am now getting most of my calories from “nutritional drinks”. (My homemade version is Orgain chocolate protein powder, organic maple syrup, and almond milk.) I am tolerating it but I can’t drink it fast without getting nauseous. I’m not getting much fat in my diet and my body is now showing that.

I took a picture of myself tonight. For the first time, I was unsettled by how I looked. I am getting very thin. I am the smallest I have been as an adult. I can certainly lose more weight before I’m in danger but it was seriously jarring to see myself. I am leaving “you don’t look sick” territory.

So here I am at 3am thinking of ways to gain back weight that I spent years trying to lose. A different kind of adversary.

 

29 Jan 2017

29 Jan 2017 2

 

 

 

The Provider Primer Series: Relevance of mast cells in common health scenarios (continued)

Reason for care Post op care
Role of mast cells Mast cells are inherently activated following surgery as they drive tissue remodeling, angiogenesis, and wound repair.[i]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Mechanical trauma or pressure, such as dressing a wound or palpating the area, can directly induce degranulation and mast cell activation[ii].

Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation and cannot be taken by some mast cell patients.[iv]

Codeine and derivatives can trigger mast cell degranulation[v].

Vancomycin, gyrase inhibitors and cefuroxime should be avoided where possible due to risk of mast cell activation.[vi]

Amide caine anesthetics are preferred over ester caines.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management.[vi]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

Adhesive allergy is not unusual and patients may require specific occlusive dressings, tapes, or wound glue.

Notes regarding mast cell treatment Antihistamines and mast cell stabilizers can be helpful in mitigating common post op symptoms such as opiate induced itching and nausea. COX inhibitors can help with pain management.[vii]
Special considerations for mast cell patients Mast cells are the largest reservoir of endogenous heparin. Patient should be monitored for coagulopathy.[viii]

Mast cells contribute significantly to post operative ileus.[ix]

Intestinal manipulation directly results in mast cell degranulation.[ix]

 

Reason for care Hypertension
Role of mast cells Mast cell mediators can impact blood pressure. Histamine acting on H2 receptor can promote hypertension.[xi]

Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II.[xi]

9a,11b-PGF2, the degradation product of prostaglandin D2, thromboxane A2, and leukotrienes increase blood pressure.[xi]

Impact of condition on mast cells Dysregulation of angiotensin II and renin levels can affect mast cell behavior.[x]
Notes regarding condition treatment ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]
Notes regarding mast cell treatment Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.
Special considerations for mast cell patients Mast cell patients taking β-adrenergic receptor antagonists (beta blockers) should carry a glucagon pen to increase efficacy of epinephrine in anaphylaxis.[xi]

As many as 31% of patients with mast cell disease demonstrate elevated arterial blood pressure secondary to mast cell activation. These elevations may be episodic or chronic.[xi]

Mast cell patients may also have hyperadrenergic postural orthostatic tachycardia syndrome (hyperPOTS), a condition that can cause hypertension.[xii]

 

Reason for care Heart disease
Role of mast cells Renin, chymase, and carboxypeptidase A all participate in hypertension by dysregulation of angiotensin II, contributing to evolution of arrhythmia.[xi]

Prostaglandin D2, VIP, PAF, IL-6 and nitric oxide are all vasodilating and can contribute to tachycardia.[xi]

Tryptase, histamine, PAF, IL-10, TNF, IL-4, IL-6, FGF, and TGFB can contribute to heart failure.[xi]

Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Impact of condition on mast cells Heart disease, especially heart failure, can disrupt release of catecholamines including norepinephrine.[xv] Norepinephrine dysregulation can impact mast cell behavior.

Dysregulation of angiotensin II and renin levels can affect mast cell behaviorx

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]

Several mast cell medications can impact levels of histamine, renin, and angiotensin II, all of which can affect blood pressure.

Epinephrine can provoke myocardial ischemia, prolong QT interval, and exacerbate coronary vasospasm and arrhythmia.[xiv]

Special considerations for mast cell patients Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

 

Reason for care Chest pain
Role of mast cells Mast cells participate in the formation, destabilization and rupture of atherosclerotic lesions.[xiii]

Histamine release is associated with acute coronary syndromes such as Kounis Syndrome, commonly known as “allergic MI” or “allergic angina”.[xiv]

Leukotriene C4, adrenomedullin, tryptase and chymase participate in the formation, destabilization and rupture of aneurysms.[xiii]

Mast cells participate in esophageal inflammation in several models, including from acid reflux.[xvi]

Mast cells contribute to GI dysmotility which can cause esophageal spasms.[xvii]

Mast cells are involved in the transmission of pain stimuli.[iii]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Psychological and physical stress can trigger an inflammatory response that involves mast cell activation.[iv]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.xx

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Fentanyl and fentanyl derivatives are the preferred narcotic for mast cell patients due to low risk of degranulation. Hydromorphone and oxycodone are suggested by some authors and see use in mast cell patients.[vi]

Benzodiazepines can provide anxiolytic and anticonvulsive support in mast cell patients are needed.[vi]

ACE inhibitors and β-adrenergic receptor antagonists (beta blockers) should be avoided. In particular, beta blockers directly interfere with the action of epinephrine and can impede anaphylaxis management. Alternatives include calcium channel blockers, renin inhibitors, and ivabradine, among others.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief of prostaglandin induced symptoms.[vi]
Special considerations for mast cell patients Mast cell patients may experience GI dysmotility which can cause esophageal spasms.[xviii]

Mast cell patients sometimes have eosinophilic esophagitis, causing esophageal spasms, food impaction, and pain.[xix]

Over 20% of systemic mastocytosis and mast cell activation syndrome patients experience palpitations and supraventricular tachycardia.[xi]

Prostaglandin D2 can cause tachycardia. PGD2 is associated with late phase allergic response and symptoms may be delayed for several hours after allergic event.[xi]

One study showed that 12/18 mast cell activation syndrome patients showed diastolic left ventricular dysfunction.[xi]

Mast cell patients can present with Kounis Syndrome. Management of Kounis Syndrome relies upon addressing both cardiovascular aspects of the episode as well as allergic aspects.[xiv]

Costochondritis can occur in mast cell patients and may present as chest pain.

Mast cell patients may also have postural orthostatic tachycardia syndrome (POTS), a condition that can cause blood pressure and heart rate irregularities.[xii]

IV contrast poses significant to mast cell patients due to the high risk of systemic degranulation. If required, premedication is advised.[vi]

References:

[i] Douaiher J, et al. (2014). Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing. Adv Immunol, 122, 211-252.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1), 113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharma,ological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. (2011). Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol, 4(10).

[viii] Carvalhosa AB, et al. (2015). A French national survey on clotting disorders in mastocytosis. Medicine (Baltimore), 94(40).

[ix] Peters EG, et al. (2015). The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil, 27(6), 743-749.

[x] Biscotte SM, et al. (2007). Angiotensin II mediated activation of cardiac mast cells. The FASEB Journal, 21(6).

[xi] Kolck UW, et al. (2016). Cardiovascular symptoms in patients with systemic mast cell activation disease. Translation Research, x, 1-10.

[xii] Shibao C, et al. (2005). Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension, 45, 385-390.

[xiii] Kennedy S, et al. (2013). Mast cells and vascular diseases. Pharmacology & Therapeutics, 138, 53-65.

[xiv] Kounis NG. (2016). Kounis Syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[xv] Florea VG, Cohn JN. (2014). The autonomic nervous system and heart failure. Circulation Research, 114, 1815-1826.

[xvi] Morganstern JA, et al. (2008). Direct evidence of mast cell participation in acute acid-induced inflammation in mice. J Pediatr Gastroenterol Nutr, 46(2), 134-138.

[xvii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xviii] De Winter BY, et al. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta – Molecular Basis of Disease, 1822(1), 66-73.

[xix] Nurko S, Rosen R. (2010). Esophageal dysmotility in patients with eosinophilic esophagitis. Gastrointest Endosc Clin N Am, 18(1), 73-ix.

Unto itself

It is hard to adjust to the idea of being sick. Not so much the daily activities of being sick but of identifying as sick and viewing the world through shaky, feverish lenses. But you do it because adaptation is instinctive. One day, you think, “I could get used to this.” And then you do.

It was harder for me to adjust to the idea of being very sick. Sick was manageable. Very sick is not. And I am very sick.

I took medical leave last fall. Things got out of control really fast. New complications stacked up quickly and crushed what control I still had. Every problem I ever had was worse than before and a whole bunch of new ones showed up. I slept in soaked sheets, shivering with fever dreams, waking shaky and foggy. I couldn’t keep food in the top of my GI tract and couldn’t get it out of the bottom. I took meds by the handful.

I have been sick like this before. The symptoms were different but the degree was the same. When I first applied for short term disability, I expected to return to work in six weeks. I have recovered before in shorter time. I thought if I could adjust my meds, add in some new ones, and get plenty of rest, that I could get back to baseline.

That’s not exactly what happened. Some things improved but my GI issues got worse. I suddenly had gastoparesis. I started having a lot of pain with eating, even things that were mast cell safe. I had epigastric pain on top of my normal abdominal and visceral pain. I have started having chest pains too from difficulty swallowing and food getting stuck in my esophagus. Things changed. My body changed. And my ability to handle it changed.

Around 11pm in Tuesday night, I was sitting on my couch, watching the end of a movie. I had had a completely unremarkable day. I ate normal safe food in normal safe amounts. I took my meds on time. I hadn’t done anything strenuous or upsetting.

As I was sitting there, my lower lip started to swell inside. Then my tongue. I’m not super prone to swelling and it’s not always part of my anaphylactic presentation. I went to the bathroom to inspect my mouth in the mirror. I wasn’t having any other symptoms so I swished some cromolyn and went back to my movie.

A few minutes later, my airway swelled. Things happened very quickly from that point. I was having trouble swallowing and I was producing a ton of saliva. My voice got raspy. I had hives all over my neck and chest and my blood pressure started dropping. I have epipens everywhere at home – next to my bed, on my bathroom vanity, on my desk, the kitchen table, my coffee table, my purse – and fortunately they were close enough for me to reach. I injected into my leg while on the phone with 911. My airway opened again and I used IV rescue meds while waiting for the ambulance to arrive. They transported me to the emergency department of the local hospital where I receive all my mast cell care.

I started rebounding about three hours later and needed a few more doses of IV rescue meds. I hung out overnight until I could talk to my doctors in the morning. I went home Wednesday.

I had an appointment with my mast cell GI specialist on Thursday. In news that shocks no one, my GI tract is pretty inflamed. It is swollen and so sore that even touching it causes reflexive guarding. (Reflexive guarding is when your abdominal muscles engage when you try to touch the abdominal organs because they are sore and inflamed.)

I am off food for a few weeks at least and am currently living on homemade rehydration solution and nutritional supplement drinks per my doctor’s instructions. (For mast cell patients in a similar scenario, I have ordered Orgain, which I have used in the past when I couldn’t eat. It is vegan, soy-free and organic. I have received excellent customer service from them in the past and they took my health issues very seriously. I generally try not to specifically endorse products but I think a lot of people in this scenario may be interested.) If this doesn’t calm things down, I will do elemental formula for a while, and then potentially TPN (IV nutrition).

Yesterday morning, I woke to a call from my disability caseworker “checking in” that I was going back to work on Monday. I didn’t laugh at her but it’s mostly because of how anxious these conversations make me. I informed her that I had been removed from my home on a stretcher less than two days before. I told her to call my mast cell specialist who agreed that I was looking at a months time table for returning to work, not weeks.

There was never a future for me that did not involve top to bottom GI failure. My GI tract is so dysfunctional from years of inflammation and damage that it has become a disease unto itself.

I knew this would happen. I just didn’t think it would be now.

Sick for a day

A story: Part Three

The vertebral injury healed perfectly but the underlying nerve injury didn’t. I developed an inversion of my right foot that persisted for eight years before it was remedied. The foot always inverted but it wasn’t always severe. There were times when I could get my heel flat and walk “normally” but it took effort.

The inconsistency in my gait generated a lot of doubt from medical professionals. I was accused of drug seeking a number of times which was especially funny because I couldn’t swallow pills until I was 19 and avoided medication at all costs. Walking with a limp most of the time gave me pain in the ankle, knee, hip and back. It impeded my ability to do most forms of vigorous exercise although I did continue to walk a lot, even when it hurt.

When I was 16, I saw a doctor who was so insistent that I was lying about my foot inversion that he told me I was taking time from real sick people and should be ashamed of myself. It’s bad enough having something wrong with your body without being told over and over again that there’s nothing wrong and you are a waste of space. I walked out of the office and didn’t pursue medical attention again for years.

Continuing the theme of never having been particularly healthy, I was not particularly healthy in college. This was probably exacerbated by not getting enough rest. I was always coming down with a cold or some awful cough. I started having GI issues in earnest with significant bile reflux into the esophagus and a hard time stooling.

I started college at 16 and full time at 17. My family didn’t have money to put me through school so I worked full time throughout college to pay tuition and living expenses. I worked 30-35 hours a week most weeks while also carrying a full course load of hard sciences with labs. I was in the honors program and worked in a lab my junior and senior years to complete my honors thesis. Throughout college, I stopped sleeping on Tuesday and Thursday nights to get through my schoolwork.

I worked in health care so I was exposed to a lot. I worked as an assistant for an 87 year old doctor in Cambridge where assistant meant performing basic bloodwork and urine testing, typing notes on a typewriter, sterilizing all of our reusable equipment, cleaning up mercury from broken thermometers, and generally learning a ton of really interesting things. This doctor was very out of touch with current medicine but one of the best diagnosticians I have ever come across. A lot of my instincts in identifying problems, both health related and otherwise, come from working for him. I learned so much from him and loved working there so much that I didn’t even mind that he referred to me as “girl” or “the girl” and hand wrote my paystubs.

He died two years after I started working there. I was already also working in a pharmacy and picked up more hours there when I was no longer needed at the office. I spent 30 hours a week interacting with sick people, many of whom were contagious. Given how overextended I was, and that getting ill is expected when exposed to contagious people, it was not surprising that it took so long for me to realize that some of my symptoms could not be attributed to my lifestyle and environment.

I finally saw a movement disorders specialist when I was in college to try and correct my pronounced limp. It had gotten bad enough over the years that I usually walked with a crutch. I gained weight from birth control (I gained 26 lbs in short order when I started the birth control shot), the fact that I didn’t exercise beyond being on my feet 10 hours a day in the pharmacy or lab, and a diet that consisted mostly of Coke and Easy Mac. Gaining weight with a back injury is never a good thing.

I got physical therapy for my foot and slept with a brace on for several months to correct the inversion. It was painful and obnoxious but it worked. While my foot still “wants” to invert, I can walk with it flat without trouble. If there’s not pressure on the bottom of the foot (if I’m sitting or laying down mostly), the foot still turns in. If I’m too tired to pay attention, or experiencing a lot of physical stress (after surgery, bad anaphylaxis, etc), the inversion is evident again.

I was in grad school when I started having GI issues bad enough to seek specialized medical care. I had really bad chest pain and my throat was always irritated. I did a bunch of testing, barium swallows, scopes, esophageal manometry, and pH testing, which at the time involved threading an NG tube with a pH sensor into my stomach through my nose and then leaving in place for 24 hours. The first time, they used the wrong sensor, so I had to do it again. I started taking regular meds at that point, including a PPI and a smooth muscle relaxer to decrease spasms pushing bile into the esophagus.

This period in my healthcare was critical for a different reason: this was one of the first doctors to treat me like an intelligent, capable person with health problems. While this gastroenterologist didn’t know what was wrong with me on a global level, she agreed that something was going on and that I wasn’t inventing my symptoms. I was only her patient for a few years but I will forever be grateful to her. Her support helped give me the gumption to figure out what was really going on in the years to come.

A story: Part Two

I was never particularly healthy. I had bad asthma as a kid, pneumonia, strep. Scarlet fever several times, my first experience with the slapped red hotness of my cheeks. I had my tonsils removed when I was 7 but they eventually grew back. I was always tired. I always had trouble waking up. Nothing terrible but I was sick often.

I was also accident prone, which figures largely into this story. I wasn’t so much klutzy as in a hurry, always. I cracked the radial head in my elbow sledding when I was in seventh grade. I broke my wrist slipping when I got out of the shower. I broke the same wrist in the same place the following year when I slipped on ice and fell onto my outstretched hand. Again, nothing awful, but frequent.

By far the most important accident was fracturing both my L3 and L4 vertebrae when I was 13. I was working in a charity haunted house called the Haunted Dungeon. Some of you may remember that I have some spooky sensibilities; the Dungeon nestled into that niche perfectly. It was in an abandoned war fort called Ft. Kellogg although we called it Ft. Banks for some reason I don’t know. Every night in October, we gave tours through the underground bunker, each room elaborately planned to scare visitors. It was a blast.

The interior of the fort was concrete and perpetually damp. It was poorly lit and there were thin gutters along the walls. One night, I had run out to use the bathroom while there was a short lapse between tours. As I was coming back to my designated room, I saw a group approaching from the other direction. I was wearing a long black dress with a long black cloak and combat boots. When I started running toward the room to get there in time, I stepped into the gutter by accident. I was wearing boots and my foot got stuck. I fell hard. I was really jarred but able to jump up and get back to the room. I had no idea that I had injured my back.

I eventually saw an orthopedist because my right leg still hurt a few weeks later. He remarked on my hypermobility. My IT band, a thick length of fascia that sits on top of the hip bone, snapped back and forth over my hip bone when I walked. This was not from the fall. It happened in both legs and had for as long as I could remember. The working theory was that the fall had irritated my IT band further. I got cortisone injections and crutches. No one even took an x-ray.

I was a freshman in high school when this happened. By the time January rolled around, I was having pain, weakness and numbness in both legs. Again, the prevailing theory was that I had inflamed my pre-existing IT band issues and also that I was exaggerating and overdramatic. In April of 1998, I sat down in my high school drama class and could not stand back up. I could feel my legs somewhat but I couldn’t really move them. I sat on the auditorium and just couldn’t move.

There is no humiliation like the kind you endure in high school when you are in a compromising position in front of a bunch of your peers, many of whom make fun of you. As soon as I realized that I couldn’t get up, I knew half of my classmates wouldn’t believe that what was happening to me was real. For those first few moments, I was legitimately more afraid of being embarrassed than of being paralyzed.

I ended up at Large Famous Pediatric Teaching Hospital where I was evaluated by a doctor who thought I was inventing my symptoms and recommended I be committed for conversion reaction disorder. The next day, I saw some other doctors who thought I was inventing my symptoms and recommended I be committed for conversion reaction disorder. One resident had the presence of mind to order some imaging since not a single picture had been taken in the six months since my injury.

Over the following few days, my symptoms fluctuated during throughout the day. I had some movement sometimes, more so at night. I was taking enough naproxen to burn a hole in my stomach. After five days, I woke up in the middle of the night and had to pee. I got out of bed and walked down the stairs into the bathroom while half asleep. I still had numbness, pain and weakness but it was much improved.

This occurrence added a new dimension to the situation: that my parents didn’t know if I had actually had a medical issue or if I was just a maladjusted teenager acting out. Not only did I have major, real mobility issues, but almost everyone related to the situation thought I was full of shit.

The following day, I had my previously scheduled MRI at Large Famous Pediatric Teaching Hospital. The MRI showed that I had crunched my L3 and L4 vertebrae together with enough force that bone fragments broke off and were floating in the space between the vertebrae. The fragments inflamed the surrounding structures and a large ball of fluid had accumulated around the fragments. The fluid compressed the root nerves which bifurcated at the site of the injury before running down into my legs.

If they had performed imaging when I first injured myself, it would have been easily seen. I would have been on bed rest for 4-6 weeks and then gradually worked back up to my normal life. Instead I was 14 years old with partial paralysis and permanent nerve damage in my right leg that still kicks up 19 years later.

The MRI was hard evidence that I did in fact have an injury, a serious one, which perfectly correlated with my symptoms. Taking so much naproxen probably decreased the fluid around the fragments, relieving some pressure on the spine and returning some function.

But there was still a conversation about whether or not I actually had anything physically wrong with me or if it were psychological, a conversation I wasn’t supposed to hear. I will never forget the way I felt overhearing that. I was suddenly freezing to the point that I had to stop my teeth from chattering.

At the ripe age of 14, I had discovered the defining tenet of my health story: that no one would believe me by default. If I wanted help to manage my health concerns, I would have to convince every last person that I met that I really did have organic health problems and that I wasn’t making them up.

A story: Part One

Trigger warning: Domestic violence, violence against women

 

I have been writing stories all my life. I have hundreds of journals from the last 27 years. A lot of it is diary writing, just a record of what I did and how I felt about it. The rest is stories, mostly fantasy and science fiction. Some fan fiction from before I know the term. Lots of magic and supernatural powers so that characters could solve their problems with a flourish.

It has only been in the last few years that I write about the darker and more emotional aspects of my life for an audience. Before I started MastAttack, I wrote exclusively for myself. I was never interested in having an audience.

For me, the word ‘story’ has a connotation of fiction. Stories can be based upon truth but they are sharpened toward a particular point. When you tell stories, you guide your audience towards an end that you have engineered. Stories are always flavored by your intention in writing them.

This is one of the reasons I have resisted writing an all encompassing version of “my story” for public consumption. I’m not sure how to tell the story of my life because I don’t know that I understand it well enough. I don’t really know what path I should take to walk people through it. I don’t know where it should end.

I have the gift of a strong voice that allows me to be heard. But I don’t always know how to use that. When you are telling the story of your life, it’s not enough to be loud.

It’s scary to write it all down. Remembering brings up fresh fear and anger and despair. But I don’t think I have a choice anymore. I think I have to. I have never been more aware of how vulnerable I am as a chronically ill, rare disease patient. This is all I have. I have a story.

Both of my parents were raised in poverty. My mother is one of five children in an Irish Catholic family who grew up close to the projects but not in them. Her parents were divorced, a scandal in a Catholic family in the 60’s. My father was raised by his mother and moved around a lot. She worked as a seamstress but also had jobs on the side. His mother was murdered in 1969 by her boyfriend. She died facedown in a pool of blood in her backyard. My father ended up in foster care.

My parents married in 1983, the year I was born. My father was a parts manager at an auto dealership. My mother ran a family daycare out of our house. They owned a little white house and my sister and I were raised in it. Both of my parents worked very hard so that my sister and I would not experience some of the hardships they were raised with. We were solidly lower middle class but the specter of poverty is hard to lose. Both of my parents were nervous about not having enough money. They instilled both my sister and I with a rock solid work ethic. We both learned to be nervous about not having enough money.

I started babysitting when I was 9 and babysat often for various families. I had a job the day I was legally allowed to work part time. By the time I was 16, I worked full time for a non-profit childcare center. I worked full time to put myself through college. In grad school, I had a research assistant position, and then a teaching assistant position, at my university. I taught Microbiology. I also worked full time as a lead pharmacy tech to pay my bills. Since the day I turned 14, I have only been unemployed for nine months.

Despite working constantly while I was in school, and not having terrible living expenses, I was broke all the time. A lot of my money was spent on health care. I wasn’t sick like I am now but I had frequent acute health issues. I had chest infections and walking pneumonia frequently. I had sinus infections so bad I eventually needed sinus surgery. I had really bad bile reflux into my esophagus. I was diagnosed with rheumatoid arthritis in 2007.

I spent so much money on copays, gas getting to appointments, prescriptions, and tests. It was expensive and inconvenient. I could still function but it was difficult and frustrating.

Eventually I started getting sick in a way that wasn’t just a nuisance. I got sick for real.

Until it’s you

I have a hard time holding it together when I’m dealing with insurance companies. I’m solid in every other aspect of my healthcare but insurance has a special taste of trauma. I get anxious before anything even goes wrong because inevitably, something goes wrong.

At the end of December, my short term disability insurance company denied my STD extension because they had assessed that I had no ongoing disabling health issues. After a lot of phone calls, emails and tears, my STD was eventually approved. In the time between my denial and my approval, I was terrified. I cannot stay alive with no insurance and no money and I certainly was not well enough to return to work.

I was notified on December 30 by phone that my STD was approved. I assumed that meant that the claim was actually approved. I will no longer make such assumptions. Because what actually happened was that I was approved on January 4 and my work was not notified until January 9. I didn’t find that out until I checked my bank account last week to discover that I had not been paid. That was also when I discovered that as far as my health insurance could tell, I did not have health insurance.

Like most people living in the US, my insurance deductible resets on January 1. I have excellent health insurance. Truly, genuinely excellent. My yearly out of pocket maximum is $3500 and I meet that within the first two weeks of January every year. So last week, when I discovered I had not been paid and clarified that it was not a clerical error, I was already expecting to pay the cash price for several of my meds as I had not yet met my deductible. A huge amount of money. Except I had not been paid and did not feel confident that I would be paid again and was told I did not have active health insurance.

So massive expenses that I would be completely unable to meet sustainably. If I sold everything I own, paid no other bills, and used every last cent I had to my name, I could have paid for about three weeks worth of routine health care (prescriptions, infusion nursing, IV meds, compounded meds, routine bloodwork, routine appointments, line supplies).

Panic does not describe what happened to me. We use the term “worst nightmare” loosely to mean anything we really don’t want to experience. In this case, I mean it literally – I literally have nightmares about losing my health insurance, or losing my medications, or not having supplies for my port. It felt like there was a snake winding around my heart, constricting and suffocating me. My hands shook. I woke up from anxiety dreams about losing my insurance and not having money to pay for medical expenses to realize that my waking life was just as scary.

I spent a lot of this week on the phone with my disability insurance, my health insurance, and the HR department at my work. My immediate terrible fear when I discovered all of this late on a Friday afternoon was that I had been fired. Fortunately, this is not what happened. (Long time readers will remember that I love my job and have been well cared for by my company – this is not lip service. They have been truly amazing at working around my complex health.) But my disability insurance didn’t tell me right away that my company wasn’t notified of my approval until January 9 so it took days to figure out why I hadn’t been paid. Meanwhile, I shelled out a ton of money for meds without knowing when I would have money coming in again.

I have dealt mostly with one person at the disability insurance throughout this process. She is the one who has repeatedly denied my claim only to later reverse that decision based upon information that had already been provided. My eyes start tearing as soon as I see her number come up on my phone and as soon as I hear her voice. I have the same conversation with her over and over. Every time, she remarks that if I say is true (it is), then how would I be able to return to work, ever? No, if I were so sick, my doctor would decide that I would never be able to return to work and thus I should not be applying for short term disability. We have the same back and forth where she tries to poke holes that don’t exist in my well documented, well described, and well proven health narrative.

I was finally paid this morning, which I did not discover until after I woke up to her calling me. We had our normal conversation in which she didn’t believe I was sick but I am anyway and we just rode that around in circles for a while. I mentioned that I am having trouble keeping food down, especially the last few days. And then, this happened:

Her: “You are just vomiting up your food all day? Well, I think that probably your doctor should recommend that you are permanently disabled.”

Me: “Why would I be permanently disabled? I do not need perfect health to return to work. I have lived with this condition most of my adult life. I can work. I just need to get back to my baseline.”

Her: “Well, I don’t know how that can be. If you’re saying that you have been throwing up all your food for three days, I don’t know how you could think that you can work. I couldn’t work if that were happening for even one day.”

Let’s review.

I vomit most days. This is not recent. I take multiple doses of three medications every day to avoid vomiting constantly and have two other meds if those don’t work. The vomiting is worse recently due to the gastroparesis but I puked a lot before that, too. I throw up at work probably 3-4 times a month. I just throw up, brush my teeth, and go back to work. Just part of my day.

This woman stated that she would be unable to work if she puked up all her food for even one day. In her mind, that is a justifiable reason to not work.

As recently as two weeks ago, this woman denied my disability claim because she did not feel I was sick enough to be unable to work. But she herself said that if she had to experience even a small portion of my daily symptoms, she would be unable to work. The hypocrisy is nauseating.

I was paid today and my insurance has been straightened out. Several times this week, this woman told me that I needed to not be so upset and that I was making things harder on myself by being upset. Spoken like a person who has never had to live in fear that losing their insurance would kill them.

It’s never real until it’s you. It never matters until it’s you.

The idea of forever

You lose a lot when you have mast cell disease. You lose a lot of things that you enjoy. Some that you love. It’s easier in the beginning because you still have so many things. You don’t miss the first few in a serious way. But then you lose another few and a few more until you are left with a handful of painstakingly engineered pieces. You lose foods and drinks and sometimes you lose eating. You lose time. You lose people. You lose experiences and independence and dreams. And you know you will lose more.

Some days it feels impossible to live completely in a space where I am not exposed to anything that makes me sick. It is a challenge of epic proportions. It requires a rigid plan and the discipline to not deviate from it. After my ostomy was placed, I received a litany of restrictions from my doctor. I committed to complying with an almost religious fervor. I wanted it to work so badly. I didn’t travel. I didn’t try new foods. I didn’t sit in sunlight. I didn’t sit outside in the heat. I didn’t do anything that increased my heart rate. I didn’t eat or drink anything that had a drop of alcohol in it. I didn’t take hot showers. I didn’t drink tea. I kept a rigid cleaning schedule with homemade cleaners. I had my carpet torn up and put down a new floor. And a million other things. It dominated my life.

In the late fall of 2013, I was pretty up a creek with my mast cell disease. That October was miserable. I was so sick again and I couldn’t figure out why. I had done everything I was told. Every last thing. I had done everything right. It was frustrating and maddening.

But some tiny place inside me, a glimmering light obscured by my fear, felt liberated. This disease will do whatever it wants. I have no power over it. I never did. I know that some people feel that they can control their disease, that “they have masto but masto doesn’t have them.” And that’s fine but that is not how I feel. This disease has me. It has me.

I spent years feeling like I was complicit in my disease. That every time I was sick that it was because of something I did. And it wasn’t. It isn’t. It’s because I have this disease. I live around these huge losses and stay safe as much as I can and try not to piss off my mast cells. But when they get pissed off anyway, I no longer feel guilty.

I spent so much time living this half life because I was so afraid of what would happen if I didn’t. Years when I was still pretty able, even with mast cell disease. It is hard to think. I lost so much time. I lost so many days when I could have had fun or been happy. So many days when I could have felt sunshine on my face or had tea on my back porch on summer mornings or slept with my windows open so I could feel the warm breeze of summer nights. I realized too late that not doing these small things I loved would buy me very little. That I could live with this disease without having a sterile and deprived life.

I want to go back and scream at myself to not waste this time. To be happy. To not wait. That if my soul needs something that I should do it right now. Because one day I will wake up and there will be no time left to do it. It happens sooner than you think with a disease like this. So fast.

Forever is just an idea. There is no endless future where there will always be time to do the things that fulfill us. There is only now. Don’t waste it.

The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

[iii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1),38-44.

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

[x] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[xv] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.