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Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 3

POTS (postural orthostatic tachycardia syndrome) is one type of orthostatic intolerance. It is defined as the increase in heart rate of 30 beats/min or more when standing in the absence of orthostatic hypotension. There are a number of mechanisms that cause POTS.

Neuropathic POTS is caused by inefficient constriction of blood vessels in the lower limbs due to a defect in the sympathetic nervous system. In these patients , the heart does not sense the change in blood pressure correctly and does not pump out enough blood volume to accommodate the pressure change. Patients with this syndrome usually do not sweat in the feet. They have insufficient release of norepinephrine upon standing.

The orthostatic intolerance in neuropathic POTS is caused by the veins not constricting enough in the legs to maintain blood pressure upon standing. When executing the Valsalva maneuver, they are unable to raise blood pressure significantly. Blood is found to pool in the leg veins when these patients do not use pressure devices like compression stockings. These patients have “high blood flow”, meaning that the total peripheral resistance (the total pressure exerted by the blood vessels) is lower than expected when laying down or standing. This form of POTS may have an autoimmune link, but this though requires further investigation.

Hyperadrenergic POTS is caused by excessive cardiac response to stimulation by the sympathetic nervous system. In these patients, the nervous system tells the heart to beat faster and harder.  30-60% of patients have this form. These patients have serum plasma norepinephrine of 600 pg/mL or higher when standing. They have fluctuating or elevated blood pressure (both consistently or during crisis), and episodes of tachycardia, hypertension and hyperhidrosis. Of note, these episodes can be triggered by orthostatic stimuli (changing position) as well as physical or even emotional stimuli.

This category has also been referred to as “low volume” POTS, in which norepinephrine levels in serum can exceed 1000 pg/mL, and in which patients often have pale and cold skin, tachycardia while laying down, elevated blood pressure while laying down and increased neurologic signals to muscles while laying down. A genetic condition affecting the norepinephrine transporter (NET) gene is responsible for some cases of hyperadrenergic POTS. Hyperadrenergic POTS can be secondary to a number of conditions, including mast cell activation disease. One study found that 38% of patients with mast cell disease also had hyperPOTS.

POTS patients may have low plasma, red cell or total blood volumes. One study found 28.9% of POTS patients to be hypovolemic, meaning they had less volume in their blood stream than normal. In some of these patients, they have low renin activity and aldosterone when standing. Others may have high angiotensin II levels. These molecules are related to regulation of blood pressure. GI conditions that result in poor oral water intake from nausea or diarrhea can cause hypovolemia with orthostatic intolerance and tachycardia. For this population, the recommendation is to consider POTS as secondary the GI condition.

POTS patients present with persistent tachycardia, reduced stroke volume (amount of blood pushed out of the heart), loss of mass in the left ventricle (this part of the heart is smaller than normal), and reduced peak oxygen uptake when standing, during and after exercise. These markers are also present in physical deconditioning, which can also cause orthostatic intolerance regardless of why the deconditioning occurred. For this reason, POTS is often associated with conditions that provoke exercise intolerance, such as fibromyalgia, chronic fatigue syndrome and deconditioning.

 

References:

Stewart, Julian M. Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 2012 November; 10(11): 1387-1399.

Figueroa, Juan J., et al. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med 2010 May; 77(5): 298-306.

Benarroch, Eduardo E. Postural tachycardia syndrome: a heterogenous and multifactorial disorder. Mayo Clinic Proceedings 2012; 87(12): 1214-1225.

Cheung, Ingrid, Vadas, Peter. A new disease cluster: mast cell activation syndrome, postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome. J All Clin Immunol 2015: 135(2); AB65.

Joyner, M., Masuki, S. POTS versus deconditioning: the same or different? Clin Auton Res 2008 Dec; 18(6): 300-307.

 

 

Back together

This winter, when my entire city struggled under walls of ice and snow, I found myself dreaming about the beach. In my mind, I stood by the water’s edge, air warm, breeze strong off the ocean, sun warming my skin. I imagined myself looking and seeing the scar where they closed my ostomy site.

It was such an impractical dream that I didn’t really hope for fruition. I am essentially allergic to the beach – sunblock, sunlight, cold water, heat. And of course my ostomy site would never be closed. It was not even an option then. I never thought it was possible.

Three months later, I arrived at the hospital to have surgery that would reverse my ostomy and reconnect the two segments of my GI tract so that stool would pass through the rectum. It felt surreal, like at any time I would find a man behind a curtain, pulling strings.

They took me right in and every person who spoke to me knew that I had mastocytosis and that I needed premeds one hour before the procedure. They went over everything with me again to make sure it was mast cell safe. “You are the boss,” one nurse told me. “You live with this all the time, just tell us what you need.” I have waited years to hear these words, for providers to believe that.

They administered my premeds and the anesthesiologist came to give me an epidural. It was painless. They taped the line with my safe tape and lay me down. They pushed some midazolam and fentanyl and wheeled me into the operating room.

“I need to tell you something about my skin,” I said suddenly, jerking awake from my semi-unconsciousness. “My skin is really reactive and hives easily, so don’t think that it’s a sign of anaphylaxis.”

“We know,” the nurse said, nodding reassuringly. “It’s in the note you gave us for your chart. We know about your disease and we will be careful.”

And the first time in a long time, I believed it. Everyone in that room understood at least the basics of mast cell disease and our special operative concerns.

I lay back and they put a mask on my face. I breathed deeply and woke up a few hours later in the PACU.

I had an epidural with a bupivacaine PCA pump that I could push as needed to numb my abdomen. I had a hydromorphone PCA pump that I could as needed for additional pain management. I couldn’t feel any pain. It was amazing. I still reacted to the anesthesia with my typical nausea/vomiting but they were prepared for it. Frankly, it was so pleasantly different from my last major surgery that it seemed like a small price to pay.

About twelve hours after surgery, my GI tract started moving. Last time, it didn’t move for five days. This time it was moving and pushing things in the right direction. It was the best possible indication that this had worked. I couldn’t believe it.

The following day I was up walking around. (If you are having abdominal surgery and have mast cell disease, ask about an epidural. It honestly was the lynchpin here and made the pain so manageable so my mast cell reactions to pain were really minor.) I was eating the day after that. I had a couple of reactions but they were easy to control because there were orders to administer Benadryl and Pepcid IV as needed, as well as steroids if the reaction was severe.

I felt so safe. The nursing care was so good I wrote a letter detailing how amazing they were. They all asked me about my disease and diluted my Benadryl and they were just generally fantastic. Instead of spending seven days fighting for things I needed, I spent seven days managing my pain and reactions in an environment with many professionals who cared and understood that I was not just a crazy person asking for crazy things.

I came home a few days ago to my kitchen table covered in presents and cards from the mast cell community. It was so humbling. It was like Masto Christmas. There were books and movies, a huge piece of amethyst, stuffed animals, cute like knick knacks, funny cards, touching cards and pictures drawn by the masto kids. It was the perfect punctuation for this experience. I try to hold things together and to be strong at the broken places, and you guys just pulled everything together for me. I will never forget this kindness as long as I live.

One of the very difficult things about mast cell disease is that we so often have to fight for things we need to be safe. We are always ready for a fight, always on edge. We wonder if it we can keep this up. We are so tired. We just want to be safe. We want others to help us be safe.

This experience was the culmination of years of educating medical professionals and of them receiving education on mast cell disease elsewhere. This time when I said I needed Benadryl, they just got it for me. No fighting. I am the boss of my body.

I write a lot about how I see the world and how I interact with it as a mast cell patient. But in my private writings, I write about how I want the world to be, how it should be. Two weeks ago, I went to the hospital for surgery and during my stay, I realized I was living in that world. Maybe it was just for a little while, but I was there. I could hear the universe whispering to me, “You can do this. Look how far you have come.” So I’m ready to fight again if I have to, because I saw this other reality, and it was real and safe and we can make it like that everywhere if we try.

So when time goes by and it gets hard again, and I’m exhausted from advocating, I’m going to remember this. I’m going to remember this win. I’m going to remember that this safe place made it easy for me to heal and rest. I’m going to remember that this fight is how we make the rest of the world safe for all of us, not just for me, at one hospital, one time.

I’m going to remember that this tired, sick body made this incredible thing possible, and when it seems like I can’t do any more incredible things, I’ll remember that I achieved this, and that I can achieve so much more.

And when you guys are tired and sick of fighting, promise me that you’ll remember that this is possible, and that we’re all in this together. When you think you can’t do it anymore, just extend a hand to the void. We will be there to hold it and put you back together.

 

 

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 2

The term orthostasis means to stand up. Orthostatic intolerance is the presentation of symptoms which interfere with or prevent standing up. Orthostatic intolerance (OI) affects heart rate, blood pressure and blood distribution in the brain. This can present as a number of symptoms with multiple root causes.

The autonomic nervous system is responsible for making quick changes to the cardiovascular system based upon changes in the environment. It adjusts the circulatory system by changing heart rate, constricting blood vessels and inducing secretion from the adrenal gland to sustain a normal blood pressure.

The sympathetic nervous system is one part of the autonomic nervous system and its function is to activate the fight-or-flight response. When it malfunctions as in OI, it causes pallor, headache, high blood pressure, palpitations, sweating, tremor and anxiety. When the autonomic nervous system is unbalanced with the parasympathetic system being more active, low blood pressure, slow heart rate, cold hands and feet and constriction of the pupil may occur. This is called vagotonia. Another principle symptom of orthostatic intolerance is intolerance to exercise.

Other parts of the nervous system are involved here as well. Misbehavior in the central nervous system can cause loss of consciousness, dizziness and cognitive issues. Malfunction of the vagus nerve can cause tachycardia, abdominal pain and nausea/vomiting.

There are three common forms of orthostatic intolerance.

Orthostatic hypotension is a consistent reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing or a head up tilt of at least 60°. Orthostatic hypotension can occur for many reasons, including dehydration, blood loss or conditions that cause acute or chronic hypovolemia. Neurogenic OH is caused by insufficient norepinephrine released from cells of the sympathetic nervous system, causing inadequate vasoconstriction. Neurogenic OH typically occurs secondary to a systemic disease.

POTS patients suffer daily OI symptoms in conjunction with excessive tachycardia when standing, but not with low blood pressure. In adults, excessive tachycardia is defined as an increase of 30 bpm when standing or over 120 bpm. In children, excessive tachycardia is an increase of 40 bpm. Tachycardia is not sufficient for diagnosis; patients must also have OI symptoms. There are multiple subcategories of POTS, which I have previously covered and will cover in more detail elsewhere.

Postural syncope can be caused by acute orthostatic intolerance, simple fainting or vagovagal syncope (VVS). Syncope, also called fainting, is the loss of consciousness due to temporarily insufficient blood supply to the brain, followed by complete recovery. In short, this means fainting upon standing up. About 40% of people will faint at some point in their lives. About half of these people have their initial episode during adolescence, most around the age of 15. Syncope can be cardiovascular, from arrhythmia or structural abnormalities, or reflex/neurologic.

Mast cell disease (both mastocytosis and MCAS) has a known propensity for causing orthostatic intolerance.

References:

Stewart, Julian M. Update on the theory and management of orthostatic intolerance and related syndromes in adolescents and children. Expert Rev Cardiovasc Ther 2012 November; 10(11): 1387-1399.

Figueroa, Juan J., et al. Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med 2010 May; 77(5): 298-306.

Medow MS, Stewart JM, Sanyal S, Mumtaz A, Sica D, Frishman WH. Pathophysiology, diagnosis, and treatment of orthostatic hypotension and vasovagal syncope. Cardiol. Rev. 2008; 16(1):4–20.

Bayles R, Kn H, Lambert E, et al. Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. Arterioscler. Thromb. Vasc. Biol. 2012; 32(8):1910–1916.

Deconditioning, orthostatic intolerance, exercise and chronic illness: Part 1

Deconditioning (also called cardiovascular deconditioning) is the acclimation of the body to a less strenuous environment and the decreased ability to function properly under normal conditions. This basically means that when you have less physical stress on the body for a certain period of time, like seen in bed rest, the body adapts to that level of functioning, so when you want to engage again in normal physical activities, it is difficult for your body. Deconditioning makes multiple systems of your body less functional.

Bed rest is the typical situation associated with deconditioning. Patients on bed rest lose muscle mass and strength rapidly.  1-3% of muscle strength is lost per day, with 10-20% decrease in a week’s time. If completely immobilized for 3-5 weeks, a patient can lose up to 50% of their strength. Loss of muscle mass is also a problem. Upper legs can lose 3% mass within a week of bed rest. The lower back and weight bearing muscles in the legs are most affected by loss of mass.

Within 24 hours of bed rest, your cardiovascular system is changing. In this time, your blood volume decreases 5%. In less than a week, 10% is lost; in two weeks, 20%. Resting heart rate also increases 4-15 bpm within the first month of bed rest. Laying down for so long means that blood that is normally in the lower part of your body is moved to the trunk. This causes excretion of water and salt, resulting in less plasma and blood volume.

In healthy controls, when you change position, your body rapidly moves fluid from one part of the body to others. This phenomenon is called fluid shifting. Normally, when moving from a laying position to standing, 500-700 ml of blood are moved from the trunk to the legs. This movement of fluid is called “functional hemorrhage”. Special nerve clusters called baroreceptors (which measure pressure in the blood vessels) tell the nervous system that there is less blood in the chest.   Your body then increases the heart rate, the force with which your heart beats, tightens up vessels so that they are less “leaky” and tells your body not to make urine temporarily. All of these functions allow your body to keep a normal blood pressure and adequate blood supply despite this large movement of fluid.

In healthy controls, when you lay down after standing, the reverse happens. 500-700 ml of fluid is rapidly transferred from the lower body to the trunk. This is called a “central shift”. This increase in fluid in the chest results in the veins returning more blood to the heart, increasing blood pressure. When the baroreceptors feel more pressure than usual from this added fluid, the heart rate and force with which the heart beats decrease, the vessels are relaxed so that fluids can move out of them more freely and your body begins to make urine again.

When you are deconditioned, your body does not make these changes correctly when you change position. The hallmark of deconditioning is reduced orthostatic tolerance. This means that when you change position, your body does not compensate correctly to maintain necessary blood pressure and adequate blood supply to the brain. Deconditioned patients often do not have sufficient blood volume to maintain blood pressure when standing. When they stand, their heart pumps out less blood than normal, so the heart starts beating faster to compensate. When it beats too fast, it is called tachycardia.

In addition to inability to maintain blood pressure correctly when changing positions, deconditioned patients also exhibit decreased blood volume pumped out by the heart, atrophy of heart muscle and decreased maximum oxygen consumption. These patients often have other forms of vascular dysfunction, diminished neurologic reflexes and reduced ability to exercise. A number of other systems are affected by deconditioning.

Though prolonged bed rest is the model with which deconditioning is most often associated, there is significant evidence that chronically ill patients may often be deconditioned, including those with chronic lower back pain, chronic fatigue syndrome, and rheumatoid arthritis.

References:

Munsterman et al. Are persons with rheumatoid arthritis deconditioned? A review of physical activity and aerobic capacity. BMC Musculoskeletal Disorders 2012, 13:202

Eric J. Bousema, Jeanine A. Verbunt, Henk A.M. Seelen, Johan W.S. Vlaeyen, J. Andre Knottnerus. Disuse and physical deconditioning in the first year after the onset of back pain. Pain 130 (2007) 279–286.

De Lorenzo, H. Xiao, M. Mukherjee, J. Harcup, S. Suleiman, Z. Kadziola and V.V. Kakkar. Chronic fatigue syndrome: physical and cardiovascular deconditioning. Q J Med 1998; 91:475–481.

Hasser, E. M. And Moffitt, J. A. (2001), Regulation of Sympathetic Nervous System Function after Cardiovascular Deconditioning. Annals of the New York Academy of Sciences, 940: 454–468.

Exercise and mast cell activity

Research on exercise induced bronchoconstriction represents a large body of work through which we can draw conclusions about mast cell behavior as affected by exercise.

Exercise has been found in a number of studies to induce mast cell degranulation and release of de novo (newly made) mediators. One study found that levels of histamine, tryptase and leukotrienes were increased following exercise in sputum of people with exercise induced bronchoconstriction. This same study found that in these patients, prostaglandin E2 and thromboxane B2 was decreased in sputum. Treating with montelukast and loratadine suppressed release of leukotrienes and histamine during exercise.

One important area of research is the interface between being asthmatic and being obese. Adipose tissue is known to release inflammatory molecules called adipokines. In particular, the adipokine leptin has been studied for its role in bronchoconstriction following exercise. Leptin (I did a previous post on leptin, which is also called the obesity hormone) enhances airway reactivity, airway inflammation and allergic response. It can also enhance leukotriene production. This last fact is interesting because obese asthmatics are less likely to respond to inhaled corticosteroids when compared to lean asthmatics, but both respond similarly to anti-leukotriene medications like montelukast.

LTE4 was found to be significantly higher in the urine of both obese and lean asthmatics following exercise. It was not increased in either obese non-asthmatics or healthy controls. Additionally, the level of LTE4 was significantly higher in obese asthmatics compared to lean asthmatics. In this same study, urinary 9a, 11b-PGF2 was elevated in both lean and obese asthmatics, but not in obese or healthy controls. The 9a, 11b-PGF2 level was also higher in obese asthmatics than lean asthmatics. The elevated LTE4 and 9a, 11b-PGF2 were found in urine testing rather than in sputum, indicating that these chemicals did not stay local to the lungs and airway.

It is thought that the high levels of leptin found in asthmatics drive the manufacture and release of leukotrienes and prostaglandins from mast cells, epithelial cells or eosinophils during exercise. Though the data are stacking up to look like this is the case, there has not yet been a definitive causal link established.

 

References:

Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Hey-Sung Baek, et al. Leptin and urinary leukotriene E4 and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117

 

Histamine depletion in exercise

A long known and often repeated finding is that regular exercise can be protective against asthma. This finding was published in 1966 by a group that found the airways of asthmatics grew progressively less reactive following intervals of exercise. This finding was confirmed by several studies that followed. At the time, the reason why exercise protected against reactive airways was unclear, but an early hypothesis was that mediators were depleted after the initial round of exercise and that time was required to restore them.

In the 1980’s, there was a wave of research around the role of histamine in airway reactivity of asthmatics. There were a few competing theories at this point for why asthmatics became less reactive following exercise: depletion of mediators, mainly histamine from mast cells; that bronchial smooth muscle became less responsive to stimulation by histamine via the H1 receptor; and that release of catecholamines (such as epinephrine) by exercise suppresses bronchoconstriction. A number of studies made relevant findings.

Histamine is known to be released in the lungs due to exercise. It is also known to become depleted and quickly metabolized. When exposed to histamine, asthmatics recover quickly from the ensuing bronchoconstriction. Some asthmatic patients show an increase in plasma histamine during exercise.

Plasma epinephrine does not rise in asthma patients as a result of exercise, or at the very least is metabolized almost immediately, and thus is unlikely to be protective. Bronchial smooth muscle was not found to become less responsive to histamine. This was demonstrated in a study that compared repeated inhalation of histamine (such as might be induced by exercise) with actual repeated exercise. This study found that repeated exercise diminished airway reactivity, while repeated inhalation of histamine did not.

Another report indicated that inhalation of cromolyn before exercise can prevent or mitigate exercise induced asthma in most patients. Administration of H1 inverse agonists was found to offer similar protection.

A more recent study (2012) looked at the role of histamine in fatigue from exercise. Histamine is now known to be involved in regulation of oxygen/carbon dioxide exchange, which is important in exercise. In mice that were persistently exercised, the level of histidine decarboxylase was increased. HDC is the enzyme that makes and immediately releases histamine in response to an immediate need. This is different from degranulation, in which histamine is made ahead of time and stored inside the cell until needed.

This study found that treating the mice with an H1 antihistamine, H2 antihistamine, or HDC inhibitor decreased endurance in the mice. Mice deficient in HDC or H1 receptors also had less endurance. This means that histamine is partly responsible for inducing tolerance to exercise and that blocking action of histamine causes fatigue to set in more quickly.

Treatment with fexofenadine, an H1 antihistamine, decreased levels of nitric oxide and glycogen in the muscles of exercised mice. Taken together, these findings mean that histamine protects against fatigue from exercise; that this effect is achieved via H1 receptors and production of nitric oxide; and that at least some of this histamine is provided by immediate production and release of histamine via HDC. This means that your body does not simply release its histamine stores in response to exercise; it makes it on the fly so as not to exhaust its supply.

 

References:

Hahn, Allan G., et al. Histamine reactivity during refractory period after exercise induced asthma. Thorax 1984; 39: 919-923.

Niijima-Yaoita, Fukie, et al. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. Biol Pharm Bull 2012; 35; 91-97.

Schoeffel, Robin E., et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax, 1980, 35, 164-170.

Graham P, Kahlson G, Rosengren E. Histamine formation in physical exercise, anoxia and under the influence of adrenaline and related substances. J. Physiol., 172, 174—188 (1964).

McNeill RS, Nairn JR, Millar JS, Ingram CG.Exercise-induced asthma. Q J Med 1966; 35: 55-67.

 

Chronic urticaria and angioedema: Part 5

Chronic urticaria has a very well described stepwise treatment standard, which I will describe briefly here. If resolution is not achieved with the method described in one step, the next step is executed.

  • A second generation H1 antihistamine like cetirizine is begun with standard daily dosing. Triggers should be avoided wherever possible.
  • Dosage of second generation H1 antihistamine is increased.
  • Another second generation H1 antihistamine is added to the regimen. (For example, cetirizine and fexofenadine taken together).
  • An H2 antihistamine is added. About 15% of histamine receptors in the skin are H2, so some patients see benefit from this.
  • A leukotriene receptor antagonist like montelukast is added.
  • A first generation H1 antihistamine like diphenhydramine is added at bedtime.
  • A strong antihistamine like hydroxyzine or doxepin is added and dosages increased accordingly.
  • If all else has failed, consider addition of medications like Xolair, cyclosporine, or other immunosuppressants.

Treatment of angioedema is dependent upon the cause of the angioedema (C1 esterase deficiency, ACE inhibitor, etc). However, it is generally agreed upon that upper airway swelling, even if mild, should be treated aggressively. Intramuscular epinephrine is indicated for this situation, with advisories in numerous papers to administer epinephrine as early as possible if airway swelling is present.

Reactions caused by IgE are the most likely to respond immediately to epinephrine. Hereditary and acquired angioedema are less likely to respond to epinephrine. If the patient is on beta blockers, glucagon is the drug of choice, as beta blockers interfere with action of epinephrine.

I am doing a detailed follow up post on treatment options for the various types of angioedema.

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med 2007; 8:72-80.

Chronic urticaria and angioedema: Part 4

There are a number of other conditions that present with similar features to chronic urticaria and angioedema.

Conditions that can present similarly to chronic urticaria are listed below.

Chronic urticarial vasculitis is associated with low or normal complement levels and confusingly can be a primary autoimmune disorder, or a process secondary to another autoimmune disease, like lupus. Urticarial vasculitis lesions sometimes resolve quickly but can last for several days. A lesion biopsy can distinguish between CU and chronic urticarial vasculitis. Painful or burning lesions suggest urticarial vasculitis, with raised lesions that don’t blanch, and may leave hyperpigmented areas in place of resolved lesions. Hepatitis B and C can cause urticarial vasculitis.

Swelling of the upper eyes can be mistaken for angioedema, but in some people may be a symptom of thyroid ophthalmopathy, thyroid driven eye disease. Development of urticaria for during pregnancy is not unusual. Cyclical urticaria can be from autoimmune progesterone dermatitis. Episodes of angioedema with accompanying weight gain can be caused by Gleich syndrome (episodic angioedema with eosinophilia).

Cutaneous mast cell patients demonstrate a variety of urticaria-like lesions, including urticaria pigmentosa, mastocytomas and telangiectasia macularis eruptive perstans. Mast cell activation syndrome can also cause angioedema and urticaria, but generally these are not the only symptoms.

Erythema multiforme looks like urticaria but is often due to viral infections, mycoplasma infections or some medications. Bullous pemphigoid can initially present with hive-like welts or small plaques that do not always blister in early disease. Swelling of the lips in the absence of eczema can indicate cheilitis granulomatosa.

Schnitzler syndrome can cause non-itching hives that exclude the face, bone pain and intermittent fevers. These patients also have IgM or IgG monoclonal gammopathy.

 

Angioedema in the absence of urticaria is rare. There are a few conditions that can cause it.

Hereditary angioedema (HAE) is caused by C1 esterase inhibitor deficiency (in type I, 80%-85% of cases); or dysfunction (in type II, 15-20%).  People with HAE do not have coincident urticaria. HAE is inherited in an autosomal dominant pattern, but up to ¼ of patients develop the condition through spontaneous mutation rather than through inheritance of the gene. About 40% of patients have their initial attacks before the age of 5.

Acquired angioedema (AAE) is caused by antibodies to C1 esterase inhibitor, which is usually caused by cancers of B cells. AAE is more likely to develop in older patients (usually fourth decade of life or later) and family history of angioedema is generally absent. AAE is also more likely to develop when an autoimmune disease or proliferative blood disorder is present.

Angioedema associated with these conditions can affect any part of the body, including limbs and abdomen. Patients with abdominal angioedema are often misdiagnosed as having an “acute” abdomen that requires surgical intervention. It is not unusual for patients to present initially only with abdominal swelling. Both HAE and AAE have a number of common triggers, including infection, emotional or physical stress. or trauma. Importantly, they are not caused directly by histamine and other mast cell mediators and as such are not responsive to antihistamines and corticosteroids.

There is also a form of angioedema specifically induced by treatment with ACE inhibitors. It can be relieved by discontinuing ACE inhibitor therapy.  Idiopathic angioedema can also occur in the absence of urticaria but is more likely to respond to prophylactic antihistamine use than HAE or AAE.

 

Edited to add: I removed the following line from the first HAE paragraph: “Type III is estrogen mediated and only found in adult women.”  This statement is inaccurate,  I mistakenly included i, as I had originally noted it when reading a paper from 2007.  I am doing a follow up post on HAE that will elaborate further on the different subtypes and treatment.  Many thanks to the reader who caught it!

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med2007; 8:72-80.

Kanani, Amin, et al. Urticaria and angioedema. Allergy Asthma and Clinical Immunology 2011, 7(Suppl 1):S9.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Chronic urticaria and angioedema: Part 3

There are several pathways that can culminate in angioedema and urticaria.

Activation of mast cells by IgE is the most well known mechanism. When IgE binds to receptors on mast cells, several things happen. The mast cells release histamine. This in turn causes dilation of the nearby vessels and causes fluid to leak from the bloodstream into the tissues. This causes nerve cells to activate and release substance P, which also contributes to vasodilation and causes mast cells to release more histamine. In response to activation by IgE, mast cells will also produce PGD2 and leukotrienes C4 and D4.

The complement system is one of the ways our body identifies infectious agents and triggers the immune system to kill them. Complement proteins are in the blood all the time, and they can be activated by three distinct pathways, all of which are triggered by pathogens: the classical pathway, the alternative pathway and the lectin pathway. Regardless of which pathway activates the complement system, the molecules C3a, C4a and C5a are produced. These molecules bind to receptors on mast cells and induce histamine release.

Following initial dilation of local vessels, proteins that normally are found in the plasma move into the skin. This activates the kinin system, which produces bradykinin through a series of steps. Bradykinin is a very powerful vasodilator and contributes significantly to loss of volume from the blood stream to the tissues.

C3a, C5a, PGD2, and leukotrienes C4 and D4 all draw other inflammatory cells to the site of activated mast cells. These cells release further molecules to stimulate histamine release. This mechanism perpetuates inflammation beyond the original insult.

Bradykinin levels are normally controlled by the enzyme ACE. When patients take ACE inhibitor medications (like Lisinopril, etc), this interferes with bradykinin degradation and cause urticarial and angioedema.

C1 esterase inhibitor regulates complement and kinin pathways. In patients who are deficient in C1 esterase inhibitor, bradykinin may be overproduced.

Many autoimmune conditions cause the formation of IgG1 and IgG3 antibodies. These molecules can interfere with the complement system and cause production of fragments that activate mast cells, like C3a.

NSAIDs are well characterized in their ability to cause angioedema and urticaria. While the mechanism is not fully understood, it is thought that since NSAIDs stop production of prostaglandins, the mast cells overproduce leukotrienes, which contribute to the angioedema and urticaria.

There are several non-immunologic methods that can result in angioedema and urticaria. Heat or pressure on the skin; radiocontrast dyes; alcohol; vancomycin; opioids; and foods like shellfish and strawberries have been linked to these conditions.

 

References:

Jonathan A. Bernstein, et al. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol Volume 133, Number 5.

Usmani N,Wilkinson SM. Allergic skin disease: investigation of both immediate and delayed-type hypersensitivity is essential. Clin Exp Allergy 2007;37:1541-6.

Zuberbier T, Maurer M. Urticaria: current opinions about etiology, diagnosis and therapy. Acta Derm Venereol 2007;87:196-205.

Ferdman, Ronald M. Urticaria and angioedema. Clin Ped Emerg Med2007; 8:72-80.

 

Premedication and surgical concerns in mast cell patients

The exact incidence of immediate anaphylaxis from anesthesia or surgery in mastocytosis patients (or mast cell patients, more generally) is not known. Only a handful of these events have been reported in literature; however, it is likely that the majority of uneventful procedures were not tracked, so statistics are unclear. To date, there have been no controlled trials investigating anesthetics in mast cell patients.

In 2014, a paper was published entitled “Perioperative Management of Patients with Mastocytosis.” This paper is excellent and addresses the specific issues that may arise for mast cell patients before, during and after surgery. I recommend you provide this reference to any doctor involved in your surgical/procedural care that is unfamiliar with mast cell disease.

Mastocytosis patients are at risk for activation by a number of triggers, some of which cannot be avoided in the surgical setting. For this reason, suppression of mediator release in advance of surgery is recommended. The following pre-medication protocol is recommended for mast cell patients for all major and minor procedures and for radiology procedures with and without dyes:

  • Prednisone 50mg orally (20mg for children under 12): 24 hours and 1-2 hours before procedure
  • Diphenhydramine 25-50mg orally (12.5 mg for children under 12) OR hydroxyzine 25mg orally, 1 hour before procedure
  • Ranitidine 150mg orally (20mg for children under 12) 1 hour before procedure
  • Montelukast 10mg orally (5mg for children under 5) 1 hour prior to procedure

This protocol was developed for the Mastocytosis Society by Dr. Mariana Castells and the original can be found here: http://www.tmsforacure.org/documents/ER_Protocol.pdf

 

Common triggers for mast cell patients in this setting include:

  • Anxiety and psychological stress regarding the procedure. Administration of medication to mitigate anxiety (benzodiazepines, etc) is recommended to avoid mast cell degranulation. It is preferable for mast cell patients to be the first surgery of the day if possible, and for a quiet, calm atmosphere to be maintained in the OR.
  • Temperature changes. Either being too cold or too hot can culminate in a mast cell reaction. Constant monitoring of patient’s temperature is required. Additionally, the OR temperature should be monitored. Head coverings, warming mattresses, and forced-air warming systems can be used to prevent hypothermia. Infusion and irrigation solutions should be warmed, and anesthetic gases should be warmed wherever possible.
  • Irritation of the skin (including use of tourniquet). This can cause mast cell degranulation that leads to urticaria, especially in patients with cutaneous mastocytosis. Blisters may form with pressure from tourniquet or face mask. Mast cell degranulation of this type releases chymase which can lead to edema.
  • The inherent physical trauma associated with surgery. This is of specific consideration when operating in the GI tract, which has a significant mast cell population relative to other organs.
  • Musculoskeletal pain from skeletal involvement in SM patients. Patients should be positioned carefully to avoid causing fractures.
  • Pain can cause mast cell degranulation. For this reason, opioid medications should be used for pain relief wherever possible.

 

Reference:

Pascale Dewachter, M.D., Ph.D.; Mariana C. Castells, M.D., Ph.D.; David L. Hepner, M.D., M.P.H.; Claudie Mouton-Faivre, M.D. Perioperative Management of Patients with Mastocytosis. Anesthesiology 03 2014, Vol.120, 753-759.