The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 20

I answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

29. Why do I swell up when I have a reaction? Where does the fluid come from and where does it go?
• Your body feeds its cells by keeping blood circulating. The blood passes by cells. The cells pull nutrients, oxygen, and other things they want out of the blood. In return, the cells release their wastes into the bloodstream to carry them away to a place where they can be broken down.
• Mast cells make and release many chemicals. These chemicals are commonly called mediators because they mediate many reactions in the body that affect the body in many different ways.
• Mast cell mediators do many things. They can make blood vessels get looser or tighter to help control heart rate and blood pressure. Their ability to make blood vessels relax is the important point when considering swelling. When mast cells release certain mediators, the vessels relax and get a little wider.
• Vessels are made of a complicated network of cells and fibers. It’s like an afghan blanket: some parts of mostly solid and in other places, there are holes you can put your fingers through. When the vessels relax, those holes get larger so it’s easier for things to fall through the holes. In this case, what falls through the hole is fluid from the blood.
• Keep in mind that blood is a mixture of many things. For right now, let’s divide it into cells and everything else. Everything else is a liquid with some stuff dissolved in it.
• When the blood vessels relax, that liquid from the blood trickles out of the blood vessel and goes into the tissue. In some cases, if the blood vessels relax enough, cells actually fall out of the bloodstream and end up in tissue, too.
• The problem is that once you fall out of the bloodstream, you can’t just turn around and go right back in. That’s why swelling takes longer to subside than other symptoms, even with appropriate treatment.
• Everyone is familiar with the bloodstream. Less familiar is the lymphatic circulatory system. Lymphatic circulation is how your body moves things that fall out of the blood back to the bloodstream. This process is slower than processes that can release other symptoms and can sometimes take days.
• When you swell up, fluid falls out of your bloodstream and gets stuck in your tissues. The cells nearby will absorb some of the fluid and take up molecules they can use. However, if there is a lot of extra fluid there, the cells nearby cannot take up all of the fluid. Gradually, your lymphatic system sucks up that fluid and brings it back toward the heart so it can get back into the bloodstream.
• When you get hives (urticaria), it happens because fluid falls out of the bloodstream in a layer of tissue in the skin called the upper dermis.
• When you get angioedema, it happens because fluid falls out of the bloodstream in lower portions of tissue in the skin called the dermis, subcutaneous tissue, mucosa, and submucosa.
• The fact that the process for hives and angioedema is so similar and really distinguished only by which tissue layer they affect is the reason urticaria and angioedema so commonly occur together and are discussed together.

For more detailed reading, please visit the following posts:
Chronic urticaria and angioedema: Part 1
Chronic urticaria and angioedema: Part 2
Chronic urticaria and angioedema: Part 3
Chronic urticaria and angioedema: Part 4
Chronic urticaria and angioedema: Part 5
The Provider Primer Series: Management of mast cell mediator symptoms and release

Symptoms, mediators and mechanisms: A general review (Part 1 of 2)

Skin symptoms    
Symptom Mediators Mechanism
Flushing Histamine (H1), PGD2 Increased vasodilation and permeability of blood vessels

Blood is closer to the skin and redness is seen

Itching Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Possibly stimulation of itch receptors or interaction with local neurotransmitters
Urticaria Histamine (H1), PAF, heparin, bradykinin Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of skin

Angioedema Histamine (H1), heparin, bradykinin, PAF Increased vasodilation and permeability of blood vessels and lymphatic vessels

Fluid is trapped inappropriately between layers of tissue

 

Respiratory symptoms    
Symptom Mediators Mechanism
Nasal congestion Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Sneezing Histamine (H1), histamine (H2), leukotrienes LTC4, LTD4, LTE4 Increased mucus production

Smooth muscle constriction

Airway constriction/ difficulty breathing Histamine (H1), leukotrienes LTC4, LTD4, LTE4, PAF Increased mucus production

Smooth muscle constriction

 

Cardiovascular symptoms    
Symptom Mediators Mechanism
Low blood pressure Histamine (H1), PAF,  PGD2, bradykinin Decreased force of heart contraction

Increased vasodilation and permeability of blood vessels

Impact on norepinephrine signaling

Change in heart rate

Presyncope/syncope (fainting) Histamine (H1), histamine (H3), PAF, bradykinin Increased vasodilation and permeability of blood vessels

Decrease in blood pressure

Dysfunctional release of neurotransmitters

High blood pressure Chymase,  9a,11b-PGF2, renin, thromboxane A, carboxypeptidase A Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

Tightening and decreased permeability of blood vessels

Tachycardia Histamine (H2), PGD2 Increasing heart rate

Increasing force of heart contraction

Impact on norepinephrine signaling

Arrhythmias Chymase, PAF, renin Impact on renin-angiotensin pathway

Impact on norepinephrine signaling

 

Gastrointestinal symptoms    
Symptom Mediators Mechanism
Diarrhea Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Gas Histamine (H1), histamine (H2), bradykinin Smooth muscle constriction

Increased gastric acid secretion

Abdominal pain Histamine (H1), histamine (H2), bradykinin, serotonin Smooth muscle constriction

Increased gastric acid secretion

Dysfunctional release of neurotransmitters

Nausea/vomiting Histamine (H3), serotonin Dysfunctional release of neurotransmitters
Constipation Histamine (H2), histamine (H3), serotonin (low) Dysfunctional release of neurotransmitters

 

The Sex Series – Part Three: Allergic reactions of the vagina and vulva

Most of what I said about kissing applies to genitally penetrating intercourse, too.  It is not uncommon for people to develop hives as a result of the vibration, pressure, heat and friction of intercourse. Swelling after sex, called postcoital edema, is also not unusual.  Sex is also a known trigger for asthma and rhinitis.  Several aspects of sex, including the heat and emotion, can activate the autonomic nervous system and cause release of mast cell mediators.  Importantly, studies have revealed that the allergic effects of sex are not due to the physical exertion (ie. exercise anaphylaxis).

While local reactions are more common, there is precedent for sex causing multisystem allergic response or anaphylaxis.  The person receiving the vaginal penetration is more likely to have anaphylaxis following sex, especially if they are strongly sensitized to food or medications.  Seminal fluid can contain food or drug allergens.  Aspirin and penicillin derivatives have been reported to cause allergic reactions from sex, called postcoital hypersensitivity. Transfer of pollens from the clothes or skin of the partner can also cause allergic reactions.

One product we have not yet discussed that can cause contact dermatitis and anaphylaxis is condoms. 25% of reactions to latex condoms cause hives over large portions of the body, angioedema and respiratory symptoms. There are latex alternative condoms, but many patients react to those as well.

Vaginally penetrating intercourse often causes microscopic tearing, mostly due to inadequate lubrication.  As a former sex educator, if you think you are using enough lubrication, you are not.  It is my personal experience that water based lubricants are better tolerated by most allergy patients for vaginal intercourse.  Silicone lubricant is popular because it’s not absorbed by the body and is therefore slicker, whereas water based lubricant often requires reapplication.  But that’s okay.  That’s why you get a whole bottle.

Contributing to the insufficient lubrication is the fact that most people don’t engage in long enough foreplay.  Foreplay provides a number of benefits: it increases naturally secreted vaginal lubrication, increases blood flow to the vagina and tells the cervix to get out of the way. 20 minutes of foreplay is often recommended as a rule of thumb in order to get the vagina in order before penetrating intercourse.

Moisture, friction and heat can cause the vulvar skin to break down. Estrogen plays a large role in keeping this tissue strong and undamaged.  Urine on the skin can cause contact dermatitis.  Malnutrition and history of genital infections can also contribute towards the reactivity of the tissue. It is also possible to be IgE positive for Candida albicans, a yeast that lives normally in the vagina.  Inflammation can upset the balance of the normal flora, resulting not only in vaginal infections but a literal allergy to Candida.

References:

Schlosser BJ. Contact dermatitis of the vulva. Dermatol Clin 2010: 28; 697-706.

Moraes PSA, Taketomi EA. Allergic vulvovaginitis. Ann Allergy Asthma Immunol 2000; 85: 253-267.

Chen WW, Baskin M. A 33-year-old woman with burning and blistering of perivaginal tissue following sexual intercourse. Annals of Allergy, Asthma & Immunology 2004; 93: 126-130.

Harlow BL, He W, Nguyen RHN. Allergic reactions and risk of vulvodynia. Ann Epidemiol 2009; 19: 771-777.

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

The Sex Series – Part One: Kissing and allergic reactions

The avenues by which a person can suffer symptoms as a result of sex are almost endless.  I am asked often about the mechanism by which mast cell patients can react to foreplay or intercourse. The reason it has taken so long to put this series together is not because of a dearth of information, but because there is so much.  The research on this topic is deep, if not always to the point: Why do some people react badly to having sex?

There are a number of reasons why sex can cause allergic symptoms, which explains why intimacy is often fraught with anxiety for mast cell patients.  So let’s start with the entry level: kissing.

It is widely accepted that kissing can transfer allergens via saliva, or contact between skin or oral mucosa.  Allergic reaction after kissing is not even especially unusual.  5-12% of IgE food allergic patients have had at least one reaction after kissing.  Peanuts, walnuts, and tree nuts are the most common offenders.  Rash around the mouth, hives around the mouth, flushing, angioedema of lips, mouth, tongue and throat, wheezing and hives all over the body have all been reported in this situation.  Usually symptoms present within minutes, but there are literature references to reactions developing up to three hours later.

In a group of 26 volunteers that ate peanut butter, the protein reached its highest concentration in saliva five minutes after consumption.  After an hour, the protein was undetectable.  Several methods for clearing the protein were tested.  Brushing teeth, rinsing mouth, or both, waiting an hour after consumption, and waiting an hour and then chewing gum, all reduced protein concentration by over 80%.  However, waiting one hour after eating was still the most effective way to clear the protein from the mouth.

Though much less common than transfer of food allergens, it is possible to transmit medications via saliva. In literature, all reports of this phenomenon involve ingestion of β-lactam antibiotics, including penicillin derivatives.  In these cases, the patients had symptoms of oral allergy syndrome with hives over large parts of the body.

The quality of the kissing is certainly a factor.  How deep is it?  How much hard? How much friction?  How wet?  Mast cell patients often react to physical stimuli like this.  It’s not hard to imagine a situation where the pressure and heat of kissing cause local mast cell degranulation.   I found a (non-scientific) article describing a woman with aquagenic urticaria who reacts to kissing because it’s wet.  For patients allergic to sweat, that could also cause a kissing reaction.

I feel like I should throw out there that you can react to allergens returned to the mouth by vomit.  Mostly because there isn’t really anywhere else to put it.  So it’s here.  The warning about vomit is in the kissing post.  How did this get to be my life?

BUT GUESS WHAT GUYS?!?!?!? Kissing can also be good for allergy patients.  One study reported that that kissing decreased wheal response (the formation of red swollen areas) was decreased 28-34% in patient allergic to dust mite and Japanese cedar pollen.  This patient group had allergic rhinitis and atopic dermatitis.  It didn’t decrease the response to injection of histamine, which means the benefit from kissing in this study is not directly blocking histamine.  Plasma levels of neurotrophins were decreased in these patients.  Neurotrophins have a complex relationship to mast cells, so it’s possible that neurotrophins block something that tells mast cells to release histamine.

I know everyone wants to know – how can I kiss safely? So hang in there, because it’s coming.  Along with the answers to all of the “embarrassing” sex questions I have ever been asked.

References:

Liccardi G, et al. Intimate behavior and allergy: a narrative review. Annals of Allergy, Asthma & Immunology 2007; 99: 394-400.

Maloney JM, et al. Peanut allergen exposure through saliva: assessment and interventions to reduce exposure. J Allergy Clin Immunol 2006; 118: 719-724.

Liccardi G, et al. Drug allergy transmitted by passionate kissing. Lancet 2002; 359: 1700.

Sonnex C. Genital allergy. Sex Transm Infect 2004; 80: 4-7.

 

 

 

 

 

Chronic urticaria and angioedema: Part 1

Urticaria is the medical term for what we commonly call hives. It is often caused by an allergic process, but can occur for other reasons. Angioedema is swelling affecting the dermis, subcutaneous tissue, mucosa and submucosal tissues. Angioedema can be dangerous, particularly when the airway is obstructed by swelling.

Notably, the two conditions are closely related and are distinguished by the tissues affected. Urticaria is affects only the upper dermis. In this way, angioedema is sometimes considered a form of “inside hives”. These symptoms can occur as a result of allergy but also occur for other reasons.

Urticaria and angioedema are considered acute if they last for less than six weeks and chronic if they last for six weeks or more. Acute urticaria and angioedema are most often, but not always, the result of mast cell and basophil activation by both IgE and non-IgE mechanisms. Activation by complement fragments, antibody binding complexes, cytokines and blood pressure changes can contribute. Importantly, acute urticaria and angioedema usually have an obvious trigger and resolve on their own. Antihistamines and brief courses of steroids are generally used to manage symptoms.

Chronic urticaria usually does not an identifiable cause. The duration of CU (chronic urticaria and angioedema) varies, but physical urticarias are more likely to be long lasting. It is thought that CU affects 0.5-5% of the population. CU patients can have urticaria and angioedema, either alone or together. In these patients, cutaneous mast cells are the driving force and histamine is the most important mediator in these processes.

When biopsied, CU lesions often reveal infiltrates of lymphocytes, but sometimes other cells are present in infiltrates. In CU patients, the clotting cascade is sometimes activated, resulting in increased prothrombin fragments F1 and 2, and D-dimer. These have been suggested as markers of CU, but have not been verified.

CU is only rarely an IgE mediated reaction and is instead associated with a number of chronic conditions. Chronic infections like hepatitis B and C, EBV, HSV, helminthic parasites and H. pylori have been found to cause CU. Complement deficiencies, cryoglobulinemia, serum sickness, connective tissue disease, lupus, rheumatoid arthritis, thyroid disease (both hypo- and hyper-), neoplasms (such as SM), endocrine disorders and use of oral contraceptives are all linked to CU.

Autoimmune diseases are so frequently associated with CU that these patients are subclassified as having autoantibody associated urticaria. Autoantibody associated urticaria and angioedema, linked to thyroid antibodies, anti-IgE antibodies and anti-IgE receptor antibodies, is a subset of chronic idiopathic urticaria. Lupus, dermatomyositis, polymyositis, Sjogren’s and Still’s disease are all associated with CU. Celiac disease has been linked as well.

30-50% of CU patients make IgG antibodies to the IgE receptor and 5-10% make IgG to the IgE molecule. This often does not correlate with skin tests with the patient’s own serum or plasma (ASST, APST) and these tests are not known to affect treatment or identify a specific subgroup of patients. The importance of these IgG antibodies is not clear. Some consider these patients to be more severe, but it is not yet fully understood.

 

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.

Third spacing

The human body essentially keeps fluids in two spaces called compartments.  The first compartment is inside of cells.  This is called intracellular fluid.  It holds about 60% of the body’s fluids.  The second compartment is outside of the cells in the extracellular fluid, which holds about 40% of the body’s fluids.  This second compartment includes spaces like the interstitial compartment and the intravascular compartment.  The interstitial compartment is the fluid that surrounds the cells in tissues.  The intravascular component is mostly blood. 

Third spacing is when body fluids collect somewhere that is not in one of the two compartments where your body can use it.  When fluids are inside cells, your body can use it for chemical reactions.  When fluids are in the interstitial and intravascular compartments, your body can use it for lubrication, chemical reactions and moving chemicals from one place to another.  Fluid in third spaces is outside of the circulatory system and cannot be used by the body.
A common third space is in the abdominal cavity.  When fluid becomes trapped between the tissues and organs of the abdomen, it is called “ascites.”  When fluid accumulates in the interstitial area around the lungs, it is called “pulmonary edema.”  When fluid is found between the layers of the skin or mucous membranes, it is called “angioedema.”
Third spacing is a problem for multiple reasons.  The first is that it compresses the structures around the fluid, like when angioedema puts pressure on the throat and makes it difficult to breathe.  The fluid sometimes affects organ function.  Another reason third spacing is problematic is because it can cause the fluid level in the circulatory system to drop.  This means the amount of blood moving through the body is less than it should be, which decreases blood pressure and increases heart rate.  This can be very dangerous.  If there is not enough blood for the heart to pump, it will stop pumping.
People with a lot of third spacing often have symptoms of dehydration.  This includes things like excessive thirst, fatigue, and reduced urine output. 
Third spacing occurs as a result of anaphylaxis.  It is also a common problem for people with mast cell disease in the absence of anaphylaxis due to “leaking” of chemicals like histamine that push fluid out of the blood vessels and into the tissues.  Fluid replacement is very important to staying stable.
There is a lot of anecdotal information that suggests that IV fluids are helpful to counteracting third spacing in people with mast cell disease.  I get 2L of fluids overnight three times a week, and it has helped immensely.  For me, the IV fluids have stabilized my blood pressure, decreased my heart rate and keep my GI tract moving.  My abdominal pain has improved significantly since starting the IV fluids. My energy is better.  I don’t think that it has been formally written up in article form, but this is a treatment that is quickly gaining momentum in the mast cell community.