The Devil’s Arithmetic

When I was in grad school, I took immunology. I still have my textbook and refer to it sometimes, my crowded notes in the margins. The chapter on allergy and anaphylaxis is highlighted in green, somehow aggressively bright after eleven years.

It’s kind of amusing to recall this time in my life, before every mast cell activation pathway had been hammered into my brain. There’s also some black humor in reading about how IgE activation is the allergy pathway. You know, THE allergy pathway. This book doesn’t cover any other pathways. As if you cannot possibly be allergic to something without IgE.

That’s the problem, of course. This is what most healthcare providers or science majors learn in school. They learn about allergy and anaphylaxis, but they learn about the textbook description which invariably refers to IgE mediated food anaphylaxis. They learn about peanut allergy.

I don’t have a peanut allergy. I literally don’t have a single food allergy that displays the hallmark swelling/closing airway that people expect. But I have major food allergies, some bad enough to require epinephrine, IV Benadryl, Pepcid, Solu Medrol, Zofran and IV fluids.

The problem is not just that I’m allergic to some foods. It’s that I’m not always allergic to the same foods as I was the day before. Or the same medications. Or the same environmental exposures. My reactions on a given day are the cumulative product of the amount of irritation my mast cells have experienced in the previous day or two. There is always a running tally in my mind.

There are a lot of analogies and models used to describe mast cell attacks both to patients and to people who don’t have them. I have always thought of it as a bank. You make deposits and you make withdrawals. Like this:

For the sake of simplicity, let’s assume you have $100 in a bank account. Any activity that can cause mast cell activation has to be paid for. The cost is proportionate to the amount of activation. Getting a splinter: $2. Being hot: $10. Being in direct sunlight: $10. Standing up for 20 minutes while being hot in direct sunlight: $35. Cardiovascular exercise: $40. Arguing with your spouse: $60. Moderate pain experienced in your day to day life: $50. A painful medical procedure: $70. Mild cold: $40.

Some things are too costly to ever attempt.  Undercooked egg whites: $9000.  Massive bleach exposure: $7500.

You can make deposits into the bank with medications and physical changes. Getting enough sleep: $30. Wearing loose, comfortable clothes: $15. Doing orthostatic manuevers before standing up: $10. Taking baseline mast cell medications on your normal schedule: $50. Eating food that is warm but not hot: $15. Monitoring your exercise and stopping for breaks: $15. Wearing a cooling vest on a hot day: $20. Oral Benadryl: $25. IV Benadryl: $50. Steroids: $50.

So you have this running tally in your head all day long. When you start getting close to $100, you get stressed. You know you can’t afford to spend more than $100. Things that you could have done four hours ago safely are no longer safe. Things you could eat on a day spent relaxing at home inside with comfortable ambient temperature cannot be eaten if your apartment is too hot or if you are in a lot of pain.

You are constantly trying to avoid running out of dollars before you can get home and go to bed. Part of this is because you don’t want to trigger a physical reaction. Part of it is that this phenomenon – allergies as a function of circulating histamine/mast cell activation rather than IgE – is hard to explain briefly to people who don’t have this disease. So people will see you on a super crappy day only being able to eat one thing at a party and then four months later, when your body is much less inflamed, will see you eat three things at a party. And then it’s a thing, because these people invariably think that you are faking/being overdramatic as if somehow it is worth the effort to “pretend to have allergies.” WHO FUCKING DOES THAT?

Cost for being around someone who gives you shit for not always having the same restrictions: $75.

So everyday, you get $100. Except this is the US and our banks hate us so we have overdraft. This means that you can spend more money than you have but then they charge a steep fee and so the next day, you don’t have $100. You have maybe $30 dollars. After overspending, it can take a few days to get back to baseline.

Sometimes it’s worth it. Sometimes you can sort of game your body into getting more than $100 out of a day. This is the purpose of premedication for procedures and surgery. This is the purpose of good sleep hygiene, eating safe foods, not getting stressed, taking medications appropriately and on a schedule. You can bank a little. Not as much as you can overdraft, but you can get ahead a little bit.

Today, I went to the supermarket to grab some things for lunch at work. They didn’t have organic apples that looked in decent shape. They had non-organic apples and my safe peanut butter/honey and my safe pretzel chips. I had to run through my entire day to determine how much physical activity and stress was likely to be in the rest of my day to figure out what I could (probably) safely eat for lunch.

It’s like this all day, every day. This math wouldn’t be hard except that it’s constant and unavoidable and controls my life.

The Sex Series – Part Five: Seminal allergy, post-orgasmic illness syndrome and burning semen syndrome

Allergy to semen has only been well documented and studied in cisgender (non-transgender) women. Some papers go so far as to state that this problem is exclusive to (cisgender) women.  Despite this, there is evidence that (cisgender) males can have allergy to semen, including their own.  Furthermore, semen allergy is not restricted to vaginal intercourse and can be seen in anal and oral sex, as well as local reactions when semen contacts skin outside of the vaginal area.

Semen contains a number of inflammatory molecules, including TGFb1, MCP-1, IL-13 and IL-17.  MCP-1 has a well described role in mast cell activation in which it draws mast cells toward an inflammatory site and directly induces histamine release.  The physical effects of orgasm use opioids made in the body.  Some patients experience a days-long reaction to orgasm.

Termed “postorgasmic illness syndrome”, allergic symptoms affecting the genitals and general flu-like symptoms present 2-8 hours after ejaculation. These symptoms can persist for up to a week, with the day after ejaculation often being the worst.  Postorgasmic illness syndrome causes excessive sweating, rhinitis, anxiety, depression and difficulty concentrating.  This condition is recognized as a rare disorder by the NIH.  It has been hypothesized that these patients are in fact suffering from opioid withdrawal caused by the rapid depletion of opioids by orgasm.

Semen allergy has been associated with serum IgE to prostate-specific antigen (PSA), a molecule involved in the kallikrein-kinin system.  Autologous semen allergy, or allergy to one’s own semen, can be confirmed by reaction to semen in skin prick allergy testing or by specific IgE in the blood. One study found that 88% of patients who experienced burning and pain after ejaculation were positive for allergy to their own semen.

The phenomenon of burning after ejaculation is called “Burning semen syndrome”. In these patients, burning, pain and swelling of the UG tract occurs following ejaculation.  This study also evaluated partners of these patients receiving vaginal sex.  In many instances, both members of the couples evaluated were positive for allergy to semen. 89% of these couples had at least one member who exhibited allergic reaction to semen.

 

References:

Van Dijk F, et al. Non-oncological and non-infectious diseases of the penis (penile lesions). EAU-EBU Update series 4 2006; 13-19.

Ghosh D, Bernstein J. Systemic and localized seminal plasma hypersensitivity patients exhibit divergent immunologic characteristics. J Allergy Clin Immunol 2014: 134 (4): 969-972.

Jiang N, et al. Postorgasmic illness syndrome (POIS) in a Chinese man: No proof for IgE-mediated allergy to semen. J Sex Med 2015; 12: 840-845.

Bernstein JA, et al. Is burning semen syndrome a variant form of seminal plasma hypersensitivity? Obstetrics & Gynecology 2003; 101 (1): 93-102.

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.

The Sex Series – Part Four: Seminal allergy

Author’s note: This series is long and covers a number of topics other than vaginally penetrating sex, including male and female orgasms, reactions of the penis, testicles and prostate, anal sex, and pelvic floor dysfunction and pelvic pain.  The first several posts are about vaginally penetrating sex because this is what I get asked the most questions about.  It is not meant to be exclusive to anyone on the basis of gender or sexual orientation.

**
It is possible to be truly allergic to semen, although this is rare.  One of the hallmarks of this condition is that it is completely preventable with condom use.

Most patients react during or after their first experience with vaginal penetration by a penis resulting in ejaculation.  Each subsequent exposure generally causes a worsening reaction. However, it is possible to develop an allergy after a number of intercourse encounters. In studies, patients with seminal allergy are allergic to semen from multiple partners, although there are anecdotes about patients reacting to semen from a single partner and not only.

This type of allergy has been linked to IgE.  The testing for this sensitivity involves skin prick tests with seminal protein that produce wheal and flare response.  Semen specific IgE is often appreciable in the blood following exposure.  Some patients have type III and type IV hypersensitivity reactions to semen and symptoms can occur days after the exposure.

Like all other forms of allergy, the range of reactions is massive.  It can range from a low level itching to anaphylaxis requiring epinephrine.  Itching, burning, redness, swelling, pain, and blistering in the vagina have all been reported. Trouble breathing, cough, wheezing, GI symptoms, generalized hives, disseminated angioedema and full anaphylaxis can occur.  Anaphylaxis has been reported in 16 cases, with one case causing loss of consciousness.

Across studies, most patients have either a personal or family history of allergic conditions.  80% of patients in one study had a family history of atopic disease.  One study found that the onset of seminal allergy often coincides with genital system conditions or procedures like hysterectomy, IUD placement or removal, pregnancy and tubal ligation.  It is hypothesized that the disruption of the normal state of immune activity in the vagina by these activities can trigger seminal allergy, but this has not been proven.

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 Two: Contact dermatitis

Symptoms affecting the genitalia as a result of vaginally penetrating intercourse are not uncommon.  Today we are going to talk about allergic and irritant reactions to products. There are other kinds of symptoms to vaginally penetrating intercourse that we will get to later on in this series.

It is not unusual for people to use specific products only in advance of having sex.  This includes things like lubrication, pleasure creams, and products for shaving and removal of hair.  Contact dermatitis can arise as a result of these products.

Contact dermatitis is inflammation of the skin following contact with a substance that irritates or generates an allergic reaction.  In case it’s not obvious, genital tissue is much more sensitive than other parts of the body.  Irritant contact dermatitis of the vulva is more common than true allergic dermatitis there.

Common irritant triggers include hygiene products like soap, shower gel, and sanitary napkins, spermicides, diaphragms, and sexual lubricants.  In some people, these triggers can also generate a true allergic dermatitis.  Additional triggers commonly associated with allergic contact dermatitis regularly include neomycin, -caine anesthetics and nickel.

Contact dermatitis of the genital (and other) areas can cause a wide range of reactions from mildly irritating to very severe.  Symptoms can include redness, swelling, itching, burning and pain, and can cause chronic thickening of the skin, fissuring of the skin, weeping of the skin and blistering.  In most patients, the substance responsible for the reaction is identified via skin patch testing.  I would not expect this to be reliable in mast cell patients given the inherently reactive nature of our skin.

Irritant contact dermatitis often shows symptoms shortly after product use. True allergic contact dermatitis is a delayed type IV hypersensitivity reaction and can take 2-3 days to appear. Many patients are able to identify the trigger by removing products and symptom resolution upon doing so. Some genital hygiene products include alcohol.  Many more include propylene glycol, a well defined trigger for vulvar dermatitis.  Products that contain sugar and/or change the pH of the internal vaginal environment disturb the natural microbial flora, causing inflammation and increased risk of infection later.

It is also possible for products used by the partner to transfer during vaginal penetration.  If the penetration is made by part of the body and not a toy, transfer can happen in either direction. For persons using toys for external or internal stimulation, it is also possible to react to the material of the product. Something to consider is that many companies sell products to clean up after sex, either to clean genitalia, toys or both.  Please look carefully at the ingredients included in those products.  Additionally, please ensure that any toys used are cleaned before and after use.

 

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.

 

 

 

 

 

Food allergy series: FPIES (part 2)

FPIES is usually diagnosed clinically. Endoscopy and biopsy are not necessary to diagnose, but is sometimes done to rule out other conditions.

Scopes have shown a variety of inflammatory changes in the GI tract of FPIES kids. Diffuse colitis, friable mucosa, rectal ulceration and bleeding have been observed.  Increased levels of TNFa and decreased receptors for TGF-b have been found in the GI tract. Baseline intestinal absorption is usually normal.

Biopsies have shown villous atrophy, tissue edema, crypt abscesses, increased white blood cells, including eosinophils and mast cells, and IgM and IgA containing plasma cells. Radiology showed air fluid levels (collection of both fluid and gas in the intestines), narrowing and thickening of the mucosa in the rectum and sigmoid colon and thickening of the circular folds in the small intestine. When surgery has been performed, distension of the small bowel and thickening of the jejunum has been seen.

Food specific IgE is not usually present. In one study, 21% of patients with solid food FPIES had detectable food specific IgE. 18-30% with FPIES to cow’s milk or soy have IgE for it. If IgE is found, the course of FPIES is longer. One study found a decrease in food specific IgG4 in FPIES patients along with an increase in food specific IgA.

FPIES is managed by removing the offending food. Exclusive breastfeeding can be protective. If not breastfed, use of casein hydrolysate formula is recommended. Less commonly, amino acid formula or IV fluids may be needed. Doctors recommend introducing yellow vegetables and fruits as solids rather than cereal at six months of age. Grains, legumes and poultry should be avoided for the first year of life. Once tolerance is established to one food in a high risk category, like grains, the child is more likely to tolerate other foods in the same category.

Oral food challenges (OFC) should be undertaken to determine if tolerance to the food has been achieved. A conservative approach recommends challenges every 18-24 months in patients without recent symptoms. OFCs are high risk procedures for FPIES children. The following procedure should be observed:

  • Any FPIES OFC must be physician supervised. Generally, inpatient settings are preferred, but if an outpatient setting can provide appropriate supportive care, it may be acceptable. Intravenous access should be secured prior to beginning and IV fluids and medications should be immediately available in case of reaction. ICU care is not recommended unless there is a history of near fatal reactions.
  • Blood should be drawn immediately before beginning the OFC to provide baseline complete count count and neutrophil count.
  • Over the first hour, 0.06-0.6g/kg body weight of food protein should be administered in three equal doses. It should not exceed 3g of total protein or 10g of total food or 100ml of liquid for initial feeding.
  • If patient has no reaction, give a full serving of food as determined by their age.
  • Observe patient for several hours afterward.
  • In the event of reaction, administer 20 ml/kg boluses of normal saline.
  • In the event of severe reaction, including repetitive vomiting, profuse diarrhea, lethargy, hypotension or hypothermia, administer 1 mg/kg methylprednisolone intravenously, up to 60-80mg total. About 50% of patients who react to FPIES OFCs will need IV fluids and steroids.
  • Epinephrine must be available during FPIES OFCs for treatment of hypotension and shock. In FPIES cases, epinephrine does not resolve vomiting and lethargy.
  • In children with positive skin tests and/or food specific IgE, antihistamines should also be available during OFCs.
  • Blood should be drawn six hours after OFC to compare to baseline values. If patient has diarrhea, stool guaiac tests should be done, and stool samples should be tested for white bloods, red blood cells and eosinophils in feces.

An OFC is considered either positive or negative. Positive means there is a reaction. Negative means there is not. It is positive if the patient experiences vomiting, lethargy or diarrhea in an appropriate time frame. In the absence of symptoms, if the neutrophil count is over 3500/ul, or white blood cells, frank or occult blood, and/or eosinophils are present in feces, the challenge is still considered positive.  More than 10 leukocytes/hpf in gastric juice at the 3 hour mark has been suggested as a positive marker, but needs further investigation. In the study that noted this marker, gastric juice was obtained via orogastric feeding tubes.

One study looked at the resolution of FPIES over a ten year period. 160 subjects were included in the study. 54% were male. Median age of diagnosis was 15 months. 180 OFCs were done for 82 patients, of which 30% had obtained an FPIES diagnosis based on previous OFCs. 44% of patients reacted to cow’s milk; 41% to soy; 22.5% to rice; and 16% to oat. 65% had only one food sensitivity, 26% had two, and 9% had three or more. Most had some form of atopic disease and 39% had detectable food specific IgE. 24% had IgE specific for the food causative for their FPIES reaction. Of the patients with IgE for cow’s milk, 41% of them moved from an FPIES reaction type to an IgE allergy reaction type.

60% of FPIES cases resolve by three years of age. This finding is an average and different populations see much different results. In South Korea, 90% of patients resolve by three years of age. In the US, only 25% resolve by this age. The differences observed are thought to be due to other factors, such as the frequency of food specific IgE and atopic disease. The median age for FPIES resolution depended largely on the food: 4.7 years for rice, 4 years for oat, 6.7 years for soy, 5.1 years for milk. If milk IgE was present, the patient did not become tolerant of milk during the course of study.

FPIES overwhelmingly affects very young children. However, there are rare cases of older children and adults developing FPIES at a later age. These cases involve fish and shellfish as the offending foods.

 

References:

Leonard, Stephanie, Nowak-Wegrzyn, Anna. Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011; 107:95-101.

Caubet, Jean Christoph, et al. Clinical features and resolution of food protein induced enterocolitis syndrome : 10-year experience. J Allergy Clin Immunol. 2014; 134(2): 382-389.

 

Food allergy series: FPIES (part 1)

Food protein induced enterocolitis syndrome (FPIES) is the most severe GI food hypersensitivity that is not IgE mediated. FPIES is thought to be caused by a delayed, cell mediated allergic pathway. This condition results in profuse, repetitive vomiting, diarrhea, acute dehydration, lethargy and weight loss. It can eventually lead to failure to thrive.

Upon challenge, an FPIES patient will typically begin with severe, repetitive vomiting 1-3 hours after ingestion; diarrhea, 2-10 hours after diarrhea; lethargy; pallor; low blood pressure; hypothermia; and abdominal distention. They will often show a spike in neutrophils, being highest around 6 hours after exposure; elevated platelets; metabolic acidosis; high methemoglobin; white blood cells in feces, including eosinophils; fecal blood, frank or occult; increased carbohydrates in stool; and elevated white blood cells in gastric juice. Vomiting is seen in 100% of episodes; lethargy in 85%; pallor in 67%; diarrhea in 24% and hypothermia in 24%.

Chronic symptoms from repeat ingestion of responsible food include intermitten, chronic vomiting; frequent, watery diarrhea, often with blood or mucus; lethargy; dehydration; abdominal distention; weight loss; and failure to thrive. Patients with chronic symptoms are often anemic; have low serum albumin; have elevated white blood cells, especially eosinophils; have metabolic acidosis, in which the body produces too much acid and the kidneys cannot remove it quickly enough; have methemoglobinemia, too much of a form of hemoglobin that binds oxygen poorly; intramural gas, gas within the wall of the bowel; and air fluid levels, a radiologic finding often associated with bowel obstruction.

About 75% of FPIES patients appear seriously ill. 15% are hypotensive enough to require hospitalization.

FPIES almost exclusively begins in infancy. Age of onset is typically between 1 and 3 months of age, but can be as late as 12 months. It is slightly more common in males, with male cases accounting for 52-60% of cases. Symptoms generally begin within 1-4 weeks of introducing cow’s milk or soy. Sometimes these substances are tolerated, but FPIES to a solid food shows, with rice being the most common offending solid. Egg is extremely rare as a cause of FPIES reactions.

FPIES has been well studied. About 30% of FPIES patients go on to develop atopic conditions, with 25-65% getting atopic dermatitis; 3-20%, asthma; and 20%, allergic rhinitis. 40-80% of patients have a family history of atopic disease and 20% have a family history of food allergies.

A history of FPIES to one grain gives a 50% chance of reaction to other grains. In cases of solid food FPIES, 80% react to more than one food. 65% were previously diagnosed with FPIES to cow’s milk or soy. 35% were breastfed.

Patients usually improve significantly within 3-10 days of beginning casein hydrolysate-based formula with or without IV fluids. In infants who have generic GI symptoms early on, switching to a hypoallergenic formula can prevent fullblown FPIES.

References:

Leonard, Stephanie, Nowak-Wegrzyn, Anna. Food protein induced enterocolitis syndrome: an update on natural history and review of management. Ann Allergy Asthma Immunol. 2011; 107:95-101.

Caubet, Jean Christoph, et al. Clinical features and resolution of food protein induced enterocolitis syndrome : 10-year experience. J Allergy Clin Immunol. 2014; 134(2): 382-389.

Food allergy series: Risk factors for developing food allergies

There are a number of factors that seem to contribute to developing food allergies. Genetics seems to play an important role. One study found that that 64% of monozygotic twins had a concordance of peanut allergy, while only 7% dizygotic twins concorded. This means that in 64% of identical twin sets, either both had peanut allergies or neither did, while that was the case in only 7% of fraternal twins. Because monozygotic twins have identical genetic sequences, this finding implies a strong genetic component. HLA haplotyping has been studied, with conflicting reports on links between HLA type and allergies.

One of the most important genetic findings regards filaggrin, a skin barrier protein. Patients with a specific filaggrin mutation are more likely to develop peanut sensitization. This indicates that a damaged skin barrier could cause food sensitization and allergy, and further supports the idea that non-oral exposures can be sensitizing. Additionally, filaggrin mutation causes increased inflammatory mediators in the skin.

Generally, children with peanut or tree nut allergies react the first time the food is ingested. It is thought that they previously encountered these allergens in their environment. Household exposure to peanut was a significant risk factor for peanut allergy in infants. Peanut responsive T cells are found in the skin homing T cells in peanut allergic patients, implying that patients may first be exposed through the skin. There is not yet enough data on maternal ingestion of allergens to know if this is a risk factor. There are conflicting data sets on whether breastfeeding is protective against food allergies, and in any case, outcome appears to be dependent on the mother’s own sensitivity profile. Now seen in multiple recent studies, it seems that early oral exposure to food allergens may actually be protective against food allergy, a change from data produced over a decade ago.

Immune dysregulation is obviously involved in food allergies. Low vitamin A and vitamin D, which modulate the immune system, have been noted as risk factors. Interestingly, food allergy frequency varies with latitude, indicating a further possible connection to sun exposure and vitamin D deficiency. High fat diet can also change the composition and behavior of the microbial content of the GI microbiome. Medium chain triglycerides can increase sensitization when given along with food antigens in mice. There are mixed results with long chain fatty acids.

The changes in hygiene, cleaning products and use of antimicrobial compounds by the general public in the last decades have been implicated in many of the immune changes we have seen, including increasing autoimmune diseases and food allergies. This is known as the hygiene hypothesis, and it states that reduced exposure to microbes changes immune defense, causing improper reactivity to harmless components, like food and self cells. In food allergic mice, the gut microbiota has a very specific composition and transferring this flora set can actually make others more likely to develop food allergies. Dysbiosis has been noted in children with food allergies and a sequencing study demonstrated that food allergic children with atopic dermatitis have reduced microbial diversity in the gut.

 

References:

Cecilia Berin, Hugh A. Sampson. Food allergy: an enigmatic epidemic. Trends in Immunology, Volume 34, Issue 8, August 2013, pages 390-397.

Cecilia Berin, Hugh A. Sampson. Mucosal Immunology of Food Allergy. Current Biology, Volume 23, Issue 9, May 2013, pages R389-R400.

Food allergy series: Food related allergic disorders

The term “food allergy” is generally used by medical professionals to refer to IgE mediated allergic responses. However, it is used in a broader sense by patients who have similar conditions because the term is more likely to be understood. The truth is that there are several types of allergic disorders provoked by foods. They are all listed below and will be expounded upon in the coming days.

IgE antibodies mediate the following types of reactions. All of them have immediate onset of symptoms following interaction with the antigen.

  • Oral allergy syndrome. This presentation is usually mild. It causes itching and mild swelling in the mouth, progressing into the throat about 7% of the time, with less than 2% of cases progressing to anaphylaxis. OAS occurs due to sensitization to pollens. These pollens have specific shapes that are recognized by the IgE molecules; certain raw fruits and vegetables may shapes that are close enough to be recognized by the same IgE molecules. This is known as crossreactivity. Cooking the food changes the shapes seen by the IgE molecules and is therefore cooked forms are usually safe. In birch pollen sensitive people, apples, peaches, pears and carrots can cause crossreaction; in ragweed sensitive people, melons can be problematic. This is usually diagnosed by skin testing with the raw fruits/ vegetables. OAS can persist and be problematic during the season when the offending pollens are most prevalent.
  • Asthma irritation, including rhinitis. This can be caused by inhaling the food protein. It is most common in infants and children with the exception of work exposures in adults, like Baker’s asthma. This most commonly occurs with the eight major allergens: egg, milk, wheat, soy, peanut, tree nuts, fish and shellfish. Skin testing and serum IgE measurement can be used for diagnosis.
  • Urticaria and angioedema. This occurs when an offending food is ingested or contacts the skin (contact urticaria.) Food exposures cause 20% of acute urticaria cases and 2% of chronic urticaria cases. It is much more common in children and usually occurs after exposure to the eight major allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • GI hypersensitivity.Immediate onset vomiting can occur in response to the major food allergens. Skin testing and serum IgE measurement can be used for diagnosis.
  • Food associated, exercise induced anaphylaxis. This occurs following ingestion of food after recent completion of exercise. It is thought that exercise affects the way the GI tract absorbs and digests allergens. This most commonly affects adults, with wheat, shellfish and celery being the most common foods to provoke this reaction. Skin testing, serum IgE measurement, component testing and exercise testing can be used for diagnosis.
  • Delayed food-induced anaphylaxis to meat. This occurs several hours after ingesting the meat. It occurs when the body generates antibodies to carbohydrate a-Gal, which can be induced by tick bites. Beef, pork and lamb are known to cause reactions in a-Gal sensitive people. Testing should include serum IgE to a-Gal.
  • Anaphylaxis. I have addressed this in detail before. It can occur in response to any food, but the eight major allergens are most common. It results in massive mast cell degranulation, leading to cardiovascular collapse.

Some allergic responses to food are due to both IgE mediated reactions and delayed cell-mediated reactions.

  • Atopic dermatitis. In children with AD, about 35% of moderate/severe rashes are due to food reactions. This is thought to be due to food reactive T cells locating to the skin. It is most common in infants and least common in adults. All major allergens can be causative, but egg and milk are the most common. AD is usually self limiting. Skin testing and serum IgE measurement can be used for diagnosis.
  • Eosinophilic GI disease (EGID.) Eosinophils are inflammatory cells that share a lot of functions and behaviors with mast cells. Like mast cell disease, eosinophilic disease can affect a variety of organs, most commonly the GI tract. Symptoms are widely variable and related to level of inflammation and infiltration. It often causes difficult or painful swallowing, weight loss, obstruction and edema. EGID is related to the activity of several mediators, include IL-5, eotaxin, which causes eosinophils to home to various inflamed locations. Much like mast cell disease, it can occur in response to a wide array of foods. Elimination diets are first line treatments for EGID. Endoscopy, kin testing and serum IgE measurement can be used for diagnosis, but elimination diets are often used empirically for diagnosis.

Some allergic type responses to food are not due to IgE antibodies.

  • Food protein induced enterocolitis syndrome (FPIES.) Usually found in infants, repeat exposure to certain proteins causes chronic vomiting, diarrhea, low energy and poor growth. Exposure again following a period of abstinence from offending substance can cause vomiting, diarrhea and 15% drop in blood pressure. These reactions occur about two hours after ingestion. Cow’s milk, soy, rice and oat are the most frequently reported sources, but many others have been recorded. In FPIES children, their cells are more responsive to TNF-a and less responsive to TGF-b. FPIES usually resolves with age, but can be difficult to diagnose due to skin testing and serum IgE testing usually being negative.
  • Food protein induced allergic proctocolitis. This causes mucuosy, bloody stools as a result of eosinophilic response in infants. This occurs in response to milk through breast feeding and resolves when the substance is removed from the mother’s diet.
  • Heiner syndrome. This rare condition is marked by pulmonary infiltration, upper respiratory symptoms, iron deficiency anemia and failure to thrive. It occurs in infants and is triggered specifically by milk. It is thought that there may be a milk specific IgG reaction.
  • Celiac disease. This autoimmune disease causes malabsorption and enteropathy. It is a response to gliadin, a gluten protein in wheat and other grains. It can cause bone abnormalities, IgA deficiency, dermatitis herpetiformis and a variety of other complications. It can present at any age and is lifelong. Blood testing during food challenges, GI biopsies, and testing for HLA DQ2 and DQ8.

Cell mediated reactions are not due to IgE antibodies.

  • Allergic contact dermatitis. This type of eczema occurs in response to metals in foods. This occurs mainly in adults. It is diagnosed by atopy patch testing.

Mast cell reactions to food are related to inappropriate degranulation which has not been fully characterized. Mast cell food reactions will be discussed more completely in an upcoming post.

 

Reference:

Sicherer, Scott, Sampson, Hugh. Food allergy: Epidemiology, pathogenesis, diagnosis and treatment. J Allergy Clin Immunol 2014, 133 (2): 291-307.

 

Food allergy series: Atopy, risk factors and frequency

Food allergy is used widely to describe any adverse reaction to food, but scientifically is considered to include only IgE mediated reactions. For the purposes of this series, I will use this term in the same way. However, there are several other conditions that can cause severe food reactions via different mechanisms and all will be addressed in upcoming posts.

Food allergy causes a reaction to a specific allergen following contact with the skin or mucosa, generally the mouth and GI tract. Colloquially, the terms sensitization and allergy are often used interchangeably, and while they are related, they are not the same. Sensitization is when the body makes allergen specific IgE in the blood or skin. Allergy is sensitization with accompanying symptoms.

Atopy refers to the tendency of a person to develop diseases of allergic nature, like asthma and atopic dermatitis. Having one atopic condition makes a person more likely to develop others. The term “allergic march” has been used to describe the progressive accumulation of atopic conditions from the first year of life through late childhood. Though first described in US patient groups, it has also been observed in several other countries. It typically begins with atopic dermatitis and progresses to include allergic rhinitis, asthma and food allergy. Severe eczema within the first six months of life is associated with increased risk of peanut, milk and egg allergies, for example.

Most food allergies are due to egg, cow’s milk, wheat, soy, shellfish, fish, peanuts and tree nuts. 30.4% of children with food allergy have multiple of them. Kids with multiple food allegies are more likely to have severe reactions, as are adolescents from 14-17 years of age. Peanuts, cashews, walnuts and shellfish allergies are most likely to be severe.

The largest studies on frequency of food allergy use self reported information. These types of surveys are not the gold standard. For example, it has been shown that a large number of people eliminate foods from their diets based on suspicion of allergy. These are often unnecessary. 89% of patients with atopic dermatitis were shown to have no reactions to suspect foods on oral challenge. Still, self reported studies are the largest body of data available.

Out of 38,480 households in the US, 2.4% had children with multiple food allergies and 3% had kids with history of severe allergic reaction. Across 9,667 Canadian households, there was an overall 8% rate of food allergy, in line with findings in the US. Australian studies have focused more specifically on frequency of individual allergens and have used oral food challenges in determining allergy frequency. Out of 2,848 one year old children in Melbourne, 3% were allergic to peanut and 8.9% were allergic to raw egg.

Risk factors for developing food allergies are complicated and will be addressed in greater detail in coming posts. Atopy, low vitamin D, reduced consumption of omega-3 polyunsaturated fatty acids, reduced consumption of antioxidants, increased use of antacids, obesity, increased hygiene, and delaying exposure to common allergens have all been cited as risks. Family history of food allergy as well as specific genetic alleles and HLA profiles have also been tied to food allergies.

In children, males are more likely to develop food allergies, with Black children being the most likely, and Asian children being more likely than White children. Children of immigrants living in the US are at higher risk than children born to American born parents in the US. Food allergy is associated with increased affluence, with people living in households earning more than $50,000/year being more likely to receive a diagnosis. However, it is not clear if this is due to increased access to healthcare.

Childhood food allergies are often thought to be “outgrowable.” Allergies to milk, egg, wheat and soy are more likely to resolve. Peanut, tree nut, fish and shellfish allergies are more likely to persist. Unfortunately, resolution of allergies is on a declining trend.

 

References:

Sicherer, Scott, Sampson, Hugh. Food allergy: Epidemiology, pathogenesis, diagnosis and treatment. Journal of Allergy and Clinical Immunology. 2014, 133(2): 291-307.

Sicherer, Scott, Leung, Donald. Advances in allergic skin disease, anaphylaxis and hypersensitivity reactions to food, drugs and insects in 2013. Journal of Allergy and Clinical Immunology. 2014, 133(2): 324-334.

Gupta, Ruchi, et al. Childhood food allergies: current diagnosis, treatment and management strategies. Mayo Clinic Proceedings. 2013, 88(5): 512-526.