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.

Inconvenient: The reality of living with food allergies

Earlier this week, a video was circulating on the internet showing a school board meeting in Michigan. In it, school board members were discussing food allergies and the effect they have on foods being allowed in school.

“Well, you should just shoot them,” a school board member said. She threw her arms up and shrugged a little after she said it. She was clearly kidding. It was a joke to her. It is the sort of thing said when forced to discuss inconveniences at length. She said it because food allergies are inconvenient and she was tired of talking about inconvenient things.

Linda Grossman did not want to harm food allergic children. She was just tired of talking about food allergies.

I am also tired. I am tired of people saying things like this that are meant in jest but are insidious and disrespectful and deeply hurtful.

I am tired of people behaving like food allergies are a personality attribute, not a life threatening medical condition.

I am tired of people feeling like they have more of a right to convenience than food allergic people have to be alive.

As of 2010, an estimated 8.96% of adults and 6.53% of children in the US are food allergic. Averaged, this means that about 1/13 people in the US have food allergies. 1/13 means that on average, each classroom in the US can be expected to have 1-2 food allergic students. Among asthmatic children, the frequency of food allergy skyrockets to a whopping 24%. Childhood food allergies cost approximately 25 billion dollars a year in the US.

Frequency of food allergy rose 50% between 1997 and 2011, with peanut allergy alone tripling in that time. As many as 40% of food allergic children have previously had severe anaphylactic reactions that could have resulted in death. Severe reactions requiring hospitalization have increased sevenfold in the last ten years in Europe.

Food allergy is the most common cause of anaphylaxis outside of a hospital setting and results in 200,000 emergency department visits yearly. This equates to one person every three minutes. It is estimated that 100-200 people die from food allergies each year in the US, with numerous conflicting reports.

I am tired of food allergic people and families having to beg for steps to help prevent DEATH.

I am tired of people feeling that making practical changes to prevent people from DYING is inconvenient.

I am tired of people making jokes about a medical issue that KILLS people.

I am tired of food allergic people being excluded from everything because their LIFE THREATENING condition is INCONVENIENT for the other people there.

I am tired of living in a world that prioritizes convenience over the health and welfare of its people.

I am tired of people who should damn well know better spouting dangerously inaccurate facts about food allergy. So I’m putting all my other posts on hold and we’re going to talk about food allergies, FPIES, eosinophilic gastrointestinal disease, celiac disease, and a-gal allergy.

This is not a joke. Anaphylaxis is not a joke. Food allergic people are not jokes. It’s time to stop pretending comments like these aren’t damaging. It’s time for us to stand up and fight.

Fragrance allergy

Public understanding of allergy pathology is often inaccurate and can create dangerous misunderstandings. The most common is that you must ingest a protein in order to have an anaphylactic reaction. Another is that inhalation or skin contact cannot cause severe reactions.

Both of these are inaccurate, especially, but not only, for people with mast cell disease. People without mast cell disease have severe reactions to IV contrast without having allergy antibodies to the protein (Singh, 2008). Inhalation can cause anaphylaxis. There are even cases of patients who can tolerate ingestion of a food but not inhalation, such as seen in Baker’s asthma, the second highest cause of occupational asthma in the UK (Ramirez, 2009). While ingestion of protein is the most common mechanism for severe allergic reactions, it is certainly not the only one.

Fragrance allergy is a growing problem worldwide. Fragrance is now one of the top five allergens in North American and European countries and can cause skin, eye and respiratory problems (Jansson, 2001). At least 100 chemicals commonly used in fragrances can cause contact allergies when applied to skin, even passively (Johansen, 2003). European Commission’s Scientific Committee on Cosmetic Products and Non-Food Products’ 1999 list of allergenic substances contained 24 chemicals and 2 botanical preparations, all used as scents (European Parliament and Council Directive 2003/15/EC, 2003).

Though the exact mechanism is not clear, perfume is known to cause asthma and other respiratory problems (Elberling J, 2009). A Dutch study found that isoeugenol, a common component of fragrances, can cause increased proliferation of cells in respiratory tract lymph nodes when inhaled (Ezendam J, 2007). However, more research is needed in this area.

A significant portion of the population also reports adverse reactions to scented products in general, even when worn by others. Products like scent lotions, perfumes, soaps and air fresheners are all cited as problematic. A 2009 paper reported on the results of two surveys of over 1000 people. 30.5% of the general population found scented products on other people to be irritating. 19% reported health effects from air fresheners, and 10.9% reported the venting of scented laundry products as causing symptoms. Percentages were higher among asthma patients and those with chemical sensitivity (Caress SM, 2009).

Symptoms reported from exposure to fragrances on others includes: headaches, chest tightness, wheezing, diarrhea, vomiting, mucosal irritation, reduced pulmonary function, asthma, asthmatic exacerbation, rhinitis, irritation of the airway, nose and mouth, and dermatitis (Caress SM, 2009).

Many of you are aware of the recent dispute over whether or not essential oils can be dangerous. They can. Even in the absence of known chemical triggers, the oils themselves can be triggering to many. As an example, clove oil, which has a large eugenol component, has been tied to severe allergic reactions (A.O. Nwaopara, 2008). Oils of citrus fruits are known to liberate histamine and make it more available to cause mast cell symptoms (Novak, 2007). Furthermore, while the reaction profile of each mast cell patient is unique, the hallmark of mast cell disease is anaphylactic reactions to seemingly harmless substances. Mast cell patients are increasingly being viewed as “canaries in the coal mine” for their ability to detect minute quantities of offensive components. While mastocytosis is rare, affecting about 0.3-13/100000 patients, some level of mast cell activation syndrome (MCAS) is thought to affect a much larger percentage of the population, in the neighborhood of 5% (Molderings, 2014).

Fragrances, from essential oil or otherwise, can cause contact allergies, headaches and respiratory symptoms. In mast cell patients, scents can cause severe full body reactions that are potentially life threatening or fatal.

Mast cells, eosinophils and the perfect storm of inflammation

Mast cells and eosinophils have a lot of common functions.  In allergic and inflammatory states, these cells come into physical contact with each other, as well as communicate using chemical signals called cytokines and chemokines.  Mast cells and eosinophils are often found together in affected tissues in disorders like allergic rhinitis, atopic dermatitis, and asthma.  Mast cells initiate the allergic inflammatory response once activated.  This signals for eosinophils to come to the tissue.  Increased numbers of mast cells and eosinophils are found in diseases like eosinophilic esophagitis, chronic gastritis, GI neoplasms, parasitic infections and IBD.  Both mast cells and eosinophils respond to eotaxins, molecules that draw eosinophils to the inflamed area.  So one signal causes both cell types to go to the affected tissue. 

Mast cells and eosinophils interact a lot by using chemicals.  Mast cell released heparin stabilizes eotaxins.  Mast cells produce IL-3 and IL-5, which lengthen the lives of eosinophils in tissue.  Mast cell mediator chymase suppresses eosinophil death and causes eosinophils to release several chemicals.   Tryptase can limit eosinophil activation.  In turn, eosinophils produce stem cell factor (SCF), which attract mast cells and protects them from cell death.  Both cell types express some common receptors, like Siglec-8, which induces eosinophil death and inhibits IgE-mediated mast cell activation.  Interactions between these cells increase activation and proliferation. 
Patients with SM may have another blood disorder, including CEL or hypereosinophilic syndrome (HES.)  SM-HES and SM-CEL with the D816V CKIT mutation has been found, and the mutation is present in both the mast cells and the eosinophils.  However, it is likely that the FIP1L1-PDGFRA fusion gene (an aberrant tyrosine kinase) is the cause of the coexistent eosinophilic and abnormal mast cell proliferations.  The FIP1L1-PDGFRA fusion has been found in several cell types, including neutrophils, monocytes and mast cells.  This finding is consistent with a mutational origin in a blood stem cell that makes mutated mast cells and overproduces eosinophils.  When these cells are not neoplastic, they are derived from separate stem cell lineages.
Shortly after the discovery of this fusion gene, there was significant debate over whether FIP1L1-PDGFRA+ disease was an eosinophilic neoplasm with increased mast cells or systemic mastocytosis with eosinophilia.  Patients with FIP1L1-PDGFRA+ eosinophilia have a lot of symptoms in common with SM: swollen spleen, hypercellular bone marrow, high numbers of abnormally shaped bone marrow cells, marrow fibrosis and elevated serum tryptase.  However, these bone marrows show less dense clusters of mast cells.  In some cases, mast cells were spindled and expressed CD2 or CD25.  Still, the WHO considers it a distinct entity and not a subset of SM.
In CKIT+ patients, GI symptoms, UP, thrombocytosis, serum tryptase value, and dense mast cell clusters aggregates in bone marrow are significantly increased.  Cardiac and pulmonary symptoms, eosinophilia, eosinophil to tryptase ratio, elevated serum B12 and male sex were higher in FIP1L1-PDGFRA+ group.
Eosinophilia in SM patients has no effect on prognosis.  Eosinophilia in MDS patients predicted significantly reduced survival.  In T lymphoblastic leukemia, eosinophilia was unfavorable for survival.  Density and activation of tissue eosinophils is related to disease progression in several neoplasms.  Mast cells and eosinophils are found in increased numbers in neoplastic disorders like Hodgkin lymphoma. 
Presence of FIP1L1-PGDFRA indicates treatment with imatinib (Gleevec), regardless of organ dysfunction.  It can show remission within 4 weeks, even at low doses.  Some patients with CKIT+ SM with HES or CEL have rapid and complete normalization of severe eosinophilia with midostaurin treatment. 

Reference:
Gotlib, Jason, Akin, Cem.  2012.  Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders.  Semin Hematol 49:128-137.