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eosinophils

Food allergy series: Eosinophilic gastrointestinal disease (Part 1)

Eosinophil gastrointestinal diseases (EGID) is an umbrella term that encompasses a plethora of primary conditions associated with inappropriate activity of eosinophils. Eosinophils are white blood cells that share a number of functions with mast cells. They are important to immune response to infections, especially parasites, as well as allergy. Eosinophils typically account for 6% or less of the total white blood cell count. They are found in a number of places in the body, but are not usually found in the lung, skin or esophagus without some underlying pathology. Like mast cells, they have granules filled with chemicals and can degranulate in response to stimulus. They release some chemicals in common with mast cells and some not.

Eosinophils are increased in a number of GI conditions, including allergy associated colitis in adults, allergic proctocolitis in infants, eosinophilic gastroenteritis and eosinophilic esophagitis. They are also elevated in inflammatory bowel disease, reflux esophagitis, celiac disease and other types of colitis. Increased eosinophils can be induced by several other conditions or disease states, including infection, use of certain medications, collagenous and lymphocytic colitis, connective tissue disease, neoplasia, graft vs host disease and autoimmune colitis. It can also be associated with allergy or idiopathic. Despite a fair amount of research, many papers use varying criteria for determination of disease and excess eosinophil count. This ambiguity has contributed to much confusion and will be discussed in detail in upcoming posts. Still, pathologically, eosinophils are rarely found in number in any tissue sample and if present indicate inflammation or disease.

A number of conditions can cause secondary increase of eosinophils in the GI tract. EGIDs are primary conditions and are listed below.

Eosinophilic gastroenteritis most often affects adults, with females being slightly more likely to develop it. Infants rarely have this condition, but some have been identified. Virtually the entire GI tract can be affected, but most often the stomach and small intestine. The eosinophils can be diffuse and localized to only one organ or portion of the organ. They can cause lesions mistaken for tumors. This condition is characterized by edema, “numerous” eosinophils in almost any layer, and ulcerations that can look like tumors. Eosinophilic gastroenteritis is idiopathic, but 50-70% are thought to be due to allergic responses, especially from medications.

Eosinophilic esophagitis usually first presents in people under 30. Males are more commonly affected. It is defined as 15 or more eosinophils/hpf (peak count) with eosinophils mostly found in the mucosa or muscular wall of the esophagus. Microabscesses and basal cell hyperplasia are sometimes found. It is subclassified as being allergic or non-allergic.

Eosinophilic colitis is a more controversial entity marked by nonspecific symptoms, unclear diagnostic criteria, and relapsing-remitting course. It is exceptionally rare. This will be discussed in detail in an upcoming post.

Eosinophilic gastroenteritis has much the same profile as eosinophic gastroenteritis, but the disease process is limited to the small intestine.

Allergic proctocolitis affects the rectum and/or colon of children under 2 years of age. Eosinophils can be found diffusely or focally in these patients. It is defined as more than 6 eosinophils/hpf in the lamina propria layer, and/or “elevated” eosinophils in the intraepithelial or muscular layers (considered 1-2 or “numerous” in various studies.) This is the result of food allergy, especially cow’s milk or soy.

References:

Mueller, Susanna. Classification of eosinophilic gastrointestinal diseases. Best Practice & Research Clinical Gastroenterology 2008, 22 (3): 425-440.

Spergel, Jonathan, et al. Variation in prevalence, diagnostic criteria, and initial management options for eosinophilic gastrointestinal diseases in the United States. JPGN 2011, 52 (3): 300-306.

Alfadda, Abdulrahman. Eosinophilic colitis: epidemiology, clinical features and current management. Ther Adv Gastroenterol 2010, 4(5) 301-309.

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.

 

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.