Celiac Disease

Given an increasing awareness of gluten-related disorders, medical professionals are encountering patients diagnosed with celiac disease or thought to have food intolerance to gluten. Green et al provide a review of the pathogenesis, clinical manifestations, diagnosis, and management of celiac disease (J Allergy Clin Immunol 2015; 135(5):1099-1106).

There are currently three major wheat-related food illnesses: celiac disease (CD), non-celiac gluten sensitivity (NCGS), and wheat allergy. CD is an autoimmune disorder involving both an innate and adaptive response in genetically predisposed individuals. Unlike food allergies, the pathogenesis of CD is not mediated by an immediate hypersensitivity reaction via an immunoglobulin (IgE) dependent mechanism. Instead, gluten protein is a pathogenic agent activated by the enzyme tissue transglutaminase (TTG) allowing its presentation to CD4+ T cells in the small intestine. NCGS is a term that refers to a spectrum of clinical phenotypes, without the identification of characteristic histologic or serologic abnormalities. Wheat allergy is distinct from both, in that it is an IgE mediated hypersensitivity response that occurs within minutes to hours of wheat ingestion.

Celiac disease has prevalence of nearly 1% among Western nations. Its distribution extends into such disparate populations as the Middle East, South America, Asia, and North Africa. A proposed reason for this trend is a globalizing world market bringing wheat-based foods into cultures that traditionally relied on gluten-free grains. There is evidence CD is a missed diagnosis in many children where infection and malnutrition are the presumed etiology for diarrheal illness. Its pathogenesis depends on the interaction of three factors. The first is predisposing genes, HLA DQ2 and DQ8, and the second is exposure to gluten. The third, environmental factors, includes many under investigation, including breastfeeding and the intestinal microbiome.

There is increasing evidence that CD includes extra-intestinal manifestations, and the terminology for describing it is changing to allow for these. Common presentations include anemia and osteoporosis. Despite increased awareness of the condition and gluten, the rate of diagnosis in the US remains low, with less than 20% of those with the actual condition having been diagnosed. The IgA TTG assay is the initial test of choice to detect antibodies associated with CD. Treatments in addition to the gluten-free diet, such as intraluminal agents, immunomodulators, and vaccination, are currently under investigation.

Question for the authors: 
Is there data available for the prevalence of wheat allergy in Western nations?

Although some overlap exists in the symptoms attributed to wheat allergy, specific pathophysiological reactions to wheat are currently classified into three categories: 1) IgE hypersensitivity associated wheat allergy 2) autoimmune IgA related celiac disease and 3) non celiac gluten sensitivity (NCGS). The prevalence of IgE related wheat allergy, which is most common in childhood, is estimated around 0.4-1.3%. Our review describes the prevalence of celiac disease near 1% in Western nations; however, the incidence of celiac disease has increased over time, and there is evidence of its underdiagnosis among the general population. NCGS is currently not as well understood as the other two wheat related allergies, and estimates of its prevalence are wide-ranging from 0.5-6%.

Immunopathophysiology of food protein-induced enterocolitis syndrome

Food protein-induced enterocolitis syndrome (FPIES) and food protein-induced proctocolitis are non-IgE-mediated gastrointestinal allergies. Our current understanding of the mechanisms of these allergies linking exposure to the typical symptoms of vomiting, hypotension, and diarrhea falls behind that of other food-induced allergic disorders. Accompanying a comprehensive review of clinical features by Nowak-Wegrzyn that also appears in this issue, Berin assesses the state of our knowledge of the immune mechanisms of FPIES (J Allergy Clin Immunol 2015; 135(5):1108-1113).

FPIES is most commonly triggered by the protein component in cow’s milk, but a host of other foods can be triggers as well. Many of the foods that trigger FPIES reactions are also IgE-mediated food allergens, such as soy, fish, wheat, and egg, but many are not common in that regard. For example, rice is the third most common cause of FPIES in US cohorts, followed by oats. The fact that a range of common foods have the potential to trigger it is in contrast to celiac disease, in which pathology is triggered by a well-defined antigen in a restricted subset of foods.

Studies have demonstrated FPIES leads to changes in the intestinal architecture in response to chronic exposure to a trigger such as milk. Avoiding milk results in normalization, and its reintroduction results in a recurrence of partial villous atrophy. While this is similar to celiac disease, the two conditions differ in pathophysiology. For example, the latter is thought to be a food antigen-triggered autoimmunity. There is a lack of evidence for an autoimmune component in FPIES, but there is an association between it and atopy. There is mast cell degranulation in common between the two, which is an important factor that requires investigation.

The facts that FPIES commonly develops in response to the first food introduced into the diet and adverse reactions can develop in response to many foods that are not typically allergenic suggests there may be a regulatory defect in patients with FPIES. The presence and phenotype of food-specific T cells in the intestinal mucosa of patients with FPIES needs to be demonstrated, as has been done with celiac patients. There is even less data to explain the immune basis of acute FPIES reactions. In one case study, milk administered via enema resulted in diarrhea and weight loss, whereas drinking the milk induced vomiting, pallor, and diarrhea in the same infant. Thus, the chronic and acute manifestations of FPIES can be triggered at different sites. Is processing of the allergen during digestion required to trigger symptoms? Much remains to be investigated about its underlying immune mechanisms.

Anaphylaxis: Unique aspects of clinical diagnosis and management in infants (birth to age 2 years)

Anaphylaxis is reported to occur with increasing frequency in infants. An illustrated Rostrum on the diagnosis, treatment, and long-term management of anaphylaxis in this age group has been published by Simons and Sampson (J Allergy Clin Immunol 2015;135: 1125-31).

Foods such as milk, egg, and peanut are by far the most common triggers of anaphylaxis in infancy, although medications and other triggers can also be implicated. Infants with anaphylaxis typically present with sudden onset of skin signs such as generalized urticaria, respiratory symptoms such as cough, wheeze, stridor, and dyspnea, and/or gastrointestinal symptoms such as persistent vomiting.

Clinical criteria for diagnosis of anaphylaxis are validated for use in children and adults, but have not yet been validated for use in infants. A high index of suspicion is required to diagnose anaphylaxis in babies, as they cannot describe symptoms such as itching, and signs of infant anaphylaxis such as flushing, dysphonia, incontinence, and behavior changes (irritability, somnolence) also occur in healthy infants.

The differential diagnosis of anaphylaxis in infancy includes unique entities such as congenital abnormalities of the respiratory tract or gastrointestinal tract, and food protein-induced enterocolitis syndrome. Epinephrine injection is the treatment of choice in both clinical and community settings.

Co-morbidities that increase the risk of severe anaphylaxis are not well-defined, but probably include croup, bronchiolitis, or asthma; likewise, amplifying co-factors are not well-defined in this age group.

Long-term management focuses on follow-up with a physician, preferably an allergy/immunology specialist who can train caregivers of infants to recognize and treat anaphylaxis in the community and help them to prevent anaphylaxis episodes.

Epinephrine auto-injectors (EAIs) are under-prescribed and under-used for anaphylaxis in infants. In a study in which a minority of infants with severe anaphylaxis were treated with epinephrine, reasons for not using it included failure to recognize anaphylaxis symptoms and being afraid to inject epinephrine.

Strict avoidance of exposure to culprit allergens (as confirmed by skin prick tests and specific IgE measurements) prevents recurrences but requires sustained vigilance from all the infant’s caregivers. Natural desensitization to foods such as milk or egg eventually occurs in many infants and children, especially those with mild initial reactions and low levels of sensitization.

Simons and Sampson have outlined specific goals for research on anaphylaxis in infancy. These include validation of the clinical criteria for diagnosis, studies of infant co-morbidities and amplifying co-factors that increase the risk of severe anaphylaxis, development of EAIs containing a 0.1 mg epinephrine dose suitable for this age group, and inclusion of infants in prospective studies of immune modulation to prevent anaphylaxis.

 Question for the authors: In addition to being alert to the possibility of some infants eventually undergoing natural desensitization to milk or egg and helping to facilitate this desensitization, what other possibilities for prevention of anaphylaxis in infants do you see?

Answer: In an important prospective randomized trial in carefully-selected, high-risk infants age 4-11 months (Du Toit G et al, N Engl J Med 2015;372:803-13), early introduction of peanut significantly decreased the frequency of the development of peanut allergy and modulated immune responses to peanut. Although it remains to be proven whether these findings can be translated to other foods such as milk and egg and additional questions need to be addressed, this research suggests that the increase in prevalence of food-induced anaphylaxis in infants might eventually be halted.