Autism Spectrum Disorders and Allergy: Observation from a Pediatric Allergy/immunology Clinic

Harumi Jyonouchi

Disclosures

Expert Rev Clin Immunol. 2010;6(3):397-411. 

In This Article

Myth of 'Allergy' – what is Allergy & what is Not Allergy

The last part of this article will address the various clinical symptoms that parents attributed to 'allergy' in the ASD children evaluated in our pediatric allergy/immunology clinic. Practicing physicians need to be aware that many of the physical symptoms and clinical features that the parents of ASD children may attribute to 'allergy' are not necessarily associated with IgE-mediated allergic reactions or other immune responses. Typical symptoms described by parent to be 'allergy' in our experience are described below. This will hopefully help streamline treatment measures and avoid unnecessary diagnostic measures such as skin prick testing.

Respiratory Symptoms

Chronic Nasal Congestion Chronic nasal congestion is frequently seen in young children.[42] It should be noted that aeroallergen sensitization develops gradually in atopic individuals, usually during the first several years of life.[42,111,112] Typically, atopic disorders manifest first as atopic eczema during infancy.[111,112] Chronic and/or seasonal aeroallergen exposure then evolves into clinical manifestations of atopic asthma and AR over the next few years of life – the so-called atopic march.[112] This is why positive skin test reactivity or aeroallergen-specific IgE are observed much less frequently in infants and young children.[111] As previously discussed, nonallergic (vasomotor) rhinitis is commonly seen in infants and young children, secondary to general hypersensitivity of nasal mucosa in this age group.[42] Thus, if the child lacks a positive family history of atopy and infantile eczema, chronic rhinitis is more likely to be associated with idiopathic 'vasomotor' rhinitis, which is commonly seen in infants and young children. Careful history taking and thorough physical examination should be helpful in differentiating AR and nonallergic rhinitis in ASD children.

Headache Headaches or sinus headaches may be attributed to 'allergy'. It is difficult to detect the presence of a headache in minimally verbal ASD children. However, behavioral symptoms, such as head banging and hitting/pressing on the ears, may be indicative of a headache. In our experience, this especially holds true if these symptoms vary from time to time. The possible causes of a suspected 'headache' should be carefully examined in these ASD children; these include nonallergic sinusitis, adenoid/tonsil hypertrophy, untreated rhinosinusitis (see case 3) and neurological causes, such as migraine and epilepsy, on the basis of the children treated in our clinic.[10,11]

GI Symptoms

Food Allergy Gastrointestinal symptoms commonly seen in the ASD children presented to our clinic include diarrhea, loose stool, GI cramping and constipation alternating with diarrhea and bloating. As previously mentioned, given these symptoms, both IgE and non-IgE-mediated FA may need to be considered as underlying medical conditions.[10] Both types of FA occur more frequently than other causes (e.g., metabolic disorders, genetic/infectious causes, neurological causes and autoimmune conditions) associated with chronic GI symptoms.[10,113] In addition, the treatment measures (restricted diet) are benign.[10,113] Therefore, possibilities of FA should be ruled out before considering the previously described less common causes associated with GI symptoms. The presence of a well-documented causal relationship between exposure to food allergens and onset of symptoms within 2 h indicates IgE-mediated FA.[10] In contrast to IgE-mediated FA, NFA, as previously discussed, may be more difficult to assess owing to the delayed onset of symptoms.[10,19] However, the presence of objective GI symptoms (e.g., constipation, loose stool and diarrhea) and a positive family history can help physicians consider if the patient should try a restricted diet.[19,72] In FPIES, the main causative food proteins are milk and soy.[72] Since many nondairy/nonsoy products are commercially available as substitutes, the trial of a dairy-free, soy-free diet may be easily implemented for a few weeks without causing nutritional deprivation if FPIES is suspected. In addition, prior to implementing a wheat-free diet, which is far more challenging to implement than a dairy- or soy-free diet, it may be helpful to run serological screenings for celiac disease,[60] which were discussed previously.

Dysbiosis It has been our experience that both ASD and non-ASD children with NFA often have candida enteritis. Etiology of this finding may be partly attributed to the deprivation of a source of probiotics (yogurt) in a dairy-free diet, since most NFA children react to cow's milk.[72] We have also noted that NFA children with chronic GI inflammation may experience invasive candida infections. In individuals with a genetic predisposition, candida enteritis can play a role in development of chronic gut inflammation, as indicated in patients with inflammatory bowel diseases.[114–116] Changes in commensal flora have also been associated with GI symptoms in ASD children.[117,118] Studies in rodent models of CNS inflammation showed behavioral effects of propionic acid, a metabolic end product of enteric bacteria, on behavioral symptoms when it was injected intraventricularly into the brain.[119,120] It should be noted that probiotics have been shown to attenuate GI inflammation in patients with inflammatory bowel diseases.[19] With this in mind, a trial of probiotics may be reasonable to consider in ASD children who are on a restricted diet or have skewed dietary habits. We have observed favorable effects from the use of probiotics in these clinical settings [Jyonouchi H et al. Unpublished Data].

Skin Symptoms

Flushing Parents of ASD children evaluated in our clinic are often concerned about flushing of their child's skin following ingestion of food or exposure to nonspecific irritants such as cold air. In general, such skin symptoms are not consistent with urticarial rash, lacking a pruritic migratory rash raised from the skin. In the cases we have examined, such flushing is generally short-lived and resolves within an hour or so with or without use of antihistamines and is very unlikely to be associated with IgE-mediated allergic reactions. Again, a detailed history will be helpful in differentiating such skin reactions, which may be associated with dysautonomic skin reactions, from IgE-mediated allergic skin reaction.

Eczema Atopic dermatitis is roughly divided into two categories: intrinsic and extrinsic eczema.[121] Allergen sensitization and Th2-mediated IgE synthesis is thought to play a significant role in extrinsic eczema but not in intrinsic eczema.[121] Recent studies indicate that impaired formation of the skin epithelial barrier plays a crucial role of in the development of extrinsic and intrinsic eczema.[121] Filaggrin is thought to play a crucial role in the formation of the skin barrier.[121,122] Impaired skin barrier formation due to mutations in filaggrin genes has been implicated in subsequent sensitization to allergens, colonization of microbes and subsequent development of severe AD.[121,122] It should be noted that food allergen sensitization is not necessarily observed in all patients with AD. Thus, the elimination diet will only be effective in patients with documented reactivity to food allergens.[123]

Adverse Reactions to Medications & Other Biological Substances

Medications Most of the adverse reactions to medications reported by parents in our clinic are not IgE-mediated. For example, more than 90% of immune reactivity to the first-generation penicillin is IgG-mediated.[124] If penicillin reactivity is mediated by IgE, the patient usually has previous exposure and experiences a rapid onset of symptoms upon their second exposure to penicillin.[124] Lack of such a history makes it very unlikely that the subject has an IgE-mediated penicillin allergy. IgE-mediated allergic reactions are much more commonly seen with medications administered intravenously.[124] Delayed-type non-IgE-mediated reactions can occur with medications given by multiple routes (orally or non-orally).[125,126] Importantly, skin prick testing is not appropriate for assessing such delayed-type reactivity.[124] Skin patch testing may be available for testing cellular reactivity to certain medications/chemicals.[125] Careful history taking is generally very useful in differentiating IgE from non-IgE-mediated reactions to medications.

Nonimmunogenic Food Components For the most part, Th2-mediated IgE responses are generated against protein antigens.[10] Certain chemicals, such as penicillin, can bind to the carrier proteins and form neoantigens, thereby inducing conformational changes; the typical carrier protein is serum albumin.[125] These small chemicals are called 'haptens'. Large complex carbohydrates/lipids can cause immune responses; however, these are not directed by Th cells and, thus, seldom lead to IgE synthesis.[127] Parents of many ASD children evaluated in our clinic have presented with 'allergy' to non-protein chemicals lacking hapten activity or nonspecific irritants. An example of this is allergy to 'sunlight' that may really indicate sensitive skin or dysautonomic conditions. Practicing physicians need to educate parents about which symptoms can be 'allergic' and which are not.

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