A consistent pattern of minor immunodeficiency and subtle enteropathy in children with multiple food allergy.
ABSTRACT Although immunoglobulin (Ig)E-mediated allergies are readily identifiable, non-IgE-mediated allergies present more diagnostic difficulty. We performed a formal retrospective analysis to determine whether there is a recognizable clinical pattern in children.
We studied 121 children (mean age, 17.3 months) with multiple food allergies who were recruited on the basis of adequate immunological assessment by using case notes and parental questionnaire.
Group 1 (n=44) had rapid reactions to dietary antigens, of whom 41 also showed delayed reactions. Group 2 (n=77) had delayed reactions only. Mean IgE was increased in group 1 but both groups otherwise shared a pattern of increased IgG1, decreased IgG2/4, and low-normal IgA. Lymphocyte subsets were skewed, with an increased percentage of CD4 and CD19 and decreased CD8 and natural killer cells. Gastroesophageal reflux, esophagitis, subtle enteropathy, and constipation were frequent in both groups. Of 55 exclusively breast-fed infants, 44 sensitized before weaning. Twenty-one of the mothers suffered from autoimmunity.
There appears to be a recognizable pattern of immune deviation and minor enteropathy in children with multiple food allergy, irrespective of the speed of reactions. Disturbed gut motility is particularly common, as is a maternal history of autoimmunity.
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ABSTRACT: Introduction Antibody production defects may predispose children to inflammatory pathologies and therefore we hypothesized that this group of immune deficiencies may be associated with food allergy. Objective of the study To better characterize the interrelated pathomechanisms of food allergy coexisting with hypogammaglobulinemia in children and to define the relationship between clinical manifestation of antibody production defects and food allergy. Material and methods Twenty-three children aged from 8 to 88 months regularly followed-up in the pediatric pneumonology, allergology and immunology clinic due to hypogammaglobulinemia concerning one or more major immunoglobulin isotypes were retrospectively reviewed in terms of incidence and manifestation of concomitant food allergy. Information regarding the patient's history of allergic diseases and laboratory data concerning serum levels of immunoglobulins, including total IgE, were obtained from chart review. Results Clinical symptoms of food allergy were identified in 17 of 23 (74%) children studied. The mean age of onset of clinical symptoms was 2.7 months. Eczema was the most frequent manifestation present in 16 children, diarrheas and abdominal cramps were noted equally in 3 children, gastroesophageal reflux disease was diagnosed in 2 children as well as vomiting was observed in 2 children. Atopy was revealed in 8 of 17 children (47%) with food allergy. Conclusions Food allergy is a common health problem coexisting with antibody production defects in infants and young children. Clinical symptoms correlate better with low immunoglobulin levels than with serum IgE, that is not a suitable diagnostic criterion for allergic disease in patients with hypogammaglobulinemia.Pediatria polska 10/2012; 87(5):444–448.
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ABSTRACT: OBJECTIVES: This review considers the potential for therapeutic advances in the management of eosinophilic oesophagitis (EoE) based on recently increased understanding of the pathophysiology of the disorder. METHODS: This is a review of publications characterising mucosal changes and leucocyte recruitment patterns in human and experimental EoE. RESULTS: EoE, although diagnosed by epithelial infiltration of eosinophils, is actually a transmural inflammation in which eosinophil recruitment occurs via the deeper layers. Penetration of eosinophils into the epithelium is variable, explaining the need for multiple biopsies to diagnose what may be a clearly visible disorder. Fibrosis and neuromuscular dysfunction both occur within the subepithelial tissues. Recent murine studies have identified that T-cell recruitment underpins antigen-specific oesophageal eosinophil recruitment. Involvement of innate immunity is also suggested by the role of invariant natural killer T cells in experimental EoE. CONCLUSIONS: Looking beyond present therapeutic options with a view to future studies, we identify T cells as candidates for "upstream therapy" if antigen specificity or homing markers are determined. Evidence of aeroallergen sensitisation suggests the possibility of lymphocyte priming within nasal-associated lymphoid tissue or Waldeyer ring, with the potential for topical therapy. We consider acquired neuromuscular dysfunction as a therapeutic target in acute symptomatic deterioration or bolus obstruction. We assess possible similarities with therapeutic stratagems for chronic asthma, recognising at the same time the anatomic specificity of the oesophagus and the difficulty in delivering effective topical medication to subepithelial tissues in this location compared with the airway.Journal of Pediatric Gastroenterology and Nutrition 10/2013; 57(4):529-34. · 2.87 Impact Factor
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ABSTRACT: Allergic colitis shows overlap with classical IBD. Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis in comparison to normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. 15 children with allergic colitis, 10 Crohn's disease (CD), 10 ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki67, eotaxin-1 and eotaxin-2. Eotaxin-2, IgE and tryptase were localized in comparison to mucosal nerves, using neuronal markers neurofilament-protein, neuron specific enolase and nerve growth factor receptor. Overall inflammation was greater in CD and UC than allergic colitis. CD3 T cell density was increased in allergic colitis, similar to Crohn's disease but lower than in UC, while eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in allergic colitis (12/15) in comparison to UC (1/10) and CD (0/1). Tryptase and IgE co-localised on enteric neurons in allergic colitis but rarely in IBD patients. Eotaxin-2+ IEL's may contribute to the peri-epithelial eosinophil accumulation characteristic of allergic colitis. The co-localisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.Journal of pediatric gastroenterology and nutrition 05/2014; · 2.18 Impact Factor
Selected Summaries Editors:
Christian Braegger, M.D.
Warren P. Bishop, M.D.
Joel R. Rosh
Steven N. Lichtman, M.D.
Jonathan E. Teitlebaum
A Consistent Pattern of Minor Immunodeficiency and
Subtle Enteropathy in Children With Multiple Food Al-
lergy Latcham F, Merino F, Lang A, Garvey J, Thomson MA,
Walker-Simth JA, Davies SE, Phillips AD, Murch SH. J Pedi-
Summary: Latcham et al. retrospectively studied 121 chil-
dren with multiple food allergies collecting clinical, histologic
and immunologic information in an attempt to find common
patterns that might identify the child at risk. The children were
divided into immediate hypersensitivty responders (group 1,
n ? 44) and delayed responders (group 2, n ? 77).
The most common foods inducing immediate responses were
milk, eggs and nuts. The most frequently recorded symptoms
were urticaria, lip swelling and skin rash (86%). Delayed re-
sponses were also present in group 1. In fact, only three chil-
dren (7%) had no delayed symptoms. The delayed responses in
Group 1 were diet-responsive eczema, diarrhea, vomiting,
wheezing and failure to thrive. The symptoms in group 2 were
mainly eczema, failure to thrive and diarrhea and were induced
most commonly by milk, soy, wheat, hydrolysates, eggs, meat
and rice. Fourteen children in group 1 and 27 in group 2 had
symptoms while exclusively breast fed. A family history of
atopy was present in 90% of the children, particularly on the
maternal side, as was a history of autoimmunity.
High immunoglobulin (Ig) E concentration, positive skin-
prick tests and positive radioallergosorbent tests were more
frequent in group 1 than group 2 (50%, 70% and 75% vs. 18%,
27% and 25%, respectively). Both groups tended to have low-
normal levels of IgA (45% of cases had IgA ?0.3 g/L), skew-
ing of IgG subclasses with increased IgG1and decreased IgG2
and IgG4, and skewing of lymphocyte subsets with increased
CD4 and CD19 and decreased CD8 and natural killer cells.
There was also subtle evidence of enteropathy with focal lym-
phocyte or eosinophile infiltrate, villous blunting and reduced
Considering the difficulty in establishing a diagnosis of non–
IgE-mediated food allergy, the authors propose that in a child
with compatible symptoms, a family history of atopy or auto-
immunity and the above described immunologic and histologic
pattern might be helpful in supporting this diagnosis.
Comment: The prevalence of food allergy seems to be increas-
ing in parallel with an increased prevalence of extrinsic asthma
and environmental allergies. It is thought that these changes
reflect changes in living conditions in western countries but
also may reflect an increased awareness by medical person-
nel and parents. Unlike other allergic diseases, there is no spe-
cific therapy except avoidance of the offending food. If there
were immediate symptoms associated with food allergy or re-
liable diagnostic tests (radioallergosorbent test or skin-prick
test) no one would be reading this commentary! Our problem is
to care properly for children with symptoms for which multiple
antigens are implicated but in whom routine tests are negative.
These children experience vomiting, failure to thrive, wheezing
and pruritis from eczema. Given that restricted diets in children
with multiple food allergy may result in unbalanced nutritional
status and that oral food challenges may involve substantial
risks, an accurate diagnosis is of utmost importance.
The article by Latcham et al. suggests possible additional
clues to the diagnosis. Besides the immediate responses asso-
ciated with increased IgE, the authors identified delayed symp-
toms as well. There were immunologic characteristics shared
by both groups which raises the question of whether these
characteristics might be more directly associated with the pre-
disposition to sensitization than is the IgE concentration.
One of the predisposing factors for allergy is immune defi-
ciency, particularly IgA deficiency (1). These children had
strong family histories of autoimmunity and low or low-normal
levels of IgA. Knowing that the shift of B cells toward IgA is
mediated by transforming growth factor ?, the authors looked
for and demonstrated a reduction in the expression of trans-
forming growth factor ? by mucosal lymphocytes in children
with food allergy (2). Transforming growth factor ? is a potent
immunosuppressive cytokine, induced by mucosal inflamma-
tion after exposure to enteric bacteria. Given the importance of
the normal gut flora to both the local and the systemic immune
repertoire, it is tempting to speculate that these children might
have a genetically programmed tendency to reduced response,
leading to inadequate induction of tolerogenic lymphocytes.
That is, rather than the classic Th1/Th2 imbalance, they might
have an insufficient Th3 response.
Decreased exposure to bacteria in developed countries is
thought to be a cause of the insufficient Th3 response. This
change might also explain the results of preliminary studies
which have shown a reduction of atopic dermatitis in children
whose mothers receive probiotics during pregnancy (3) and a
decreased severity of atopic dermatitis in children with cow’s
milk hypersensitivity treated with probiotics and an elimination
diet (4). This mechanism may be common to allergy in general
when one considers that a person’s exposure to environmental
endotoxin may have a role in the development of tolerance to
allergens found in natural environments (5). Again, the evi-
Journal of Pediatric Gastroenterology and Nutrition
39:101–102 © July 2004 Lippincott Williams & Wilkins, Philadelphia
dence is compelling: allergies increase as material conditions
Many studies indicate that there is a critical time early in
infancy, possibly even during fetal life, when the genetically
programmed atopic infant is at higher risk of becoming sensi-
tized to food allergens. This might also be true with autoim-
munity. This article raises the question of whether children with
a strong family history of atopy and autoimmunity are also at
increased risk of later autoimmunity. There are examples sug-
gesting that this is indeed the case. Exposure to gluten before
the age of 3 months in children genetically predisposed to
diabetes type 1 (those with HLA DR3/DR4–DQ8 genotype,
born of parents with type 1 diabetes) carries a fivefold higher
risk for the development of islet autoantibodies (6). First ex-
posure at the age of 7 months or older may also increase the
risk for islet autoimmunity, possibly related to the larger
amount of exposure at initial introduction (7). The timing of
first exposure may influence immune tolerance to food anti-
gens, and there may be an exposure time window that best
allows tolerance to be achieved. Early introduction may lead to
inflammation in the gut, altering the immune cell repertoire or
leading to changes in islet ? cells that may still be immature
(6). MacFarlane et al. describe a wheat storage globulin protein,
G1b1, that may be associated with islet cell damage. They also
demonstrated that the sera from patients with type 1 diabetes
has antibodies to G1b1, in contrast to sera from patients who do
not have the disease (8).
Many questions remain unanswered and sometimes a new
look at an old problem helps. Searching for other markers of
allergy rather than the classic ones may be a productive line of
†Jorge Amil Dias
*Hospital Santo Anto ´nio
†Hospital S. Joa ˜o
1. Stern M. Allergic enteropathy/food allergy. In: Walker A, ed. Pe-
diatric Gastrointestinal Disease. Hamilton, Ontario: B.C. Decker;
2. Perez-Machado MA, Ashwood P, Thomson MA, et al. Reduced
transforming growth factor-beta1-producing T cells in the duode-
nal mucosa of children with food allergy. Eur J Immunol 2003;
3. Kalliomaki M, Salminen S, Arvilommi H, et al. Probiotics in pri-
mary prevention of atopic disease: a randomised placebo-
controlled trial. Lancet 2001;357:1076–9.
4. Majamaa H, Isolauri E. Probiotics: a novel approach in the man-
agement of food allergy. J Allergy Clin Immunol 1997;99:179–85.
5. Braun-Fahrlander C, Riedler J, Herz U, et al. Environmental ex-
posure to endotoxin and its relation to asthma in school-age chil-
dren. N Engl J Med 2002;347:869–77.
6. Ziegler AG, Schmid S, Huber D, et al. Early infant feeding and risk
of developing type 1 diabetes-associated autoantibodies. JAMA
7. Norris JM, Barriga K, Klingensmith G, et al. Timing of initial
cereal exposure in infancy and risk of islet autoimmunity. JAMA
8. MacFarlane AJ, Burghardt KM, Kelly J, et al. A type 1 diabetes-
related protein from wheat (Triticum aestivum): cDNA clone of a
wheat storage globulin, Glb1, linked to islet damage. J Biol Chem
SELECTED SUMMARY 102
J Pediatr Gastroenterol Nutr, Vol. 39, No. 1, July 2004