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Claude MOLINA* & Jacques GAYRAUD**

1. Eosinophilic esophagitis (EoE) : identification in children and adults
2. Eosinophilic esophagitis (EoE) : pathology and immunopathogenesis
3. Eosinophilic esophagitis (EoE)  treatment
4. Air quality at school and respiratory allergy
5. Indoor air quality (IAQ) at school and student’s performance


1.  Eosinophilic esophagitis (EoE) : identification in children and adults


Theme: Food allergy
Key words: Eosinophilic esophagitis, gastroesophageal reflux disease, eosinophils, specific IgEs

An excellent review presented by a US-Swiss group (A.Straumann et al Allergy  2012 67 477-490) sums up the different phases of disease identification by the combined action of allergists and gastroenterologists.
In the 1990s, several cases of adult dysphagia with eosinophilic infiltration of the mucosa, different from gastroesophageal reflux disease (GRD), were published. Then, in allergic children were reported symptoms similar to GRD but refractory to medical treatment by the Proton Pump Inhibitors (PPI). From then on, an International Symposium define EoE as a primary clinico pathological disorder of the esophagus characterized by symptoms of the oesophageal tract with adult dysphagia for solids, and more frequently  regurgitation and vomiting in children, together with mucosal inflammation on biopsy specimens containing at least 15 intra-epithelial eosinophils /high-power field (hpf) and in the absence of GRD confirmed by pH monitoring.
Symptoms are marked in adults by pain or retrosternal burning, the dysphagia being often due to the presence of a long-lasting food impaction and, in children, by irritability with abdominal pains, food refusal together with vomiting.
In most cases, the general condition is good and the diagnosis often late; as to blood eosinophilia, associated with a rise in specific IgE levels, it is generally moderate and is mostly due in children to a food allergy, whereas in adults an aeroallergen sensitization was observed.
The several occurrences of the affection within the same family led to suspect a genetic predisposition, which has not been established so far.
Finally, oesophageal biopsy by endoscopy confirms the diagnosis by revealing  inflammation with eosinophil predominance, associated to IgE-carrying B and T lymphocytes and mast cells, and presence of a  slight sub-epithelial fibrosis.


2.  Eosinophilic esophagitis (EoE) : pathology and immunopathogenesis

Theme: Food allergy
Key words: Eosinophilic esophagitis, eosinophils, remodeling, TH2 lymphocytes

Beside eosinophilia and the metabolites of its degranulation (MBP, ECP, EPO), the remodeling of the mucosa, with prior deposit of the extracellular matrix, is the hallmark of EoE and confirms its Th2-type immunologic mechanism, thus differentiating it from GRD inflammation and defining it as an allergic entity like rhinitis or asthma. Moreover, it is remarkable to note that this esophageal infiltration is strictly limited, sparing at the same time stomach and duodenum.  In order to study the mechanism of this remodeling, a Chicago multidisciplinary team (A.F.Kagalwalla et al JACI May 2012 in press) has examined, through histologic and immunologic markers, a series of esophageal biopsies in 60 children, exploring and quantifying the role of epithelial  mesenchymal, transition
Out of 17 EoEs (+15 undetermined EoEs) compared to 7 GRDs and 21 normal controls, the authors observed that signs of subepithelial fibrosis (such as tissular presence of TGFβ1) were statistically correlated to tissue eosinophilia and its metabolites, a difference with GRD and control biopsies, all these elements being reversible after treatment, whether it be elimination diet or local glucocorticoids.

From an etiological point of view, considering that allergy is the initiating mechanism (over 50% of EoEs have a history of atopy : rhinitis, asthma, eczema), a classical allergic investigation is imperative (skin and immunologic tests). If, with children, some food allergy is found to be the origin, it is relatively easy to confirm it by prick and patch  tests, elimination, or allergen reintroduction  whenever possible and safe (peanut, soybean, egg white, cow milk).
In adults, where aeroallergen sensitization seems to be more frequent, the association with a food allergy is however not rare.
Two largely documented cases of eosinophilic esophagitis occurring 24 to 48hrs after a provocative test for milk proteins, were recently reported by Spanish authors (S.T.Cepeda et al JACI 2012 129 5 1416-1419).


3.  Eosinophilic esophagitis (EoE) : Treatment

Theme: Food allergy
Key words: Elimination diet, proton pump inhibitors (PPIs), glucocorticoids, esophagoscopy, skin tests

Three main options are open to the practitioner : drugs, diet, esophagoscopy (for the removal of a food bolus or a dilation in case of stenosis).

As for drugs, the particularities of PPIs must be underlined. In principle, they are useful for differentiating EoE from GRD. But, with a long term treatment, symptom improvement can be observed, without eosinophilic regression and persistence of a subepithelial fibrosis, but without complications, as in the recent work conducted in 38 EoE patients who were monitored and treated for 2-3 years (J.Levine et al Annals of Allergy,Asthma et Immunol  May 2012 363-366).
Corticotherapy represents the 2nd alternative, albeit with risks of relapse when prematurely terminated : Fluticasone (inhaled then swallowed : an average 440µg twice daily for adults, over 50 weeks,  depending on age and weight) or Budesonide (same dosage, including viscous form for young children) ; more recently, in case of failure of these steroids, Ciclesonide (Alvesco®) was proposed ( S.Schroeder JACI 2012 129 5 1419-1421), a non-halogenated compound whose efficacy as a topical glucocorticoid is due to its conversion by epithelial esterases into a much more active substance on the mucosal surface. As to biotherapies (mepolizumab among others), they have not so far proved efficient.
The 2nd big therapeutic option is diet : 3 diets were statistically compared (C.Henderson JACI May 2012 in press) :
1)    Elemental diet, of the type used against Crohn illness, not very appetising and difficult to use with children ;
2)    A diet based on empirical elimination of the 6 main food allergens : milk, egg, soya, wheat, peanut and nuts, fish and sea-food ;
3)    A diet based on prick- and patch-tests.
The remission, confirmed by biopsy, showed that all 3 diets were efficient, but the 1st one was statistically clearly superior to the 2 other ones, themselves equal in effectiveness.

Nevertheless, for the authors, skin tests are not reliable enough for establishing a valid personalised elimination diet.


4.  Air quality at school and respiratory
allergy

Theme:
Respiratory allergy, allergy and environment
Key words: Indoor air quality, schools, fine particles, NO2, aldehydes, maximum breathing airflow, prick tests, rhino-conjunctivitis

A very large survey, designed for establishing a relationship between air quality at school and respiratory health of school-age children, was conducted in six French cities by a team of well-known Allergo-Pneumologists and Statisticians (I.Annesi-Maesano et al.  Thorax   21/3 2012 on-line).

It concerned 6 590 children of an average 10.4 years of age, attending 401 classes in 108 primary schools of Bordeaux, Clermont-Ferrand, Creteil (Paris), Marseille, Reims and Strasbourg. It is true that these growing children spend, apart from the summertime, at least 80% of their time indoors, either at home or at school, and it was recently shown in the USA that indoor pollution could be 2 to 5 times higher than outdoor pollution.
The methodology consisted in measuring the concentration in classroom air of fine particles (? 2.5µm or PM2.5), NO2 and 3 aldehydes (formaldehyde (F), acetaldehyde, acrolein), for 5 days out of 7. In addition, 4 643 of these children underwent a medical examination with skin prick-tests for 10 major allergens, a peak flow meter to measure exercise-induced bronchospasm. A parental questionnaire was also completed.
Results mainly reveal the poor air quality in French classrooms since 30% of pupils are exposed to pollutant concentrations which exceeded international standards for PM2.5 and for NO2. Clinically, rhinoconjunctivitis (RC) is the most frequently observed symptom, followed by exercise-induced bronchospasm (EIB) and asthma (A). One child in three reacts positively to aeroallergen prick-testing, 31 of them to trophallergens;
After statistical adjustment and elimination of confounders, such as family history, sex, parental smoking habits, and taking into account inter- and intra-school variance, it appears that past year RC is correlated to high levels of F in classrooms.
The increased prevalence of A is linked to high levels of PM2.5, NO2, and acrolein in some classrooms, and particularly for allergic asthma as defined by positive skin prick-tests.
Finally, a significant correlation was observed between EIB and high levels of PM2.5 and acrolein.

This excellent study is thus sending an important message for families, school health authorities and France public health in general.


5.  Indoor air quality (IAQ) at school and student performance

Theme: Respiratory allergy, allergy and environment
Key words: Indoor air quality, school performance, CO2, d2-test

Another approach to the role played by classroom air quality among children is its influence on school performance, as assessed by student concentration and acquired knowledge.
This is the subject of an experimental survey conducted in Germany (D.Twardella et al Indoor Air 2012 on-line) where IAQ was assessed by CO2 concentration in 20 random-chosen classrooms of Bavarian primary schools. It must be stressed that these classrooms are, as often in Germany, mechanically ventilated.
The methodology consisted in measuring CO2 levels for 2 consecutive days of the week  in each class for 3 weeks, together with temperature and humidity, and in sorting them into 3 categories depending on ventilation (without opening the windows) : usual, ‘better’ (? 1000 ppm) or ‘worse’ (2000 to 2500 ppm). To assess the students’ concentration performance, and also their discrimination capability and response rapidity, the authors used the d2-test consisting in orally asking the subject to underline and highlight the letters d and p of a 14-line text within a time limit (normally 20 seconds per line). Using the number of letters picked out and the number of errors, one can calculate the student’s performance.
The students were half grades 3 and 4 and also half boys and girls, a level corresponding to CM1 and CM2 in France, i.e. children aged 7-9 or 9-11.
2 366 d2-tests were then recorded with 417 students. After hierarchical linear statistical regression, taking into account the variance of CO2 levels for the 20 classes and the various confounders, the authors could conclude as follows :
1)    Low air quality in classrooms has no significant statistical effect on students’ concentration, nor on the total number of letters processed.
2)    However, the number of observed errors increased significantly (P=1.65, IC 95% 0.42-(2;87) in the ‘worse’ IAQ compared to the ‘better’.
On the whole, although this was a randomised study, relatively limited in number and time, and although its conclusions are a little contradictory to those of other comparable studies, German students (or their parents) will not be able to blame the school’s poor IAQ for any low or bad marks obtained !!
Comments and questions welcome :

Pr. Claude Molina    and/or    Dr Jacques Gayraud
* **