Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Cross allergy : cough suppressants – neuromuscular blocking agents
2. Bronchial mucosa Mast cells and severe asthma (SA)
3. Obesity and asthma in children
4. Childhood acute urticaria
5. Prenatal fatty acid exposure and risks of early childhood allergy

1. Cross allergy : cough suppressants – neuromuscular blocking agents

Theme: drug allergy, anaphylaxis during anaesthesia
Key words: Muscle relaxant, Pholcodine, Suxamethonium

Everything started with the observation by Norwegian doctors of the abnormal frequency of anaphylactic reactions during anaesthesia (1 case in 20 vs  only 1 in 5200 in Sweden or other European countries), quickly linked to the use of muscle relaxing agents of the suxamethonium (SUX) type. After thorough investigations, it appeared that Norwegian patients were over-using a cough suppressant : Tuxi which contains Pholcodine (PHO), a powerful sensitiser which, like SUX, carries the quaternary Ammonium epitope.           Pr Johansson’s Stockholm team highlighted the presence of PHO- and SUX-specific IgEs in 5 to 10% of treated subjects. This cough suppressant was then withdrawn from the Norwegian market in March 2007. The Norwegian authors (E.Florvaag et al., Allergy 2011 17 January early view) wished to know the situation 3 years later concerning anaesthetic reactions as well as the patients’ immunologic condition.
First of all the occurrence of anaesthetic accidents thought to be SUX-induced has considerably and significantly decreased according to the figures.
In a group of 300 subjects monitored yearly from 2006 to 2010 and having been diagnosed for PHO- and SUX-specific IgEs and also some morphine (MOR) derivatives, antibody prevalence of PHO and SUX had significantly decreased after one year (respectively from 11 to 5% and from 3.7 to 0.7%).
At the 3rd year SUX had fallen to 0.3%, PHO to 2.7% and MOR to 1.3%.
The authors consequently emphasize the benefits of having withdrawn cough suppressants from the Norwegian pharmacopeia and the relevancy of the sensitizing role of Pholcodine. At a time when in France a considerable number of cough suppressants contain this product, when a great number of medicines are under increased surveillance, and taking into account the fact that practically no cough depressants are now used in Respiratory diseases, this raises the question of maintaining such substances in the pharmaceutical nomenclature.

2. Bronchial mucosa mast cells and severe asthma (SA)

Theme: asthma, bronchial histology
Key words: asthma, tryptase mast cell, tryptase-chymase mast cell

A group of American doctors has tried to establish a correlation between the phenotype of the bronchial mucosa mast cells (MCs), their number, their location and their activation, and the severity of asthma, by studying a cohort of asthmatics spread over 7 specialised centres throughout the US (S.Balzar et al : AJRCCM 2011 183 299-309).             We already know that MCs are differentiated according to their enzymatic equipment identified by immuno-histo-chemistry into : tryptase mast cells (MCTot), most frequently found in the lungs, and tryptase-chymase mast cells (MCTC), normally accounting for less than 20%.
The study was carried out on 157 asthmatics (A), aged 18-65, mostly female (an average of 2/3), and divided into 4 groups by the authors : 57 with Severe Asthma (SA), needing high doses of corticosteroids, taken per os in half the cases, with frequent exacerbations and some hospitalisations during the past year ; 22 said to suffer from Type 1 Mild Asthma (MA), i.e. with a normal respiratory function and without inhaled corticosteroids (IC) ; 31 with Type 2 Mild Asthma (MA²) with ICs ; and 13 with Moderate Asthma   (Mod A) with FEV1 ?  80% of normal and treated by ICs +/-β2 and/or anti-leukotrienes. Finally, the addition of 34 healthy paired controls to the study allowed a statistical approach (multiple logistic regression). All these subjects were submitted to biopsies and epithelial brushings leading to the identification of MCs, and bronchoalveolar lavages (BAL), making it possible to dose tryptase and prostaglandin D2 (PGD2), two markers of mast cell activation.
Results were as follows :
1) In the submucosa : the number of MCT is higher in Type 1 MA, it is significantly lower in SA but with a predominance of MCTC.
2) In the epithelium : MCT are still the majority in Type 1 MA, but they persist in SA, always in the MCTC phenotype.
3) While the tryptase dosage cannot differentiate between MCs, that of PGD2 is highest in SA.
Thus, the predominance of the Chymase-positive phenotype in bronchial mucosa and high rates of PGD2 are the most significant predictive factors for Severe Asthma.
The authors suggest that it may be interesting to aim at PGD2 metabolic pathways to fight against the severity of asthma.   

3. Obesity and asthma in children

Theme: asthma, metabolic abnormalities
Key words: asthma, obesity, diabetes, triglycerides

Both diseases have individually reached worrying heights throughout the world and the question has been raised of a link between them. The work of L.Cotrell, of the Virginia Paediatrics Department (USA), justly draws attention to the frequency of metabolic troubles in obesity which could thus explain this link, regardless of course of mechanical consequences of excess weight on the respiratory function (AJRCCM,2011-183 441-448).
A cross-sectional analysis of a representative sample of a rural community including 17 994 school-age children (4-12) was carried out through a questionnaire with demographic informations : family history, parental smoking, reported asthma diagnosis, body mass index (BMI), evidence of acanthosis nigricans (AN) a brown to black skin rash around the neck and armpits as a marker for developing insulin resistance, and fasting serum lipid profile including total cholesterol, triglycerides, HDL and LDL lipoprotein cholesterol.
While a little less than half the subjects were male, it is here that obesity was the highest ; most asthma diagnoses were also to be found in this group ; finally a family history of diabetes was found in half the cohort.
At the end of the statistical study it appeared that, regardless of BMI, the asthmatic children had a higher rate of triglycerides than the non-asthmatics; they also show a higher frequency of AN, whatever the age and the possible exposure to parental smoking. Besides, the prevalence of asthma with obese or morbidly obese children is higher than in children with normal or slightly increased BMI.
This study thus shows a significant association between asthma and abnormal lipid and glucose metabolism, without making it possible to prove which is the primum movens nor to establish the chronological sequence from metabolic troubles to  inflammation observed in asthma and obesity. It is nevertheless possible to imagine that dyslipidemia and insulin resistance, precursors of diabetes, can be associated with the development of asthma and constitute, by interaction with immune mechanisms, the missing link with obesity.
Such data also stress the benefits of a dietary and metabolic monitoring in the management of childhood chronic asthma.

4. Childhood acute urticaria

Theme: skin allergy, paediatric allergy
Key words: urticaria, temperature, humidity, season

A retrospective study on childhood acute urticaria (AU) was undertaken by a Greek-English team with a view to comparing the possible role of environmental factors on the occurrence of the disease, between the English Norwich (N) and the Greek Heraklion (H) Hospitals (GN.Konstantinou et al  Ped.Allergy & Immunol 2011 22 36-42), with the hypothesis of cyclical trend.
Conducted between 2005 and 2007, it concerned 729 children under 14 (324 in N and 405 in H), respectively on cohorts of 28 931 and 27 653 subjects. Climate and demographic data, as well as associated clinical factors, were recorded and compared, all then submitted to a Poisson regression curve for the meteorological data and Edwards tests for seasonality.
In N, the incidence of AU was more frequent from October to April, but not significantly so. In H, the incidence was significantly higher from December to May.
Temperature was inversely associated to incidence of the disease, whereas humidity was variable in both geographical sites.
As to the associated factors, which cannot be considered as etiological, they reveal that seasonal respiratory infections were statistically the most commonly triggers and (that is largely unexpected) food allergy was the least.

On the whole, the only plausible element derived from the study is the seasonal factor which could explain the association between AU and respiratory infection. However, there were no notable epidemiological differences between the observations made in northern and southern Europe.
Such somewhat disappointing conclusions can also be found concerning chronic childhood urticaria (CU), reviewed in a paper (Church MK meme revue 2011 22 Issue  1 Fevrier 1-8) insisting on the need for intensive research on AU, as on CU, both affections which are not rare in the paediatric field and always difficult to treat.

5. Prenatal fatty acid exposure and risks of early childhood allergy

Theme: atopia
Key words: fatty acids, diet, pregnancy, allergy risk

A Dutch team (ML.Nottenboom et al : Clin &Exp.Allergy 2011 early view), emitting the hypothesis of a pro-inflammatory effect of maternal diet fatty acids (polyunsaturated ?6 FA in such as Linoleic Acid, LA, which can be found in vegetable oils and margarine and is a precursor of Arachidonic Acid, AA) on the risks of atopy in children, has monitored in a prospective study a cohort called KOALA from birth and periodically up to age 6-7.
Other studies, including researchers of the same group, have suggested on the contrary that polyunsaturated ?3 FA such as the α Linoleic acid ALA (found in green vegetables) and the Long Chain FA ?3 (LCP) (found in oily fish) or even the n3 LCP of breast milk (C.Thijs et al Allergy 2011 66 58-67), had a protective role against allergy.
To check those assumptions, the authors took blood samples from 1374 pregnant women between 34th and 36th week and dosed the polyunsaturated long-chain fatty acids in ?3 and ?6, in order to establish a fatty acid status for each subject. At the same time, by questionnaires or visits by trained assistants, the whole range of atopic manifestations among the children was recorded: wheeze, asthma, rhino-conjunctivitis, atopic dermatitis, and a total serum IgE.
The comparison between all these data, meticulously recorded and submitted to a precise statistical analysis (multiple logistic regression), gave the rather unexpected following results :
-  No association was found between the maternal fatty acid status (whether it be the sum of FA in n6 or n3) and atopic disorders or IgE levels.
-  However associations were found between high n6/n3 ratios and lower eczema risk in children, above all during the first 7 months of life and particularly when AA rates were high.

It can be concluded that the development of atopic disorders is not a function of maternal diet alone (although the foetus’s lipid metabolism is entirely dependant on the mother) and that other factors, no doubt including genetics, play just as important a role.

For further information, questions or comments, you can get in touch with Prof. Claude Molina or Dr Jacques Gayraud at the following addresses:

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Last updated 28 July 2014