September 2008
Claude MOLINA and Franz MARRACHE

• Puberty and Bronchial Hyperreactivity in young asthmatic patient
• Maternal Food during Pregnancy and Risk of Childhood Asthma
• Wheeze , Atopy and Bronchial Pathology
• Hypersensitivity to Chemotherapy: desensitisation technique
• Arginine Metabolism and Asthma

Puberty and Bronchial Hyperreactivity in the young asthmatic patient
Although Asthma affects mainly males in early childhood, it is a disease primarily of girls in adolescence. Since bronchial hyper reactivity is an important component of Asthma throughout life, it is interesting to know how such reactivity evolves, particularly spanning puberty. A group of American physicians, within the framework of multicentre treatment programme for childhood asthma, attempted to analyse this factor in a longitudinal epidemiological study that included 1041 , 5-12 year old children with moderate asthma and followed for a period of 8.6 +/- 1.8 years. (K.G Tantisira et al. Airway Responsiveness in Mild to moderate Childhood asthma. Am. J. Respir. Crit. Care Med. 2008; 178: 325-331).

The authors performed methacholine provocation tests in these patients, at the beginning of study, and yearly at 1 and up to 8 years, and evaluated PC 20 (the lowest dose inducing a 20% decrease in FEV1). 7.748 methacholine tests were carried out in order to determine the influence of sex and age on bronchial reactivity. The results were analysed using multiple linear regression tests with adjustment for confounding variables.

The principal conclusions of this important study were :
1) PC20 increases with age (thus, bronchial reactivity decreases) more clearly in boys older than 11 years than in girls (p¡Ü 0.001)
2) Reactivity significantly increases in girls after puberty, independently of any potential confounding factors

Overall, bronchial reactivity was more severe in girls than in boys and persists after puberty . The authors suggest the role of hormonal factors (but without any hormonal study in support of their hypothesis).

This interesting work is also a long term prospective study covering puberty and whose conclusions may be useful for considering changes in asthma therapy and prevention in the adolescent.

Maternal Food diet during Pregnancy and Risk of childhood Asthma
It is known that maternal food consumption during pregnancy may affect the development of airways in the child and promote a Th2-type response to allergens during foetal life, with the risk of subsequent development of allergies or asthma during childhood.

A group of Dutch researchers has therefore carried out a longitudinal, questionnaire-based study assessing the influence of the consumption of certain foodstuffs during pregnancy on the eventual development of asthma in children followed up between 1 and 8 years of age (M. Willers et al. Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am. J. Respir. Crit. Care Med. 2008; 178 : 124-131). 4146 pregnant women (1327 atopic and 2819 non atopic) were submitted to a questionnaire about the frequency of their consumption of 1 to 8 principal food categories, particularly during the last month of pregnancy : fruits, vegetables fish, eggs, milk, nuts (including peanut), and peanut butter (commonly used in northern countries and which was included within the nuts group, in this study).

2832 children were followed up and the obtained data were complete.
The authors did not find any significant association between maternal food consumption and asthma in children. Nevertheless, consumption of fresh fruits seemed to protect children against the risks of asthma or allergies (borderline statistical significance), whereas daily ingestion of nuts increased the risk of asthma in comparison with an intermittent consumption.

The limitations of this study derive from the difficulties in the statistical interpretation of the data as well as from the various confounding factors such as life style, socio-professional class and region or country concerned. Thus, the study does not allow professionals to advise a precise food diet for the pregnant woman, apart from a diversified diet avoiding regular ingestion of a single food, particularly nuts.

Wheezing, Atopy and Bronchial Pathology
Various studies have shown that, in the atopic child, wheezing tends to persist into the adulthood, occasionally becoming asthma, whereas they generally regress during adolescence in non-atopic children.

In order to assess whether bronchial histology is different in these 2 types of individuals, the Italian authors from the Universities of Padua and Modena performed bronchial biopsies in 38 wheezing children, who had repetitive multitrigger episodes of cough, dyspnoea and wheezing, apart cold periods (18 were non atopic and aged between de 2 and 10 years, 20 were atopic and aged between 2 and 15 years, and 17 were healthy controls between 2 and 14 years old. (G.Turato et al. Non atopic children with multi-trigger wheezing have airway pathology comparable to atopic asthma. Am. J. Respir. Crit. Care Med. 2008 ; 178 : 476-482).

All pathological and histochemical criteria were similar in the 2 groups of children. When compared to healthy controls, patients had a statistically significant thickening of the basal membrane (p=0.0001), with an increased loss of the epithelium (p= 0.03 and p = 0.002, respectively). In the mucosa, there was also an increase of respectively angiogenesis, number of eosinophils, and expression of IL-4, all criteria statistically significant (only borderline significant for IL-5).
As in adults, a tendency towards the presence of more severe symptoms with a clearer decrease in FEV1 was observed in non atopic patients.

Thus, histological and histochemical changes were identical in wheezing children responsive to bronchodilators, and whose symptoms persisted, whether the child was atopic or not. So, when suggestive symptoms such multitrigger wheezing occur in non atopic children, the pathology is typical of asthma.

Hypersensitivity to Chemotherapy : desensitisation technique
In the presence of a hypersensitivity reaction to a chemotherapy drug, the doctor
faces a cruel dilemma : either to risk an anaphylactic reaction upon reintroduction of the product or to stop the treatment and use a less efficacious or ill tolerated drug.

A Boston university team (M.C. Castells et al. Hypersensitivity reactions to chemotherapy. J. Allergy Clin. Immunol. 2008 ; 122 : 574-580 ) developed a rapid and standardised desensitisation protocol in order to obtain at least temporary tolerance to 7 different drugs : carboplatin, cisplatin, oxaliplatin, paclixatel, liposomal doxorubicin, doxorubicin and, which is original in this work, a monoclonal antibody: rituximab.

98 patients were thus treated using a rapid 12-step protocol, administered intravenously or peritoneally. The first injections were performed at an Intensive Care Unit and subsequent injections were given in an outpatient setting.
Safety and efficacy of the protocol were proven in all the cases.

In fact, out of 413 desensitisations performed, 94% were concluded without any side-effects or only with minimal reactions. There were no anaphylactic reactions or deaths and all the patients received the full target dose.
Reactions were more commonly reported during the final steps of the procedure.
Intravenous and peritoneal routes were equally effective.

Such a type of protocol had already been utilised for desensitisation to platin in some isolated cases as we had mentioned in our December 2004 Allergy Newsletter (www.egora.fr).

The interest of this study lies in the extension of this technique to a large number of patients and its application to several chemotherapy drugs including a monoclonal antibody.

Arginine metabolism and Asthma
As unique donor of a N ion in the synthesis of Nitric Oxyde (NO) as well as key participant in the urea cycle, Arginin (Arg) and its metabolites namely ornithin and citrullin are linked to cell respiration and inflammation.
Physicians involved in the Severe Asthma research programme of the NHLBI, USA, put forward the hypothesis that bioavailability of Arg might be associated to the inflammation and bronchial problems in asthma and also account for its severity.
Such bioavailability was therefore assessed by plasma Arg. dosage, relative to its metabolites and to NO synthase inhibitors and by the arginase activity in serum. This was performed in 258 patients : 232 asthmatic patients out of which 84 were severe and 148 who were moderate as well as 26 controls Simultaneously, were also studied lung function and inflammation parameters, including the fraction of expired NO (FE NO), but also IgE, skin prick tests to allergens, blood eosinophilia, and eventually broncho-alveolar lavage fluid. (A. Lara. Alterations of the Arginine metabolome in Asthma Am. J. Respir. Crit. Care Med. 2008; 178 : 673-681).

Results were the following
Asthmatic patients had higher levels of Arg. bioavailability than healthy controls, but also an increased catabolism of Arg as shown by serum arginase activity and elevated levels of FE NO.

Inflammation parameters were related to bronchial obstruction, in a paradoxical way, in patients with moderate asthma but not in severe cases. By contrast, Arg bioavailability was related to bronchial obstruction in severe asthma, but not in moderate cases. This means that bioavailability of Arg is not a surrogate measure for inflammation (in contrast with FE NO) but it is strongly associated ,like arginase activity, with airflow abnormalities in severe asthma, and particularly with bronchial remodelling.

These results are all the more important that Arginase inhibitors are studied as protection against allergen induced bronchospasm in a experimental model of asthma in the guinea pig (H. Maarsing. Am. J. Respir. Crit. Care Med. 2008 ; 178 565-573) thereby opening new therapeutic avenues.

Source: CEFCAP