Claude MOLINA and Franz MARRACHE

• Can paracetamol be a cause of Asthma in children ?
• Objective assessment of Cough in Asthma
• Is Helicobacter pylori (HP) a preventive factor for Allergy ?
• Parasitosis in children and Allergy
• Birch-induced allergic Rhinoconjonctivitis treated with recombinant allergens

Can paracetamol be a cause of Asthma in children?
This is the guesswork of a large European survey: ISAAC in its phase 3 (Association between paracetamol use in infancy and childhood and risk of asthma, rhinoconjunctivitis and eczema. R. Beasley et al. Lancet 2008 ; 372 : 1039-1048). Indeed, since the 80s, paracetamol (P) completely replaced aspirin as anti-pyretic and analgesic in children. This is due to risk of asthma, triggered by aspirin, particularly in atopic children but also Rye’s syndrome (encephalopathy with epileptic attacks and ocular problems.
The authors tried to find out whether exposure to P during intra-uterine life, or the first year of life in infant, as well as at the age of 6-7 years and also in adult, increased the risk of Asthma and/or Allergy. 205,487 children 6-7 years old, from 73 centres in 31 countries were included in this study (questionnaire given to parents). The results showed (multivariate analysis) that the administration of P (at least once per month) during the 1st year of life was significantly associated (OR 1.46) with an increased risk of Asthma at 6 to 7 years of age. Furthermore, usual utilisation of P was associated, in a dose-dependent fashion, with a risk of asthma (OR 1.6 to 3.23, according to moderate or high drug dose, respectively). Morover, use of P during the 1st year and at 6-7 years of age was associated with an increased risk of rhinoconjunctivitis and eczema. Although impressed by the size of the sample and its multi-nationality, the methodology and the power of this statistical analysis, one cannot exclude recall bias (in the responses given by the parents to the questionnaire, translated into various languages), or reporting bias (use of other antipyretics or viral infection).
So the doubt persists. In fact, if the association is plausible, the causal relation between P and Asthma or Allergy cannot be stated, as the authors acknowledge.
Moreover, what antipyretic or analgesic drug one should use in the young child ?. Ibuprofen suggested by some authors does not gather unanimity. Aspirin has not said its last word. Thus, we think that P at moderate doses, because its efficacy and safety profile spanning 50 years, should continue to be the first choice for the treatment of fever and pain, even in allergic or atopic children.

Objective assessment of Cough in Asthma
Few studies have focused on the prevalence of cough in Asthma, and most of those are based on subjective criteria. Some authors suggest that 61% of asthmatic patients complain of cough. Whether it occurs during the night or day, whether it is productive or not, it is not the main symptom mentioned by asthmatic patients. The interesting work reported by P.A. Marsden et al, from Manchester ( JACI 2008 ; 122: 901-907) is the first which performed comparative study between subjective and objective criteria. These latter were obtained through ambulatory monitors allowing 24 hour-long recordings with a count unit : the number of seconds of cough per hour.

The methodology is original and precise: it included a questionnaire (Leicester) with 19 questions on physical, social and psychological aspects, a thorough study of asthma involving lung function studies, a test of bronchial reactivity, an analysis of FeNO, as well as reflex sensitivity through inhalation of citric acid. The subjective scores included an analogue visual scale graded from 1 to 100 and a frequency score graded from 1 to 5. 54 asthmatic subjects were included (these patients were not selected on the basis of their cough) and were compared with a similar number of healthy control subjects. Results were thoroughly analysed statistically.
The conclusions were surprising and very interesting: It is obvious that the frequency of cough was higher in asthmatic patients than in healthy subjects of similar age.
However, the median time spent by asthmatic patients coughing was little , averaging 2.6 seconds per hour (range: 0.0 to 14.0).
In patients with asthma, Cough was more frequent during the day than at night (3.9 seconds per hour versus 0.3 Overall or daytime cough rates were not significantly different between female and male patients. However, women spent more time coughing at night than men. In addition, cough rate showed a weak but significant positive correlation with the subjects age.
Objective time spent coughing was weak to moderately associated with subjective cough scores and visual analogue scales. but was not correlated with functional tests, namely bronchial reactivity, FeNO or reflex sensitivity to citric acid.
In contrast, objective time spent coughing was strongly correlated with scores of quality of life questionnaire. These notions underline the interest of objective cough recordings for all therapeutic interventions directed towards this Asthma symptom, but also for all cough-inducing causes. In this regard let us also remember a physical discipline : strioscopy, which studies the dynamics of gas flows; its application to the study of cough has shown that its generates warm air with a mean speed around 8 metres/second.

Is Helicobacter pylori (HP) a preventive factor for Allergy?
The inverse relationship between bacterial colonisation by HP and the presence of Asthma or Allergy reported by Chen and Blaser (J. Infect. Dis. 2008 ; 198 : 553-60) led some scientists to study the mechanism accounting for this possible protective effect. Thus, an Italian team (G. Del Prete et al. Immunosuppression of Th2 response in Trichinella spiralis (TS) infection by HP neutrophil-activating protein. JACI 2008 ; 122 : 908-913) infected various murine strains with the TS parasite, which triggered eosinophilia, and increases in the serum levels of total and specific IgE, as well as those of IL-4 and IL-5. In this model, the authors showed that in animals treated with Neutrophil activating protein (NAP) there was an anti-Th2 activity with a decrease in eosinophilia and in the plasma concentrations of IgE, IL-4 and IL-4, associated with an induction of IL-12 and INFã expression.
In addition, the simultaneous administration of an anti-Toll Like receptor 2 monoclonal antibody abrogated the immunosuppressive action of HP-derived NAP on Th2 activity as well as its Th1-inducing activity.

This HP-NAP-derived immunosuppressive activity was confirmed by Codolo et al belonging to the same working group(Cell Microbiol. 2008 August 15) who showed, in a murine model of ovalbumin-induced allergic asthma, that systemic and mucosal administration of recombinant NAP abrogated pulmonary eosinophilia, and reduced the serum levels of IgE and Th2 cytokines.

Thus, the HP- NAP / asthma antagonism, suggested by clinical observations and confirmed experimentally, deserves to be considered.
In this context, recombinant NAP might represent, in the future,
a novel strategy for prevention of Allergic disorders

Parasitosis in children and Allergy
A group of doctors from Latin America (Brazil and Ecuador), in collaboration with the London School of Hygiene and Tropical Medicine, UK, has tried to find if, like Hygiene hypothesis in developed countries, intestinal helminthic infestation during early childhood might account for a lower prevalence of allergic reactions and asthma later in childhood and intervene upon the immune system, to induce a lower allergen skin test reactivity.

The investigators have, therefore, selected 1055 children whose stool examination had shown, in another previous study, intestinal infestation with an helminth : Trichuris Trichiura (TT) in early childhood. Then they performed skin prick tests in these children, a few years later, with common aeroallergens and collected information on potential confounding variables in their statistical analysis (L. C. Rodrigues et al: Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood. Clin. Exp. Allergy 2008 ; 38 : 1769-1777). The results are as follow: Children with heavy infections with TT in early childhood had a significantly reduced prevalence of allergen skin test reactivity in later childhood, even in the absence of intestinal infestation at the time of skin testing.

Thus, for these authors and in emerging countries, massive infestation with TT
in early childhood seems to play a protective role against skin reactivity to aeroallergens. Novel treatments programming immune regulation in the early child by mimicking the effects of the TT parasite might offer a new research avenue for the prevention of allergic diseases.

The chapter of correlatins between Parasites and Allergy, which is quite complex and has been the subject of many but not always concordant results, , is thus enriched with an innovative study showing an unexpected positive relationship.

Birch-induced allergic Rhinoconjonctivitis treated with recombinant allergens
The European task force of Recombinant allergens, led by Gabrielle Pauli (Strasbourg) reports a randomised, multicenter, study on birch-induced allergic rhinoconjunctivitis treated by the recombinant (r) allergen (JACI 2008;122: 951-960). Three types of allergens were compared: rBet v1, a patented birch pollen extract ; nBet v1, a purified natural allergen and a placebo group. 134 adult subjects participated in this study. They were given a weekly injection of the product for 12 weeks, followed by a monthly maintenance administration of 15µ Bet v1 for 2 years (2004 and 2005). All subjects were followed up on a regular basis in clinical and biological terms : 33 subjects on rBet v1, 29 on nBet v1, 29 on Birch pollen extracts and 36 on Placebo.
Results were as follows:
A significant reduction in about 50% of symptoms, rescue medication and cutaneous sensitivities in the 3 treated groups, as compared with the placebo.
group. Clinical improvement was accompanied by an increase in the levels of Bet v1-specific IgG, which was higher in the Recombinant Bet v1 group.
No new IgE specificities were observed in the rBet v1 and nBet v1 groups, whereas there were 3 in the one treated with pollen extract. There were no severe side effects in the Recombinant group. This study thus confirmed the efficacy and safety of recombinant allergens for the treatment of birch pollinosis and the skill of genetic recombination DNA technology for the manufacture of allergen extracts for vaccines.

A novel approach for conversion of allergens as vaccines is the dissociation of allergen molecule between IgE and IgG immunologic activity. This approach was carried out in an animal model by N. Mothes-Luksch et al (Disruption of allergenic activity of the major grass pollen allergen Phl p2 by reasembly as a mosaic protein. J. Immunol. 2008 ; 181 : 4864-4873) who fragmented Phleum allergen into peptides of similar length, then re-assembled them in a different order, which lead the mosaic protein so expressed to the loss of its tridimensional structure, its capacity to bind IgE, and its allergenic activity whereas induced high levels of IgG molecules bind to Phl p2 blocks its binding to IgE.

Source: CEFCAP

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