Claude MOLINA and Franz MARRACHE

• Predictive evaluation of serum specific IgE / total IgE  ratio
• Allergy and elite sports
• Predicting risk of Asthma in later development of allergic Rhinitis
• Total IgE and Asthma
• Filaggrin, Atopic Dermatitis (AD) and Allergy
• A New and mysterious Cytokine : Activine-A

Predictive evaluation of serum specific IgE / total IgE  ratio
1)    For therapeutic approach :
The Swedish team of S.G.O. Johannsson used anti-IgE (Xolair®) at recommended doses for 16 weeks to treat a group of patients with cat allergy-induced bronchial asthma, and compared 20 individuals with a high specific IgE / total IgE ratio (≥  3.8%) with 18 individuals with a low ratio (≤ 1.0%)  (Allergy 2009 ;  64 : 1472-1477).  Treatment efficacy was analysed both clinically (some patients do not become symptom-free) and biologically (Basophil allergen threshold sensitivity (CD-sens test, as a marker of IgE-dependent inflammation). Treatment with Xolair decreased CD-sens in both groups (when compared to the placebo group), evidence of IgE elimination, but the test became totally negative in only the low ratio group.
Thus, the authors state that in asthmatic patients with high levels of this IgE ratio, the dose of anti-IgE generally recommended may not be sufficient.  This highlights the necessity to calculate an appropriate dose, taking into account this fraction and the total amount of  IgE molecules directed towards the whole of allergens.
2)    For  Assessment of Prognosis in Immunotherapy
An Italian team from Palermo and Verona ( G. Di Lorenzo et al. JACI 2009 ; 123 : 1103-1110) sought to evaluate pre-treatment parameters that might be useful to predict  a favourable clinical response to immunotherapy (IT). IT was administered for 4 years in 279 cases of allergic rhinitis associated with monosensitisation (house dust mites, grass pollens, Parietaria, or olive tree), 76 by the sub-cutaneous route (SCIT) and 203 by sublingual administration (SLIT).
Clinical efficacy was obtained in 145 cases (52%) of which 42 by SCIT (55.2%) and 103 by SLIT.
The rigorous statistical analysis (in spite of absence of a placebo group in this retrospective study), carried out at each step, showed that the best criterion  was serum specific IgE / total IgE ratio, which was more sensitive and more specific than total or specific IgE alone or the rate of blood eosinophils. The best clinical response was obtained when this ratio was high and greater than 16.2.
These 2 publications are not contradictory since their objectives were different, but they underline the need for allergists to have an increasingly greater precision in interpretation of biological tests and their therapeutic applications.

Allergy and elite sports
Can allergic individuals or asthmatic patients become elite athletes?
This is a recurring question which is the subject of recent contradictory publications.
- In a paper by V. Bougault et al. (Eur. Respir. J. 2009 ; 33 : 740-746), the relationship between exercise-induced bronchial constriction (EIBC), training in cold air (TCA) and bronchial epithelium damage was analysed in 3 types of individuals: elite swimmers and cold air athletes, individuals with moderately severe asthma and healthy subjects. Analysis and quantification of cell populations in induced sputum and methacholine challenge tests were performed.
The authors observed a close correlation between cellular markers of inflammation and the development of EIBC, suggesting the potential role of epithelial damage in the development of airways responsiveness.
- Similarly, Lars Peterson et al (JACI 2008 ; 122 : 322-327) described a relationship between bronchial epithelial lesions and  development of airways responsiveness in adolescent elite swimmers.
By contrast, in the editorial of the same journal (JACI 2008; 122: 249-250), entitled « Yes, with allergy we can » S. Bonini does not agree with the deleterious effect of elite sports upon allergic individuals, taking into account their significant participation and the number of medals obtained by these athletes at the 24th Olympic Games.
Overall, one should, in each case, take into consideration the type of sport, the number of training many hours, the different weather conditions, and the immune and bronchial status of the elite athlete.
This careful evaluation must be carried out throughout all the sports career.
This allows to apply the most adequate treatments and avoid excessive prescription or usage of drugs that are not free from , sometimes severe, side-effects.

Predicting risk of Asthma in later development of allergic Rhinitis
A Swedish study (L.P Nielsen et al. Allergy 2009 ; 64 : 733-737) focuses on 44 patients with seasonal rhinitis (allergic to Timothy grass) who were reviewed after 6 years. A complete clinical and biological evaluation performed under similar conditions that those at the beginning of the study, showed the persistence of the same symptoms in 10 patients, a worsening in 4 patients, asthma-like symptoms in 14 and a well-characterised asthma in 7. Thirteen of the patients had acquired additional sensitisations.
Among the characteristic parameters of deterioration such Asthma or Asthma-like symtoms, the authors observed a statistically significant increase in the levels of serum eosinophil-derived proteins: ECP (Eosinophil cationic protein) and EPO (Eosinophil peroxydase ) but, paradoxically, neither nasal lavage parameters, nor blood eosinophil numbers were associated with Prognosis.
Thus, the markers of eosinophil granule proteins ECP and EPO should to be taken into consideration in the outcome of seasonal rhinitis, their presence suggesting a high probability of subsequent development of Asthma.

Total IgE and Asthma
In a large epidemiological study carried out in the US between 2005 and 2006, entitled « Health and Nutrition » (P.J. Gergen et al. JACI 2009 ; 124 : 447-453) the authors determined the association between  total IgE levels and  prevalence of Asthma, in a representative sample of U.S. population 6 years of age and older.
The median total IgE level was 40.8 kU/L, with variations relating to age, weight, gender, ethnical factors and tobacco smoking (serum cotinin) ;
The prevalence of Asthma was 8.8%.
By contrast, the prevalence of Atopy (as defined by at least 1 positive allergen-specific IgE test out of 15 performed) was 42.5%.
Furthermore, the level of total serum IgE was only predictive of Asthma (significant OR) in atopic individuals.
Among atopic subjects, the association between total IgE level and asthma became stronger as the number of positive specific IgE test results increased (from 6 to11 positive IgE tests for 92% to 99% of the atopic population, respectively). In conclusion, Asthma is not statistically associated with the levels of total serum IgE unless there is, simultaneously, positive allergen-specific IgE tests at least to one allergen. The global identification of atopic individuals requires a large panel of such tests for IgE.  Finally, non IgE-dependent Asthma is relatively frequent in the US population. These notions, known by allergists from developed countries, are usefully remembered and confirmed in this study

Filaggrin, Atopic Dermatitis (AD) and Allergy
It is well known for many years that dysfunction of the skin barrier plays an important role in the development and progression of AD and also that mutations (loss of function) in the FLG gene which codes for the epidermal structure protein Filaggrin are important risk factors for the disease.
Identification of these mutations showed their responsibility in the early onset and severity of AD but also in risk of development of asthma (what the paediatricians call «atopic march»).
Based upon experiments carried out by M.K. Oyoshi (JACI  2009 ; 124 3 :  485-493) and by P.S. Gao (507-513),  D.Y.M. Leung (494-495) explains the observed Th2 polarisation of AD lesions in individuals who are deficient in FLG by the increased trans-cutaneous penetration of aggressive agents such as allergens or viruses, associated with a loss of extra-cellular water and dominated Th17 inflammation..
But researches involving Filaggrin go even further. In a general review with a meta-analysis of 319 epidemiological publications of which 24 were regarded as reliable (family studies and case-control studies), R.Van den Oord and QA. Sheikh (BMJ 2009 ; 339 : 86-89) observed , not only a significant association between deficiency in Filaggrin and AD (a solid association, in this case) but also between Filaggrin mutations and allergic rhinitis. By contrast, the authors did not find any association with asthma (except when the latter was associated with AD). neither with food allergies nor anaphylaxis. Overall, these studies underline once again the importance of genetics in interpretation of many manifestations of atopy.

A New and mysterious Cytokine : Activine-A
A Greek and English team reveals the functions of a novel cytokine – Activine, whose pro- or anti-inflammatory action is not well elucidated. This cytokine was analysed in  two studies: an experimental model in the mouse (M. Semitekolou et al. J.Exp.Med 2009 ; 206 8 : 1769-1785) and a human study in asthmatic patients (H.H. Karyawasam et al. JACI 124 ; 3 : 454-462).
In the model of asthma in mice, the authors administered an antibody which blocked Activin, just before an allergen pulmonary challenge, and observed a worsening of asthma symptoms. By contrast, the administration of Activin improved breath. This cytokine, which may be found in large amounts in  blood of asthmatic patients and   allergic mice, acts by stimulating regulatory T cells (Treg) which inhibit, via their secretion of IL-10 and TGF-β, the maturation of dendritic cells, essential for the Th2-mediated response to allergens.
In the corresponding clinical study, performed in 15 young adults (mean age of 25 years) with moderately severe atopic asthma, immunohistochemistry of the bronchial mucosa after an allergen challenge confirmed  implications of  pathogenic pathways of TGF-β and Activin in Asthma, Activin contributing to the resolution of inflammatory process. This is a novel line of research in allergic Asthma developed by the team headed by Prof. A.B. Kay.

Source: CEFCAP

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