The Monthly choice - September 2016

Claude Molina & Jacques Gayraud

1) Asthma risk in Amish and Hutterite Farm Children

2) News in venom Hypersensitivity
3) Corticosteroid response in pediatric patients with severe asthma
4) Safe drugs for young asthmatic patients
5) Early polysensitisation is associated to allergic mutimorbidity

1) Asthma risk in Amish and Hutterite Farm Children
M.M Stein et al NEJM 2016 375 411-421
US agricultural populations whose lifestyles as well as genetic ancestry, are remarkably similar but whose farming are distinct, the former follow traditional practices, the latter use industrialized farming practices.
The authors knowing striking disparities in prevalence of asthma in the two populations tried to explain these disparities in studying and comparing, in 30 Amish and 30 Hutterite children, environmental exposures and immune profile (levels of allergens, serum IgE levels and endotoxins, gene expression, cytokine responses, blood peripheral leucocytes phenotyping ) and microbiome composition of indoor dust samples. Moreover the effects of dust extracts were assessed in a murine model of experimental allergic asthma
The results of this important study showed that the prevalence of asthma and allergic sensitization is 4 to 6 times as low in the Amish , whereas levels of endotoxins in Amish house dust is 6,8 times as high. Profound differences are observed in innate immune cells between the 2 groups of children. Intra-nasal instillation of dust extracts in mouse model from Amish, but not Hutterite homes inhibited airways hyper reactivity and eosinophilia . This protective effect was abrogated in mice deficient in MyD88 and Trif, molecules critical in innate immune signaling;
In conclusion, in humans and mice the Amish environment provides protection against asthma by engaging and shaping the innate immune response.

2) News in venom Hypersensitivity
G.Sturm :EAACI Newsletter 2016 43 2 27
Hymenoptera Venom Allergy (HVA) is responsible for more than 10% of all cases of Anaphylaxis and accounts for more than 40% in the 13-17 years age group and 20- 50% in mastocytosis rising to 6o- 80% in indolent systemic mastocytosis without skin lesions.
Current available tests are not able to distinguish between asymptomatic sensitization, large local reactions and severe systemic reactions. However recent developments had improved diagnostic precision in HVA in particular sIgE in Honey bee marker allergens such rApi m3 et rApi m10 which allows the detection of genuine sensitization in 46-65% of Api m1negative sera and useful in case of double sensitization or cross reactivity. But until the end of 2016, 5 bee venom components are available for routine diagnosis : Api m 1 2, 3, 5 , 10.
A recent study showed that high levels of sIgE to rApi m1 and rApi m2 could be predictors of severity of a sting reaction. Another development is focused on biomarkers of HVA : So the serum concentration of CCL5/RANTES is reduced after 6 days of Venon Immunotherapy (VIT) independantly of sIgE .
There is also in venom allergic patients an up-regulation of CD 26, CXCR4, CXCR3 CD 150 and ICOS and conversely a down regulation of CD 30 CD 154 and 152 a decrease of basophil degranulation and increase of INF gamma in T cells after 4 month of VIT.
Moreover precision medicine is also reached by means of analysis of gene expression : a predictive model could be used in clinical practice to assesss the efficacy of VIT.
As for adherence to subcutaneous VIT, a recent five years follow-up study indicates excellent results. Moreover we must recall the physicians and patients concerns about excessive price of Epipen in USA

3) Corticosteroid response in pediatric patients with severe asthma
C.J.Bossley et al JACI 2016 138 2413-420
Severe therapy-resistant asthma (STRA) is heterogeneous thus response to steroids in not uniform in all patients. The English authors thought to evaluate the utility of multidomain approach incorporating symptoms, lung function and inflammation (eosinophilia).
82 children, median age 12 years with STRA received a dose of intramuscular steroid (triamcinolone) Changes in 4 separate domains were assessed 4 weeks later : symptoms score, spirometric results (FEV 1), fraction of exhaled NO2 levels, sputum eosinophils counts .
- 54 had complete data in all 4 domains.
- A similar proportion of children responded in each domain (43-54%).
- Only 7 (13%) were complete responders in all domains 8 were no-responders.
These results confirm that STRA is heterogeneous. However individual response patterns might be useful in guiding the choice of add-on therapies (mainly monoclonal antibodies) in each child as a step toward achieving personalized medicine.

4) Safe drugs for young asthmatic patients
a) Acetaminophen as Ibuprophen are commonly used in USA for the alleviation of pain or fever and studies have suggested that they are responsible for complications among asthmatic children. In a multicenter prospective randomized parallel group trial , W.J Shehan and al NEJM 2016 August 18 375 619-630 300 children were enrolled age range 12 to 59 months and assigned to receive A or I during 48 weeks. The results showed that A as needed use, was not associated with a higher incidence of asthma exacerbations or worse control than was as-needed I.
In conclusion the two drugs are harmless in young children with moderate asthma
b) Safety of adding Salmeterol to Fluticasone in children with asthma
LABAs (Long acting-beta agonists ) has been shown to increase the risk of asthma-related hospitalization among children (and even death in adults) D.A Stempel et al NEJM 2016 375 840-849 1 september: in a trial among children 4 to 11 years of age showed that salmeterol in a fixed dose combination with fluticasone, during 28 weeks was associated with the risk of a serious asthma –related event similar to the risk of fluticasone alone.

5) Early polysensitisation is associated to allergic mutimorbidity
(S.Gabet et al Ped All Immunol 2016 8 august ) A population-based prospective birth cohort in Paris (France) studied allergic sensitization to 12 foods and 4 inhalant allergens assessed at 18 months and health data collected at 2 and 6 years. In a cluster analysis 3 profiles of increasing severity were identified and compared with regard to allergic morbidity and multimorbidity
It appears that early sensitization can predict multimorbidity (asthma, rhinitis, eczema, food allergy) in childhood and in case of early multisensitisation, multimorbidity is more frequent as soon as in infancy.