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BIBLIOGRAPHIC UPDATES IN ALLERGY

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1. Chronic Inducible Urticaria : Treatment Options           
2. Cat exposure in early life decreases asthma risk in genetically susceptible subjects
3. Asthma severity, diagnosis criteria, high prevalence in a large random population
4. Asthma Severity: Remission and Outcomes
5. Biologics for Severe Asthma, role of Dupilumab
6.Inhaled combined Budesonide-Formoterol as needed in Mild Asthma

1. Chronic Inducible Urticaria (CindU): Treatment Options
C.Dressler et al JACI 2018 141 1726-34
Characterized by the appearance of recurrent wheals, angioedema, or both as a response to specific and reproducible triggers, CindU was identified in 30 studies that included patients with cold urticaria, symptomatic dermographism, delayed-pressure urticaria, or cholinergic urticaria.                                                                         
The authors sought to systematically assess evidence on the efficacy and safety of treatment options. Randomized controlled trials and controlled intervention studies were searched systematically in various databases. Where possible, results were meta-analyzed, by using a random-effects model. Risk of bias was often rated as unclear or high.                       
Overall, second-generation antihistamines were more effective than placebo, and available data indicate that up dosing might be effective. Omalizumab proved effective in patients with symptomatic dermographism, who did not respond to antihistamines.
The available evidence is limited by small samples, heterogeneous efficacy outcomes, and poor reporting quality in many of the studies. A stepwise approach is suggested for the treatment. However, the findings do not allow for drawing specific conclusions for specific subtypes of  CindU.


2. Cat exposure in early life decreases asthma risk in genetically susceptible subjects
J.Stockholm et al JACI 2018 141 5 1598-1606
Early-life pet exposure has been studied extensively as a suspected risk factor for childhood asthma. Many observations suggested host genotype-specific effects with most of the studies showing beneficial effect from dog but not cat exposure. The Danish authors report a novel interaction between early-life cat exposure in a cohort of 377 children and genetic variation in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma, as follows:                                          
- Cat exposure from birth attenuated the risk of asthma development during the first 12 years of life in children with the high-risk 17q21 genotype. (SNP rs7216389 variants).                                                   
- Increased levels of cat allergens in the children's homes were associated with protection from asthma in children having the high-risk 17q21 genotype. No interaction existed between dog exposure and this genotype.
 - Children exposed to cat had reduced risk of pneumonia and bronchiolitis if they had the high-risk 17q21 genotype.                     
The observed gene-environment interaction suggests a role of early-life exposure to cats in genetically susceptible subjects.



3. Asthma severity, diagnosis criteria, high prevalence in a large random population
R. Mincheva et al JACI 2018 June 6 2256-2264
Severe asthma is notoriously hard to define, The Swedish authors propose a novel definition, based on multiple signs, including daytime and nighttime symptoms, lung function, high degree of medication, (oral corticosteroids) and exacerbations. This algorithm was applied to a large-scale epidemiologic study: A total of 2.006 subjects were carefully phenotyped, the patients being grouped as having 1, 2 or more, signs of severity. The following was concluded:                 
- Asthma severity phenotypes are exceptionally diverse.
- Asthma severity is present in 13% to 36% of all asthmatic patients, 
- A total of 36.2% of asthmatic patients expressed at least 1 sign of asthma severity, and 13.2% had 2 or more signs.
- The group with 2 or more signs was older in age and had higher body mass index, a higher rate of tobacco smoking, and lower lung function.
- Bronchial hyperreactivity, airway inflammation, and sensitization were significantly different among the 3 groups, but the most prominent were smoking and obesity.
In summary, every third asthmatic patient shows at least 1 sign of asthma severity.


4. Asthma Severity: Remission and Outcomes
G.A Westerhof et al JACI 2018
In a recent study on 170 adult onset asthma in Netherland (JACI 2018 January 141 1 104-109) clinical remission is defined as an absence of symptoms ore medication use for 1 year or more and occurred in 16% after a median duration of 45 months. Theauthors also identify nasal polyposis associated or not with bronchial responsiveness, as the main predictive factors for the presence of symptom persistence.
Moreover, in a follow-up of more than a decade B.E.Chipps et al JACI May 2018 141 5 1590-1597 on 341patients enrolled in TENOR II American cohort and representative of the TENOR I group, showed that the most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%), and gastroesophageal reflux disease (46.3%). Mean percent predicted prebronchodilator and postbronchodilator FEV1 were 72.7% (SD, and 78.2% respectively). A total of 231 (72.9%) of 317 patients had positive test responses to 1 or more allergen-specific IgEs. The mean blood eosinophil count was 200/μL. Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention, oral corticosteroids, or both. More than half (197/339 [58.1%]) had very poorly controlled asthma. Medication use suggested undertreatment.
So TENOR II provides longitudinal data to characterize disease progression and the need for accurate and personalized management.


5. Biologics for Severe Asthma, Role of dupilumab (D)
D is a monoclonal antibody directed against the α-subunit of IL 4 receptor that inhibits IL4 and IL 13 signaling. 2 articles are recently published in the same issue, designed by respected investigators and funded and by pharmaceutical companies:           

A) K.F.Rabe et al NEJM 2018 May 20-21                           
In 210 patients from a multicenter, randomized cohort with glucocorticoid-dependent severe asthma, D reduced oral glucocorticoid use, while decreasing the rate of severe exacerbations and increasing the FEV1. Transient eosinophilia was observed in approximately 1 in 7 patients.                                                                   
B) M. Castro et al NEJM 2018 May 20-21
Assigned 1902 patients with uncontrolled asthma treated by subcutaneous D 200 or 300mg every 2 weeks during 52 weeks, and observed a lower rate of exacerbations than those who received Placebo as well better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. D. belongs to the family of recent new biologics directed against severe Asthma, namely: Mepolizumab and Reslizumab (anti-IL5) Benralizumab (anti-IL5 receptor). However in a small group, these drugs, largely equivalent in effectiveness, have almost no clinical effect and do not render the patients “asthma-free”. More research is needed to practice for them precision medicine.

6. Inhaled combined Budesonide-Formoterol as needed in Mild Asthma
2 trials are reported in the same issue of the NEJM, and   funded by a pharmaceutical sponsor:                                                         

   A) O’Byrne et al NEJM 2018 378 1865-1876 
In 3849 patients with mild asthma, as-needed budesonide–formoterol provided superior asthma-symptom control to as-needed terbutaline, but was inferior to budesonide maintenance therapy. Exacerbation rates with the two budesonide-containing regimens were similar and were lower than the rate with terbutaline. Budesonide–formoterol used as needed resulted in substantially lower glucocorticoid exposure than budesonide maintenance therapy.

    B) E.D Bateman et al NEJM 2018 1877-1887
In 4215 patients with mild asthma, budesonide–formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide–formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group. Finally, the decision belongs to the patients who prefer a total absence of symptoms with a regular treatment or others who accept occasionally mild symptoms but free them from the daily use of inhaler, while preventing loss of lung function and exacerbation.

Your comments and questions are welcome at the following addresses:
Claude Molina - claude.nelly.molina@orange.fr                                                     
Jacques Gayraud - gayraud65@wanadoo.fr

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Please find the previous bibliographic updates of allergology below:
- Archive of 2018
- Archive of 2017
- Archive of 2016
- Archive of 2015
- Archive of 2014
- Archive of 2013
- Archive of 2012
- Archive of 2011
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