Bibliographic updates

The Monthly choice - September 2014
Claude MOLINA* & Jacques GAYRAUD**

1. Fatal Anaphylaxis with Neuromuscular blocking-agents
2. Bitter Taste Receptors in the Lungs: Recent findings
3. Dupilumab (D) treatment in adult Atopic Dermatitis
4. Clinical features of Food-protein-induced Enterocolitis syndrome
5. Depression and Risk of Incident Asthma in Adults
6. Mepolizumab revisited in the treatment of Severe Eosinophilic Asthma

1. Fatal Anaphylaxis with Neuromuscular-blocking agents (NMBA)

Theme: Drug allergy
Key words:
Fatal anaphylaxis – Neuromuscular blocking agent

Evaluating mortality rate from Anaphylactic Reactions (AR) to NMBAs in France, between January 2000 and December 2011,M. Reitter et al from the National Pharmacovigilance Center (Allergy July 2014 69 7 954-959) retrieved 2022 cases of NMBA hypersensitivity. Among the 1247 cases of severe AR, 84 were fatal: 4,1%. Multivariate analysis showed that the significant risk factors, independent of the type of NMBA, are : male gender, undergoing surgery in an emergency setting , a history of hypertension or other cardiovascular disease, obesity and ongoing β-blocker treatment. 31 patients with a fatal outcome received epinephrine according to international guidelines. This high mortality rate suggests some epinephrine resistant cases and a need to develop new therapeutic approaches.

P.S. In this connection we must mention the new EAACI guidelines in the treatment of Anaphylaxis edited in Allergy 2014: A. Muraro et al :vol.69 N°8 1026-1045.

2. Bitter Taste Receptors in the Lungs: Recent findings

S.Grassin-Delyle et al Rev.Pneumol.Clin2014 70 148-155.

Theme: Physiology of Asthma
Key words: tastes: salty, sweet, bitter, umami – Taste Receptor – Mastocytes

Among the receptors responsible for the 4 basic tastes: salty, sweet, bitter and umami, the bitter taste type 2 ones (TAS2R) are G protein coupled including 25 subtypes. Initially confined to the oral cavity, their expression has been described in the gastro-intestinal tract but mainly in the lungs at 3 levels: on the cilia of epithelial cells responsible for the increase of cilia vibration, in bronchial smooth muscle cells which leads to bronchial relaxation and on immune cells involved in the modulation of inflammatory cytokines and particularly in mastocytes, leading to inhibition of release of histamine and PGD2 from IgE activated receptor. M. Ekoff et al: JACI 2014 June Letter to editor 02.029 and JACI 134 2 August 2014 285-286).

3. Dupilumab (D) treatment in adult Atopic Dermatitis (AD)

(L.A.Beck et al NEJM 2014 10July 130-138)

Theme: Skin Allergy
Key words: Atopic dermatitis – Dupimumab – IgE - Thymus & Activation Regulated Chemokine – Transcriptome – Kératin 16

D. human monoclonal antibody that blocks IL 4 and IL 13, performed in randomized trials involving adults who had AD not controlled with topical medications (glucocorticoids and calcineurin inhibitors) was evaluated as monotherapy in two 4 weeks trials and one 12 weeks trial; end points included Eczema area and severity index Score , investigator’s global assessment, pruritus score, serum biomarker levels and disease transcriptome (TARC, IgE , RNA expression and Keratin 16 levels). In the 4 weeks monotherapy studies, D resulted in rapid, significant and dose-dependent improvement in clinical indexes, biomarker levels and the transcriptome. These results were confirmed and extended in the 12 weeks study. The side effects were mild and not dose-limiting.

In conclusion D has shown rapid and marked efficiency in AD in adults and may benefit to all atopic diseases which share Th2 mediated inflammation.

4. Clinical features of Food-protein-induced Enterocolitis syndrome (ES). (J.C Caubet et al : JACI 2014 134 2 382-389)

Theme: Food allergy – Pediatrics allergy
Key words: Enterocolitis – Food Protein

It is a non IgE-mediated food allergy frequently observed in USA. 160 subjects, median age of diagnosis being 15 months, were recruited, medical features recorded and oral food challenge performed. The symptoms are vomiting and lethargy 2 to 4 hours after ingestion of the suspected food followed 10h later by diarrhea. The diagnosis is often delayed in absence of classic allergic symptoms and lack of biomarkers. The most common foods were cow’s milk (44%), soy (41%), rice (22,5%), oat (16%). Spontaneous resolution is usual. Median age for tolerance is 4 to 6 years except for cow’s milk if specific IgE occurs over time (41% of subjects changed from a milk Es to an IgE mediated phenotype).

A recent British pediatricians experience (S.Ludman et al Annals of Allergy, Asthma, Immunol September 2014 113 3 290-294) confirms, among 54 children, median age 8 months, these clinical features, and relates a frequent delay in the diagnosis of this syndrome (more than 12 months).

5. Depression and Risk of Incident Asthma in Adults

(W.M.Brunner et al : AJRCCM2014 May 189 9 1044-1051)

Theme: Respiratory allergy - Asthma
Key words: Depression – Asthma – CARDIA Cohort

The temporality of the association between Asthma and depression has not been established. So American epidemiologists (Minnesota and New Mexico) examined bidirectionally this association in the CARDIA cohort including 3614 participants free of Asthma in search of elevated depressive symptoms and 3016 participants, free of depressive symptoms in search of self reported current asthma, prevalent or not. After adjustment for covariates, the relative hazard of incident Asthma was 1,26. Therefore Depression appears as a marker for incident adult Asthma.

Health care providers must be aware of the potential for new-onset asthma in their patients with depression.

On the other hand, prevalent Asthma is not associated with incident depression in middle age.

6. Mepolizumab (MP) revisited in the treatment of Severe Eosinophilic Asthma (SEA)

NEJM Alert 7-8 September 2014 On-line first

Theme: Respiratory allergy - Asthma
Key words: Mepolizumab – Severe Eosinophilic Asthma

Unlike previous studies, two recent randomized trials report successful results in SEA treated with MP, this monoclonal antibody directed against interleukin 5.
  • One published by H.G Ortega et al, involves patients whose asthma is uncontrolled despite high doses of glucocorticoids and long acting bronchodilators. MP was administered either as 75mg intravenously dose or 100mg subcutaneous dose, every 4 weeks, during 32 weeks, in patients selected by the characterization of their eosinophilic phenotype based not on IgE levels or sputum eosinophils but on the basis of blood eosinophilic count of at least 150 to 300 cells per microliter. On the other hand, considering the balance between this expensive drug and the clinical benefit expected, adherence to the prescribed therapy recommended by international guidelines must be effective. The result was a clear decrease of A. exacerbations (47 to 53% according to the dose).
  • In the other study E.H Bel & al, the sparing effect by MP of glucocorticoids was impressive, the mean percentage reduction in the dose being 50%.
In these two studies MP was safe and had an acceptable side-effects

In conclusion, Mepolizumab significantly reduced asthma exacerbations, was associated with improvements in markers of asthma control and had a sparing effect on the high doses of glucocorticoids used in SEA.

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Last updated 31 October 2014