Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Th17/IL17, severe asthma and vitamin D   
2. Dupilumab (D) in eosinophilic asthma (EA) 
3. Occupational asthma in cleaning workers   
4. Occupational asthma and skin tests   
5. Red meat allergy : an enigma lastly solved?

1. Th17/IL17, severe asthma and vitamin D

Theme: Asthma – Severe asthma
Key words: Severe asthma – Vitamin D – Lymphocytes TCD4, Th17 – Interleukins IL17, IL22

We already drew attention (September 2012 BUAs) to the advantage of checking vitamin D blood levels (25 OH D3) in allergic and asthmatic patients. More recently (April 2013 BUAs) we recalled the role of TH17 and IL17 in Allergo-Immunology. This issue has again been addressed by a group of London researchers (A.M.Nanzer et al JACI 2013 in press) who, assuming the role of TH17 in severe, steroid-resistant (SR) asthma (A) and the benefit brought about by vitamin D3 in enhancing anti-inflammatory action of steroids, performed on asthmatic culture cells a series of in vitro investigations intended to determine IL17A levels.

28 patients of an average age of 50, 18 suffering from severe asthma defined by their resistance to steroids (SR) and 10 sensitive to steroids (Ss) according to usual criteria (BTS), as well as 10 healthy controls, gave blood samples (after a 2-week weaning from steroids). The T CD4 lymphocytes isolated were put in culture and submitted to a range of tests (flow cytometry, PCR, cytokine levels). It appears that:
1. SRAs cell cultures synthesize IL17 and IL22 to significantly higher levels (7 times as much) than Ss and controls; these cytokines can be found in the culture supernatant.
2. Steroids added to the cellular environment do not inhibit IL17A and IL22 synthesis in SR A or Ss A, unlike controls.
3. Vitamin D (1α,25(OH)D3) inhibits IL17 and IL22 expression in SRA and SsA cultures, irrespective of steroid addition.

These observations, together with a number of clinical and experimental references exposed in papers, justify the use of vitamin D3 in the treatment of severe asthma, particularly to enhance action of steroids.

2. Dupilumab (D) in eosinophilic asthma (EA)

Theme: Asthma – Severe asthma
Key words: Dupilumab – Eosinophilic asthma – Interleukins IL4, IL3

A new monoclonal antibody (MA) targeting the alpha subunit of Interleukin-4 receptor, inhibiting both IL4 and IL13, was the topic of  a US multicentre study (Pittsburgh, Denver and Los Angeles Universities) (S.Wenzell et al NEJM 2013  29 May online). It concerns moderate-to-severe EAs with high eosinophil levels (≥ 300/ml in blood and ≥ 30% in sputum), treated for at least 1 year and poorly-controlled by Fluticasone (F) and Salmeterol (S).

Among 491 patients, 52 aged 18-65 were enrolled (and 52 in the placebo group). D was administered by subcutaneous injections of 300mg once a week for 12 weeks, while F was stopped at week 4 then S between weeks 6 and 9.

The first endpoint was the occurrence of  an A. Exacerbation (Ex), the second ,was a range of measures of A. Control, during the trial period, and the third,the study of D feasibility and tolerability.
• At the end of the treatment there were 3 Exs in the treated group (6%) versus 23 (44%) with placebo, corresponding to a significant 87% reduction ; Any one of them required hospitalisation.
Clinical monitoring included symptomatic score, morning and evening peak-flow measurement, frequency of nocturnal awakenings. The results were significantly favourable to D, especially for morning peak-flows. FEV1 showed a 200ml average increase, much appreciated by patients with marked initial lung obstruction.
• On biological level, a large number of Th2-type inflammatory markers were compared: FENO, IgE, CCL 17 and 26, all clearly reduced by D, with the paradoxical exception of eosinophils.
• As for tolerability, it was satisfactory albeit with some more frequent reactions in group D (such as nausea, nasopharyngitis, headaches, or injection-site reactions).

True, as pointed out by M.E. Wechsler’s critical review in his Editorial, it is not yet the magic potion, and length of the trial was limited. However and compared with the other active MAs, particularly targeted on IL13 (Lebrikizumab, Tralokizumab), D active both on IL4 and IL13 deserves further investigation.

3. Occupational asthma (A) in cleaning workers

Theme: Asthma – Occupational allergy
Key words: Occupational asthma – Cleaning staff – Total IgEs – FEV1 - FeNO

A joint study by Spanish and Canadian authors (D.Vizcaya et al Respir.Med May 2103 5 673-83) of 42 cleaning workers suffering from A and recent respiratory symptoms, carefully selected, compared to 53 healthy controls, of the same age, sex and social condition, clarified their functional and biological characteristics.

These cleaners were 93% female, average age 42 years, recruited in Barcelona within 37 cleaning companies, between 2008 and 2009. Before clinical examination, the questionnaire covered symptoms, personal history, and above all information on cleaning products used at work as well as at home. A complete table presents 10 varieties: bleach, detergents, degreasers, waxes, polishes, limescale removers etc...

The study measured FENO, FVC and FEV1, and its reversibility post-bronchodilators,  and, in serum, total IgE, pulmonary surfactant protein D and the 16kDa Clara cell secretary protein, as well as in exhaled breathe condensate, 10 interleukins, 2 growth factors, cys-leukotrienes, and 8-isoprostane.

The statistical study by multivariable logistic regression analysis showed:
• A high prevalence of atopy (42% vs 10%) as well as a level of total IgE 2.9 times higher in As than in controls; worth noting however was the lack of eosinophilia.
• A slight decrease (8%) in FEV1 under bronchodilators, asserting the low reversibility of these Asthma of adult onset; Moreover the high FENO observed in patients and controls is not discriminating.
• Respiratory biomarkers did not reveal any significant association, thus excluding the role of impaired permeability of the alveolar epithelial barrier or of oxidative stress. Among cleaning products, irritants and sprays were most used by As at work (although their domestic use could have been an extra risk factor). The same can be said of glass cleaners, polishes and multi-use products (of various chemical compositions).
• All these informations deserve to be taken into account in the field of  occupational safety, socio-economic point of view and also public health

4. Occupational asthma and skin tests

Theme: Occupational allergy
Key words: Occupational allergens – Skin tests - Standardisation

An EAACI Task-Force gathering 15 allergist centres in 6 European countries (Germany, Austria, Spain, France, Italy, Poland) undertook a detailed investigation on the value of skin prick-tests (SPT) in IgE-dependant occupational allergies (OA) (V.Van Kampen, F.deBlay et al Allergy 2013 68 651-658).

It is obvious that this value depends essentially on the quality of the allergenic extracts (AE) and of which depend confirmation of occupational origin of the disease and all the forensic and socio-economic consequences, from prevention to possible compensation and possible unemployment.

116 bakers, 47 farmers, 33 latex-allergic patients (mostly health professionals) of an average age of 48 were selected, 89 suffering from asthma.

Allergenic extracts from 7 European producers were used. The main allergens were: wheat flour, rye flour, soy, storage mites, animals’ hair (cow) and latex. Respective AE content in proteins and antigens were estimated.
SPTs ≥ 1,5mm were considered as positive. The basic reference was specific IgE values. Sensitivity (S), specificity (Sp), Youden Index (computed from these two values) were calculated, as well as predictive SPT positive and negative values with the different solutions.

The conclusions, also published in the same journal (Allergy 580-584) reveal a very high disparity of manufactured AEs in their protein and antigen contents, even with an overall Sp of about 80%, the richest content solutions giving the best results. But, wheat and soy flour AEs for bakers and farmers showed a low sensitivity and a wide variability between manufacturers. The highest consistency was obtained with the latex allergen.

The authors recommend using simultaneously solutions from different sources, until the occurrence of hypothetical standardisation.

At the same time, it should be noted that in 10 cases of severe work-related asthma (2 farmers, 2 bakers, 2 vets and 4 persons allergic to chemicals) a successful treatment, by Omalizumab, made it possible for 7 of them to maintain their activity with a significant improvement (F.Lavaud et al Allergy 2013 Mai 651-658).

5. Red meat allergy: an enigma lastly solved?

Theme: Food allergy - Allergen
Key words: Red meat – Alpha Gal - Ticks

The T.A.E Platts-Mills team was among the first to identify, in patients having shown severe allergic reactions after ingesting red meat (beef, pork or lamb), the presence of IgE against the carbohydrate epitope : galactose α1,3-galactose (α-Gal). The same IgEs were observed in patients treated with Cetuximab.

Later on, an association between meat allergy, tick bites and α-Gal IgE was observed in Australia, in the USA (in the Rocky mountains) and more recently in Spain and Sweden. Swedish researchers of the M. van Hage school (C.Hamsten et al  Allergy  2013 68  549-552) have just demonstrated the presence of α-Gal in the gastro-intestinal tract of the Ixodes ricinus tick.

So they studied the serum of 4 patients having presented allergic reactions, both severe and late (urticaria, anaphylaxis), to red meat ingestion (beef), and they observed in them the presence of high levels of α-Gal IgE (≥ 100 kA/L in two of them) while the control serum of an atopic subject having eaten chicken was negative for both α-Gal and beef. Moreover, Ixodes ricinus extracts inhibited patients’ IgE response. And finally cross-sections of tick intestine revealed the presence of mono and polyclonal antibodies against α-Gal.

The study authors conclude that it is the 1st time that the epitope was detected in the Ixodes ricinus gastro-intestinal tract. Moreover, red meat allergic patients have a strong IgE response to beef and α-Gal epitope but also a clear response to I.ricinus, regardless of this epitope. It is likely that in Europe, following global warming, an increase in the rodent and deer (tick vectors) populations may induce higher risks of meat allergy.

Comments and questions welcome:
*Pr. Claude Molina
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**Dr Jacques Gayraud
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Last updated 25 July 2014