Everything you wanted to know
" Have you got asthma?"


Claude MOLINA* & Jacques GAYRAUD**

1. Asthma and Hollywood
2. Periostin: a systemic biomarker of eosinophilic asthma
3. Latex immunotherapy
4. Sublingual immunotherapy (SLI) and cow’s milk allergy
5. Antioxidant (AO) diet and allergy

1. Asthma and Hollywood

Theme: Asthma
Key words: Asthma, Cinema, Inhaler, Stress, Will power

In a major paper (Asthma episodes, Stigma, Children and Hollywood. Med. Anthropol. Quarterly 2012 26 1 92-115) an anthropologist (from Chicago USA), C.D. Clark, addressed this issue by viewing 66 films up to 2008 that contained one or several asthma-related scenes, then by interviewing a dozen asthmatic boys and girls of 9-12 who had watched the most representative scenes, in order to record their reactions as well as those of non-asthmatic children of their age, generally their best friends. Since children in the USA spend an average 8 hours a day in front of a screen, 3 of those hours watching TV, it is easy to grasp the interest of such a psycho-sociological study.

The first notion that asthmatic children get from these images is that of stigmatisation; asthmatics in fact almost never inhabit the hero role, being rather relegated to secondary characters, often socially outcast. The second notion is the importance of the inhaler as a technological symbol of the disease, sometimes regarded as a way of safety but also as a social exclusion factor.

A deeper analysis of the films leads the author to distinguish 4 types of asthma-related episodes:

1) Asthmatics are weak, set-aside characters; in Toy Story 2, Wheezy the asthmatic penguin which has a broken squeaker, seems destined for an imminent yard sale, before being rescued by Woody the hero.

2) Asthma is a stress response (47% of cases); in Goonies, a teenage favourite, Mikey, one of the 4 boys in search of treasure, suffers an attack after an intense encounter with pirates and has to use his inhaler; many ‘suspense’ scenes confirm this notion.

3) Asthmatics show their will power by overcoming their crises and rejecting their inhalers (3% of cases), a sign of protest against the usual stereotype.

4) More rarely, asthma is used as an offensive medium; in Jimmy Neutron the young asthmatic uses his inhaler as a weapon to scare off the enemy.

Generally speaking, Hollywood does not have a glorious history of social responsibility vis-à-vis asthmatic children, who are often victims of mockery and/or marginalisation, something they are find unacceptable and call upon filmmakers to present positive connotations when filming their handicap.

2. Periostin: a systemic biomarker of eosinophilic asthma

Theme: Asthma
Key words: Steroid-resistant asthma,  Eosinophilia, Periostin, IL13

Eosinophilic (E) asthma (A) is a particular phenotype of A, often severe, but sometimes responsive to inhaled corticosteroids (ICs). It is difficult to diagnose because neither blood nor sputum eosinophilia are reliable enough, and the invasive procedures of pulmonary aspiration or lavage are not easy to perform under normal conditions. Thus, clinicians are looking for a non-invasive, if possible blood-based test. Dosing serum Periostin seems to be the answer (G.Jia et al JACI 2012 August on line).

It should be recalled that EA results from Th2 type airway inflammation, induced by IL4, IL5 and IL13 cytokines. While the role of IL4 is well known in atopic asthma, that of IL5 and IL13 are not and anti-IL5 medications have not established their efficacy. But higher levels of IL13 have been observed in the airways of an EA sub-type and the authors have shown that 3 genes are clearly expressed in the lung epithelium and induced by IL13: Periostin, the secondary protein of CLCA1 chlorinated canals, and Serpine B2. In doing so, they define a type of asthmatic population characterised by eosinophilia, lung remodelage, and sensitivity to ICs, but with no connection to atopy.

Periostin (P) is a matri-cellular protein, secreted and detected in the sub-epithelial layer of the bronchial mucosa and correlated to the thickening of the basement membrane ; it is also overexpressed in nasal polyps and in allergic oesophagitis. It can be measured in serum.

The authors then followed 67 IC refractory (+1000 µg/j) adult asthmatics with  FEV1≤60% of the predicted value, for 5 weeks. At the same time they measured eosinophilia of blood sputum and broncho-alveolar lavage, as well as blood markers (P. IgE, YKL-40, a Th2 marker) and FE NO. It appears that P. is the best indicator of airway eosinophilia, and its high  level (over 25 ng/m) is statistically correlated to the severity of eosinophilia  and  resistance to ICs.

Admittedly, in moderate As, ICs do bring down the expression of the whole set of Th2 markers, but they prove insufficient in severe A. On the contrary, the monoclonal antibody Lebrikizumab, specifically anti IL13, as tested with 218 EA, has shown efficacy, particularly in high serum P. level Asthma: QED.

What is happening is a differentiation of EA with an IL13 induced sub-type. This is a typical example, and an important step in the ever more accurate profiling of A treatment.

3. Latex immunotherapy

Theme: Specific immunotherapy, Allergens
Key words: Immunotherapy, Sublingual immunotherapy, Latex

A general overview of this theme has just been conducted, based on all the publications in English of the past 12 years (E.Nettis et al Annals of Allergy, Asthma, Immunol 2012 160-165).

It should be remembered that this allergy does not only concern healthcare workers using latex articles (gloves, catheters, among others) but also hairdressers, gardeners, patients undergoing multiple surgery (spina bifida or other congenital malformations), as well as  users of everyday products such as teats for baby bottles and sports equipment.

The principal allergen is derived from Hevea Brasilensis: Hev bl, followed by 13 other minor allergens, the clinical manifestations concerning mainly the skin (urticaria or contact dermatitis), more rarely the airways or the eyes, and total avoidance is difficult.

The immunotherapy trials, strictly selected according to a number of validity criteria (double blind trials with placebo controls), included 3 subcutaneous (SCI) and 8 sublingual (SLI), of which 1 by the authors themselves.

The first serious study was that by Leynadier and colleagues (in 2000) among 17 doctors and nurses, treated with Stallergen ® extracts, progressively reaching a maximum tolerated dose of 1 to 2 µg kept constant for 1 year. The comparison of the beneficial effect among the Placebo group is clearly in favour of the treated group, but there are more local and general side-effects.

Two other studies, one Spanish (Sastre) and one Italian (Tabar), both carried out in 2006, end up with similar conclusions, but the risks incurred have led the allergists to virtually abandon this type of administration.

The sublingual route (SLI) is also justified by the fact that the oral mucosa, highly vascularised, contains a large number of antigen-bearing cells and few inflammatory ones, which establishes its innocuousness.

Finally, the whole set of trials only concerns 200 patients treated with Stallergen extracts or ALK Abello, among them twenty children aged 4 to 15. With the latter, the use of 2 drops/day of a 40 µg solution for one year, has been remarkably successful, with no side-effects over the next 3 years. This dosage is insufficient for adults, for whom the beneficial effect appears with a maintenance dose of 300 to 500 µg/week, producing some benign local or general reactions. Very long-term effects remain to be investigated, but SLI is still a possible alternative, albeit to be used with caution, and pending  new approaches to immunotherapy (recombinant allergens).

4. Sublingual immunotherapy (SLI) and cow’s milk allergy

Theme: Immunotherapy, Food allergy
Key words: Sublingual immunotherapy, Cow’s milk, Specific IgE, Prick tests

Cows’ milk allergy (CMA) is the most frequent food allergy in children, and strict avoidance is for the time being the only method advised, before spontaneous regression in 70% of cases at the age of 3. SLI is currently under investigation.

Between 2006 and 2011 the Barcelona team of paediatricians (M.Vazquez- Ortiz et al: Clin.Exp.Allergy 2012 September on line Accepted articles) therefore undertookon a study of 81 children aged 5 to 18, all suffering from clinically-confirmed CMA (Sampson severity score), skin prick-tests, specific IgEs and prick tests. The Committee of Ethics-approved technique included an induction period of 16-week in hospital, with hourly administration of 1, 2, 4, 8, 16 ml of milk (diluted 1:100 on the first day, then 1:10 + 2.5 ml non-diluted on day 2) and every day for one week, then with progressively increasing doses, in consultation every week, reaching the tolerated dose of 200 ml cow’s milk. All these subjects were followed up over an average 2 years.

60 of then (75%) were considered as desensitised (1 case in 5 still presenting some minor temporary reactions)

20 others had more or less severe and unpredictable reactions which persisted in spite of the treatment and have driven 6 of them to stop the immunotherapy.

The authors mainly focused on these latter cases in order to try, through probability statistics (Kaplan-Meier), to define their profile in order to detect the factors responsible. Over and above a number of co-factors (exercise, emotion, NSAI intake, infection), it appears that 3 main bio-clinical, independent factors emerge from the multiple regression statistical models, i.e.:
1) The persistence of IgE ≥50 UI,
2) The size of prick-tests ≥9 mm, and
3) The baseline clinical severity, broken down into 5 grades.
The combination of 2 or 3 of these factors induce a risk of reactions, of 2.26 (95% CI, 1.14-4.46 p=0.019) and 6.06 (95% CI, 2.7-13.7 p=0.001) respectively.

The authors can conclude that SLI, still an experimental method, is efficient and harmless in 75% of the subjects. Nevertheless before undertaking it is necessary careful analysis of the predictive factors of hazardous side effects, in order to detect from the start the subjects for whom SLI is contra-indicated. The absence of a control group in this study must not obliterate the sound personal clinical experience of these paediatricians and the large number of statistics presented in their research.

Finally it seems worth noting the possible interest of measuring MIP-1α and MCP-1 chemokines as efficacy markers of the desensitisation to cows’ milk (P.Poza.R.Glez NEJM 2012 367 282-284).

5. Antioxidant (AO) diet and allergy

Theme: Physiotherapy, Atopy
Key words: Diet, Antioxidants, Allergy, Magnesium

Since the hygiene hypothesis, the role played by the Western way of life, and particularly its diet, has often been pinpointed.

It is well known that immunological surveillance of the organism resorts to a defence system using oxygenated radicals which destroy foreign cells. Adopting an antioxidant diet to strengthen the natural AO system seems all the more logical since the latter is based on the type Th1 immune response, itself being likely to foster a chronic inflammatory process through NF-κB et du TNFα.

Major AOs are found in fruits and vegetables (which contain β-carotene, α-tocopherol and vitamin C) as well as in meat and milk (where magnesium and zinc predominate).

The Swedish authors (H.Rosenlud et al Clin.Exp.Allergy 2012 42 1491-1500) wanted to study the relationship between AO intake and allergy by using the data from a cohort of 4489 children followed since birth.

2242 of these, boys and girls of an average age of 8, were enrolled in this study, which included a personal and parental questionnaire (2614 families answered) as well as a dosage of common allergen IgEs. The questionnaires were very detailed and precise as regards food intake frequency (taking into account the basic data of the National Food Agency and also the qualification of allergic diseases), and contained 98 items. Their validity was confirmed by Spearman correlation consisting in comparing answers after several (up to 14) repeated questions.

Gross results show a statistically significant, inverse association between intake of β-carotene and rhinitis and between asthma and magnesium, and also between magnesium and atopy. Continuing their survey, they excluded 285 children who had mentioned previous signs of allergies (including cross-allergies, such as apple and birch pollen), and results become less significant with only the inverse association between asthma and magnesium remaining. Despite the large number of participants, which lends indisputable weight to this study, it has been the target of some criticism, mentioned in the editorial of the same journal (D.Fuchs 1491-1500) and above all the unexpected lesser role played by AO intake in the epidemiology of allergic diseases. Besides, the food industry by adding - without informing the consumers - vitamins such as vitamin C, preservatives such as sulphites, and colouring agents, all of which are AOs, is likely to provoke an inverse consequence: “antioxidant stress”. Which means that, in terms of diet, common sense must be the rule.

Comments and questions welcome:

*Pr. Claude Molina:

**Dr Jacques Gayraud: