Claude MOLINA & Franz MARRACHE

• Vitamin D, allergy and asthma

• Specific Immunotherapy (SIT) in the US and in Europe

• Do anti-IL4 medications have a future in allergy ?

• High resolution CT scans and severe asthma

• New allergens coming from China

Vitamin D, allergy and asthma

Since the discovery that a great number of cells express vitamin D receptors, the beneficial role of vitamin D in many diseases has been recognized, apart from its classical role in skeletal conditions :they include cancers such as colorectal cancer, and cardiovascular, neurological or autoimmune diseases. What about asthma and allergy ?
It is well-known that low maternal vit.D intake during pregnancy has been associated with an increased likelihood of childhood eczema and asthma.
It is also accepted that 90% of human’s vit.D stock comes from sunlight exposure and 10% from food intake. 
1) However J.M.Brehm (AJRCCM 2009 179 765-771) observes that out of 616 asthmatic children living in Costa Rica, a supposedly sunny equatorial country, 175 (28%) show vit.D insufficiency (≤ 30 ng/ml.), itself associated with an increase in the rate of serum IgE , number of eosinophils as well as airway hyper-responsiveness. That is to say that deficiency in vitamin D can be associated with the markers of asthma severity.
2) The beneficial role of vitamin D on lung function and on adult asthma responsiveness to steroids is also backed up by figures in T.G. Rand Sutherland’s excellent study (AJRCCM 2010aheahd of print 14 January) on 54 adult asthmatics, for whom any increase in vit.D level is associated with a significant proportional increase in FEV1 and with the expression on the peripheral blood mononuclear cells of the MKP-1(MAP kinase-phosphatase) induced by dexamethasone. The conclusion is that supplementing vitamin D levels in patients with severe asthma may be useful and improve responsiveness to steroids.
3) This is also the opinion of P. Majak’s Polish group (Clinical Experim.Allergy 2009 39 12 1830-1841) who notes that associating vitamin D3 with steroids increases the efficiency of specific immunotherapy in children.
4) In fact, as mentioned by G. Devereux (AJRCCM 2009 179 739-740), it is all a question of dose, since some authors think that high levels of vit.D intake during childhood increases risks of atopy and asthma in adult life. Therefore, as sunshine, which is useful against rickets or osteomalacia, cannot alone play a therapeutic role, it is necessary to recommend optimal doses of vit.D (200 to 400 UI/d i.e. 5 to 10 µg) while avoiding overdosing which inhibits its anti-inflammatory properties expressed through IL10 and T regulators.

Specific Immunotherapy (SIT) in the US and in Europe

Comparing the use of Specific Immunotherapy (SIT) in the US and in Europe (Linda Cox et al. – Annals of Allergy, Asthma and Immunology, Dec 2009, Vol 103, pp451-495 ) shows that, despite a few fundamental similarities, there are substantial differences between the two continents.
In the US, regulation is carried out by the Food et Drug Administration (FDA).
In Europe it is the European Medicine Agency (EMEA) which issues EU marketing authorisations (MAs) and competent national authorities for single-country MAs.
On the other side of the Atlantic, standardisation methodologies depend on the Centre for Biological Evaluation and Research (CBER) : the biological activity of an extract is titrated through intradermal skin tests in a cohort of highly allergic individuals. After dilution, the extract is scaled in active biological Units : BAU (100,000, then 10,000).
The activity potential indicated corresponds to the extract’s overall allergenicity.
In Europe the so-called northern technique, the prick test, is used, and the reference is the extract dilution which produces a reaction equal to that of the histamine control. The targeted allergenicity potential is that of the major allergen. As for Units, they are company-defined, some directly expressed in mg of major allergen.
In the US, the therapeutic extract formulation is done by allergists in their offices. It is multiple for the same bottle.
In the EU, formulation is performed by the extract manufacturer and generally includes only one allergen. It is often, but not always, named-patient: 95% of cases in France, over 50 in Spain, 25% in Germany and almost 0% in northern Europe.
Extract types are similar in both continents : either non-modified, water and glycerine based, or alum precipitated depot extracts, with a clear predominance of depot extracts in Europe (20 % for allergoïds, under 5 % for products with adjuvants.
Administration routes : the sublingual mode (SLIT), using drops or tablets, has taken root in Europe (45 % of the prescribed SIT), but remains rare in the US (5.9 %).
SIT reimbursement : considered as a medical act by the US government and the private insurance companies, prices are being negotiated nationwide, while this negotiation in the EU varies according to companies and states.
As a conclusion, and beyond the differences observed on both sides of the Atlantic, it is important to keep in mind that the absolute lack of uniformity between the different extracts, at the different stages of their fabrication, in Europe as well as in the US, practically forbids all bioequivalence between two products marketed by different companies.

Do anti-IL4 medications have a future in allergy ?

In November 2007 we already analysed the work of Wenzel et coll. (Lancet 2007 370 1422-1431) on Pitrakinra, a recombinant protein derived from human IL4 that binds to IL4Rα, and acts as a competitive antagonist of cytokines IL4 and IL13. It is active by subcutaneous administration on the immediate reaction triggered by allergen challenge, and by inhalation , mainly on the delayed reaction.

1)    In an experimental randomised study with monkeys on the basis of an Ascaris suum allergic asthma model, A.Tomkinson et al (Allergy 2010 65 69-77) look for the product’s action site and observe the same significant decrease in allergen-induced  bronchospasm whether allergen is administered subcutaneously or by inhalation, the latter being active even in absence of a significant drug blood rate. The drug has no effects on eosinophilia, thus dissociating airway hyperresponsiveness from eosinophils, the causative effect of which was hitherto taken for granted.
This innovative drug, developed from biotechnology and acting on a main component of asthma, deserves, according to the authors, new clinical tests.

2)    Another antagonist of IL4 Rα , a monoclonal antibody, AMG 317, which blocks IL4 and IL 13 pathways, was the subject of an experiment by J.Corren (AJRCCM 2010 ahead of print 7 january) on 73 asthmatics (compared to 74 control) treated once a week for 12 weeks (75-300 mg).
The first objective, i.e. the symptom score obtained with the classical Asthma Control Questionnaire (ACQ score), did not reveal any significant drug action.
The 2nd objective, i.e. the number of exacerbations and the timing of their occurrence, did show some improvement albeit with no statistical significance, whereas 3 severe adverse events were observed with no relation to the product.

This disappointing conclusion draws again our attention on the complexity of asthma and the little efficacy to be expected from targeting only one of the many components of the disease.

High resolution CT scans and severe asthma

The work of the English S.Gupta team rightly draws our attention to the interest of High Resolution CT (HRCT) scanning in the management of severe asthma (Chest 2009December 6 136 1521-1528).
Between 2000 and 2006, among 463 patients in their specialised hospital, 175 underwent a detailed qualitative analysis of their observed HRCT scan abnormalities, taking into account the statistical interobserver variability. By confronting them to the clinical data, 3 kinds of abnormalities were observed : bronchiectasis (BE), bronchial wall thickening (BWT) alone or in combination, and emphysema (E).

80% of subjects presented one or more abnormalities : BWT (62%), BE (40%) and E (8%), with a substantial interobserver agreement (the radiologists being themselves unaware of the clinical data).

Comparing results and patient types shows that those who underwent HRCT scanning were older, had longer disease duration, had poorer lung function, were receiving higher doses of corticosteroids, and had increased neutrophilic airway inflammation ; ultimately, the FEV1/FCV ratio emerged as an important predictor for both BE and BWT but had poor discriminatory utility for subjects who did not show radiologic abnormalities.

As a conclusion, the authors believe that only HRCT scans can reveal important bronchial wall changes during asthma and that asthma specialists should not neglect this efficient, radiologic technique, mainly in severe forms of the disease.

New allergens coming from China

The Chinese restaurant syndrome is well-known, i.e. the intolerance to glutamates used as taste enhancers. Now, in the wake of globalisation, there appear Chinese allergens, hitherto hardly known.
Here are, as example, some observations reported at the French Society of  Dermatology  8-12 December 2009 :

1) An  Angioedema following the intake of a Chinese pomelo (M.Guillet, from Poitiers) by a 42 year old woman, having a history of allergy to sea food, and for whom only fruit pulp prick-tests were positive. This is a new allergy to a citrus variety (oranges, lemons, mandarins) belonging to the rutaceous family which includes : the grapefruit, a very large, thick-peel fruit originating in South East Asia (Citrus maxima), the pomelo, a grapefruit and orange hybrid, sweeter and with a thin peel (Citrus paradisi) and the Chinese pomelo or shatian pomelo, an easy-to-prepare, newcomer among products from overseas.

2) Contact dermatitis in subjects having used armchairs made in China. This matter had raised some scepticism among medical circles despite widespread media coverage. In fact, as shown by the 3 cases reported by Munsch et coll (Toulouse), the dermatitis is caused by contact with dimethylfumarate, an antifungal substance widely used in China and injected as powder into the sofa and armchair upholstery ; the severe inflammatory lesions which can present aspects of lichenoïd, lymphoma, or even fungoid mycosis (Grange-Prunier), should be recognised by dermatologists and allergists who more and more often have to be familiar with foreign food and household products.


Source: CEFCAP
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