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Claude MOLINA* & Jacques GAYRAUD**

1. Vitamin D and allergo-immunology
      1.1 In asthmatics
      1.2 Vitamin D and immunology
      1.3 The therapy
2. Is an explosion of food allergy cases to be feared ?
3. Egg allergy (E.A.)
4. Tiotropium and asthma poorly controlled with standard treatment


1. Vitamin D and allergo-immunology

Theme: Allergy physiopathology
Key words: Vitamin D, Severe asthma, Macrophages, Dendritic cells, T.Reg Fox p3. TGF β. IL 10 lymphocytes, Sunshine. Diet

A dozen recent publications have been dedicated to this theme, following the French Académie de Médecine’s full report on vitamin D (B.Salles, JF Duhamel et JC Suberbielle  Juin 2012). It appears that if 25 OHD (hydroxy derivative and vitamin stock marker) levels were measured, half the French population would be found to be suffering from either insufficiency (between 30 and 10 ng/ml) or deficiency (under 10 ng/ml). Admittedly there are regional disparities linked to sunshine, but some subject categories are more affected (the elderly, the obese, those with kidney failure, or immigrant or black-skinned populations, and veiled women).
Allergists may be confronted with variations in their patients’ vitamin status.


1.1 In asthmatics

Low levels are often associated with child asthma and its severity (J.M.Brehm et al AJRCCM  July 15 186 2 140-146). The authors studied 560 Puerto Rican children aged 6-14 (287 asthmatics and 270 controls, where 25 OHD blood levels were measured, and they investigated atopy, asthma evolution, lung function and genotypic data (search for African ancestry). Vitamin D insufficiency is statistically associated with severe, atopic asthma, (with markedly lower FEV1, and severe exacerbation the previous year) and independently of racial ancestry.

Another publication (A.C.Wu et al AJRCCM 2012 published online July 12) concerns a cohort of 1024 US children, participating in an asthma research programme, and divided into 3 groups according to their vitamin status : 65% normal (>30 ng/ml), 25% insufficient (30 to 20 ng/ml) and 10% deficient (<20 ng/ml). All subjects underwent FEV1 measurement and metacholine tests, before inhaled corticosteroid treatment. The detailed statistical study shows that deficient subjects are older, more often African-American, have a higher BMI and a much poorer lung function compared to the other two groups. In the same cohort (SM.Tse et al AJRCCM 2012 130 1 53-60) of 780 children aged 5-12, vitamin D intake at the same time treats the vitamin deficiency, enhances the anti-inflammatory effect of inhaled corticoids and minimises its adverse effects on children’s bone metabolism and growth velocity.

1.2 Vitamin D and immunology

It has been established that vitamin D modulates the way the immune system functions. As for innate immunity, it plays a stimulating role on macrophages and dendritic cells, which has above all be proven in experimentally but is becoming more and more obvious in children and adults as a preventive factor against viral or bacterial infections, be it among normal subjects or asthmatic children.

As for adaptive immunity, vitamin D may induce several types of T regulator Fox p3 TGFβ - or IL10- secretor cells. Thus, in corticosteroid-resistant adult poorly-controlled asthmatics, T.reg Fox p3+ levels are lower in the serum, in correlation with vitamin D deficiency and a low serum IL10 level, but vitamin D intake restores both the IL10 level and the efficacy of the response to corticosteroids (Chambers et al JACI 2012 1302 542-544).

It has also been shown that vitamin D has a protective role by preventing or postponing lung function decline in smokers (N.E.Lange et al AJRCCM July 2012 on line).

Even food allergy appears to be involved, depending on certain genotypes (KS Wimaleswaran et al Allergy 2012 in press). Thus, in carriers of IL4 gene C allele (present in 86% of Europeans, 26% of Chinese and less than 20% of Africans), vitamin D deficiency is associated with high levels of serum IgE and risks of food allergy for children.

1.3 The therapy

What results from all these data is that a vitamin status check appears necessary in a large number of our patients, with 3 possible treatments for deficiency: sunshine, diet and medication.
  • Sunshine brings vitamin D without causing over dosage, thanks to auto-regulation, as shown by the Tanzanian example, the average level of the  population of which being 46 ng/ml (or 115 mol/l).
  • Diet: an intake of 400 to 600 UI/d (800 to 4000 for children) is advised. It can be found in oily fish (salmon, cod, halibut) but also in eggs, milk, oysters, veal liver. JM.Bourre’s book (La chrono-diététique I vol O.Jacob 2012) provides a series of comparative tables of vitamin D content of foodstuffs.
  • Medication: 1 vitamin D dose = 1 mg = 40000 U, its  frequency depending on test results, but above all patients under corticosteroid treatment.


 
2. Is an explosion in food allergy cases to be feared?

Theme: Epidemiology, Food allergy
Key words: Food allergy, Genetics, Environment, Public health, Food industry

This is the crucial question to which the Australian authors (S.Prescott et al Ped.Allergy.Immunol 2011 22 155-160) give a positive answer, in a historical epidemiological paper.

Firstly they draw our attention to the fact that during the last 50 years of the 20th century they were the first to point to the “epidemiologic wave” which swept the Western world in the form of respiratory allergies: rhinitis, asthma, sinusitis.

Much research has been undertaken to try to explain this outbreak, successively and/or jointly incriminating the Western way of life, the diet and changes in intestinal bacterial flora, vehicular urban pollution, and above all environmental aeroallergens (dusts, dust mites, pollens,…) sensitising genetically-prone organisms (atopy).

This wave seems to have reached its peak around the year 2000 whereas it now affects emerging and developing countries, which are increasing adopting a Western lifestyle.

The authors point then to a second wave which is looming: that of food allergy which was relatively rare in Australia but which now affects more than 10% of children and may turn into a real ‘tsunami’ flooding countries which already suffered from the first wave, i.e. Australia, the USA, Europe.

Researchers must concentrate on identifying the etiological factors responsible, particularly genetic or environmental, and on discovering whether they are the same as in the first wave. However, for the governments of those countries concerned, these allergies are already the cause of a number of problems in public health and hygiene but also regarding the food industry which is required to identify the most frequent allergens such as milk, eggs or peanuts in everyday food products.


 
3. Egg allergy (E.A.)

Theme: Food allergy
Key words: Egg, Desensitisation

This is, in terms of frequency, the second food allergy after cow’s milk. It is known to affect infants as early as one year of age, with manifestations that may be cutaneous (urticaria), digestive, even respiratory or anaphylactic. Treatment is uncertain and avoidance is difficult to enforce and control.

Thus, a group of paediatricians from Madrid have recently analysed the circumstances of accidental reactions, 50% moderate and 8% severe, observed in 92 children of an average age of 4 and a half years, between 2004 and 2005 : ingestion of egg often hidden in cakes, sweets, mayonnaise. Besides, high IgE levels seem to be one of the risk factors. Finally, spontaneous regression of the allergy is observed with age: 26% at 8 years, 48% at 12, 68% at 16.

Two new publications are dedicated, each with its own protocol, to per os desensitisation, in a progressive manner and for several months.
The first one uses egg white powder, administered in 3 steps: the first, daily, taken in small but increasing doses, followed by a maintenance phase leading to the tolerance of 2g of powder (i.e. 1/3 of an egg) then a challenge at 10 and 22 months, confirming the desensitization and allowing the consumption of one whole egg (A.W.Burks et al NEJM 2012 19 July 233-243). This is a randomised survey, conducted in the USA over 5 different sites, and with 55 children aged 5-11, 40 active and 15 placebo. After 10 months of treatment, 55% of the active (vs none of the placebo) could be considered as desensitized. This proportion reached 75% at 22 months. A decrease, even a disappearance extinction, of positive of skin prick-tests was observed with them, reflecting the deactivation of mast cells and basophiles and the significant serous increase in IgG4s. The same subjects, examined again at 30 and 36 months, confirmed their egg tolerance.

The other publication, by Spanish authors, uses a liquid mixture of egg yolk and egg white: 1 drop at a 1:100 dilution, equivalent to 0.27 mg of egg protein, administered at home daily, the dose being doubled every 8 days, to reach in 6 months the dose of 25 ml corresponding to 3 hen’s eggs weekly (P.Meglio et al Ped.Allerg.Immunol 2012 september early view). 20 children (half with placebo) were treated that way, 8 out of 10 successfully and without adverse reaction. A very similar technique of  oral specific tolerance-induction  (Iride Dello-Iacono et al Ped All.Immun2012 September early view) in 20 Italian children, of an average age of 8 years, using egg in the form of emulsion led to similar results and equally conclusive immunologic tests.

 
4. Tiotropium and poorly controlled asthma with standard treatment

Theme: Asthma
Key words: Tiotropium, Non controlled asthma

Tiotropium (T), a long action cholinergic bronchodilator mostly indicated in COLDs, has not yet acquired full recognition in the treatment of asthma (A), although some studies, of limited duration,  already mentioned in these pages, have revealed an indisputable efficacy in some, more or less resistant cases of A.

The colossal survey which was recently reported to us (H.MKerstjens et al NEJM  2012  3 Septembre) concerns more than one thousand patients spread over 15 countries (except France) and several continents, and aims to associate T (Spiriva ®) with the standard treatment of severe A (inhaled corticosteroids and LABA of the Salmeterol type) in order to improve lung function and prevent exacerbations.

Two similar randomized studies, performed between 2008 and 2011, concern cases of A which have been known and treated for more than 5 years, in patients aged 18-75 (average 53) with FEV1 of 80% or less of the predicted value. Usual questionnaires on the quality of life and the satisfaction felt by the patient (7 or 32 questions) were handed out. All these subjects received the standard treatment plus T (two 2.5 µg/d puffs, i.e. 5 µg/d) through a soft-mist inhalator, Respimat. This treatment lasted 48 weeks interspersed with 9 visits and, after 11 months , a complete check up. The results were as follows:
In both trials a statistically significant FEV1 improvement is observed in the patients treated, of 86ml and 154ml respectively, that is to say a modest bronchodilation (less than 10%), but a sustained one which is appreciable in severe cases of asthma, and above all a decrease in exacerbations or a delay in their appearance (282 days vs 226) as well as a 21% reduction in the risk of a severe exacerbation.
As to the questionnaires’ scores, they did not reach the significance threshold, not surprising given the geographic spread of the surveys. The secondary effects were limited to some cases of mouth dryness. There were no deaths.

On the whole, T appears to be a non-negligible complement to the treatment of severe A, all the more that the possible alternatives are limited: theophylline or the modestly efficacious anti-leucotrienes, or omalizumab (limited to certain forms of A with high IgE levels) or else thermoplasty, an invasive method, not easy to apply to fragile subjects.


Comments and questions welcome:

*Pr. Claude Molina:

**Dr Jacques Gayraud: