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Claude MOLINA* & Jacques GAYRAUD**

1. The allergist faced with HIV and AIDS
2. Specific IgEs and molecular allergens
3. Urinary leukotriene E4 in asthmatic children exposed to passive smoking
4. Anaphylaxis to Argan oil
5. Two new monoclonal antibodies in asthma treatment : Lebrikizumab (anti-IL13) and Reslizumab ® (anti-eosinophil)


1.  The allergist faced with HIV/AIDS

Theme:
Immunodeficiency
Key words: HIV, AIDS, allergic rhinitis, adverse drug reaction, skin manifestations, asthma, chronic bronchitis

The use of highly active antiretroviral treatments (tritherapy: i.e nucleoside reverse transcriptase inhibitor: NRTI + non-NRTI + Protease inhibitor) has completely modified HIV infection prognosis. Whereas the life expectancy of AIDS syndrome used to be less than 10 years, HIV-infected patients live over 25. This means that affection has practically become a chronic illness, with more complications or co-morbidities like allergic manifestations. This is the theme of a recent review based on 62 references (Medline) and published in the Annals of Allergy, Asthma & Immunology (S.C Stokes and M.S Tankersley 2011 107 July 1-9).

Already before the era of tritherapy, some symptoms were noted in the course of AIDS, suggestive of allergy such as higher serum IgE levels (in inverse correlation to CD4+ cell count) or rhinitis, rhino-sinusitis, symptoms becoming rarer as HIV developed into AIDS. Adverse reactions to drugs such as Bactrim ® (Trimethoprim-Sulfamethoxazole) and Abacavir (a NRT) were also observed.
With antiretroviral therapy, the situation has completely changed.

True, the most serious complications needing to be monitored during the first months of treatment, remain the opportunistic diseases, lipodystrophy, renal, neurologic or psychic (nightmares) and cardiovascular complications, but allergic skin manifestations are appearing, as well as respiratory syndromes akin to bronchial hyper-reactivity and asthma, accompanied among smokers, by risks of chronic bronchitis, all symptoms possibly linked to immune reconstitution, which the allergists and pneumologists must take into consideration. The use of vaccines against influenza, measles or chicken pox can now be even envisaged in asymptomatic HIV infected children under treatment.                          

Finally, let us not forget the ongoing research for new better tolerated antiretroviral drugs such as rilpivirine (JM Molina et al  Lancet July 2011 378 9787 238- 246) which is proving as efficient as efavirenz, non-NRTI, one of the ‘pillars’ of tritherapy.


2.  Specific IgEs and molecular allergens

Theme: molecular allergy / specific IgEs
Key words: CRD (Component-resolved diagnostics), Micro-array ISAC, Advia Centaur

Hitherto specific IgE detection techniques were based on total allergenic extracts, i.e. on the allergen source. Recombinant DNA technology makes now possible to reproduce purified allergens in large quantities and at a reasonable cost, and to identify the individual molecules to which patients are sensitised. These molecular diagnosis methods (component-resolved diagnostics, CRD) are clearly explained in three articles of the June 2011 15-20 CIAB, respectively by H .Chabane, V.Doyen,  and J.Vitte, as well as in the Annals of Allergy,Asthma & Immunology 107 July 201135-41 (M.T Lizaso et al). This could lead to more accurate diagnoses, better immunotherapy indications, and also offers an explanation of cross-reactions between airborne and food allergens (e.g. birch / apple)and to definitely rule out non-IgE related Allergy.

The most current technique, and currently the only one available in France (although not yet covered by Social Security) is the micro-array technique, which simultaneously tests a range of allergens on a glass surface and in the form of micro spots. This is known as a biochip which, thanks to the ISAC concept (Phadia ® : Immuno-Solid-phase Allergen Chip), maps a large number of natural and recombinant molecular allergens on a 1cm2 chip. Other techniques (Avia-Centaur) detecting individual allergens, are being developed and improved, and compared with usual IgE dosages.
Thus, out of the 103 allergens identified on the ISAC biochip, 36 were not available in individual detection; and in comparison with the traditional ImmunoCAP, the ISAC technique may be less reliable for dust mite allergy. By using the Advia-Centaur technique for pollen allergy, the diagnosis was modified in 30% of the cases, through either the detection of new sensitisations (to Olea for instance), or the ruling out of those irrelevant to clinical data and skin tests. Moreover, some allergenic sources were absent: nuts, vegetables, some milks, plantain for ISAC, cypress for Advia-Centaur.
Finally, according to R.C.Aalberse & R.Crameri (Allergy 66 2011 1131-1132t ahead of print 02/08 2011), the range of IgE epitopes is so vast that it would be illusory to pick just one of them as a realistic target for diagnosing or treating an allergy.
All this means that these new techniques, albeit representing a breakthrough in the biological diagnosis of allergy, must be reserved for multiple or IgE-related allergies, or when molecular profiles are not available for unit identification, or even for non-elucidated anaphylactic shocks. In any case, the results must be interpreted in the light of clinical, biochemical, immunological data, and must take into account the relevance of the diagnosis. This is another case for calling to collaboration between biologists and clinicians.


3.  Urinary leukotriene E4 in asthmatic children exposed to passive smoking (PS)

Theme: children’s asthma
Key words: leukotriene LTE4, uLTE4 (urinary leukotriene), asthma exacerbation

A group of US paediatricians from Denver (N.Rabinovitch et al JACI 2011 128 2 August 323-327) thinking that asthmatic children exposed to PS were running the risk of severe exacerbations, have been looking for useful and convenient biomarkers for testing sensitivity to this environmental factor. LTE4 urinary dosage was used for this purpose. 44 children suffering from moderate to severe asthma and being treated with inhaled corticosteroids (ICS) were monitored for 5 months with repeated urinary LTE4 measurement, PS was revealed by preliminary questionnaires and repeated measurement of urinary cotinine, and asthma exacerbations were counted by emergency hospital consultations (EC) or intensive care hospitalisations (IC).

The results were as follows :
-    9 out of the 20 PS-exposed children (45%) did suffer exacerbation of their asthma requiring EC or IC, compared to 3 of the 24 not exposed to PS (12.5%), i.e. a relative risk of 3.6 (95% IC 1.1-11.5 P=.02).
-    uLTE4 was a significant predictive factor of exacerbation risk in PS-exposed children (area under the curve 0.85 P=.003). Other factors such as the frequency of nocturnal symptoms, the pre- and post-bronchodilation pulmonary function, or  expired NO, were unrelated to exacerbations.
-    As to uLTE4 levels of 106 pg/mg and above, they revealed 67% sensitivity (6/9) but 100% specificity (11/11).
In conclusion, asthmatic children exposed to PS run a higher risk of exacerbations and the urinary LTE4 levels constitute, despite the use of ICS, the most reliable predictive factor.


4.  Anaphylaxis to argan oil

Theme: particular allergen
Key words: argan oil, argan bush, oleosins

Argan oil is extracted from nuts contained in the fruits of the argan tree (Argania spinosa of the Sapotaceas group), which grows in arid or semi-arid zones of south-western Morocco ; oil is extracted by heating, roasting and pressing the nuts according to ancestral processes and is traditionally used locally for its cosmetic but also medicinal and nutritional properties.         

The observation reported has already been published and summarised in Allergy Net (2010 65, 662-63Astier et al), but it was developed more recently by Y.El Alaoui (Journees Pneumo-allergologiques d’Agadir, organised in collaboration with Cefcap in June 2010). The case is that of a 34 year old man, without allergy history, who suffered from rhinitis and conjunctivitis when smelling argan oil ; the ingestion of the oil also induced hypersalivation and epigastralgia.

The prick tests to argan paste (residue after oil extraction) were positive and after a few minutes provoked generalised erythema and urticaria as well as pharyngo-laryngeal discomfort. Proteins extracted from the oil were analysed by SDS-PAGE and IgEs by immunoblotting and immuno-competition in contact with the patient’s serum. Oil electrophoresis revealed a protein profile close to that of the argan fruit stones, and serum IgEs recognised a 10KDa band which disappeared after inhibition with extract of the nuts. These proteins probably belong to the oleosin family, known to be powerful allergens like those described for peanut or sesame.
This first case should attract our attention, as argan oil is used more and more frequently, locally where the price is rising but also in the West and the Far East, without forgetting the many tourists who visit Morocco. Its unsaturated fatty acid profile has made it attractive from a nutritional point of view.

The argan tree is 8-10m high and lives for an average of 250 years. It is generally estimated that 100 kg of fruit and 8-10 hours of work are necessary to obtain 1 to 1.2 litres of oil. Three types of producer can be distinguished : individuals (i.e. village women using traditional methods), cooperatives (of which there are over 40, using more or less mechanised extraction), and private industries (set up in Casablanca and which only buy nuts or kernels).

Attention should also be drawn to the need to further refine the oil, a step likely to inhibit its allergenicity.


5.  Two new monoclonal antibodies in asthma treatment : anti-IL13 Lebrikizumab (L) and anti-eosinophil Reslizumab (R)

Theme: anti asthma treatment
Key words: anti IL13 Lebrikizumab, anti eosinophil Reslizumab, asthma, uncontrolled asthma, cytokine IL13, periostin, FEV1

Two simultaneous articles, one from the USA (J.Corren et al NEJM 2011 August 3), the other from Quebec and  USA  (M.Castro AJRCCM 2011 August 18), have been focusing on asthma which are poorly controlled by Inhaled Corticosteroids (ICS).

Type-Th2 IL13 cytokine plays a part in the allergic asthma mechanism, but, while ICS theoretically inhibit its production, large quantities of it are found in sputum from uncontrolled asthma, which could account for resistance to corticoids. Besides, IL13 induces the secretion by bronchial epithelial cells of a protein of the extra-cellular matrix: periostin (P), which causes the production of mucus and acts upon fibroblasts, thus capable of intervening in bronchial remodeling. L is an anti-IL13 IgG4 humanised monoclonal antibody, and the authors of the article made use of serum P as a marker of its activity, easier to dose than IL13.
219 randomised patients, presenting high levels of IgE (?100 UI/ml) and eosinophils (?0.14?109) which revealed a Th2 status, were treated by a monthly injection of 250mg of L (or Placebo) for 6 months.
-    After 3 months, FEV1 was 5 points higher than that of the placebo group (P=.02) and 8.2 points higher for the high P-rate group. But, the number of exacerbations at the 6th month was no different from the placebo group.
-    From a biological point of view, the decrease in IgE level and Th2 chemokines (CCL13 and CCL17) proves the efficiency of L. Side effects were musculoskeletal, generally benign.

The anti-IL5 monoclonal antibody R was applied to eosinophilic asthma :
53 patients and as many placebo patients received infusions of 3mg/kg over 15 weeks. In addition to significant reductions in the number of exacerbations (P=0.083), a modest FEV1 increase was observed, particularly among subjects also suffering from nasal polyposis. Adverse effects were mostly naso-pharyngo-laryngeal and the treatment was well tolerated on the whole.

Thus, a breakdown of asthmatic disease into several phenotypes is on its way, with therapy aiming at different targets : IgEs with Omalizumab (Xolair®), IL13 with L, eosinophils with R. But these treatments are heavy, costly and not without long-term risks. They should be reserved for particularly difficult cases.

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Comments and questions welcome :

Pr. Claude Molina    and/or    Dr Jacques Gayraud
* **