Claude MOLINA & Jacques GAYRAUD

1.    Allergy to nickel : recent advances
2.    Remission in asthma
3.    Prediction of occupational asthma among apprentices
4.    Conjunctivitis mechanisms during allergic rhinitis
5.    Anti-cholinergic agents and asthma treatment

Allergy to nickel : recent advances
As Pr Marc Rothenberg aptly recalls (Nature Immunology 2010 11 781-782), among the heavy metals nickel (Ni) is the chief driver of allergic contact dermatitis: the usual vector being jewellery (bracelets, rings, ear-rings), the victims are mostly feminine, but they now include bearers of cardiovascular stents, and of dental or orthopaedic implants. Finally cellular phone users also appear extremely vulnerable, to the point that the author with humour says that he is hesitating between Blackberry and iPhone.
It is a fact that Ni2 (salt or ion) induces a delayed-type hypersensitivity with stimulation of dendritic and endothelial cells ; but the specific receptor (or binding protein)  has not been identified so far, by lack of an experimental model (mice are not nickel-reactive). But Schmidt et al’s recent study (Nature Immunol 2010 11814-819) has identified the Toll-like receptor 4 (TLR4) as the exclusive receptor for nickel and has located its binding region by presenting a model using human endothelial cells. It appears that Ni2, an inorganic ion, directly impacts the TLR system, inducing the production of inflammatory cytokines by means of activated NF-κB. But human TLR4 alone is sufficient to ensure reactivity to nickel regardless of other TLRs (human or murine). Moreover, the authors have identified within TLR4 the amino-acids responsible for the inflammatory reaction (369-616). Finally two histidines (456 and 458) located at an optimal distance to interact with ion Ni²+, are necessary to activate NF-κB (their introduction by transgenesis, within the mouse’s inefficient TLR4), provokes the reaction to nickel. Indeed, LPS (lipopolysaccharides) also activate the TLR system, but the authors show that the Ni2 binding region is distinct, thus suggesting the possibility of treatment targeted on this human TLR4 specific site, without affecting the other vital immune responses.


Remission in asthma
As recently underlined by a group of Dutch researchers (Martine Broekema et al : AJRCCM 2010 Septembre a.o.p doi10.1164) remission in asthmatic subjects can be of two main types : either outgrowing symptoms even without treatment in spite of the persistence of underlying inflammation (clinical remission); or total absence of airway obstruction and bronchial hyperresponsiveness (complete remission).
165 asthmatic subjects were thus monitored and the authors noted 18 complete remissions (CoR) for at least 3 years, 44 clinical remissions (ClinR) without treatment for at least 12 months, compared to 103 current asthmas (CuA) of which 64 were treated by inhaled corticosteroids (ICS) and 39 were not.
In all subjects the following were measured : inflammatory cells in blood and sputum, histamine and ECP rates in sputum, lung function with bronchial hyperreactivity (BHR) and bronchial biopsies : remodelling (basement membrane thickening, collagen deposition), epithelial changes and Eosinophil Peroxydase (EPX) immunopositivity,  indicating eosinophilic activation.
The results are the following : blood eosinophil rates are statistically lower from CoR than from CuA, and above all bronchial EPX immunopositivity is significantly lower in CoR than in ClinR and CuA. By contrast, basement membrane thickening is similar in all groups (somewhat lower with ICS users) ; the atopic level measured by the Phadiatop score is higher with CuA than with CoR or ClinR.
The conclusion of this major work is that remission is always, even when it is complete (CoR), accompanied by basement membrane thickening, and that only activation of eosinophils (and not just their quantity) best differentiates the 3 groups, thus revealing its importance in the clinical expression and severity of bronchial hyperreactivity.
These observations are similar to those made by the Quebec Hopital Laval Group (J.Chakir et al : Europ.Resp.Journal 2010 35  48-53) who also insisted on the importance of sputum eosinophils as a target for asthma treatment strategy, and pointed to the persistence of collagen deposition and bronchial remodelling in spite of treatment.


Prediction of occupational asthma among apprentices
A French group bringing together INSERM researchers, Nancy university-hospital staff and Rennes Public Health Services has tried to evaluate the incidence on bronchial hyper-responsiveness (BHR) in baker, pastry maker and hairdresser apprentices by studying the variations over time of the level of exhaled nitric oxide (FENO), a well known marker of airway inflammation in asthma (P.Tossa et al AJRCCM 2010 182  738-744).
441 apprentices – 161 bakers and 111 pastry makers, mainly male, and 169 hairdressers, almost entirely female, averaging 17.5 +/- 1.4 years of age – were thus examined from the beginning of their occupational exposure, then 6, 12 and 15 months later, through clinical and lung functional tests, particularly metacholine challenge (to detect BHR) and measurement of FENO, as well as skin prick-tests for common and specific occupational allergens, and via a standardised questionnaire. 351 of them completed the study.
It appears that the increase in FENO level since the beginning of the training is statistically associated with the incidence of BHR, both in atopic and nonatopic subjects, and with no relation to past or current smoking habits or training track. It should be noted that bakers’ atopy to allergens (high molecular weight allergens) and hairdressers’ sensitisation to persulfates (low molecular weight) were also independently associated with the incidence of BHR. The latter also occurred sooner among bakers apprentices than among hairdressers but its incidence levelled off later. Indeed BHR can exist without asthma and vice-versa, but it constitutes a very important risk factor.
As a conclusion, regular measurement of FENO, a simple and reproducible test seems useful among workers newly exposed to asthmogens agents, and helps to avoid occupational asthma by early screening of bronchial hyperresponsiveness.


Conjunctivitis mechanisms during allergic rhinitis
It is well known that allergic rhinitis is associated in 70% of cases with a conjunctival reaction in the form of oedema, ocular pruritus and lacrimation. But the mechanism of this conjunctival inflammation is not clear. Some suggest  direct exposure to allergen (in case of pollen for instance), some evoke a systemic immunological reaction through inhalation of allergen, and others a neural mechanism by naso-ocular reflex through a chemical mediator such as substance P.
To explain this phenomenon, a group of Belgian and British ENT specialists (I.Callebaut et al :Allergy 2010 65 1173-1181) submitted twelve grass pollen allergic subjects to a series of extra-seasonal  provocative tests. Instead of the usual nebulisation or spraying, thus avoiding direct exposure, they used a micropipette to instil an allergen solution on the lateral and median walls of the nasal cavity (a control simulation with physiological serum was performed during an early visit) and carried out a series of tests 15 minutes, 1 hour and 24 hours after the provocation.
As expected, nasal provocation induced ocular pruritus, lacrimation and conjunctival inflammation. The decrease in the peak nasal inspiratory flow (PNIF) which expresses nasal congestion significantly correlated with lacrimation and ocular pruritus which were scored using the visual analogue scale (VAS). 4 patients out of 11 (one patient was excluded at the day 7) showed conjunctival eosinophilia. Besides, tear fluid contained high levels of histamine and substance P statistically correlated with ocular symptoms.
As a whole, this study confirms naso-ocular interaction in allergic rhinitis : induced by a mixed mechanism, which occurs both through liberation of chemical (histamine) mediators  and reflex provoked by substance P itself liberated by the activated sensory nerve endings.
Finally, the authors have provided objective tools for  evaluation of conjunctival inflammation in any rhinitis.


Anti-cholinergic agents and asthma treatment
Although well established as bronchodilators, anti-cholinergics (AC) such as Ipratropium have only a limited role in the treatment of asthma and are mostly reserved for the treatment of COPDs. The emergence of a  new drug :Tiotropium bromide (T) (Spiriva®), a long-acting AC, has driven a large number of US researchers and practitioners of the NHLBI  (S.P.Peters et al NEJM 2010 September 19) to reconsider the matter and try to know whether T could be an alternative to long-acting β²agonists such as Salmeterol (S) (Serevent®) or Formoterol.
Consequently, the authors undertook a double-blind study involving 210 patients with asthma poorly controlled by inhaled corticoids alone (ICS) at the rate of 80µg twice daily. The first testing was to compare effect on those patients of either doubling of the ICS dose, or adding Tiotropium T. to ICS ; the other  to compare the addition of T to ICS with the association ICS + Salmeterol S.
After 14 weeks the results were as follows :
1) Compared to the doubling of the ICS dose, the outcome with T was superior, as shown by :
-    the morning peak expiratory flow (PEF) with a difference of 25,8 l/minute (P?0,001) and 35.3 l/minute (P?0,001) for the evening PEF,
-    the symptomatic score,
-    the number of days without symptoms (P?0,01),
-    and, above all, the FEV1 (P=0,004)
2) Not only was the addition of T (18µg once a day) to the CS non-inferior to that of S for all criteria (PEF, symptomatic score, days without symptoms), but it also increased the initial FEV₁. Thus T associated with IG can improve symptoms and lung function of an inadequately controlled asthma. All in all its effects are similar to those of the addition of S.
Indeed this investigation is relatively limited compared to the numerous studies on the S+ICS association. Moreover T, administered as a powder in capsule for inhalation with an ‘Handihaler’ device, is contraindicated for the under-18s and those suffering from a moderate or severe kidney or liver deficiency. Cardiovascular complications have been also reported and the risks of a long-term use are not known.
Nevertheless and finally, T deserves a real place in the therapeutic arsenal against asthma, particularly when long-acting β2 agonists are ineffective, or even hazardous.

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₁ National Heart, Lung and Blood Institute



Source:  CEFCAP
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