Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Atopic dermatitis (AD) : inflammatory disease of the epithelial barrier
2. The role of immunosuppressive agents in AD treatment
3. Chronic Rhinosinusitis (CRS) in the elderly
4. Crenotherapy and Chronic Rhinosinusitis in children
5. Football and Exercise-Induced Bronchoconstriction/Asthma (EIB)

1.    Atopic dermatitis (AD) : inflammatory disease of the epithelial barrier

Theme: physiopathology, eczema
Key words: atopic dermatitis, epithelial barrier, atopic pathway, filaggrin

The French Academie Nationale de Medecine has just allotted a session to this theme under the guidance of J.Bazex and M.Bagot, and two reports were presented : Alain Taieb (Bordeaux) on AD physiopathology and Y. de Prost (Paris-Necker) on  immunosuppressive treatments.
We know that AD is very common in industrialised countries and affects approximately 15 to 30% of children and 2 to 10% of adults. The immunologic vision considers it as the 1st stage of the atopic pathway followed by asthma, rhinitis and food allergy. And yet, the discovery of mutations in the Filaggrin gene (FLG), a major protein in the maturation of the stratum corneum, has refocused attention on skin and, as A.Taieb underlines, has produced a Copernician revolution in the understanding of the affection which appears to be a model of inflammatory disease of the epithelial barrier (ANM Bulletin 2012, in press).

Irvine and Mac Lean’s experimental works have indeed shown that FLG-lacking mice have a thin, dry and porous skin, and that the gene mutations and lack of FLG in children are associated with a severe form of eczema. Moreover, although FLG has no expression in the lungs, it was observed with surprise that some of its mutations were strongly associated with asthma and others with peanut allergy. Simultaneously, the Holgate team from Southampton underlines the frailty of the bronchial epithelium in asthmatic patient whose mucous membrane is poor at self-repair after aggression. Such epithelial deficiency also affects nasal mucosa (hence the risk of rhinitis) and intestinal mucosa, (hence  food allergy).

But dermatologists go even further, for skin appears no longer to be a simple mechanical barrier but an agent of immunity, as keratocytes secrete cytokines which play a part in the atopic path. The search is therefore on-going for molecules capable of stimulating the production of FLG, while avoiding or by-passing mutations: such is the case of  gentamicin or growth factors like the Keratocyte Growth Factor, which is present in skin and intestinal mucosa and which reduces inflammation and epithelium leakiness of the airways in rats.

2.    The role of immunosuppressive agents in AD treatment

Theme: eczema, treatment
Key words: eczema, atopic dermatitis, immunosuppressive agents, tacrolimus, pimecrolimus, cyclosporine, biotherapies

Y. de Prost, whose great experience must not be overlooked, believes that the severe AD, in the form of impetigo and intense pruritus alter the quality of life ; they constitute 13 to 20% of cases in children and 15% in adults (an extreme form was observed in a 91-year old female patient). He gives a reminder of the treatment basics, i.e. dermocorticoids, limiting of infection and xerosis (emollients) and hygiene advice.

The most frequently used immunosuppressives (IS), when classic treatment fails and even for local medium or moderately intense affections, are Tacrolimus T (Protopic®) 0.1% and 0.03% ointment for children and Pimecrolimus P (Elidel), not  yet on sale in France, equally effective and acting as calcineurin inhibitors.

T, particularly recommended in the zones where corticoids should be avoided, such as the face, eyelids, buttocks and deep folds in adolescents, is extremely effective and well-tolerated apart from some local irritation in the 3 days following its application; 6 weeks of treatment is advised. The only counter-indications are herpes and exposure to the sun. The risks of Carcinogenesis (Lymphomas), which were evoked when T was administered in case of organ grafts, are not confirmed for local short-term treatment.

P offers the same indications and results as T.

As for per os IS, these are mainly represented in France by cyclosporine (4 to 5 mg/day), clearly effective but requiring careful monitoring of kidney function and blood pressure, and gradual reduction in dosage before the end of treatment to avoid rebound occurrences.

Methotrexate has also been suggested when cyclosporine is ineffective.

Finally, biotherapies : Omalizumab or Retuximab have shown interesting therapeutic test results, but a larger number of patients is necessary to confirm their possible efficiency and justify their high costs.

3.    Chronic Rhinosinusitis (CRS) in the elderly

Theme: ENT allergy, immunologic markers
Key words: rhino-sinusitis, elderly patients, nasal polyps

The physiopathology of CRS, little studied in elderly subjects, is the theme of the following article (S.H.Cho et al  JACI 2012 129  3 858-860 e2). The US-Korean authors distinguish two types : 1°) CRS with nasal polyps (CRSwNP), polarised toward a Th1-type immunologic reaction, and 2°) CRS without NPs, with eosinophilia and tendency to Th2 skewing, and point to the increasing evidence that these are linked to impairment of the barrier function of the airway mucosal epithelium 

The aim of the study was to evaluate the age-related differences in the clinical characteristics and to assess the respective immunologic markers.

A 1st retrospective study of 252 patients led to identification of a lot of demographic and clinical characteristics, by subdividing the group into adults (230 aged 16-49) and the elderly (22 aged 60-77). In the latter, asthma and associated NPs tended to be more frequent, but with no statistical significance; only the sinus opacification score, assessed by tomography and CRS severity marker, was statistically higher.

In a 2nd stage, in different subject groups (58 with NPs, 51 without NPs, and 50 control, with the same age range), they went further and studied nasal lavages and immunologic markers. Among them, ECP (Eosinophil Cationic Protein) blood counts were higher, above all in adults with NPs than in elderly subjects, a sign that the eosinophilic inflammation was lower in the latter. However, the neutrophilic inflammation detected by HNE (Human Neutrophil Elastase) was not discriminated by age or by CRS type.

As for markers of the epidermal differentiation complex, S100 A7 (psoriasin) and S100 8/9 (calprotectin), levels of which are generally reduced in CRS, were significantly lower in elderly subjects, above all for calprotectin in CRSwNP.

On the whole, and despite the skew toward severity and more frequent association with NPs, CRS eosinophilic inflammation subsides with age, whereas simultaneously the epithelial barrier dysfunction, as revealed by the lower levels of corresponding markers and above all of S100 A8/9, plays an important role in the pathogenesis of lesions and therefore indicates a need to develop modified treatment strategies for elderly patients with CRS.

4.    Crenotherapy and Chronic Rhinosinusitis in children

Theme: ORL allergy, nasal  thermal aerosol
Key words: crenotherapy, rhino-sinusitis, child, inflammation markers

Thermalism for treating allergic or non-allergic rhinosinusitis, which had its golden age in France in the past century, has been more or less dropped over the past years. But a recent article by Italian authors published in English (A.Passariello et al :American Journal of Rhinology & Allergy  January-February 2012  26  1 15e-19e), based on precise clinical, biological and statistical studies, now rehabilitates this treatment by the inhalation of sulphate-sodium chloride water from a thermal site in the island of Ischia.

65 children of an average 3.3 years of age received thermal aerosol inhalations for 15 days and 15 minutes per day. A complete preliminary ENT check up with sino-nasal severity score and sampling of nasal mucus by lavage, was performed with quantitative determination of inflammation markers such as TNFα, and immune-regulator anti-microbial peptides such as calprotectin and Hβ2 defensin. 60 other healthy children from a paediatrics ward were used as controls. All these parameters were compared in a thorough statistical study.

At the end of the treatment a marked improvement in symptoms (essentially nasal obstruction, and impairment of the sense of smell) and in the sino-nasal score was observed with significant values, whereas levels of calprotectin TNFα and Hβd-2 were also reduced in statistically significant proportions.

Crenotherapy is thus now taking on a new dimension, for it has already long been recognised as harmless, well accepted and perfectly tolerated, as well as an alternative to drug-based treatment. From now on it also appears as an inhibitor of cytokines and nasal inflammatory mediators.

Admittedly, one can be surprised, just as the authors were, to note a difference between the observations made in adults with CRSwNP for whom, as already said above, calprotectin and Hβd-2 levels are lower than controls. But in this study carried out with children, CRS is not associated with polyps or with eosinophilia, but rather with a mixed inflammatory cell population composed of lymphocytes, macrophages and neutrophils, which could account for a difference in the occurrence mechanism of lesions.

In any case and despite the absence in this study of an accurate allergist check-up (one single note pointing out the regression of allergic symptoms), the thermal treatment of chronic rhinitis in children, which was very fashionable a few decades ago, deserves to be  taken once again into consideration

5.    Football and Exercise-Induced Bronchoconstriction/Asthma (EIB)

Theme: asthma
Key words: exercise-induced asthma, football, bronchial provocation, bronchial dilatation, doping

The diagnosis of asthma or Exercise-Induced Broncho-constriction (EIB), which is well-known in sportspeople, relies heavily on athletes’ statements and is treated by bronchodilators or even corticosteroids, which are then authorised in high level sports competitions. Football, the most popular sport around the world, exposes its players to many factors of aggression: prolonged hyperpnoea causing loss of water, exposure to multiple and irritating aero-allergens during training or competition (10 to 13km run during each match, on grass or in cold weather).

Now, following a series of doping incidents with elite athletes in 2009, a change in the regulations of international competitions such as the Olympics Games for instance, allows the use of sympathomimetic or anti-asthma drugs, on condition that this is justified by a confirmed diagnosis after accurate pulmonary function testing.

A group of British authors from Newcastle, Liverpool and London (Ansley et al Allergy 2012 March  67 3 390-395) thus interviewed and examined 65 elite professional soccer players (English Premier League) thought to be suffering from EIB, in order to check the accuracy of the diagnosis.

They recorded by questionnaire the symptoms and the drugs used and conducted a bronchial provocation test with dry air (6 minutes of eucapnic voluntary hyperpnoea) in 42 players, and a mannitol challenge in 18 players. Five players with abnormal resting spirometry underwent a bronchodilator test. The results were surprising : in fact, of the 65 players assessed, 57 (88%) indicated regular use of asthma medication and 57 (88%) indicated EIB symptoms during a match. And yet only 33 (51%) had a positive bronchodilator or bronchial provocation test. Moreover neither symptoms nor the use of inhaled corticosteroids were predictive of the outcome of pulmonary function tests.

Thus, a high proportion of English elite professional soccer players are wrongly medicated for asthma, some of them using as reliever therapy only, while they present neither bronchial obstruction nor hyper-responsiveness to possible environmental stimuli.

This is an important piece of information which should be brought to the attention of sports authorities and all Olympic sports teams. It once more underlines the fair play of the British medical and sporting community.

Comments and questions welcome :

Pr. Claude Molina    and/or    Dr Jacques Gayraud
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Last updated 15 October 2014