Claude MOLINA and Franz MARRACHE
Paris (France)

• Occupational respiratory allergy in apprentices and Atopy
• Insight into the pathophysiology of asthma and bronchial hyperreactivity
• Asthma during pregnancy and congenital malformations
• Bêta-blockers and asthma :
• Are beta-blockers useful in Asthmatic patients ?
• Are beta-blockers a good option in elderly asthmatic patients ?
• Can all proteins become allergens ?

Occupational respiratory allergy in apprentices and Atopy :

The team of JL Malo, in Montreal, specialised in occupational allergy and asthma, has carried out a long term (8 years) study on the outcomes of 408 apprentices exposed to high molecular weight allergens, such as flour, latex, and laboratory animal allergens (Long term outcomes in a prospective cohort of apprentices exposed to high-molecular-weight agents : American J. Resp. Crit Care Medicine 20008 177 871-879 D.Gautrin et al). The objectives of the study were to assess the frequency of new and persisting sensitisation, rhino-conjunctival symptoms and bronchial hyperresponsiveness in relation with job history after ending apprenticeship and to examine characteristics significantly associated with the incidence and remission of these outcomes.

A respiratory symptom questionnaire, skin prick-tests with the suspected allergens, spirometry and metacholine challenge test were used for this study together with an appropriate statistical analysis. Within the group of individuals who, at a given time of the observation period of the study, held a job related to their apprenticeship (78% of the cases) the incidence of sensitisation, rhino-conjunctival symptoms, bronchial symptoms or bronchial hyperreactivity was, respectively, 1.3, 1.7, 0.7 and 2.0 per 100 person-years. Within the group of individuals who started a job different from that of their apprenticeship, a remission was observed respectively in 18.5, 9.6, 9.6 and 12.4 per 100 person-years. The authors stressed that allergic reactions acquired during apprenticeship did not dissuade individuals from engaging in an activity in the same field (8 out of 10) and they don’t seem to have regretted it since, overall, the incidence of allergic manifestations was lower during the work period than during their apprenticeship. In addition, a high proportion of individuals who started an activity different from the one they had during their apprenticeship had a remission of symptoms. This is a particularly interesting result for atopic individuals who are normally advised to avoid careers where they may be exposed to the inhalation of high molecular weight particles (Laboratory Animal Caretaker or Dental Hygienist or Baker). As mentioned in the editorial of the review, this may be the “end of the tunnel” in this context for atopic individuals.

Insight into pathophysiology of asthma and bronchial hyperreactivity
In a previously work GL. Chupp et al, observed that the serum and pulmonary levels of a component of human cartilage, YKL-40 protein, also known as chitinase 3-like 1 protein, was correlated with asthma severity and bronchial remodeling.

The genetic aspects of this finding is related in a recent publication (Ober et al : Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma and lung function ( NEJM 2008; 358 : 1682-91,).

The study involves 1893 individuals from various populations: 753 Hutterite farmers, a sect of German descent living in South Dakota, Two control groups of European descent, with one including 638 children living in Freiburg, and the other 296 adults and children living in Chicago, as well as 206 children from Wisconsin, of European descent at high risk of asthma, belonging to COAST (Childhood Origins of Asthma Cohort Study),.

Links between the genetic polymorphism found at the CHIL3 (SNP – 131 C→G) susceptibility locus and the serum levels of chitinase-3 like 1 (YKL-40) protein were investigated.

Within the Hutterite population, increased YKL-40 levels were conditioned by the – 131 C allele (found in CC and CG genotypes) which was correlated with asthma, bronchial hyperreactivity, and lung function changes, in contrast with the protection afforded by the -131G allele. The -131C allele also allowed the prediction of asthma within the two control cohorts at Freiburg and Chicago.

In addition, within the group of children from the COAST study, analysis of CHI3L1 SNPs allowed to predict the levels of YKL-40 in the cord blood and as well as in peripheral blood, until children were 5 years old.

Given the proliferation of genetic studies in asthma, these findings need for large epidemiological studies to be confirmed. However it may be observed that the switch at a single amino acid within the terminal portion of the CHI3L1 gene is associated to disease or to protection against asthma.

In spite of absence of correlation between the levels of YKL-40 and asthma beyond 6 years of age, or between YKL 40 and atopy, this work opens the way to research projects on pathophysiology of asthma and bronchial hyperreactivity.

Are beta-blockers useful in Asthmatic patients ?

This is an apparently paradoxical question since it is known that they are clinically contra-indicated in asthmatic patients where they may cause acute bronchospasm.

However, the concept of such antagonism as defined by Sir James Black (Medicine Nobel Prize 1972) between â2-agonists such as Salbutamol and Beta-blockers (Bbls) has been discarded by a recent experimental study (L.P.Nguyen et al :Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model Am.J.Cell.Mol.Biol 2008 38 256-262).

Chronic administration of beta-blockers for 7 to 28 days, in a mouse model of ovalbumin-induced asthma, decreased bronchial hyperreactivity, reduced eosinophilic inflammation, decreased IL-13, IL-10, IL-5 and TGF-â1 secretion and reduced mucin content within the bronchial epithelium. This was achieved using 2 types of Bbls : a non selective one : Nadolol (Corgard®) and a selective one : ICI 118551 (not yet sold in pharmacy) .

Can we extrapolate these results to humans?

Various recent studies on the effects of Propranolol (®) and Metoprolol (®) in asthmatic or COPD patients with heart failure have shown deleterious side-effects on their respiratory status. Only Celiprolol (Celectol(®)) and, possibly Nadolol would be relatively tolerated by asthmatic patients, maybe at low doses in mild asthma and in prolonged administration. However, in any case, it is necessary to assess benefit/risk ratios. This implies a close collaboration between allergo-pulmonology and cardiology specialists. In practical terms it is still advisable to avoid Bbls in asthmatic patients, even by ocular route (as one of us had the opportunity to note in a patient). The taboo is still valid!

Are beta-blockers a good option in elderly asthmatic patients ?

In order to try and answer this other question, a meta-analysis including 29 prospective studies was performed in 2002 by Salpeter SR et al (Cardioselective beta-blockers in patients with reactive airway disease. a meta-analysis : Ann intern Med. 2002 ;137 :715-725). These authors did not observe any changes in FEV1, or in the clinical status, after the administration of beta-blockers (Bbls) in individuals with bronchial hyperreactivity. However beta-blocker administration did not exceed 4 weeks and the study only involved a limited number of patients 40 to 51 years old.

Another retrospective study (M.A. Rank et al: â blockers prescription in elderly patients with asthma. J Allergy Clin Immunol. 2008 Apr;121(4):1061-2.) included 390 individuals between 65 and 85 years of age, who were selected by randomisation between 2004 and 2006. All had asthma and coronary disease . 200 patients with isolated coronary disease, and similar age range, form the control group.

The authors aimed at answering four questions :

- Are Bbls prescriptions on the increase ?

- Are Bbls less frequently prescribed in elderly asthmatic patients ?

- Are doses prescribed to this type of patients lower ?

- Does the degree of asthma severity influence Bbls prescription ?

Taking as a reference the pilot study by Gottlieb et al, ((Effect of Beta-Blockade on Mortality among High-Risk and Low-Risk Patients after Myocardial Infarction….NEJM 1998339 :489-497 ), we can observe, , a clear increase in the rate of Bbls prescriptions, which went from 34% to 56%. Such prescriptions were, however, less frequent in the group of patients who had both coronary disease and asthma (45% versus 75%). In contrast, Bbls doses prescribed are equivalent in both groups, and prescription rates are independent of asthma severity degree, which allows to think that the elderly patients tolerates Bbls more than is currently accepted.

However the results of this study should be confirmed by prospective studies.

Asthma during pregnancy and congenital malformations

Are asthma exacerbations during the first trimester of pregnancy associated with congenital malformations? This has been the object of a study involving a cohort of 4344 pregnant asthmatic patients (Lucie Blais et al : Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women, JACI 2008 Apr 12; [Epub ahead of print] ). Clinical episodes were recorded on the basis of corticosteroid prescriptions, visits to emergency departments and hospitalisations due to asthma, whereas the presence of malformations was assessed at birth and during the first year of life. Thus, within this cohort of asthmatic patients, 398 (9.2%) newborns had at least one malformation and the latter had a major feature in 261 of them. The prevalence of these congenital malformations was 12.8% and 8.9%, respectively in pregnant women that had had asthma exacerbations during the first trimester of their pregnancy or not, with an adjusted odds ratio (OR) for malformations of 1.48 (95% IC, 1.04-2.09) in favour of the former. If applied to major malformations, OR would be 1.32. These statistically significant results demonstrate, according to the authors of this study, the risk of fetal congenital malformations in case of asthma inadequately controlled in early pregnancy and suggest that increased surveillance of the respiratory status of asthmatic pregnant women should be increased during the first trimester.
(Cf Consequences of asthma on pregnancy)

Can all proteins become allergens ?

We know that allergens are most frequently proteins. The question is to know whether allergenic proteins have features that are different from those that are not allergenic and whether the sensitisation to the former depends upon their concentration, their source and/or exposure route (respiratory, cutaneous or digestive) . The usual classification between aero-allergens and food allergens had allowed the realisation that there were common features between some protein families (Profilins, Tropomyosin, Bet v1) .

In a recent study based on the fusion of european (Allergome) and international (Allfam) databases, a group of Austrian and Italian authors have put forward a new classification based on sequence, structure and functions of proteins.

Allergens are distributed into few protein families and possess a restricted number of biochemical functions C. Radaeur et al JACI 2008 124 847-52.

Thus it seems that out of 3012 known families of proteins, only 5% of them contain allergens and most can be grouped into some functional classes such as : hydrolytic enzymes, metal-, lipid- or polysaccharide-linked proteins, storage proteins and proteins of cytological skeleton. For instance, the Der p1 major allergen of house dust is a cystine protease which directly acts on immune system cells, particularly on dendritic cells, by cleaving surface proteins. Food allergens are characterised by their high content in dissulphide bridges which ensure their stability and allow them to resist to heat and digestive secretions.

Thus, structural and functional features that turn a restricted group of proteins into allergens, allow a better understanding of the molecular mechanisms of allergen sensitisation and open the way to novel therapeutic targets, at the onset of such allergic process.

These texts have been translated by L. Taborda, Covilha (Portugal).

Source: CEFCAP

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