Bibliographic updates

Claude MOLINA* and Jacques GAYRAUD**

1. Asthma in school children and psychological problems (behavioural problems)
2. Statins and asthma
3. Lipids and allergy
4. Ten year follow-up and evolution of three European asthma cohorts
5. Contrasts in the effects of yeast and fungi in triggering infant asthmatic wheezing (AW)

1. Asthma in school-children and psychological problems (behavioural problems)

Theme: Asthma – Allergy and psychology
Key words: Asthma – Psychological factors – Internalizing – Externalizing problems

The relationship of asthma (A) to psychological problems is an ongoing subject of controversy: are these the cause or the consequence? The extensive multicentre work carried out by the French team (I. Annesi-Maesano et al. Allergy Oct 2012 68 1471-1474) in six cities : Paris, Marseille, Clermont-Ferrand, Strasbourg, Bordeaux and Reims, has provided an original contribution to the discussion. 6880 children with a mean age of 10.4, attending 108 schools and 409 classes in the two last years of primary school, (CM1 CM2 in France) took part in the survey.

This included 2 components:
- an internationally recognized psychological questionnaire (SDQ) with 5 items and several scales, dividing subject behaviour in 2 types: internalizing (emotional) problems or externalizing (conduct problems) and 3 categories : normal, borderline and abnormal;
- a parental ISAAC type questionnaire to detect A cases in this general population and to classify them in 4 categories : early onset, current, moderate and severe.

The detailed statistical analysis, after elimination of confounding factors, revealed that:
- children with abnormal behaviour, either due to emotional (I) or conduct problems (E) are more asthmatic than others (significantly higher prevalence P ≤ 0,05)
- among these asthmatic children , 15% of I presented abnormal and 10% borderline conduct, whereas 14% of E presented abnormal and 5% borderline conduct ; in all cases, conduct abnormalities were significantly associated with early, generally moderate asthma ;
- in addition, borderline conduct subjects were found to be negatively related to parents’ knowledge on how to prevent asthma attacks;
- overall, some causes of these conduct abnormalities are : family difficulties, insufficient treatment (not the case here), and stress which provokes type Th2 immune reactions.

2. Statins and Asthma

Theme: Asthma – Allergy treatment
Key words: Asthma – Statins – Asthmatic exacerbation - Corticosteroids

At a time when the extensive use of cholesterol-lowering statins (S) is questioned in the treatment of cardiovascular diseases, the work of a Boston team (S.M.Tse et al AJRCCM 2013 4 October in press) brings a timely contribution, underlining the anti-inflammatory role of these drugs and their interest in preventing exacerbations of adult asthma.

The research objective was to examine the effect of Statins on asthma exacerbations using a large cohort from five major sites, including health data from a population of over 1 million subjects who were monitored from 2004 to 2010.

Statin users aged over 31 years (around 8000 asthmatic subjects) were identified and observed over a 2-year period and - after adjusting for age, anti-asthma treatment, season, demographic factors and co-morbidity – compared to an approximately equal number of non users.

Asthma aggravations were divided into 3 groups: need to prescribe oral corticosteroids (other than inhaled), hospital or doctor’s visit, emergency admission to hospital.

All these data were analysed by logistical regression. After adjustment for confounding factors, results were as follows:
- the use of Statins was significantly associated with a reduction in emergency hospitalisations; the same was true of the need for extra per os corticosteroids;
- however no difference was observed for asthma-related doctor’s visits or simple hospitalisation.
In conclusion, among Statin users with asthma, this treatment is associated with reduced risks of emergency hospitalisation or oral corticosteroids dispensing.

3. Lipids and allergy

Theme: Asthma – Allergy treatment
Key words: Lipids – Sphyngo-lipids - Lysophosphatidic acid – Asthma - Magnesium

The role played by lipid mediators is well known; these are derived from arachidonic acid which, under the influence of Phospholipase releases the two main types of allergy mediators: prostaglandins via Cyclo-oxygenase and Leucotrienes via Lipo-oxygenase.

Attention has recently been drawn to Sphyngo-lipids (S) and their role in genetic predisposition to asthma. Metabolism of these lipids is related to modifications in magnesium homeostasis and, as there is an association between S and bronchial hyper-reactivity, it has been suggested (B.D.Levy NEJM 2013 5 Sept 976-77) that genetics may account for the variable reactions observed in the treatment of serious forms of asthma by intravenous magnesium injections.

However, another lipid mediator well known in oncology, LPA (Lysophosphatidic acid) today appears as an important mediator of allergic reactions, particularly in the airways, as is underlined in the paper published by G.Y.Park et al (AJRCCM October 15 2013 188 928 – 940).

In this mixed study, both experimental and clinical, the authors recall that Lysophatidylcholine (LPC) releases, under the influence of Lysophospholipase D (LPD) also known as Autotaxin (ATX), LPA which binds specific receptors resulting in an array of biological actions : cell proliferation, migration, survival, differentiation, explaining its function in the pathogenesis of asthma.

To prove it, the authors used broncho-provocation on volunteers suffering from moderate asthma caused by common allergens (dust, ragweed, Aspergillus) and observed in the broncho-alveolar lavage fluid a remarkable increase in LPA, enriched in its two polyunsaturated metabolites LPA 22.5 and 22.6. At the same time ATX concentration was also higher.

Using a murine asthma model, the same authors demonstrated that transgenic mice with a high ATX level had more severe asthma, whilst blocking the enzyme activity and knocking down the LPA receptor caused attenuation of bronchial inflammation and Th2 cytokines.

In conclusion, the ATX-LPA lipidic pathway appears to have a prominent role in certain asthma phenotypes, which would explain the evermore widely recognized link between asthma and obesity.

These mediators probably also play a role in the bronchial remodelling of certain forms of asthma.

Finally, in so far as they also play a role blocking tumour growth, some anticancer drugs may also be beneficial in allergy.

4. Ten year follow-up and evolution of three European asthma cohorts

Theme: Asthma – Epidemiology
Key words: Asthma phenotypes – Allergic asthma – Non allergic asthma

An impressive epidemiological study, covering several thousand European asthmatics and using the ‘cluster’ statistical method together with ‘latent transition analysis’, allowed a large international team (France, Germany, Sweden, Italy and Spain) to establish the trajectory and 10-year evolution of several asthma phenotypes.

3320 adults were recruited in three cohorts: the European Community Respiratory Health survey (ECRH), the Swiss cohort study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA), and a more recent European cohort on Genetics and Environment (EGEA) (Anne Boudier Inserm Paris et al.. AJRCCM 2013 188 5 550-560), all three cohorts being followed up after 10-12 years from 1990 to 2012, i.e. 58% from first diagnosis and 42% during follow-up.

The asthma model was based on standard protocols and usual questionnaires filled in by the patient: 1) Level of symptoms (low, moderate, high), 2) Importance of the allergy factor as shown by skin tests and IgE levels, 3) Pulmonary function: FEV1, and in certain cases testing for bronchial hyperactivity.
7 asthma phenotypes were categorised as follows:
A Allergic asthma with few symptoms, often untreated (21% of cases)
B Non allergic asthma with few symptoms (17%)
C Non allergic asthma with strong symptoms (8-12%)
D Non allergic symptomatic asthma (18% with bronchial hyper reactivity)
E, F, G. Allergic asthma with moderate symptoms.

Statistical results show that:
- After 10 years, the different phenotypes are extremely similar, with 2/3 of subjects remaining in the same category .
- Allergic asthmas A, D, E, F show great stability.
- Transition from moderate asthma to a strong and severe symptom phenotype is more frequent in non allergic asthma: the 3 corresponding phenotypes (B,C,D) are usually observed in elderly subjects, often obese, female, with high co-morbidity.

In conclusion the interest of this survey resides essentially in its statistical robustness and the use of new epidemiological tools in the search for greater understanding of adult asthma and its long term evolution.

5. Contrasts in the effects of yeast and fungi in triggering infant asthmatic wheezing (AW)

Theme: Asthma allergens
Key words: Asthma – Fungi – Yeast – Bronchial wheezing – Indoor air quality

It is known that exposure to fungi often causes wheezing in infants (AW) either through irritation or allergy, but little is known of the different effects of indoor and outdoor fungi.

For this reason, a group of Boston researchers (B Behbod et al Allergy 2013 68 11 1410-1418) observed a cohort of 499 at-risk infants, aged 2 to 3 months, cultivating yeast and fungi in the bedroom and also in indoor and outdoor air dust.

AW diagnosis and its characteristics (intensity and frequency) were determined by bi-monthly parental phone questionnaire; samples, cultures and concentrations being carried out through usual techniques defining an exposure index and highlighting the fungi responsible.

The data were statistically analysed according to fungi concentrations and adjusting for possible confounding factors, such as season, infant birth weight, smoking and/or maternal mould sensitisation, and child exposure to home allergens.

Findings show that:
AW risks at one year are significantly positively associated with the indoor dust Alternaria, and Cladosporium. These risks are also associated with indoor air concentration of Penicillium and outdoor Cladosporium levels.

In contrast, indoor dust yeast concentration was associated with a reduced AW risk. They therefore reveal as protective.

Finally, frequent wheeze was borderline associated with dust and indoor air yeasts.

As for Alternaria, this was only associated with AW in children with maternal mould sensitization.

In conclusion, while AW levels were high during exposure to different types of mould considered as irritant or allergenic, indoor yeasts and unicellular moulds were associated with strong protection against AW.

Molecular microbiological studies on immunity may perhaps elucidate the contrasting effects of moulds on infant wheezing, which often leads to asthma.

Comments and questions welcome:

Pr. Claude Molina

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Dr Jacques Gayraud

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Last updated 29 October 2014