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BIBLIOGRAPHY UPDATES IN ALLERGY

April 2011

Claude MOLINA* & Jacques GAYRAUD**

1. Decreased response to inhaled corticosteroids (ICS) in obese asthmatic children
2. Anti-acid medication as a risk factor for food allergy
3. Drug hypersensitivity reactions : current data
4. A non-invasive method of diagnosing asthma
5. Risks of using Inhaled Corticosteroids (ICS) for asthmatic women during pregnancy

1.  Decreased response to inhaled corticosteroids (ICS) in obese asthmatic children

Theme : Asthma
Key words : asthma, obesity, BMI, emergency hospitalisation

We have already analysed the possible interrelations between asthma (A) and obesity (O) in children. E.Forno’s paper (JACI 2011 127 3 741-749) brings in a new contribution to this “exchange of bad conduct” between the two diseases.
This US group of Paediatricians and Physicians (Boston and St Louis) isolated, within a cohort of moderately asthmatic children enrolled between 1993 and 1995, 1041 subjects (aged 5-12, 65% boys, 2/3 whites) split for a post hoc analysis into 2 large groups : 322 (31%) obese (O, 146) or overweight (W, 176) in consideration of their BMI (Body Mass Index), and a placebo-treated control group. Hypothesizing an inflammatory activity of  Obesity, the aim of the research was 1) to assess the efficiency of an ICS (Inhaled Cortico- Steroid), Budesonide ®, 200µg twice a day, by comparing respiratory function before and after treatment, and 2) to monitor (carried out over 4 years) outcome of A and  risks of exacerbation and/or hospitalisation.
The functional tests included mainly FEV1 and the FEV1/FVC (Forced Vital Capacity) ratio ; blood samples were also taken for IgEs, eosinophils and Vitamin D levels (a decrease in Vitamin D is possibly a severity marker). Monitoring comprised 2 phases of 2 years each. After a statistical analysis it appeared that :
-    During Phase 1, there was no significant difference between the 2 groups in lung function improvement after Budesonide, which causes a more or less marked bronchodilation ;
-    However, while this improvement carried on through Phase 2 for the non-O group, it was  absent in the O group, for which each BMI increase caused a significant decrease in ICS efficiency.
-    And finally, whereas the risks of emergency hospitalisation for the non-O asthmatic subjects dropped 44% over the survey period, there was no decrease at all for the Os. This is something to be remembered in the treatment of A in overweight children, both diseases needing to be treated at the same time.
To this paper on A/O relations should also be added a recent Australian work (C.Farah et al : Chest 2011 18 03 early on-line) which shows, after a thorough functional and statistical study of 49 asthmatic children treated by ICS, that BMI is an important and indisputable determinant of A treatment, but regardless of inflammatory or mechanical factors. The chapter is not closed


2.    Anti-acid medication as a risk factor for food allergy

Theme : Food allergy
Key words : anti-acid medication, Proton Pump Antagonist (PPA), AntiH2

Two Austrian physicians (Isabella Palli-Schol et Erika Jensen-Jarolim Allergy 201166 469-477) have published a very well-documented and convincing paper, drawing our attention to the risks of food allergy in taking anti-acid gastric medication, research based on personal clinical and experimental observations.
Everything started from the observation of a patient who became allergic to Beluga caviar (!!), whereas he had been taking Proton Pump Antagonists (PPAs) like Omeprazole ® for a few years and could remember the starting point of his sensitisation. An identical allergic reaction, with IgEs and positive skin tests, was reproduced in mice, using PPAs but also Ranitidine ® type anti-H2s and other allergens different from caviar such as hazelnut, fish or ovalbumin.
The authors’ argument is developed in 3 points : the molecular characteristics of food allergens, the role of gastric digestion, and the mode of action of the anti-acids.
As for allergens, it is recalled that eight groups of ingested foods represent 90% of the sensitizing proteins : crustaceans, eggs, fish, milk, peanuts, nuts, soy, wheat. The gastric function is decisive in discovering their allergenic potential. On a physiological level, indeed, it is gastric acidity which induces digestion through activation of gastric pepsin and release of pancreatic proteases through Secretin.
This means that drugs which neutralize gastric acidity leave  intact allergenic foods, hence the risks of sensitisation which sets in insidiously. The same is true of atrophic gastritis, often caused in old patients by long NSAID treatment, or of achlorhydria in the context of alcoholism or gastro-intestinal surgery.
As to gastric anti-acid medications, they consist, apart from Bismuth which has no longer been authorised in France for several years, of PPAs and anti-H2s which blocks acid  production.
True, they are necessary to treat ulcers or heartburns, particularly in the elderly, or for gastro-oesophageal reflux in pregnant women or as co-medication in the treatment of rheumatism or intestinal inflammation.. Therefore long term use should be avoided as much as possible,
In any case, two practical conclusions can be drawn from this research :
-    It is essential in anamnesis of an allergic patient to include a question on possible PPA or anti-H2 treatment.
-    These drugs must not be authorized as self medication (“over the counter”) as is the case in some European countries, but must be medically and appropriately prescribed.


3.    Drug hypersensitivity reactions : current data

Theme : Drug allergy
Key words : drug hypersensitivity, immediate allergic reaction, non-immediate allergic reaction, patches, intradermal tests, habituation

An update paper on this vast theme, subject of the Rome 4th April 2010  Congress, has recently been published ( A.Romano et al  2011 JACI 127  3 Suppl.1 67-73 et  74-81 W.J.Pichler et al).
The distinction between Immediate Reactions (IR) and Non-Immediate Reactions (NIR) should first be re-underlined.
The former, most often IgE-dependent, occur within one hour in the form of urticaria, angioedema, rhinitis, or bronchospasm, sometimes even anaphylaxis. The responsible agents are mostly antibiotics (β–lactams) and neuro-muscular blocking agents, among others.
The latter, non-immediate reactions, mostly through cell mediation (T lymphocytes), consist in maculo-papular eruptions but also urticaria. Some are severe : bullous exanthema, sometimes with eosinophilia and malaise, or pustulous exanthema, even toxic epidermal necrolysis (Lyell or Stevens-Johnson syndrome) caused by Non-Steroidal Anti-Inflammatory Drugs (NSAID), but mostly, for the past few years, agents of anti-cancer chemotherapy (platinum salts or monoclonal antibodies) and biological medications in general.
With IRs, allergic tests : prick, ID or patch-tests or serum IgEs (possible only for some drugs), help to avoid drug reintroduction : a “gold standard” diagnosis, but neither a 100% reliable nor a harmless one. New biological tests using basophils or lymphocytes are currently being assessed, but none provides total certainty.
The same is also true of the NIRs, for which the Nancy dermatological team (Barbaud), as well as Haddad (Creteil), stress the benefits, to start with harmlessness patch-tests in severe skin forms, but also the necessity, in some cases, to use higher sensitivity IDs.
Finally, desensitisation,  when medication is indispensable (or  there is no other alternative) is mentioned with interesting results obtained, particularly by Castells (Boston) with a 6-hour protocol for drugs such as Rituximab, Infliximab, Trastuzumab and with no cases of fatal side-effect.
As for immune mechanisms, where dendritic cells and T lymphocytes, particularly T regulators play an important role, they already make it possible, thanks to progress in pharmacology and genetics, to foresee, for certain medications, a personalised therapy.
An interesting bibliography is given at the end of these papers, providing details on the attempts and results obtained by the major speakers at this International Congress.


4.    A non-invasive method of diagnosing asthma


Theme : Asthma
Key words : airway inflammation, NMR (Nuclear Magnetic Resonance), NMR spectrometry

Looking for an objective, non-invasive measurement of airway inflammation in asthma, particularly among children, a group of Canadian authors (E.J.Saude et al JACI 2011 127 757-764) has attempted to study its metabolic profile in urine by Nuclear Magnetic Resonance (NMR). Urine appears indeed as a biological fluid whose chemical composition can be easily studied, particularly its protein and cell content. NMR spectroscopy led to identification and quantification of 70 metabolites and to application of this method to children aged 4-16, divided into 3 groups: 33 stable asthmatics under ambulatory treatment and examined in consultation, 20 asthmatics hospitalised for exacerbation, and 20 controls. In a first stage, the authors did not observe any significant difference between those 3 groups.
They then eliminated the least important metabolites and drew up a list of 23 chemical substances which validated a model applicable for discrimination between asthmatics and healthy controls. In so doing, they could correctly diagnose 31 asthmatics out of 33, with a 5% error margin, 94% sensitivity and 95% specificity ; only one of the controls, i.e. 1 out of 20, was erroneously classified as asthmatic.
Similarly, by comparing urine metabolites of stable and exacerbated asthmatics, they could draw up a statistically valid model of 28 metabolites, which lead to the correct discrimination of 31 asthmatics out of 33, i.e. a  reliability of 94%.
Many tables illustrating this paper list these metabolites. Among them, we could quote those of the citric acid cycle (succinate, fumarate, threonine,…) which seem the most useful in the model differentiation, and the best known such as adenosine, creatine, histamine and methyl histamine, with high levels in severe asthma, and decreased by anti-allergic drugs.
The authors admit the limits of this important work, spread over 2 years of observation and monitoring. They nevertheless found it interesting for improving the differential diagnosis among infants and children between asthma and a simple cough of viral origin.
As a practical conclusion, the sophistication of these techniques is such that they are not within the reach of all laboratories, even if possible improvement through robotised versions allows those researchers to predict a drop in the cost of examinations. They however hope to be able to refine a diagnostic method which is the only one known so far based on NMR urine analysis, and think that the metabolic approach of the asthmatics’ airway dysfunction will lead to new research tracks and to the discovery of anti-asthma drugs.


5.    Risks of using Inhaled Corticosteroids (ICS) for asthmatic women during pregnancy

Theme : Asthma
Key words : asthma, inhaled corticosteroid, cortisol, estriol, osteocalcin  

At a time when the French Academy of Medicine devotes a theme session to the perinatal determinants of health on children’s and adults’ pathology, the Australian authors’ paper (N.A.Hoidyl et al AJRCCM 2011 183716-722) will be helpful in reviewing the possible risks of ICS among pregnant asthmatic women. It must be said that asthma affects 14% of pregnant women in Australia (vs 8% in the USA). ICS are accused of being responsible, not only for deleterious effects in the mother (eclampsia) but above all in the foetus : prematurity, congenital malformations, low birth weight, hormonal balance disorder.
The study concerned 156 asthmatics and 51 controls. Concentrations of cortisol, estriol (a marker of the foetus’s adrenal activity), osteocalcin and corticotrophin were measured in the mothers. Besides, the cumulative dosages of ICs used were recorded each trimester of the pregnancy and ultrasound was performed at weeks 18 and 30, and the foetus’s weight and sex were noted.
Results were as follows : the mother’s hormonal concentrations, among which estriol, were not affected by the presence of asthma. That is to say that the foetus’s adrenal function was not modified and therefore that ICS do not influence foetus growth and development.
However, in the mother, everything depends on the sex of the foetus: whatever the dose, ICS had no effect on cortisol, estriol or osteocalcin if the foetus was male; but they increased corticotrophin rates during the 1st trimester of pregnancy.
On the contrary, if the foetus was female, then ICS did inhibit 1st trimester maternal cortisol and 2nd and 3rd trimester osteocalcin, and in a dose-dependent manner.
The Australian members of Women’s Lib have not yet expressed their worries about such discrimination, already present in utero !!
As for ICS, they are, once more, found innocuous, since it appears that the appropriate control of asthma is beneficial, both for the mother and the foetus.


You may address your comments and questions to:

Pr. Claude Molina    or    Dr Jacques Gayraud
* **