Bibliographic updates

Claude MOLINA & Jacques GAYRAUD

1. Stress and asthma
2. Commemorating 100 years of Allergen Specific immunotherapy :its mechanisms
3. Oral (sublingual) immunotherapy and cow’s milk allergy
4. Omalizumab (O) as add-on therapy to corticosteroids for asthma
5. Sick building syndrome and allergy

1.  Stress and asthma

Stress is often invoked by patients as a trigger factor for asthma outbreaks or even its cause, provoking scepticism from doctors who see there an obstacle to the continuation of deeper etiological research.
The recent article by American physicians (T.Ritz et all  AJRCCM 2011 183 26-30) brings in a new point of view on this possible interrelation.
A group of 20 adult patients with asthma aged 20-30 (compared to 19 healthy control subjects, of the same age, gender, race, social and professional status) was submitted to a ‘psycho-social’ test involving a 5-minute talk (after 5 minutes of preparation) in front of a panel of 3 experts with the view to selecting the best possible applicant for an important position in an international company. This was followed by a mental arithmetic problem.
For the next 45 minutes they were measured every 15 minutes for exhaled FeNO levels (as an airway inflammatory marker), respiratory function by plethysmography, and salivary cortisol levels (as a marker of the activation of the hypothalamic-pituitary-adrenal axis).
Results were as follows :
Exhaled FeNO levels were statistically higher for asthmatics than for controls independently of changes in ventilation. However, endogenous cortisol levels were statistically lower (and independently of steroid therapy stopped before the test). An inverse relationship between exhaled FeNO and cortisol was revealed, since the post-test increase in cortisol levels measured in all subjects was associated for asthmatics with smaller increases in FeNO. As a whole, acute stress therefore increases airway inflammatory markers, although in a manner attenuated by stronger stress-related activity of the hypothalamic-pituitary-adrenal-axis.
Indeed, such a short test is not representative of the often prolonged stresses of daily life and the small number of patients means that these observations cannot be generalised. However, we have here a quasi-experimental demonstration of the possible role of stress in the development of asthma.

2. Commemorating 100 years of Allergen Specific immunotherapy :its mechanisms

The anniversary of NOON first publication (1911) is giving rise to numerous articles by the American Allergy Academies among which an impressive 774-pages, 99-chapter and 479-references document, a real allergist’s handbook (JACI 2011 Suppl.1. 127 1 81-588). We shall only analyse here immunological mechanisms which underlie this subcutaneous allergen SI and can be summed up in 4 steps :
1)    Immunologic response is characterised by decreases in specific sensitivity of end organs : skin, conjunctiva, nasal mucosa and bronchi, to allergen challenges, as much for early as for late response ; a decrease in tissue cell infiltration : eosinophils, mastocytes, basophils ; a decrease in nonspecific bronchial reactivity to histamine and acetylcholine, all associated with blood and cellular changes.
2)    Shortly after the first injections there is an increase in CD4+CD25+ regulatory T lymphocytes secreting IL-10 and TGF-β associated with immunologic tolerance. With continued immunotherapy there is some waning of this TH2 response to TH1 cytokine response.
3)     Specific IgE levels initially increase and then gradually decrease .Levels of specific IgGs increase : IgG4 (formerly known as a blocking antibody), IgG1, and IgA. However, none of these changes in antibody levels have been shown to consistently correlate strongly with clinical improvement.
4)    Increases in IgG levels are not predictive of the degree or duration of efficacy of immunotherapy, but the functional alterations in these immunoglobulins, such as high affinity for allergen, might play a non-negligible role in clinical efficacy.

On the whole the authors prefer the term Immunotherapy to desensitisation which they consider as a faster technique to obtain a more or less sustainable tolerance and which applies to some substances such as drugs and chemical products.

Still along this line of immunological mechanisms, the paper by E.M.Shakir et al. (Annals of Allergy,Asthma & Immunol 105 2010 340-347) deserves to be mentioned, which presents a historical perspective.

3.  Oral (sublingual) immunotherapy and cow’s milk allergy

If sublingual (or oral) immunotherapy initiated by Italian authors has been widely adopted in Europe, particularly for treating grass pollen: Oralair ® (Grazax®), or dust mite or animal dander allergic rhinitis, this is not the case in the USA where this technique, to which a short chapter is devoted in the above-mentioned report, is limited to a few trials in the case of peanut, milk, eggs or kiwi allergy. So far,results have been modest, risks of side effects non negligible, and treatment looking like a desensitisation or a kind of adaptation more than immunotherapy, the obtained tolerance often proving only temporary.

That is why the Sicilian trial (G.B.Pajno et al Annals of Allergy Asthma & Immunol 2010 105 376-381) seems an interesting therapeutic approach. The protocol consists in orally administering, for 18 weeks and in hospital, progressively increasing weekly doses of milk, from 1-2 drops to 200ml.

Thirty children, with cow’s milk allergy established by double-blind food challenge and high specific IgE levels, were submitted to this treatment while 30 others acting as controls were treated with soy milk.

At the end of the trial, 10 subjects presented full tolerance confirmed by (again) double-blind challenges and an increase in IgGs for 4 patients, which, for the authors, is the marker of a true immunotherapy. It should be noted that there were 2 severe reactions leading to interruption of treatment, whereas the control group did not present any side effects. True, this was not a real ambulatory treatment at home, but under an easy-to-understand, hospital control.

Besides, as observed in some previous trials, tolerance may disappear when the food is reintroduced. Nevertheless, this interesting trial offers hope in the future for the complete recovery from these cases of food allergy, more and more frequent and severe in Europe.

4.  Omalizumab (O) as a add-on treatment for asthma

While Europe recommends the use of O to be limited to the severest forms of the disease, given the risks inherent to any monoclonal antibody, two recent papers have underlined efficacy and safety of O (Xolair®) but as add-on therapy to the basic treatment of asthma in adults and children.

1) The first is a meta-analysis of 8 random / placebo trials, conducted between 2004 and 2009 in the USA and Europe by 8 teams for a total 3 429 patients, 1843 treated with O and 1546 by placebo (G.J Rodrigo et al Chest 2011 139 28-35). The aim was at first to reduce the use of corticosteroids (C), to prevent exacerbations and then, to improve symptoms and respiratory function, keeping an eye on side effects. In all the trials, the treatment recommended by the pharmaceutical laboratories included two phases: a 16-week adjustment phase with a subcutaneous injection of O every 2 or 4 weeks   (0.016g/kg) followed by a reduction phase of steroids use .
The overall results are as follows : at the end of the reduction phase, the O-treated subjects were more likely to be able to withdraw from C than the controls. Moreover, at the end of each stage, they showed fewer exacerbations. The thorough analysis revealed that this effect was independent of subject’s age and treatment duration. The frequency of side effects was practically identical in both groups (3.8% as opposed to 5.3%) but injection site reactions were more frequent in group O (19.9%, i.e. 1 out of 5, vs 13.2%). No sign of increased risk of hypersensitivity reactions, cardiovascular effects or malignant neoplasms was observed.

2) The more recent personal trial conducted by New York authors (J.Karpel et al Annals of Allergy.Asthma & Immunol 2010 105 465-470) on 1 071 patients in 2 groups, all aged 12-75 and suffering from moderate or severe asthma, with the same protocol, and for 52 weeks, leads to the same conclusions of efficacy and safety as the above mentioned studies.
All the studies, albeit perfectly clear but sponsored by pharmaceutical firms, merely confirm the benefits of O in the treatment of asthma, but do not, in our opinion, allow practitioners recommend O, a biological and fairly costly medication, as an add-on to the treatment of moderate asthma in adults and above all children.

5.  Sick Building Syndrome and allergy

A recent epidemiological work by Japanese authors puts back in the spotlight the famous ‘Sick Building Syndrome’ (SBS) which made such a media buzz in the 1990s, explained as ‘Syndrome of unhealthy buildings’ (not to be confused with unsanitary flats). This syndrome appears in modern, air-conditioned, office buildings and is characterised by symptoms of discomfort and itching (skin, eyes, nose) with no objective signs but felt by numerous occupants. In a survey initiated by the Ministry of Housing and following the report we had prepared for the Commission of the European Communities, we visited some large buildings with an average of 1800 clerks. We observed with occupational physicians that, beside physical, chemical, and psychological factors, ergonomic ones played an important role, and that 30% of the complaining subjects had an atopic history, SBS being a diagnosis of exclusion.

The Japanese authors (Y.Saijo et al :  Indoor Air : December 2010  on-line) conducted a survey through questionnaires with 1 479 residents in 425 new housings, 80% of them in wood, in 6 Japan regions and during the autumn (to eliminate possible pollen allergy).The subjects, aged 19-60, answered yes or no to questions on their symptoms. Physical, chemical (13 aldehydes and 29 VOC, Volatile Organic Compounds) and biological (dust, mould) factors were targeted in the indoor environment.

After a step by step statistical study, by multiple logistic regression, it appeared that : 46% of the patients had a history of allergy.
The careful research of a correlation between each of the biological or chemical elements discovered and the symptoms (Odd-ratio, OR) produced the following results :
Derp1, Aspergillus, and Rhodotorula have a significant correlation with SBS.
The house dust mite DerP1 with nose symptoms,
Aspergillus for eye symptoms with a significantly high OR, and
Rhodotorula for all the symptoms.
As for Cladosporium which is the most frequent of the collected fungi, or Eurotium, they have a very low OR with clinical signs and might have a protecting role.

This interesting survey stresses the importance of biological SBS factors, although they only represent part of the etio-pathogenic factors of the disorder.

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Last updated 28 July 2014