1.    Preventive Inhaled Corticotherapy (IC) with pre-school children at high risk for asthma
2.    Monitoring honeybee venom immunotherapy with the Basophil Activation Test (BAT)
3.    Type-1 diabetes (T1D) and atopy.
4.    Adrenaline auto-injection by children and teenagers
5.    Particularities of severe asthma (SA)

1.    Preventive Inhaled Corticotherapy (IC) with pre-school children at high risk for asthma

Theme: paediatric allergy, asthma
Key words: preventive Inhaled Corticotherapy (IC) – Low-dose daily IC – High-dose intermittent IC – Frequency of exacerbations – Oral corticotherapy

A US paediatrician multicentre study led by the California Allergy Department (R.S Zeiger NEJM 2011 365 1990-2001) was conducted among pre-school children considered at high-risk for asthma, in relation to a predictive index based on the frequency of wheezing and/or hospitalisations in the past year. The official recommendation in these cases was the use of IC, at varied doses but daily and for a long period. The major drawback observed was retarded growth and parents’ reluctance concerning continuous treatment. As a result the authors undertook a new randomised study comparing the benefits of a daily low-dose regimen to an intermittent high-dose.

Thus, 278 children aged 12 months to 5 years, enrolled in 7 different US centres, following an ethically validated protocol, received for 1 year either a nightly dose of 0.5mg IC (Pulmicort® in an inhalation suspension) or a 1mg twice-daily dose, from the onset of respiratory symptoms and for periods of an average 7 days. (Note : the protocol also included the on-demand addition of a bronchodilator, Albuterol, similar to Salbutamol® for 48hrs). The primary objective was the decreased frequency of exacerbations requiring oral glucocorticoid therapy.

At the end of the study, there appears no statistically significant difference between the two regimens, both equally efficient in the prevention of exacerbations and other symptoms (side effects or others). However, there is a notable reduction in the exposure to glucocorticoids (104mg over 1 year) in the intermittent as compared to the daily regimen, which is not negligible for young children in full growth.

As a conclusion, the authors recommend the intermittent rather than the daily regimen, something that clinical common sense could predict, but which from now on is supported by a precise statistical study and a clear protocol.

2.    Monitoring honeybee venom immunotherapy with the Basophil Activation Test (BAT)

Theme: allergy to insect venom
Key words: immunotherapy – honeybee venom – rush treatment – specific IgEs – IgG4

31 Slovenian children with a history of honeybee venom-induced anaphylaxis were submitted to a specific, rush- immunotherapy , in a single-blind prospective study, monitored  through the new Basophil Activation Test (S.E.K Zitnik et al Pediatr.Allergy&Immunol 2011, early view). This test is based on the biology of basophil cells whose degranulation is quantified by the expression of the CD63 marker and gauged by flow cytometry followed by fluorescent staining. Indeed, in non-active basophils, CD63 is strictly localised inside the granules, then, at the time of exocytosis and fusion with the cell membrane, transferred to the cell surface and measured through venom concentration.
BAT results are considered positive when CD63 gives a positive reaction in at least 15% of basophils, for 1µg/ml of venom. Moreover there exists a correlation between CD63 positivity and histamine liberation. The test was applied before starting the treatment, 5 days later and after 6 months or even 2-4 years in some subjects.

Before treatment, the BAT helped identify the culprit insect in 74% of the cases, while specific IgE reactivity was only observed in 52% of the children. Five days later, i.e. at the end of the rush-treatment, there is no statistically notable BAT modification.

However, after 6 months of regular immunotherapy (100µg every 4 weeks) specific IgEs remain at comparable levels (22.8kU/l on average, with a maximum of 100kU/l) whereas IgG4 levels are significantly higher. As for the BAT, it revealed in 85% of the children a marked CD63 decrease in the presence of 0.1µg/ml allergen (limit of cellular sensitivity) four times lower than at the start of treatment. The same observation is made after 2-4 years, whereas specific IgEs levels are also now significantly reduced.

In addition the authors observed that, during rush-treatment, BAT positivity was associated with the appearance of side effects.

In conclusion, the Slovenian authors recommend the BAT as a reliable monitoring method of hymenopterous insect immunotherapy. Senior French-speaking allergists will certainly rejoice in the rehabilitation and renovation of the basophil degranulation test, much favoured by our late colleague J.Benvesiste : it was known as the TDBH (Test de Degranulation des Basophiles Humains)

3.    Type-1 diabetes (T1D) and atopy.

Theme: atopy
Key words: Type 1 diabetes – Atopy – atopic dermatitis – Allergic rhino-conjunctivitis – Th1/Th2 balance

On a schematic point of view, T1D is controlled by the Th1-type immune response whereas atopy is considered as dependent on Th2-type immunity. Early studies had suggested an inverse association between T1D and allergic diseases. The Danish authors (S.F.Thomsen et al. Allergy 2011 66 645-647) therefore undertook a retrospective study of the association in a population of twins. They sent a questionnaire to 54,530 Danes, mono or dizygous, aged 3-71, having suffered from asthma, hay fever or atopic dermatitis, and who had been treated or hospitalised for T1D between 1931 and 2000.
After statistical crossing and adjusting for age, sex, and zygosity (96% confirmed), it appears that in the 3-20 year groups there exists an inverse association between T1D and the 3 symptoms of atopy (asthma, rhinitis, dermatitis) but only statistically significant for atopic dermatitis (AD). This AD risk is indeed 4 times lower in type-1 diabetics when compared to non-diabetics. Finally, with the dizygous T1D subjects (except for 91 pairs of twins) there is always a statistically lower risk than with their non-diabetic twin.
As to the genetic factors responsible for susceptibility to T1D or AD, they are also negatively correlated. For the authors, these findings substantiate the T1D/AD antagonism and the Th1/Th2 dichotomy.

This article was contested by an Italian group (Tosca et al. Allergy 2011 1612-14) who, in a prospective study of 112 children, aged 11 on average and suffering from T1D, on the other hand observed a positive correlation between this affection and allergic rhino-conjunctivitis. Besides, within the framework of the ISAAC epidemiologic study – which compares the incidence of T1D in the preceding 12 months in a group of 12-14 children from 31 countries, and the prevalence of atopic diseases – the authors (P.Fsadni et al Clin Resp.J 2012 6 18-25) also observe a positive T1D/AD correlation but no correlation at all with rhino-conjunctivitis.

It is clear that these conflicting findings can be explained by differences in methods of research, and also by the probable role of environmental factors. Whatever the case, these reports do not particularly affect diabetes or allergy therapies, but fuel the classical Th1/Th2 paradigm .

4.    Adrenaline auto-injection by children and teenagers

Theme: anti-allergy treatment
Key words: auto-injectable adrenaline – anaphylaxisfood allergy

Although adrenaline is unanimously recommended for first-aid treatment of anaphylaxis, its use in autoinjectors continues to be a subject of discussion as to its indications and practical implementation.

That is why a group of English allergists (L.Noimark et al Clin.&Exp. Allergy  2011 early view  1-9) undertook a multicentre prospective study involving 14 paediatric hospitals spread throughout the United Kingdom.
In this study 969 patients, aged 4-18 (average age 8), for whom an adrenaline autoinjector had been prescribed for a previous anaphylactic episode or food allergy the year before  answered a validated questionnaire.
503 of them had no new reaction and did not use adrenaline. 466 had an another allergic reaction, 221 a serious but non-anaphylactic episode, and 245 an anaphylactic shock (A) defined in the protocol as : loss of conscience, dysphagia, feeling of imminent fainting, wheezing, dyspnea, hoarseness. Among them, 97 even suffered 2, 3 or 4 episodes in the year. Most of the time and by order of frequency, the responsible allergens were peanuts and nuts, egg, milk, shellfish. As for the most frequent symptoms of these allergic reactions, they were : urticaria, skin redness, oedema, and wheezing.

Statistically speaking, in a united or multi-varied model, apart from the symptoms mentioned, oedema, throat prickling and stomach ache are associated with A. while A. risk factors are : a previous episode by non-identified allergen, milk cow allergy, ethnicity (non-whites) and associated asthma.
Most allergic reactions were treated by oral anti-histamines (83.3% for A, 86.4% for others, P=0.3). Finally, out of the 245 As., only 41 did receive adrenaline (16.7%, 95% CI :11.7-21.3), either by their parents or by a health professional and 2.4% by the patient himself. 13 patients who used their autoinjector needed another dose of adrenaline. The reason for not using autoinjectors were : 54.4% because it was not considered necessary and 19.1% probably not useful.
Thus, in the British community, adrenaline is only used by a minority of patients suffering from anaphylaxis. It is probable that a similar survey in Western Continental Europe would give the same results. This goes to show the need to explain more thoroughly the benefits of this process to families and young patients.

5.    Particularities of severe asthma (SA)

Theme: asthma
Key words: severe asthmacorticosteroids – smoking habit – obesity – gastro-oesophageal reflux – bio markers – Vitamin D – Pet-scan – FeNO – Super Dismutase Oxide– Anti-cholinergic bronchodilators – Macrolides

A large research programme on SA carried out in the USA is providing a better understanding of its definition, aspects and treatment (Nizar et al : AJRCCM 2011  November  17 in press). To define SA the authors propose two major criteria for treatment : use of high doses of oral or inhaled corticosteroids (IC), and 7 minor criteria based on : symptoms, frequency and severity of exacerbations, with or without hospitalisation possibly in Intensive Care Unit, troubles of respiratory function tests, extra medications, insensitivity to C. One major criterion and at least two minor criteria were considered as meeting the study conditions.

Lessons drawn from these researches confirm a large number of (sometimes classic) notions :

1)    Risk factors : active and passive smoking, obesity, gastro-oesophageal reflux, ethnicity (black skin), post-puberty females.

2)    Anatomical and functional aspects : incomplete bronchodilation and bronchial thickening, detected by tomography and MRI – a better technique for children than bronchial biopsy -, major alteration of small airways with alveolar inflation (trapping), and predominantly neutrophilic inflammation which can be detected by molecular imaging (Pet-Scan).

3)    Severity biomarkers : high FeNO due to respiratory obstruction and hyperinflation, but also lesser activity of the Super-Oxide Dismutase (SOD) associated to a severe drop in FEV1, increased expression of pro-inflammatory cytokines in relation to the molecular asthma phenotype (for instance, with predominant Th2 or Th1), as well as lack of vitamin D in children (A.Gupta et al AJRCCM 201101034 1342-1349).

4)    Therapeutically, it is often insufficiently regular treatment which is one of the causes of severity , together with either the brutal weaning from C or, on the contrary, the use of too high doses of β² agonists. Also worth noting (P.Barnes et al JACI 2012 1 129 48-59) is the benefit from long term anticholinergic bronchodilators of the Tiotropiun type, without forgetting the macrolide-type antibiotics in cases of neutrophilic predominance, and anti-inflammatory and blocking medications for incriminated mechanisms or mediators (anti-IgEs, or anti-IL13, IL, IL9, PGD2) as well as the products likely to invert the corticosteroid-resistance such as “old” theophylline and nortryptiline. Thus, research is more and more oriented towards biomarkers of different subtypes of SA in order to respond by appropriate and more and more specific therapies.

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Claude MOLINA  –  claude.nelly.molina@orange.fr

Jacques GAYRAUD  –  j.gayraud@orange.fr

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