Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Asthma risk for children born after infertility treatment
2. Intralymphatic (IL) specific immunotherapy (SI) of pollen allergy
3. Childhood obesity (O) and asthma (A)
4. Late-onset asthma (LOA) and metabolism of NO
5. Allergenic extracts and their regulation: the French exception

1. Asthma risks for children born after infertility treatment

Theme: Asthma - Prevention
Key words: Asthma – Infertility – In Vitro Fertilization IVF – Assisted Reproduction Technique – ICSI :Intra Cytoplasmique Sperm Injection

This is the subject of a major British prospective and randomized study (C.Carson et al Hum. Reprod. 5 December 2012 on line) on a cohort of more than 18,000 children recruited at 9 months and followed-up to 5 and 7 years of age. It was predominantly focused on children born after ART (Assisted reproduction Techniques) either IVF  or ICSI .
Several birth categories were analysed: planned, unplanned, welcome or not, those with a prolonged (over a year) time to conception (TTC) and the ovulation induced, IVF or ICSI.

Asthma, wheezing and use of anti-asthma medications were taken into account; a total of 13,041 children aged 5 (72%) and 11,585 aged 7 (64%) were included.

Statistical results show that, compared with planned children acting as control, children born from subfertile parents were significantly more likely to experience asthma or to be taking anti-asthmatics respectively at 5 and 7 years of age, this being particularly true with singleton children born after treatment for maternal infertility.

True, the latter are relatively few in number (104 subjects) but all the possible confounders were analysed and data weighted for non-response to minimize selection bias.

On the whole, and given the Scandinavian bibliographical references with similar observations, the researchers are convinced that the treatment of maternal infertility is a factor favouring childhood asthma.

2. Intralymphatic (IL) specific immunotherapy (SI) of pollen allergy

Theme: Therapeutic - Immunotherapy
Key words: Intralymphatic specific immunotherapy – Pollen allergy

This is a Swedish pilot study intended to determine whether this SI mode is a valid and harmless alternative to the classic technique of pollen rhinitis treatment which requires, as we all know, a number of subcutaneous injections (around fifty, according to the researchers), normally continues for 3 to 5 years and at a significant cost.

The IL technique consists in injecting into a superficial inguinal lymph node, possibly guided by ultra-sound, 3 times at approximately 4-week intervals, a dose of about 1000 Units of  aluminium-hydroxyde absorbed depot allergens, either grass of birch pollen.

A first ‘open’ test on 6 patients, intended to check the safety, feasibility and benefits of the technique, was followed by a 2nd controlled and random test on 15 patients, including 8 Placebo.

In addition to the clinical examination with scores, the classic protocol of course included: possible side-effects monitoring, skin prick tests, nasal provocation tests, blood paarameters (specific IgEs, IgG4 but also immuno-cytochemistry aiming at T lymphocyte activation), cytological (inflammatory cell content) and biological (cytokines) study of nasal lavage fluids.

At the end of the study, it appears that IL treatment is perfectly tolerated, that its clinical efficacy is significant (despite the small number of subjects), and that, biologically as well as classically, it induces an initial increase in the IgE levels (but not IgG4), together with an activation of the peripheral T lymphocytes (CD69 and CD98 expression), an improvement in the nasal cytological inflammation and a decrease in IL8 levels.

As a conclusion, IL immunotherapy constitutes a beneficial advance, from all clinical, biological, and socio-economic points of view (4 injections only as opposed to €9,000 for the conventional technique).

3. Childhood obesity (O) and asthma (A)

Theme: Asthma – Allergy paediatrics
Key words: Obesity – Asthma – Asthma control – Home pollution

Two major studies focus on this association: a US one (L.N.Borrell et al JACI Feb 7 2013 ahead of print) focused on ethnic and environmental factors, and a European one on the chronology and compared development of these two entities (D.Rzehak et al JACI 2013 a.o.p).

In America, 2,174 children, aged 8-19, from across the USA, Mexico and Puerto Rico, and suffering from A and O, were examined in order to determine how efficiently they are controlling their A, particularly how they respond to inhaled corticosteroids. Only 17.6% of cases were found to be under control (383 subjects: 192 boys and 191 girls), 48.9% were partly under control (1,063 subjects: 605 boys, 458 girls) and 33.3% were poorly controlled (403 boys and 325 girls).

After adjusting for all confounders (passive smoking, recruitment season…), O children had a 33% greater chance of having worse asthma control than their normal weight counterparts. However, for girls, African-Americans had lower odds of worse asthma control than Latino-Americans.

The longitudinal European survey concerned 12,050 children belonging to 8 cohorts from different countries and suffering from A and allergies; its aim was to study A incidence as a function of weight gain profile: 3 categories were analysed according to WHO criteria:
  • One, normal
  • One with early and rapid weight gain in the first 2 years of life
  • One with progressive weight gain from age 2 to age 6
After adjusting for different child development factors, it appears that rapid weight gain in the first 2 years is the most predictive risk factor for A, and this up to age 6.

Finally, a 3rd study of 148 A and O children, aged 5-17 and predominantly African-American (KD Lu et al JACI Feb  2013 aop), points to an increase in the sensitivity to home and urban pollutants (PM 2.5 and NO2) in A and O subjects, and also that a control of home pollution is also beneficial for O.

4. Late-onset asthma (LOA) and metabolism of NO

Theme: Asthma
Key words: Late-onset asthma – NO (Nitric Oxide) – FENO (Fractional Exhaled Nitric Oxide) – ADMA (Asymmetric Dimethyl Arginine)

Late-onset asthma (LOA) is today considered as a particular phenotype, clinically severe, with a neutrophilic inflammatory profile, often occurring in obese persons, and responding little to inhaled corticosteroids. It thus differs from early-onset A (EOA) in young children, which is rather atopic and eosinophilic.

The recent multicentre US study (F.Holguin et al AJRCCM 2013 187 2 153-159) adds a new, metabolic, dimension concerning arginine, a NO substrate amino acid, whose synthesis is thus diminished because of its methylation.

155 subjects aged 18-69, belonging to a cohort of severe As, 73% women and 27% men but 47% obese were the object of the study:
  • One group suffering from LOA (76 cases)
  • Was compared to the EOA group (79 cases)

Given the known association between weight gain (frequent in LOA) and FENO decrease caused by the increase in ADMA plasmatic concentration and the decrease in the L-arginine/ADMA ratio, the research aimed to verify whether this mechanism was comparable in the 2 A groups.

Statistical results show that the ADMA average plasmatic concentration is indeed high in LOAs (and not in EOAs) whereas that of L-arginine was lower. And such a decrease in the L-arginine/ADMA ratio is associated with persistent respiratory symptoms, lower FEV1 and lung volumes, and lower IgE levels, which are all markers of LOA.

All in all, the study confirms that the L-Arginine/ADMA ratio may account for the inverse relationship between IMC and FENO, and that its decrease which reduces NO synthesis strips the latter from its protective role on the respiratory function.

The resulting conclusion in practice would be to treat these LOAs by L-Arginine or L-citrulline so as to restore the NO metabolism, but the first trials have so far not been convincing.

5. Allergenic extracts and their regulation : the French exception

Theme: Therapeutic - Immunotherapy
Key words: APSI (Allergens Specially Prepared for Individuals) – AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) – APSI Group

Like all medicines, allergenic extracts (AEs) have required a marketing authorization since 2001 in Europe. Two categories must be distinguished: usual, industrially produced allergens (APs), and “named patient products” (NPPs) specially prepared for an individual person by medical prescription.

They are regulated at the national level. In France, and in line with EU guideline, AFSSAPS (the French Agency for Health Products’ Safety) has introduced new requirements for all APs:
  • For each one a detailed technical file must provide all the pharmacologic, toxicological and clinical data supporting its quality and security but also its diagnostic and therapeutic interest.
  • The selection process first began by defining a list of relevant aeroallergens (pollens, dust mite, pets, fungi) and creating an ASPI/NPP work group composed of the main allergist organisations (teachers, scientific societies, continuing education institutions, trade unions) as well as representatives from the 2 AP manufacturers.
  • For an allergen to be authorized, it must be validated first by the ASPI/NPP group then by the two expert AFSSAPS Commissions.

The methodology is based on 5 assessment criteria, of which 2 are compulsory: evidence of the patients’ sensitivity to the allergen and proof of their exposure to it. A first list of 84 APs was drawn up and 73 retained ; then in 2008, and given the absence or insufficiency of valid published studies, only 66 were authorized (of which 29 were validated by scientific studies establishing their efficacy) and about 1/3 standardised. This strict French process, similar to that in the USA, has not been adopted by all European countries. But it guarantees that our APs are clinically relevant and safe, before a consensus on their standardisation.

Comments and questions welcome:

*Pr. Claude Molina

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**Dr Jacques Gayraud

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Last updated 29 October 2014