Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Allergic reactions to vaccines
2. Health, economic and environmental impacts of rehabilitating asthmatic children's homes (simulation model)
3. Neonatal health of infants born to mothers with asthma
4. Immunity receptors and upper airways
5. Onset and evolution of allergy-like respiratory symptoms , in preschool children

1. Allergic reactions to vaccines

Theme: Allergy to vaccines
Key words: Vaccines - Vaccine constituents

The reluctance shown by many adults, for themselves and their children, toward vaccination in general, comes from the presumed risks of side-effects, among which allergic reactions, albeit relatively rare, come high. What is the reality? This is the question R.Wood attempts to answer (Pédiatric allergy and Immunol 2013 24 521 26).

Like all medications, any vaccine is likely to provoke an anaphylactic reaction; but statistically speaking, these reactions vary from 1 in 50 000 doses to 1 in 1 million doses. The timing and variety of symptoms already distinguish between immediate and delayed allergy.

In fact it is rather the vaccine constituent that the microbial components which usually causes these reactions; the author quotes the following :
1) Gelatine (measles, rubella, mumps).
2) Egg protein (influenza, yellow fever).
3) Milk casein (anti-diphtheria and anti-tetanus vaccines).
4) Preservatives (Tiomersal, Aluminium, usually responsible for delayed local reactions).
5) Latex (syringe or medical equipment).
6) Traces of antimicrobials
7) Yeasts (hepatitis B and papillomavirus)

The clinical approach to these reactions is based on classical algorithms, depending on the urgence or not of vaccination, subject's age, first vaccination or booster shot, patient's history (allergic or otherwise), intensity of symptoms on previous vaccinations.

The allergist may thus need to carry out vaccine or constituent skin tests; biological tests will complete the information (in the known allergic subject : gelatine, egg). He may also have to divide the vaccine into 2 or 3 doses.

Finally, new developments are likely to arise; there are influenza vaccines without egg protein (Optaflu, Flublok) which have been validated by European and US authorities. With regard to this, the author underlines the specific guidelines for the administration of influenza vaccine to egg allergic patients i.e. the care that should be taken with adults or children who have shown + severe reactions to egg, thus requiring medically administered injections; and, in any case, avoid inhaled vaccines (which contain egg traces) since data on their harmlessness are still lacking. Moreover the author recognizes that these recommendations may change over the coming years.

2. Health, economic and environmental impacts of rehabilitating asthmatic children's homes (simulation model)

Theme: Allergy and indoor environment
Key words: Housing – Asthma – Indoor air quality – Combustion pollutants

This original article uses environmental, statistical, medical and economic techniques to compare a complex system, that is, the evolution of asthma in children and its consequences, according to building interventions aimed at improving the quality of indoor air and reducing energy costs (M.P Fabian et al JACI 2013 early view).

The study concerns asthmatic children living in Boston in low-income families whose + polluted housing required energy-saving interventions. At the same time the effect on asthma improvement was evaluated, together with the reduction in health care costs (provided by medical insurance in the USA: Medicare, Medicaid), all of which was compared to the cost of these interventions.

The method consisted in perfecting a pediatric asthma simulation model, validated by data from other papers. It is classified as moderate or severe according to FEV1, daily symptoms, evolution, medication given and any hospital admissions. Then follows indoor air pollutants evaluation: combustion pollutants: NO2, particles under 2,5µg (PM 2.5), cockroach allergens (Bla g 1 et 2 often found when pets lived in the home) and damp (witness of fungi).

The characteristics of the housing were then analyzed with a view to improving quality and conformity with public regulations and energy saving measures.
These interventions could be isolated or form part of a bundle: replacing gas stoves by electric ones , repairing kitchen exhaust fans, eliminating pets and smoking in the household, fitting high-efficiency particle filters, double-pan windows, weatherization of the building, (partially financed by the US government); outcome of asthma symptoms and costs of health care were evaluated according to each intervention.

Among others, results showed that elimination of pets (responsible for reduction in cockroach allergen concentration), associated to the repair of kitchen exhaust fans, produced a drop in asthma exacerbation of 7 to 12% with one to three year payback periods. Many other examples are quoted (together with their estimation in monetary terms). In this way the housing rehabilitation program (aiming at improved insulation) has indeed led to a 20% increase in the frequency of asthma symptoms due to a rise in damp level from 19 to 67%, but this was mitigated by repairs to air vents in the kitchen and bathroom, and by elimination of pollution sources such as the replacement of gas stoves.

The findings of this simulation model which can be applied to other populations, means that the savings from each intervention can be calculated, and its efficiency evaluated.

After consideration of these different examples (in this case young asthmatic living in deprived housing conditions), it is clear that physicians must not only take into account the treatment of the patient but also look at patient environment, particularly indoors, and the economic and health impact of interventions aimed at improving it. Assistance from public authorities is justified since they too are interested in the air quality in more salubrious housing and in energy savings. This work bridges the gap between clinical and environmental health sciences

3. Neonatal health of infants born to mothers with asthma

Theme: Asthma- Atopy
Key words: Newborns – Maternal asthma

Maternal asthma is the most common chronic affection during pregnancy, labor and delivery with a frequency which almost doubled between the 1990s and the 2000s (P.Mendola et al JACI 2013 August in press).

It is well known, for many years, that maternal asthma has been the cause of risks of obstetrical complications (pre-eclampsia, placenta abruption, pulmonary embolism) as well as premature birth, loss of weight and size for the newborn, and increased frequency of hospital admissions, intensive care, malformations, perinatal mortality.

A group of US gynecologists from 12 clinical centers, including 19 hospitals in 9 US districts, undertook an extensive retrospective study using the 2002-2008 US survey on 225512 newborns (NB) with a recorded birth after the 23rd week of gestation. 17044 of them, born to asthmatic mothers, were compared to as many non-asthmatic mother NBs, using logistic regression statistical methods :adjusted odds ratios with a 95% confidence interval (CI).

The methodology consisted in recording the data on the number of weeks of gestation, all the classical manifestations observed in the previous epidemiological studies, i.e. : respiratory complications (apnea, tachypnea, asphyxia and respiratory distress), cardiac manifestations, intra cerebral hemorrhage, enterocolitis, as well as prematurity and perinatal mortality (death between the first and third week).

The findings:
1) Firstly, and contrary to previous studies, which linked the frequency of perinatal complications to preterm delivery, this was only significant after the 33rd week of gestation, that is, between the 33rd and 37th week.
2) The risk of neonatal complications is statistically higher among newborns with asthmatic mothers than with controls, after adjustment for delivery method and the mother`s clinical and demographic factors.
3) The most frequent complications noted: undersized NBs, admission to NICU, hyperbilirubinemia, jaundice and respiratory complications as well as intra-cerebral hemorrhage and anemia, less frequently and among at-term NBs.

It should be noted that the risks of jaundice observed in many other statistics and which were considered as the effect of corticoids administered to the mother, have not been observed here ; there was no sex-related increased risk either.

The authors finally point out the statistical power of their study, higher than all those previously published. Admittedly its limitation was the lack of precise information on the characteristics of the maternal asthma, exacerbation risks, and treatment; it should be noted however that, a poorly controlled asthma leads to an increased risk of prematurity and undergrowth; in other words is efficient treatment is the safest security of a favorable evolution of the NB's health.

To conclude, the authors point out that maternal asthma is significantly associated with prematurity and undersized NBs and that complications (respiratory and jaundice primarily) are more frequent in NBs with asthmatic mothers even among at-term deliveries.

4. Immunity receptors and upper airways

Theme: Immunology
Key words: Immuno-receptors – Upper airways – Bitter taste receptors

Among the natural or adaptative immunity receptors, the most well known are the Toll-like receptors (TLR) expressed in the cilia cells of the upper airways. They play an important role in recognizing microbials (TLR4 for Gram (-) bacterial polysaccharides, TLR2 for Gram + peptidoglycans and lipoteichoic acid.

But a new class of receptors has recently emerged: the T2R bitter taste receptors.

In the January 2011 BUA we mentioned the subject, these receptors intended to play a defensive role against the ingestion of toxic substances, these new receptors were observed in the airways (A.Deepak et al. Nature Med 16 Nov 2011 1299-1304), which could mean that when activated, they triggered a bronchial spasm, protective factor against atmospheric pollution.

More recently a group of US authors (American journal of Rhinology et allergy: R.J.Lee et N.A.Cohen 2013 27 283-286) has pointed out the presence of these receptors (T2R) in sino- nasal cavities and suggest that their essential role was to neutralize bacteria. As there are 25 isoforms, the group tested several of them on cultivated nasal mucous biopsies from 56 patients with chronic rhinosinusitis (CRS), in order to study their neutralizing role on Pseudomonas aeruginosa.

Whereas T2R 19, 30 and 46 are ineffective, T2R38 appears to be the most important in the struggle against microbial flora, particularly Gram-, by means of biochemical mechanisms leading to activation of cilia cells and secretion of NO. But the authors go even further, knowing that T2R38 is encoded by the gene TAS2 R38 which includes two polymorphisms, depending on the position of aminoacids: an active haplotype, due to the proteins (Proline, Alanine, Valine, PAV) and a non-functional haplotype (Alanine, Valine Isoleucine AVI). Thus PAV/PAV homozygotes present greater defense against germs and are known as super tasters (as opposed to non tasters).

The authors therefore put forward the hypothesis that patients suffering from CRS react differently to treatment according to genotype, and in a pilot study of 26 subjects they observe, after genotyping, that the only PAV/PAV homozygote subject reacted favorably to the medical treatment, whereas surgery proved necessary for the 9 PAV/AVI and the 4 AVI/AVI subjects.

The small number of cases rules out formal conclusions, but our attention is now drawn to the importance of genetic studies in treating CRS.

In conclusion, this mucociliary clearance function, due to bitter taste receptors, is crucial both in treating and preventing upper airway infections. Moreover, the well known role of activators as flavor enhancers (natural sugars, saccharine) could help us understand the importance of these substances in empirical treatment of some cases of rhino-pharyngeal chronic cough

5. Onset and development of allergy-like respiratory symptoms in preschool children

Theme: Atopia
Key words: Allergic pathway - Preschool children - Night cough – Parental smoking – Allergens – Atopia – Antibiotherapy.

Following up on the epidemiological study of a cohort of Parisian preschool children (the PARIS cohort, Pollution and Asthma Risk in Infant Study), the French authors, whose recent night cough study we analysed (BUA May 2014), have attempted to understand the onset and evolution of allergic type symptoms, identifying different phenotype trajectories in these children aged 3 months to 4 years (F.Rancière et al ,of the group I.Momas : Allergy 2013 68 1158-1167). The children were examined several times between 2003 and 2006.

From the whole cohort of 3840 children, the authors selected 2522 for this new study. A series of relevant statistical tools were used with the aim of overcoming researchers' subjectivity. K-means algorithm (a sort of data partitioning/clustering) while associating these phenotypes with IgE sensitization, and multinomial statistic regression for risk factors studied, Details of symptoms and their evolution are presented in many statistical tables.

The authors thus isolated four phenotypes: 2 transient (T), 2 persistent (P). Using a control group with few or no symptoms at all (1236 cases, i.e. 49%), they observed that the 2 T phenotypes were marked: T1 essentially by rhinitis in 295 children, i.e. 11%, and T2 by wheezing, essentially nocturnal, in 399 cases i.e. 15%. As for the two P phenotypes: P1 was characterized by rhinitis with cough in 234 subjects, and P2 by dermatitis in 308 cases (12%).

At the final age-4 examination, the authors noted, taking these phenotypes and corresponding risk factors, that for T1 the greatest risk factor is parental smoking. According to statistics, T2 mainly concerns boys, and the risk factor is daycare attendance source of promiscuity and probable exposure to infection risks.

As for the two other phenotypes, P1 and P2, these are considered as the result of exposure to allergens, either respiratory (dust mites in the bedding, fungi) or food allergens, but they are also associated with family allergy history essentially parental, and with high frequency stress. All these factors point to later development of allergic reactions. As for atopic dermatitis, which like P1 is accompanied by high IgE levels and often hyper eosinophilia, it has its own risk factor: the frequency of maternal antibiotic treatment during pregnancy.

Thus, the two transient phenotypes could be interpreted as expression of irritated airways associated with infection in a smoking environment.

On the other hand, the two phenotypes P1 and P2 with permanent symptoms both present IgE sensitization, which appears to correspond to the classic atopic march: evolution from dermatitis to asthma during the child's growth (11% of cases, which is equal to the prevalence of asthma in French school-age children). Also in these statistics, the authors confirmed the importance of psycho-social factors and the protective role of breastfeeding in the development of allergy.

Comments and questions welcome:

Pr. Claude Molina

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Dr Jacques Gayraud

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Last updated 29 October 2014