Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Respiratory infection or allergy in infancy (or : Semiology rehabilitated by statistics)
2. Breastfeeding (BF) and allergy prevention – 1° : Epidemiologic data
3. Breastfeeding (BF) and allergy prevention – 2° :  Mechanisms
4. Nutrition and allergy : prebiotics and/or probiotics
5. Tuberculosis, BCG and allergy

1.    Respiratory infection or allergy in infancy (or : Semiology rehabilitated by statistics)

Theme: Asthma, infection
Key words: Asthma – Cough – Dyspnoea - Medoid

We know how difficult it is with coughing or breathless young children to differentiate between respiratory infection and allergy.

This is why a team of French researchers and paediatricians (Fanny Ranciere et al of the Health-Environment group : Isabelle. Momas : Ped.All. Immunol 2012 early view) undertook a very interesting and original study. They had previously monitored 2632 children of less than 1 year of age from a ‘Pollution and Asthma Risk’ cohort. Using the ‘medoid’ algorithm (Partitioning around medoids) which leads to a silhouette-graphed clustering, they had isolated 2 respiratory phenotypes : cough phenotype (CP) and dyspnoea phenotype (DP). They wanted to check whether these phenotypes were still valid at the age of 3, by following 2,084 children between 2003 and 2006 and clustering them according to symptoms, that is: sleep disturbing night cough, or dyspnoea. Purposefully, the term ‘wheezing’ was not used.

Parental questionnaires, family history of allergy, comorbidity, risk factors, domestic pollution, all the data analysed by multinomial logistic regression confirm the ‘medoid’ regrouping in 2 main profiles :
1)    CP : 14% of children, with dry night cough without dyspnoea, genetic factors of atopic predisposition, frequent allergic symptoms and presence of domestic allergens, as well as family problems such as parent separation or very ill mother.
2)    DP : 30% of subjects, with more severe symptoms, breathlessness disturbing sleep and daily life, day care centre attendance and infection risk factors, vulnerability to pathogens, domestic pollution (often chemical : tobacco, volatile organic components).

Thus, the 2 main symptoms of respiratory problems in 1- to 3-year old infants, i.e. cough and dyspnoea, when correctly analysed, help in discriminating between infection and allergy. Our Parisian colleagues should be thanked for having thus rehabilitated symptomatology, at a time of the apparent triumph of technology, and this, paradoxically, thanks to a cutting edge statistic tool.

2.    Breastfeeding (BF) and allergy prevention – 1° : Epidemiologic data

Theme: Atopy, atopy prevention
Key words: Breastfeeding – Asthma – Eczema - Infections

The role of breastfeeding in protection against allergic diseases is still arousing controversy : no less than 6 recent publications discuss it, mostly a confrontation between Europeans and Australians.

In ‘A tale of two cities’ (Brew et al: Ped.Allergy & lmmunol 2012 23 75-82), the authors confront the randomised data from 2 cohorts, one from Sidney (419 subjects) and the other from Stockholm (463), i.e. 882 subjects in whom the definitions for breastfeeding (at least for 3 months), asthma and allergy, were harmonized, and who were enrolled if they had at least one atopic or asthmatic parent and had a gestational age of more than 36 weeks.

After statistical analysis, it appeared that BF reduces the risk of asthma at the age of 4/5 and 8 years in children with family history of asthma. This effect is more marked in the Swedish than in the Australian cohort. It is also the opinion of some New Zealand authors (KM Silvers et al J. of Pediatrics 2012 January in press).

However a sceptical opinion can be found in a paper from Melbourne (Matheson et al : Clin & Exp. Allergy 2012 31 01 early view) which evokes an apparent protective effect of BF against asthma, but none against eczema or food allergy, nor any prevalence of sensitisation to airborne allergens. The authors believe that several confounders exist in the numerous epidemiologic studies, and wonder whether BF is not merely active in the prevention of infection, rather than actually reducing the risk of asthma. In the Australian cohort itself, BF may even act as risk factor for sensitisation to cow’s milk, eggs and peanuts at the age of 4/5 and, in both cohorts, at 8 years. Some authors had even suggested stopping it for under 1-year old children if some eczema or wheezing occurred, but the Melbourne authors found no evidence, in their joint study, that BF might have influenced any allergic manifestation.

On practical grounds, it is difficult for the clinician to adopt a dogmatic attitude in this matter, knowing however that in our Western countries it is recommended, depending on circumstances and environment, to breastfeed without exceeding 3 months.

3.    Breastfeeding (BF) and allergy prevention – 2° : Mechanisms

Theme: Atopy, atopy prevention
Key words: Maturation of innate immune responses – Cytokines – Polyunsaturated fatty acids

Epidemiologic data being not always convincing, BF supporters, including the WHO which recommends 3 to 6 months depending on the country, have tried to better define possible mechanisms.

Thus, a recent Anglo-Swiss study (C.M Dogaru et al. AJRCCM 2012 3 early view) of 1458 children, concludes that breast feeding has a favourable effect on the child’s future respiratory function by direct action on lung growth, particularly if the mother is asthmatic.

But a biology-focused Dutch group (M.G Belderbos et al : Ped.Allergy & Immunol 2012 2365-74), considering that the 1st month after birth is the most sensitive to environmental factors which can modulate the infant’s innate immune responses, undertook a prospective study of 291 healthy neonates (NN). They then statistically treated 6 exogenous factors (mode of delivery, BF, birth month, atopic siblings, passive smoking, pets), 7 types of total blood cells measured by flow cytometry (neutrophils, eosinophils, basophils, dentritic myeloid cells, monocytes, natural killers, T lymphocytes) and 9 types of cytokines induced by Toll-like receivers (TLRs 1 to 9) revealed by the ELISA technique.

On the whole, it can be said that BF was found to be the determining exogenous factor for neonatal immunity, with 5 associated parameters : the production of TLR7-induced IL10 cytokine which is 4 times lower than for a formula-fed NN, whereas the TLR3-induced cytokine IL12p70 is 2 to 3 times higher, a sign of fast immunity maturation. On the other hand, the reduction of this latter cytokine is associated to the caesarean mode of delivery and could express an asthma risk for the infant. So, it is the 1st month immunity maturation which appears to provide the protective effect of BF.

Let us also quote the Barcelona survey (Eva.Morales et al Clin.Exp.Allergy 2012 30 January) conducted by parental questionnaires, with 580 children submitted to predominant BF during the first 4 to 6 months and whose long-chain polyunsaturated fatty acids (LC-PUFA) were dosed in colostrum. With high levels, a reduction in risk of wheezing and atopic eczema in 7- to 14-month old children is observed, as well as a lower risk of gastroenteritis in the first 6 months. This may account for the possible role played by nutritional factors in the preventive effect of BF, which some authors also attribute to the presence of TGFβ in mother’s milk.

4.    Nutrition and allergy : prebiotics and/or probiotics

Theme: allergy prevention
Key words: Intestinal micro flora – Infection – Antibiotics – Fatty acids – Prebiotics - Probiotics

The significant role of Intestinal Microflora (IMF) in the modulation of immunity is well known, with any change in its composition likely to trigger inflammation or allergy. Such is the case of antibiotics which, administered to children of less than 1 year, lead to allergic sensitisation. The high frequency of urban as opposed to rural allergies is also often explained by the presence in the former of a more limited microbe range. Food or ingredients are also likely to affect IMF. This is the case for long-chain polyunsaturated fatty acids, but also for polyphenols and substances like prebiotics and probiotics, supposed to preserve or restore the microbial balance.

Prebiotics are carbohydrates, non-digestible by man, which, like inulin (produced by plants) or galacto-oligosaccharides, have a positive impact on IMF, by allowing the proliferation of bifido-bacterial type germs, the same germs that can be found in the breastfed baby. The International Association of Pre- and Probiotics has recorded more than 700 therapeutic trials with no formal conclusion, because the specific Prebiotic of a given microbial population is not known, neither the proper dosage.

As for Probiotics, which are living micro-organisms, these are under intensive research, both experimental and clinical, particularly in the food industry. One thinks particularly of yoghurts or other fermentation products, and of Lactobacillus (C.Wylliard  Nature 2011 479 S5-7). Many studies have been published of Lactobacillus casei administered to newborns in order to prevent eczema or asthma, or of Lactobacillus rhamnosus to infants or mothers before giving birth : more than 25 in 2008, randomised and often contradictory. In a recent Swiss paper (Wassenberg et al : Clin.Exp.Allergy 2011 4 565-573) the use of L.paracasei ST11 administered per os for one month in about 30 subjects, has shown some efficacy on the signs of pollen rhinitis. Other Japanese experiments were conducted successfully on mice with Clostridium (which has 46 different strains). But, on the whole and with the risk of playing the sorcerer’s apprentice, care must be taken in modifying or regulating IMF in order to combat or prevent allergic manifestations.

5.    Tuberculosis, BCG and allergy

Theme: allergy prevention
Key words: Tuberculosis – BCG (Bacille Calmette-Guerin) – Asthma - Eczema

An Anglo-Algerian epidemiologic retrospective randomised study, under the authority of the International Union against Tuberculosis and in the framework of the ISAAC study Phase 2 (C.Flohr et al Ped.Allergy & Immunol 2012 February early view), has attempted to discover whether previous tuberculosis (TB) or BCG vaccination in the first months of an infant could have a protective effect against the risk of allergy. 23,901 subjects, aged 8 to 12 and attending 20 different centres in developed and underdeveloped countries were the object of this study, conducted both by questionnaires and clinical examinations, concentrating on flexural eczema, and using skin prick tests. The odd ratios corresponding to a 95% confidence interval were calculated in the different centres according to the classical model. There were 245 TB cases and 66.3% of the children had received the BCG vaccine.

Findings showed that all allergic manifestations (asthma or wheezing, hay fever, signs of eczema) were significantly associated with TB the previous year. This was all the clearer for severe asthma and clinically established eczema. However, there is no association between TB and skin prick tests. As for BCG vaccination during the first year of life, it was in no way associated with subsequent allergic manifestation and does not seem to have a preventive effect against allergy.

All in all, this curious, positive association between TB and allergy does not, as the authors acknowledge, point to a causal relationship, but in view of the high number of subjects albeit in a cross-sectional study, it is possible to grant some value to this epidemiologic survey. It is above all interesting for those countries still struck by endemic tuberculosis.

Comments and questions welcome :

Pr. Claude Molina    and/or    Dr Jacques Gayraud
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Last updated 15 October 2014