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RESOURCES

Claude MOLINA* & Jacques GAYRAUD**
 

1. ALLERGY
OR RHINOVIRUS AS THE CAUSE OF CHILDHOOD ASTHMA
2. CROSS SENSITIZATION OF FOOD AND ENVIRONMENTAL ALLERGENS
3. PRACTICAL ASPECTS OF THE HUMAN GENOME STUDY IN ASTHMA
4. THE PROTECTIVE EFFECT OF FARM MILK CONSUMPTION ON CHILDHOOD ASTHMA AND ATOPY
5. TREATMENT OF PERENNIAL RHINITIS BY NASAL INSUFFLATION OF CO2
 
 

1.
ALLERGY OR RHINOVIRUS AS THE CAUSE OF CHILDHOOD ASTHMA
Theme: asthma
Key words: aeroallergen sensitization, rhinovirus, respiratory syncitial virus (RSV), serum IgEs, asthma
 

The chicken or the egg paradox
 

For many years now, allergists and pneumologists have been wondering which of aeroallergen sensitization (AS) or rhinovirus (virus-induced wheezing) was the initial cause of childhood asthma. As suggested by some animal models and clinical studies on severe RSV bronchiolitis, it is the virus which induces AS. But,if AS precedes and predisposes to viral wheeze, it is allergy prevention which must be the strategy in fighting asthma. In order to answer this question, D.J.Jackson et al (AJRCCM 29 Sept 2011 ahead of print) of Madison University (Wisconsin) selected within a cohort of USA children, 285 subjects at high-risk for asthma, given their family histories, and followed them from birth to age six.
 
The chronology of events during these 6 years was studied in great detail with : precise virus identification, obtained in 90% of the cases (HRV or Human Rhinovirus, RSV or Respiratory Syncitial Virus, Adenovirus, Influenza virus, Coronavirus…), and corresponding clinical manifestations in the form of asthma-like wheezing, clinically diagnosed and requiring appropriate treatment (anti-infection and bronchodilator). At the same time serum IgEs to common aeroallergens were assessed each year. These data were treated using a multi-states Markov statistical model in continuous time. Results are significant :
1) children who were sensitized to aeroallergens have a greater risk of developing viral wheezing than non-sensitized children and, if this absolute risk is greatest at 1 year of age, the relative risk is consistently increased at every age assessed ;
2) AS leads to an increased risk of HRV- but not RSV- viral episodes ;
3) By contrast a viral wheezing episode does not induce a greater risk of AS.
 
Thus, for the authors, these results are indisputable:  AS precedes HRV viral wheezing and the converse is not true. So the prevention of allergy can indeed limit the development of viral wheezing, and consequently of childhood asthma.
 

2. CROSS SENSITIZATION OF FOOD AND ENVIRONMENTAL ALLERGENS
 
Theme: food allergy
Key words: tropomyosin, shell food allergy, dust mites, D.Farinae, cockroach, Blatella Germanica
 

It is known that food allergens such as shrimp, dust mite or cockroach, own a common protein : tropomyosin, which could account for the cross sensitization (CS) in subjects exposed to one or the other allergen, and who present high rates of specific IgEs, without clinical manifestations.
 
Based on data from USA national cohorts, which indicated that food allergy was particularly frequent – with an increased prevalence of high IgE shrimp allergy – in a population of inner-city black children, Julie Wang et al (JACI 128 4 834_837) wanted to check the possible correlation between IgE-mediated sensitization to shrimp and allergen exposure to dust mite and cockroach.
For this purpose, they studied the serum of 500 subjects in a cohort of 1528 children aged 4-9 and living in New-York, St Louis and Baltimore inner-cities, while their homes were checked for concentrations of Dermatophagoides Farinae and Blattela Germanica.
 
They first observed a strong correlation between shrimp, cockroach and dust mite specific IgE levels. Furthermore, high exposure to cockroach in the home, particularly in the bedroom and television room, was significantly correlated with higher shrimp and cockroach IgE levels. In contrast, high exposure to dust mite in the home was highly correlated with IgE levels to D.Farinae but not with shrimp IgE levels. Besides, exposure and presence of cockroach IgEs are predictive of high shrimp IgE levels.
Thus, in children with evidence of joint IgE-mediated sensitization to cockroach and shrimp, having high exposure to cockroach in their inner-cities’ home can contribute to higher shrimp IgE levels, which might not correlate with clinical allergic reactivity.
 
This notion should be taken into consideration for the interpretation of a shrimp sensitization in such subjects, and before any attempt of provocative tests usually recommended for confirmation of the corresponding food allergy.
 

3. PRACTICAL ASPECTS OF THE HUMAN GENOME STUDY IN ASTHMA
 
Theme: genetics, asthma
Key words: asthma, Single Nucleotide Polymorphism, inhaled corticosteroids, genome, gene GLCC11, allele rs37972, allele rs37973
 

The explosion in genetic research, the speed and accuracy of new generation techniques, call for acquaintance with interpretation of results and their present and future relevance for allergic diseases. A recent review does this with reference to respiratory diseases (J.Todd et al AJRCCM 2011 184 873-880). Up to February 2011 a total of 22 studies had been published, 13 of which on the genetic basis of asthma. The validity of results depends on an accurate classification of the disease, a great rigor in the genetic study, a platform large enough to cover the whole genome, quality controls, a study of the many genotypic nucleotides (SNP : single nucleotide polymorphism), a bio-informatic and statistical analysis and a confirmation in other patient groups (replication populations). The difficulty with asthma comes from the heterogeneity of clinical phenotypes, and the probable role of associated environmental factors in the development of the disease. Hence, the limited practical relevance of this research at present.
 
In contrast, by addressing a well-targeted category of asthmatics, i.e. subjects where inhaled corticosteroid therapy is ineffective (1 in 3 on average), the genome study (Genome-Wide Association) has led to identifying a genetic variant associated to the pharmacological treatment response (K.G.Tantisira et al NEJM 2011 365 1173-83).
 
The authors followed 1041 asthmatic children aged 5-12, enrolled in a large cohort (Childhood Asthma Management Program : CAMP) clinically and functionally monitored and random-treated either by Budesonide(®, Nedocromil® or Placebo, for an average of 4.6 years. 422 subjects were selected and genotyped (DNA) as well as their parents ; out of this group 118 trios (child + both parents) were isolated. From these examples, the researchers identified, based on family statistics, 13 possible SNP candidates among the 534290 tested ones. These SNPs were replicated in 4 different patient groups, which made it possible to isolate within gene GLCC11 (gluco-corticoid transcript) an allelic variant, rs37972, associated with a lower FEV1 in response to inhaled corticoids (ICs).
 
To confirm this observation, the authors made use of cell lineages isolated in vitro and managed to isolate re37973 which is in total correlation (linkage disequilibrium) with rs37972, both associated with decrements in gene GLCC11 expression, i.e. the absence of response to ICs.
 
This substantial pharmacological effect, prefiguring personalised treatment (according to J.M.Drazen in an Editorial on this research)  , is not however outstanding : if, in the IC-treated CAMP patients with rs37973 the FEV1 decrease is statistically 3 times lower than in those who do not own this allele, the values are low and only concern a small number of asthmatic patients.
 

4. THE PROTECTIVE EFFECT OF FARM MILK CONSUMPTION ON CHILDHOOD ASTHMA AND ATOPY
 
Theme: prevention, atopy
Key words: asthma, farm milk, raw milk, boiled milk, whey
 

This is the new factor identified by the German and Swiss epidemiologists of the E. Von Mutius group, among those which have been suspected to account for the protective effect of the rural life against asthma and atopy. The authors again used their data base (GABRIEL), sent a questionnaire to the parents of 8334 school children and obtained serum samples from 7606 of these children for the detection of specific IgEs. Moreover, on 800 samples of milk from the parents’ farm, they conducted bacteria counts and measured fat content and whey protein levels; this data was confronted to asthma, atopy and pollinosis, and statistically analysed by multiple regression (G.Loss et al JACI 2011 128 766-773).
 
It appears that raw milk consumption is inversely associated with asthma, atopy and hay fever, independent of other farm exposures. Boiled farm milk did not show this protective effect, nor bacterial counts or total fat content of milk.
 
In contrast, the whey proteins account for the protective effect against asthma, but not against atopy. It is the case for the bovine serum-albumin, α-lactalbumin, and β-lactoglobulin, all proteins pertaining to the residual liquid from milk skimming and contributing to the production of cheese and buttermilk.
 
On the whole, the protective effect of raw milk consumption on asthma could be attributed to the whey protein fraction of milk.
 
But, in cauda venenum, the authors admit that, even if this research is interesting from an epidemiological point of view, the consumption of raw milk for protection on asthma or atopy cannot be recommended in practice because it could contain a number of pathogenic elements !
 

5. TREATMENT OF PERENNIAL
RHINITIS BY NASAL INSUFFLATION OF CO2
 
Theme: ORL, allergy
Key words: allergic rhinitis, nasal CO2 insufflation
 

The authors, who in 2008 had already pointed out the effect of CO2 administered by nasal insufflations, without inhalation (Casale et al JACI 2008 121 105-109), have extended their research by a multicenter random study with a view to confirming the efficacy and safety of this treatment, a symptomatic but non-pharmacological treatment which can be useful in certain persistent forms of rhinitis affecting quality of life of patients (Casale et al : Allergy,Asthma,Immunol 2011 107 364-370).
 
The technique consists in administering CO2 out of a standard gas high-capacity cylinders, fitted with a regulator and valves to control the flow rate (5 to 10 ml/s in the random trial), connected to a tube ending with an adaptable and disposable nasal piece. The insufflation is performed under medical supervision, for duration of a few seconds in each nostril (10 to 30 depending on the group) while the patient is asked not to inhale the gas, but invited to breath by mouth if necessary. At the same time, symptom scores are assessed from 1 to 6 according to the severity of nasal symptoms (congestion, rhinorrea, sneezes, itching) and non-nasal symptoms (eye and ear itches, pharyngeal lacrimation, red eyes).
 
Thus, 6 groups (including the Placebo ones) are formed, totalling 348 subjects suffering from rhinitis for over 2 years and presenting signs of allergy to common aeroallergens (except pollens).
 
It is group B (70 subjects), treated for 10 seconds at 10 ml/s in each nostril, which showed the most statistically significant results, with regression of all symptoms (nasal and non-nasal) in less than 30 minutes and for several hours (4 to 6) ; in the previous trial conducted by the authors the improvement could last up to 24 hours.
 
The other groups (5ml/s for 30 seconds, or 5 and 30 or 10 and 30) are more efficacious than the 2 Placebo groups, but not significantly enough. As to adverse effects, these were limited to some headaches and temporary nasal discomfort.
 
As a conclusion, we have evidence here of the treatment of symptoms, almost immediate but short in duration, which could be useful in young or elderly subjects, intolerant to drug treatments. But the effects of insufflation of CO2 several times a day, as well as the still unknown action mechanism of this treatment, call for further researches.
 
 

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Comments and questions welcome:
 

Pr. Claude Molina and/or Dr Jacques Gayraud
* **