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Claude MOLINA* & Jacques GAYRAUD**

1. ATOPY HEREDITY : PATERNAL OR MATERNAL?
2. PEANUT ALLERGY : CAN SEVERE REACTIONS BE PREDICTED?
3. THE PSYCHOLOGICAL IMPACT OF DIAGNOSTIC FOOD CHALLENGES TO CONFIRM THE RESOLUTION OF PEANUT ALLERGY
4. NASAL POLYPOSIS (NP) AND ANTI-IL5 MONOCLONAL ANTIBODIES (MA)
5. RHINOVIRUS AND RISKS OF ASTHMA EXACERBATION


1.    ATOPY HEREDITY : PATERNAL OR MATERNAL?
Theme: atopy, asthma
Key words: heredity, asthma, cytokines, atopy

A Danish university team involved in research on child asthma and hereditary transmission of atopy hypothesized different parental imprinting on the cytokines and chemokines in the upper airway mucosa lining fluid of neonates (NN), a set of chemical mediators considered as markers of natural and adaptive immunity.

This team developed an original, clever and non-invasive technique (N.V.Folsgaard et al AJRCCM  November 2011 ahead of print) of sampling by absorption on a filter (of the blotting paper type) of the nasal mucosal lining fluid, applied for 2 minutes, thus avoiding the dilution coming from lavage, for mediator concentrations just above the detection threshold. This technique proved safe for neonates and later for children.

It was applied on 309, 1 to 31-day-old NNs of a Danish cohort, and 18 cytokines and chemokines were quantified. At the same time, atopy was diagnosed among 173 mothers and 142 fathers (47%). In all, 241 NNs had either an atopic father or mother, without showing different characteristics from non-atopic parents’ NNs. These data were statistically treated (principal component analysis).

The results showed that atopic mother NNs presented a significant decrease in cytokine levels (IL10, IL12p, IL2, IL4, TNFα, Eotaxin 3, MCP-1, CP-4 and TARC) as compared to NNs with atopic fathers and non-atopic mothers.

Generally speaking, maternal (but not paternal) atopy shows a strong down-regulation in all these mediators, suggesting some delay in NN’s immunity maturation and therefore a notable influence of the maternal milieu on his immunity programming, either in utero (depending on nutritional factors or pregnancy microbiome) or perinatal life by placental transfer of IgEs.

…And the answer is… the Mother !


2.    PEANUT ALLERGY : CAN SEVERE REACTIONS BE PREDICTED?
Theme: food allergy, allergens
Key words: peanut, food challenge, specific IgE, eliciting dose, age, atopic dermatitis

Dutch paediatric allergists (Groningen et Amsterdam :T.Van der Zee et al JACI2011 128 1031-6), noting that severe reactions can occur after accidental ingestion of peanuts, have attempted to look for risk factors in children. They based their research on the eliciting dose in double-blind, placebo controlled food challenges (DBPCFC) as a marker for clinical responsiveness.

This was a retrospective study of a 2001-2009 data base of 126 peanut-positive DBPCFC
in subjects aged 3-17, two-thirds male, a majority with family atopic history, and having suffered themselves from a severe reaction to peanuts 4-36 months before the test. Specific IgEs were high (18.6 kU/L on average, with a dispersion of 3.8 to 76.6 kU/L). Some subjects were also suffering from atopic dermatitis (79 cases), asthma (79) or rhinitis (53).

The symptoms observed after the challenges (the eliciting dose varying from 200 to 820mg, with an average of 310mg) were either: Objective (angioedema, urticaria, dermatitis, rhino-conjunctivitis, coughing, wheezing, vomiting, diarrhoea) or Subjective (itching, nausea, dyspnoea). A score was given on the basis of these data and then statistically analysed (Cox regression model).

Results reveal that the eliciting dose (ED) is statistically correlated with 3 main risk factors:
1)    Subject’s age : those over 10 years of age have the lowest ED and therefore the severest clinical response, a somewhat surprising result in view of the usual belief that peanut allergy is becoming milder as time goes by.
2)    Specific IgE levels : over 5.6kU/L, which is understandable.
3)    Absence of associated atopic dermatitis, which is unexpected.

As to other factors, incriminated in other research or in clinical experience, such as gender, association with asthma or rhinitis, or previous severe reactions, no significant correlation was shown.

The authors however, knowing that  a risk of accidental ingestion is still possible recommend a strict eviction diet and a self-injectable epinephrin kit in case of accidental ingestion of peanuts.


3.    THE PSYCHOLOGICAL IMPACT OF DIAGNOSTIC FOOD CHALLENGES TO CONFIRM THE RESOLUTION OF PEANUT ALLERGY
Theme: food allergy, allergens
Key words: resolution diagnosis, peanut, food challenge, skin test, specific IgEs, anxiety, quality of life

Publications on the psychological factors of allergy are often   of limited interest in current practice. The originality of this work by a British team from Southampton- (R.C.Knibb et al Clin. Exper Allergy 2011 November ahead of print) is that it is based on precise scientific criteria (case-control study).

The authors point out that peanut allergy resolves itself in 20% of children and walnut and hazelnut allergy in 10%. Such resolution, clinically established by absence of reaction over several years and negative skin tests and specific IgEs, has to be confirmed by a per os food challenge ; it was interesting to evaluate anxiety, stress and quality of life of children and their mothers, on the day of the test and during the following 3-6 months.

103 families took part in this research and completed the corresponding questionnaires, which were validated in Great Britain. 40 children, aged 6-16, underwent the challenge and answered the questions on their social, school and emotional life. 63 children, with persistent allergy in the opinion of the allergist, were used for comparison and answered the same questions (the mother rather than the father being interviewed).

Results : 17 tests (43%) were positive, indicating the persistence of the allergy ; 50% of the children had a negative test. From a psychological point of view:
1)    Mothers reported raised anxiety on the day of the challenge (P=0.007) whereas children were less anxious than usual.
2)    Children (P=0.01) and mothers (P=0.01) had improved quality of life with regards to the role of peanut in their diets, but not concerning food allergy in general.
3)    Children reported lower anxiety levels in the 3-6 months following the negative test (P=0.02) but mothers’ anxiety remained unchanged.
4)    Finally, the improvements in children’s and maternal anxiety and quality of life were independent of the test results.

So, as could be expected, and unlike their children, mothers were more anxious on the challenge day, thus reflecting differences in risk perception. But what is curious is that children’s and mothers’ quality of life was improved even in the case of a positive food challenge. The authors believe this reveals a real appreciation of the challenge, considered as both a diagnostic and therapeutic tool by the parents  and  even is disappointing, as a clarification  of information that influences management and imparts psychological benefits.  


4.    NASAL POLYPOSIS (NP) AND ANTI-IL5 MONOCLONAL ANTIBODIES (MA)
Theme: ORL allergy, immuno-physiopathology
Key words: nasal polyposis, anti-IL5 monoclonal antibodies, Mepolizumab, essinophils, cytokines

The Belgian university hospital ENT team (Gand et Liege P.Gevaert et al JACI 2011 128 989-95) famous for its expertise in NP, assisted by a group of English specialists, has in a recent paper rehabilitated the anti-IL5 MA Mepolizumab (M) which, presumably due to inaccurate indication, had been considered as inefficient in the treatment of asthma.

It should be remembered that, contrary to Chinese patients, in white Europeans 85% to 90% of nasal polyps are infiltrated by eosinophils, for which IL5 is the key driver of cell differentiation and survival. The authors sought to investigate the efficacy and safety of two intravenous injections (28 days apart) of M in severe NPs with chronic rhino-sinusitis, after a period of 11 months.

30 patients refractory to corticosteroids, some having relapsed after surgery and nearly half suffering from concomitant asthma, were randomised and treated (20 active and 10 placebo) ; the first objective was a reduction in NP size, to be seen via endoscopy and scanner, while at the same time monitoring the symptoms which usually accompany NPs (rhinorrhea, loss of smell, nasal peak expiratory flow, obstruction) and the biological signature  of activity (blood and tissue eosinophils, IL5, IL6, ECP and IgE dosage on nasal secretions),  are on the whole, subjected to statistical analysis.

At week 8, 12 patients of 20 in the active-group had a significantly improved NP size (compared to 1 of 10 placebo), calculated at 60% as opposed to 10% in the placebo group. The first objective was then achieved and confirms the authors’ first trial with a single M injection. As to the other symptoms, improvement was noted, except for rhinorrhea, but not statistically significant....

Finally, on a biological level, the treatment shows a significant reduction in blood eosinophilia, whereas the eosinophilia rebound observed with Reslizumab (another anti-IL5 mentioned in our September BUAs) was not observed, albeit frequently reported with these two anti-IL5 AMs. At the same time, blood and nose cytokines levels were also reduced.

Indeed, these improvements persisted until the 36th week and with no notable side effects, but the authors remain reserved on the long term use of M.


5.    RHINOVIRUS AND RISKS OF ASTHMA EXACERBATION
Theme: infection and allergy, asthma
Key words: rhinovirus, asthma exacerbation, neutrophilic inflammation

We have already reported (cf. November BUAs) the frequent appearance, even if not decisive, of rhinovirus in atopic children, as shown in the work of the Madison university team (Wisconsin, USA). The same authors, whose expertise in this field is prominent, now study the question with adults to assess its role in asthma exacerbations (L.C.Denlinger et al AJRCCM 2011 184 1007-14).

In other words, can an asthmatic’s routine seasonal cold be followed, in all cases, by greater viral multiplication and an infection of lower airways with neutrophilic inflammation ?

For this survey, during 9 consecutive winter seasons, they enrolled 52 asthmatics and 10 control, all volunteers, who were monitored daily at the first sign of a cold for the next 10 weeks, and with whom they went to specify, over and above the symptoms, the use of drugs, and the peak expiratory flow, performing periodical nasal lavage and sputum sampling for viral (including molecular) identification, and respiratory functional exploration, all this until all symptoms have disappeared.

25 participants developed an asthma exacerbation, preceded 5 days earlier by detection of human rhinovirus HRV. But among all the viral infections (3/4 being due to the rhinovirus), it is subgroup A’s rhinovirus which was statistically 4.4 times more likely to cause exacerbation.

However, it should be noted that neutrophils, and even virus, were present in sputum, in the non-atopic control lower airways and in the asthmatic group, which shows that these virus can behave no longer like pathogens but as ‘guests’ of these airways.

Nevertheless, asthma exacerbations were marked, and significantly so, by greater neutrophil counts.

On the whole, among adult asthmatic patients likely to catch a routine seasonal cold due to a rhinovirus, those who, over  ...upper airway infection, experience asthma exacerbation, have a high neutrophil count and a greater viral proliferation in sputum than i nasal samples. But the authors cannot specify by which mechanism ...allergic inflammation influences the antiviral response, or on the contrary sensitizes lower airways to viral injury.


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Comments and questions welcome :

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