Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Allergy Testing  in children
2. Food challenge (FC) in children sensitised to peanuts/treenuts
3. Dry Night Cough (DNC) as allergy marker in pre-school children
4. Antihypertensive medication use and anaphylaxis (A)
5. Risks of stepping down Inhaled Corticosteroids (IC) in stable asthma (adults and children)

1. Testing children for allergies

Theme: Paediatric allergology – Allergy diagnosis
Key words: Skin tests – IgE – Allergist – Primary Care Physicians – Molecular biology – Challenge test – Eczema – Urticaria – Respiratory allergy – Gastro-intestinal symptoms - Anaphylaxis

In an important review, the Geneva university hospital team (P.A.Eigenmann et al Ped. AllergyImmunol 201324 3 195-2009), in collaboration with 13 paediatric centres in Europe, points out his large experience in this field. Recalling the need for close collaboration between Allergists and Primary care Physicians who are the first to confront the symptoms and often diagnose allergy in their young patients, the authors put forward a number of recommendations, particularly for skin tests (prick and intradermal) which are difficult to interpret before the age of 2 and must be used in correlation with clinical relevance.. The same can be said of the biological tests : particularly total and specific IgE whose sensitivity and specificity must be defined before any therapeutic decision.
At that time, Allergists comes in to confirm a diagnosis by molecular biology techniques (Immuno-Cap) looking for recombinant allergens, or through challenge tests, a core activity of Pediatric Allergist trained physicians, which in well-equipped centres are safe and lead to either the confirmation or the elimination of the diagnosis, thus avoiding useless treatments or, in the case of food allergy, excessive and sometimes unpleasant eviction measures.

The paper then reviews the different symptoms which justify the use of tests (who does what, when and how?).
- For skin manifestations:
Eczema: Think of food allergy, the most frequent allergens in Europe being eggs, milk, peanuts, wheat, fish and soybeans; beware of skin tests made with raw extracts, which often  generate false positive results.
Urticaria: Either acute within 2 hours of the suspected trigger factor, for which skin and IgE tests can be sufficient, or chronic, seldom allergic or specialist-relevant (medication ?).
- Respiratory manifestations: Rhinitis and conjunctivitis, either seasonal (role of pollens, different according to areas) or perennial, with coughing and wheezing (dusts, dust mites, fungus) that are difficult to treat and need other procedures but should be differentiated from asthma.
- Gastro-intestinal disorders: with colic and other digestive symptoms. In excessive, inconsolable crying infants, consider cow’s milk allergy.
- Finally, special cases of Anaphylaxis by allergy to hymenoptera (bee or wasp) or even to latex, anaesthetics or antibiotics: they call for hospitalisation in reference centres.

2. Food challenge (FC) in children  sensitised to peanuts/treenuts

Theme: Paediatric allergology – Allergy diagnosis
Key words: Food challenge – Peanut – Hazelnut – Atopy – Specific IgE

Food challenge is at the very heart of the paediatric allergist’s field.    
When carried out in double-blind placebo-controlled testing, it is the gold standard of the diagnosis. It supplies conclusive confirmation, leading to appropriate and customised therapy. But, even in expert hands and harmless in principle, it is time-consuming and anxiety-causing in the young patient and his/her family. It can then sometimes be replaced by an ‘open’ test. On the other hand, it can be the solution for a child without yet clinical signs but with a high IgE level.
This is the situation described by the Lausanne and Geneva Swiss paediatricians concerning peanut and tree nut allergy in children (S.Ludman et al Ped.Allergy.Immunol  May  2013 276-28), who attempted to clarify the risk factors in case of accidental ingestion, given that tolerance to these allergens develops with age and that 1 child in 2 with a ≤ 5 kU/l specific IgE level, and  after 4 years has a 1 in 2 chance of becoming tolerant.
The retrospective study concerned 98 children aged 9 to 13 who had never ingested peanuts or hazelnuts and who had undergone a FC: 47 to peanut and 51 to hazelnut, with 29 positive, 67 negative and 2 inconclusive. The whole set of data on family history, patients’ personal history, extra examinations, and possible associated allergies, were subjected to a multivariate logistic regression analysis.
The results were the following:
- The association of maternal atopic history and a specific IgE ≥ 5 kU/l induces a significant increase the risk in the likelihood of positive FC.
- After adjusting for age, this positive FC probability in 3 year old children is 67%, 5 times more frequent than in older subjects.
- As for other factors, such as patient’s atopy, type of food allergen (peanut or tree nut), other associated allergy, or severity of previous food reactions, there was no significant association.
These results should help the allergist, for each particular case, to decide on a FC or not. As concerns the test technique and although there are no standard rules, it seems that it is similar in Switzerland and United Kingdom (St Thomas Hospital) where the allergen (peanut/tree nut) dose used is twice as large (S. Ludman, Allergy 20132 68 539-541) with similar outcomes.

It must be emphasised that these trials were performed between 2005 and 2011, a period during which using Immuno-cap looking for recombinant allergens was not yet common. We know they can set guidelines and sometimes eliminate the need for FC.
However we must interpret IgE reactivity to these components (cf Aalberse et al Allergy 2013 in press) whose heterogeneity is well-known, taking account of their clinical relevance and remembering that evolution of sensitivity towards clinical manifestation, is a slow and progressive process.

3. Dry Night Cough (DNC) as allergy marker in pre-school children

Theme: Paediatric allergy – Respiratory allergy
Key words: Night cough – Asthma - Atopy

In a first epidemiological study on a cohort of infants from the Paris area (PARIS: Pollution and Asthma Risk in Infants Study) the authors (F. Rancière et al Ped.Allergy.Immunol 2013 24 131-137) had observed a frequent association between DNC and allergic manifestations.
To confirm this hypothesis, they undertook a new trial by following the cohort of 3840 infants from birth to age 4 between 2003 and 2006 with this methodology:
- parental questionnaires of the ISAAC type ;
- blood markers of atopy at 18 months of age : total and specific IgEs ≥ 45 kUI, blood eosinophilia ≥ 470/µl and more recently for some subjects ImmunoCap Phadiatop) ;
- presence of a DNC without infection, with or without wheezing.
The whole set of data, gathered from 1869 infants was submitted to a series of statistical analyses . It should be noted that 4 infants on 10 having presented at least one DNC episode between 1 and 4 years,
Three types of trajectory were identified:
-    a 1st group (72.4%) : never or infrequent pattern, this group being then used as control
-    a 2nd group (8.8%) : transient pattern, with moderate DNC occurring in year 1 but cured by year 4
-    a 3rd group (18.8%) : rising pattern, with DNC starting at year 2 and persisting at age 4, or beginning later but still present at age 4.

The statistical study reveals in group 2 a high proportion of smoking mothers, without any marker of atopy. In group 3, apart from a frequent family history of allergy, there is a significant association between DNC and atopic markers at 18 months (high IgE and sensitisation to respiratory and/or digestive allergens) and presence in the fourth years of clinical allergic manifestations, mainly eczema and pollen rhinitis.

Thus, while wheezing is regarded by English-language publications as predictive of allergy and sometimes asthma, DNC in itself, without infection or wheezing, is shown here to be an excellent risk-marker for allergic morbidity.

4. Antihypertensive medication use and anaphylaxis (A)

Theme: Allergy and anti-hypertensive medications (AHT)
Key words: Hypertension – Anaphylaxis – Beta-blocker – Diuretics – Angiotensin-converting enzyme inhibitors – Angiotensin-receptor blockers – Calcium channel blockers

Following several papers on A in patients treated both by Angiotensin-converting enzyme (ACE) inhibitors and venom immunotherapy, or patients taking β-blockers and contrast products, the authors from Mayo Clinic Emergency Department in Rochester USA (S.Lee et al JACI 2013 131 1103-8) conducted a retrospective study on subjects over 18 who had consulted the department for an A episode between 2008 and 2011 and who were being treated for hypertension (AHT).

302 patients were enrolled, of which 204 females (68%), with an average age of 44; they were clustered in 3 groups according to their A severity:
- group 1 (55 cases, 18%) : hypotension, hypoxia or syncope
- group 2 (139 cases, 46%): signs and symptoms involving 3 or more organ systems (pharynx, lungs, digestive tract, excepting AHT-linked heart disease)
- group 3 (57 cases, 19%): the most severe cases with hospitalization (intensive care for 17)
The anti AHT involved, ranked by order of frequency, were:
- β-blockers (BB): 49 cases
- Diuretics (D): 48 cases
- ACE inhibitors: 34 cases
- Calcium channel blockers: 22 cases
- Angiotensin-receptor blockers: 8 cases.
The trigger allergen was food (82 cases, 27%), medication (78 cases, 26%), bee or wasp venom (29 cases, 10%), a contrast product (17 cases, 6%), latex (2 cases, 1%), and no particular factor identified for the remaining cases.
Several statistical analyses of single and multiple logistic regression were performed.
After adjusting for age, gender, trigger factor and pre-existing lung disease, it appears that BBs, ACEs and Ds are significantly associated with A symptoms of group 2 (odds ratio 2.8, CI 1.5-5.2, P=.0008) and 3 (odds ratio 4.0, CI 95% 1.9-9.8, P=.0001).
NB: the conjunction of 2 or 3 anti-AHTs, including CCBs, is also associated with A severity.

The authors tried to clarify the mode of action of these hypotensive drugs: role of bradykinine for ACEs, cardio-vascular co-morbidity accounting for the need to associate several anti-AHTs (at least two are usually recommended). But what clinicians must retain from this interesting study is that the subjects under anti-AHT treatment run a severe A risk, regardless of age, gender or allergic trigger factor.

5. Risks of stepping down Inhaled Corticosteroids (IC) in stabilised asthma (adults and children)

Theme: Asthma – Allergy treatment
Key words: Stabilised asthma – Inhaled corticosteroids – FEV1 – Peak expiratory flow – Adults - Children

The Mayo Clinic’s respiratory-allergists (M.Rank et coll JACI2013 131 3724-729 e2) addressed this issue through a meta-analysis of the numerous papers in English on the subject. Two independent readers went through the full-texts and summaries of the major international data banks, up to 21st January 2012, i.e. 1798 papers, 172 full-texts, out of which 7 were selected which satisfied the chosen criteria: random studies, follow up at least for 3 months after stepping down ICs, and a clinical lung function check-up by FEV1 and Peak Expiratory Flow (PEF).
It is, first of all, necessary to define what is meant by stable asthma (A). According to common guidelines, it is a well-controlled A, with no exacerbations for one year, and treated by low doses of ICs.
The study encompasses papers which compared patients who had stopped their treatment with those who continued for 6 more months. (NB: the authors do not distinguish those who progressively stepped down ICs and those who stopped at one go).
Gathering all the available statistics, they calculated that the relative risk of an exacerbation within 4 months of stepping down by comparison with those who continue is 2.35 (P≤ .001). The absolute risk is 0.23 (P≤ .001).
At the end of the study, patients who stopped ICs show a significant decrease in their FEV1 (130 ml, P≤ .003) and their PEF (18L:min, P≤ .004) and a slight increase in their symptomatic score (P≤ .001).
So, the authors conclude that in stabilised asthmas, those who stop the regular treatment by ICs show an exacerbation risk compared to those who continue.

The same author (M.Rank et al: Annals of All. Asthma Immunol. 2013 in press) gets to less negative outcomes when he turns to children.
In a retrospective study on 477 children aged 5-18, observed between 2009 and 2011,  following US paediatric recommendations, and after statistical treatment, they noted that those who tried to stop taking ICs did so successfully in approximately 3 cases out of 4. NB: the season to avoid when stopping ICs is autumn.
The authors consequently conclude that stepping down the treatment of stable A in children is frequently successful; a slightly different conclusion from that made in adults.

Comments and questions welcome:

*Pr. Claude Molina
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**Dr Jacques Gayraud
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Last updated 25 July 2014