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Claude MOLINA* & Jacques GAYRAUD**

1. A new approach to Immunotherapy: the intradermal injection?
2. Unexplained chronic cough and old remedies
3. Effect of Inhaled Glucocorticoids (ICs) in childhood on adult height
4. Fish and shellfish allergy in children
5. The metabolomics of asthma


1. A new approach to Immunotherapy: the intradermal injection?

Theme: Treatment, Immunotherapy
Key words: Immunotherapy, Intradermal injection, Cutaneous late response, Grass pollen

While traditional specific immunotherapy (IT) uses allergens administered subcutaneously or sublingually, at high and progressively increasing doses, a group of English researchers at Brompton Hospital (G.Rotiroti et al..JACI 2012 October 130 4 918-924) tried to understand what would happen with low-dose allergens administered less frequently, and by intradermal injection, the dermis being an immunologically active zone, rich in dentritic cells and lymphatics. They were surprised to discover that this mode of IT suppressed cutaneous late response.
To confirm this discovery, they selected 30 adults sensitized to grass pollen (Phl p 5) but not to birch pollen (Betula), and divided them into 3 categories:
A. receiving 6 repeat intradermal injections at 2-week intervals of low-dose pollen extracts (10 BU corresponding to 7 ng),
B. receiving the same dose twice with an interval of 10 weeks, and
C. a control group with a single injection at the end of the test.

The size of the papules occurring after prick-tests on the forearm or the back, at each visit, was measured very accurately (blind), at the same time as grass-specific total IgE (all isotypes) were measured.

Whereas a similar injection of birch pollen carried out for comparison had no effect, the authors observed with group A at the 10th week a 90% suppression of cutaneous late response (after 24h) to grass pollen with a significant increase in specific IgG, unlike groups B and C where a comparable impact on early response was observed, whereas impact was negative on late response.

So, repeated and spaced out intradermal injections of low-dose grass allergens, 1000 times lower than the usual total dose classically injected, induces a suppression of cutaneous late response.

Can this phenomenon of tolerance be transposed in clinical settings? The authors refer to Rinkel’s unsuccessful clinical trials using intradermal injection, albeit with a different methodology. Trials are underway.


2. Unexplained chronic cough and old remedies

Theme: Asthma
Key words: Unexplained chronic cough, Vanilloid receptors, Vagal afferents, Camphor, Menthol

Physicians ( particularly allergists) are more and more often confronted with symptoms of Unexplained Chronic Cough (UCC) which occur in adults and do not result from allergic etiology, nor from gastro-oesophageal reflux, nor from upper airway infection (with post-nasal drip), nor from use of angiotensin converting enzyme inhibitor type medications. The common feature is an upper airway heightened reflex sensitivity favoured by air pollution or smoking (active or passive).

At a time when some retired colleagues, fishing for notoriety, are casting suspicion on a large number of drugs, it is worth reminding of the therapeutic value of old remedies whose modes of action are better known.

Indeed, this cough reflex could be caused by the hyper-expression of receptors named vanilloid (Transient receptor potential vanilloid or TPRV1) located on the vagal afferents  which are inhibited by camphor. K.W.Patberg et al (AJRCCM 2011 184 382) recall an old US children’s song: John Brown’s baby had a cough upon his chest and they rubbed it with camphorated oil.
But another type of receptors may be involved (P.Geppetti et al AJRCCM 2012 185 342): TRP A1 (ankyrin) inhibited by menthol, an agonist to the cold receptor (TRPM8), responsible from the fresh sensation associated with mint. This receptor is thought to sense a series of  endogenous or exogenous irritant molecules.

So, these recent pharmacological advances about the blocking properties of these old remedies seem to open the way for future challenges in drug discovery for the treatment of  this heightened cough sensitivity of individuals with UCC.

A more radical approach, but not without many side effects, is presented by an Australian team (N.M.Ryan et al Lancet 2012 Nov. 380 9853 1583-1589) who, in a randomised trial, did successfully treat 32 patients with UCCs which persisted beyond 2 months (30 placebo) with Gabapentin ®, an anti-epileptic medication, also successful in peripheral neuropathic pain. This effect would suggest, for the authors, a central reflex sensitisation.

On a practical level, the recent development of  automated cough monitors had enable to objectively assess the cough frequency and therefore its severity, as their 4-hour recordings  could be a practical tool to validate response to trials of therapy  in clinical settings (KK Lee1 et al  Chest 2012 on line).

Finally it should be remembered that coughing is a defence reflex, to be respected as much as possible, and the UCC should essentially remain an elimination diagnosis.


3. Effect of Inhaled Glucocorticoids (ICs) in childhood on adult height

Theme: Asthma, Treatment
Key words: Inhaled glucocorticoids, Height, Reduction in growth velocity

We know that the glucocorticoids inhaled by asthmatic children cause a reduction in their growth velocity. The US authors (H.W.Kellyet al  NEJM September 2012 904-912) in charge of the well-known Childhood Asthma Management Program wanted to know whether in the long run IC treatment had an influence on the children’s attained adult height.

To that end, they studied the development of 942 children (of 1041 participants) aged 5 to 13, who could be re-examined at an average age of 25. These subjects had been randomised between 1993 and 1995 to receive :
  • Group 1 (311 cases): 400 µg/day of budesonide (Pulmicort ® with Turbuhaler) in 2 doses for at least 2 years; 281 of them were re-examined.
  • Group 2 (312 cases): 16 mg/day of nedocromil (Tilade ®), an anti-allergic medication, not in use any longer, in 2 doses; 285 subjects were re-examined.
  • Group 3 (418 cases): the placebo group, 377 were seen again.

The accurate statistical studies (multiple linear regression with adjustment for demographic characteristics, children’s age and height at trial entry) produced the following results:
  • In Group 1 (ICs), adult height was significantly lower (1.02 cm) than in the placebo group.
  • In Group 2, it was 0.2 cm lower.
Depending on the IC dose received by the child, it appears that the higher the dose, the greater the impact on adult height. However, treatment duration had no long term influence, beyond 2 years of treatment. The authors therefore concluded that this decrease in height was neither progressive nor cumulative. Finally, it was primarily when these ICs were administered to pre-pubertal children that the impact on growth was the most marked.

On the whole, in answer to the question of whether ICs are the cause of a simple delay or a complete stop in growth, the authors choose the latter, pointing out that the efficacy of treatment must always be compared with the risks of side effects, which are relatively moderate in these cases.


4. Fish and shellfish allergy in children

Theme: Food allergy
Key words: Fish, Shellfish, Gad c 1, Parvalbumin, Tropomyosin, Toxins, Anisiakis, Sulfites

Frequent in countries with a high consumption of fish and shellfish, the adverse reactions to their ingestion do not all result from allergy. True allergies are relatively rare in children, but they can trigger anaphylactic reactions and, when they settle, they are long-lasting, unlike milk or egg allergies which generally decrease with age.

A group of Greek researchers (S.Tsabouri et al Ped.Allergy Immunol 2012 23 608-615), having in a very well documented review compiled 32 studies between 1985 and 2011, distinguish 2 main types of allergy:
1. Allergy to fish: tuna, cod, salmon, and hake, whose major allergen is Gad c 1.
The common chemical content consists of 12kDa of parvalbumin (P), a calcium-linked sarcoplasmic protein ;
2. Allergy to shellfish (molluscs and crustaceans): shrimps, lobster, scampi, mussels, whose chemical composition is based on tropomyosin (T).

There is no standard cross reactivity between P and T. However, shellfish T has a homology with that of invertebrates such as arachnids and cockroaches, so that positive skin reactions to shellfish can be found in religiously abstinent subjects like orthodox Jews (Fernandes et al Clin. Exp. Allergy 2003 33 956-61) who are also allergic to dust mite.

In diagnosis, it is first necessary to eliminate non-allergic adverse reactions due to:
- either toxins: the most frequent are due to anisiakis, a fish parasite nematode common in Spain (killed by 20-minute cooking at 60°)
- or sulfites, used for canning the fish, often the cause of severe clinical manifestations.

The simplest positive diagnostic is the skin prick-test using commercial extracts but which are not very specific, so that it is preferable to use raw extracts of each variety of fish or shellfish. For shrimps, for example, it has been observed that cooked extracts were more allergenic than raw ones.

As to specific IgE, these are reliable in the case of allergy to fish like cod or hake but less so for shellfish.

Proof is provided by means of a Double Blind Placebo Control Food Challenge (DBPCFC), but it must not be performed on children under 3 and is useless when symptoms are obvious. It can be used, in Open Food Challenge (OPC) without placebo, for elimination diagnosis. The only proved therapy is a strict avoidance, but it is important, in children not to introduce an unjustified restriction diet.

Vaccination with hypoallergenic fish proteins may constitute a promising therapy in the future.


5. The metabolomics of asthma

Theme:
Asthma, Physiopathology
Key words: Asthma, Metabolism, Inflammation, Mass spectrometry, Bromo-tyrosin, Electronic nose, Volatile Organic Compounds (VOC), Nuclear Magnetic Resonance.

A few months ago, we mentioned the studies carried out by paediatrician and biochemical teams at Canadian universities (Edmonton, Alberta and Saskatoon) on this theme, i.e. the study of small molecules generated by metabolic activity, due, in asthma, to upper airway inflammation. The idea of studying the metabolic profile of a disease, a priori different from that of a normal subject, is not new: glucose surveillance in diabetics is one of the most common examples. Besides, diagnosing asthma is sometimes difficult in children when one is always looking for non-invasive procedures. True, the study of urinary leucotrienes or blood ECP are possible but they are not commonly practiced.

In an general review dedicated to the different modern techniques for detecting the main markers, three are explained in detail (D.J.Adamko et al Chest 2012 141 5 1295_1302):
- Mass spectrometry (MS), applicable on airway and urine biofluids: compounds are of the order of a pico mole. These are delicate and tedious techniques, the results of which are so far not specific enough, except the urine analysis where over 1000 metabolites have been identified and where it appears that the level of Bromo-tyrosin, a marker of eosinophilic peroxydase activity, is statistically high in the case of risk of asthma exacerbation.
- The Electronic nose was developed to measure the different fractions of VOC (Volatile Organic Compounds) in expired air. For some, it may differentiate asthma from COPD, but results are still to be validated.
- Nuclear Magnetic Resonance (NMR), which identifies atomic nuclei inside a biofluid. Its advantage is a more rapid diagnosis than with MS but it is less sensitive and the measured compounds are of the order of a micro mole.
The Canadian authors’ studies have enabled the differentiation in children between stable and severe asthma requiring emergency admission to hospital, with an accuracy rate over 90% (Saude et al JACI 2011 127 3 757-764). Admittedly, few hospitals have the sophisticated equipment necessary for regular use of such methods. But this research pathway is promising.
To prove this point, a very recent experimental study (W.E.HO et al AJRCMB2012 on line) has shown through MS that an allergic lung was the centre of intense metabolic activity, concerning carbohydrates (increase in mannose, galactose, arabinose) non-affected by corticosteroids, lipids (decrease in phosphatidylcholine, sterols) and amino acids.
It remains to develop the metabolomic profile of different phenotypes of Asthma in children and Adults


Comments and questions welcome:

*Pr. Claude Molina:

**Dr Jacques Gayraud: