June 2008
Claude MOLINA and Franz MARRACHE
• Recent data on Peanut Allergy
• Multiple sensitisation to Pollens : its interpretation
• Persistence of Di-isocyanate-induced asthma
• Angioedema due to angiotensin -converting -enzyme inhibitors
• Bakers’ asthma: an alternative to challenge tests
Recent data on Peanut Allergy
A comprehensive review on this topic reminds us that it is a major health problem in developed countries (A. Wensley Burks. Peanut Allergy Lancet 2008; 371: 1538-1546). It is important to point out : the increasing frequency of this type of allergy, particularly among under 3 years of age children, the characteristic symptoms (cutaneous, respiratory, gastro-intestinal, anaphylactic) that may arise within a few seconds to 2 h after ingestion of some mg of protein (let us remember that a single grain is equivalent to 300mg) or, among older patients after a simple skin or mucosal contact (the famous fatal kiss: Wuhtrich 1997); the treatment of anaphylactic shock, the prevention by correct labelling of food products (12 allergens of the European Directive 2003) are also mentioned.
Nevertheless the quality of life of these allergic patients and their families is severely impaired by the permanent anguish of a possible anaphylactic reaction.
Among recent data, let us stress the identification and cloning of various allergens (Arachis hypogea) : 8 are known : Ara h 1 and 2: the major allergens which are storage glycoproteins, Arah 5 is a profilin, Arah 8 belongs to the PR10 family. However, whereas in the case of aeroallergens IgE binding is conformational, it is linear for epitopes on Arah 1, 2 and 3 allergens, which might explain the severity of clinical signs. The diagnosis is most often made on the basis of clinical history, skin prick tests and specific IgE (CAP-RAST) whose levels must be higher than 14 kU/l. In doubtful cases, it is possible to perform skin prick tests with recombinant allergens . Only rarely is it necessary to perform double blind, placebo controlled peanut challenges.
The recent development of transgenic plants that produce hypoallergenic peanuts or the introduction of anti-sense RNA copies of the allergen or even the degradation of post-translational messenger RNA should be highlighted (one can question whether it is still a peanut after all these manipulations).
Indeed there is not yet a preventive treatment having proven its efficacy and tolerance in humans. Trials that are currently ongoing with recombinant allergens and eventually sub-lingual immunotherapy may be promising (as has been done with hazelnuts). However the author thinks that we will have a valid treatment within 5 years.
Multiple sensitisation to Pollens : its interpretation
Allergist has frequently to face this situation, often asks how to interpret skin and biological tests and wonders about their pertinence. J.F. Fontaine (Reims) has attempted to answer to the problem, by studying the molecular basis of cross-reactions among pollens as well as between pollens and foodstuffs, showing the contribution of recombinant allergens. (Les recombinants des panallergènes polliniques; application à l’interprétation des polysensibilisations Rev.Fr.d’Allergol. et Immunol.Clin 2007 47 129-132) A multiple sensitisation may include an allergy to grass pollens (Phleo p1 or p5) in association to a cross-sensitisation to other vegetals (birch, for example). Allergy to birch is either symptomatic, eventually associated with an oral syndrome (due to the allergen Bet v1) or asymptomatic (due to Bet v2). The author therefore suggests that, in cases which are difficult to interpret, one should resort, besides the classical RAST tests, to the CAP-RAST technique (Pharmacia®) using recombinant allergens of the profilin family (rBet v2 or rPhleo p12) or of the polcalcin family : calcium-binding allergens (rBet v4 or Phl p7).
Thus, for example, the presence, in an individual who is allergic to grass pollens, of specific IgE to rBet v2- or rPhl p 12- IgE without sensitisation to rBet v1 means that a positive skin test to birch is in fact, a reaction to profilins . A hypersensitivity to grass, tree and weed pollens corresponds to a sensitisation to polcalcines (rPhl p7).
Another example is related to the presence, in individuals with pollinoses.
of Bet v2-specific IgE frequently responsible for pauci-symptomatic or biological sensitisations to various foodstuffs These different molecular families of allergens that are called “ pan-allergens”, and the corresponding vegetables and foodstuffs, are detailed in a well documented table which completes this interesting article.
Persistence of Di-isocyanate-induced asthma
The Finnish Institute for Occupational Diseases has analysed the outcome of 17 patients with diisocyanate (DIs)-induced asthma after cessation of exposure and administration of inhaled corticosteroids (P.L. Piirilä et al (Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure. Allergy 2008: 63: 583-591.
Exposure to DIs had stopped, on average, 7 months before the beginning of the study, and all reexposure was excluded after diagnosis. A challenge test with DIs was carried out and was followed, 48h afterwards, by a check-up including: spirometry, bronchial challenge test with histamine, bronchial fibroscopy with biopsy, and bronchoalveolar lavage. It was followed by the prescription of budesonide ®, 1600 ìg/day, given again after 6 months and 2-3 years.
Fifteen healthy subjects made up the control group. At the end of the study there was a decrease or vanishing of bronchial hyper reactivity (BHR) in many patients, except 5 individuals.
Spirometry showed a progressive and significant reduction of forced vital capacity (FVC), and a nearly significant decrease in forced expiratory volume /second (FEV1), without any changes in total lung capacity (TLC).
These changes were independant of smoking habits of the patients.
In terms of histochemistry, the most important aspect was the return to normal of the numbers of lung mast cells and an increase in the number of macrophages. In addition, there was an increase in the levels of interleukin-6, interleukin-15 and TNF-á, whose source are macrophages, in patients with BHR.
Overall, this study showed that there was a decrease in Th2-type inflammation and an association between BHR and inflammation, linked to the production of pro-inflammatory cytokines mainly derived from macrophages.
This study allows us to understand that Dis-induced asthma, even upon cessation de l’exposition, may become perennial. Furthermore, it also demonstrates the absence of efficacy of inhaled corticosteroids, which underlines the need for therapeutically targeting the macrophage and its cytokines.
Angioedema due to angiotensin converting enzyme inhibitors
A retrospective, multicentre study involving 5 hospitals in US recorded the cases of Angioedema hospitalised in an Emergency Department following ingestion of drugs with cardiac and anti-hypertensive properties such as the angiotensin converting enzyme inhibitors (ACEI).
Between 2003 and 2005, 220 patients were thus identified and demographic and etiological data from each patient were analysed namely in statistical terms (Multicenter study of patients with angiotensin-converting enzyme inhibitor-induced angioedema who present to the emergency department. A. Banerji et al ; Ann. Allergy Asthma Immunol 2008; 100: 327-332).
Thirty percent of the cases of Angioedema diagnosed in these 5 centres were caused by ingestion of ACEI (95% CI : 26-34%).
The mean age of these mostly hypertensive patients was 60 years. There was a slight predominance of female patients; the prevalence of atopy was lower than in the general population (11% had asthma, 6% had food allergies, 4% had rhinitis, 1% has atopic dermatitis).
The most frequent clinical symptoms were : dyspnoea and swelling of lip, tongue and larynx.
Most patients had been treated with corticosteroids and anti-histamines ; 58% of them were discharged upon hospitalisation, but 11% had to be monitored in a specialised setting and 12% had to be admitted to an Intensive Care Unit, where intubation and ventilation was needed in 10 individuals . There was no death.
The involved drugs were Lisinopril® in 60% of cases, Enalapril ® in 12% of cases, and Benazepril® in 6% of cases . The patients had been on that medication for 6 months, on average (1 to 18 months). For most patients, that was the first episode of Angioedema.
The mechanism of this side-effect of these drugs may be related to the increased levels of bradykinin in the blood and it must be pointed out that clinical trials involving bradykinin receptor antagonists are currently ongoing, particularly for the treatment of Hereditary Angioedema.
The authors acknowledge the limits of interpretation of data in their study but insist upon the relative frequence of this etiology of Angioedema, and the severity of certain clinical forms.
Baker’s asthma: an alternative to challenge tests
V. van Kampen et al (Prediction of challenge test results by flour-specific IgE and skin prick test in symptomatic bakers. Allergy 2008; 63: 7: 897-902) attempted to see whether it was possible to predict challenge test results from the determination of specific IgE or skin prick tests, in flour-related baker’s asthma, like it has been done for other allergens, particularly food-related ones .
All 107 recruited individuals, who had oculo-nasal and/or bronchial manifestations, were submitted to bronchial and nasal challenge tests, serum specific IgE levels were determined and skin prick tests performed: 71 bakers were tested with wheat flour and 95 with rye flour. Positive and negative predictive values, as well as sensitivity and specificity were calculated for different concentrations of specific IgE and different sizes of skin prick test weals. A comparative analysis of IgE levels and weal size in relation to the challenge test, as well as sensitivity / specificity curves were carried out.
It became apparent that the minimal cut-off values, for a positive predictive value of 100%, were 2.32 kU/l of specific IgE (5 mm weal) for wheat, and 9.64 kU/l (4.5 mm weal) for rye. Although the combination of both techniques does not significantly raise the predictive values, their association is useful for quality control.
Indeed the determination of specific IgE is more sensitive, but the recommended lower threshold for skin prick tests seems to have a higher predictive value (particularly for rye flour).
Thus, these 2 criteria are good diagnostic markers among sensitised symptomatic bakers, which makes unnecessary the challenge test.
These texts has been translated in collaboration with L.TABORDA - Covilha (Portugal).
Source: CEFCAP
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