Claude MOLINA and Franz MARRACHE
- Puberty and Bronchial Hyperreactivity in young asthmatic patient
- Maternal Food during Pregnancy and Risk of Childhood Asthma
- Wheeze , Atopy and Bronchial Pathology
- Hypersensitivity to Chemotherapy: desensitisation technique
- Arginine Metabolism and Asthma
Puberty and Bronchial Hyperreactivity in the young asthmatic patient
Although Asthma affects mainly males in early childhood, it is a disease primarily of girls in adolescence. Since bronchial hyper reactivity is an important component of Asthma throughout life, it is interesting to know how such reactivity evolves, particularly spanning puberty. A group of American physicians, within the framework of multicentre treatment programme for childhood asthma, attempted to analyse this factor in a longitudinal epidemiological study that included 1041 , 5-12 year old children with moderate asthma and followed for a period of 8.6 +/- 1.8 years. (K.G Tantisira et al. Airway Responsiveness in Mild to moderate Childhood asthma. Am. J. Respir. Crit. Care Med. 2008; 178: 325-331).
The authors performed methacholine provocation tests in these patients, at the beginning of study, and yearly at 1 and up to 8 years, and evaluated PC 20 (the lowest dose inducing a 20% decrease in FEV1). 7.748 methacholine tests were carried out in order to determine the influence of sex and age on bronchial reactivity. The results were analysed using multiple linear regression tests with adjustment for confounding variables.
The principal conclusions of this important study were :
1) PC20 increases with age (thus, bronchial reactivity decreases) more clearly in boys older than 11 years than in girls (p¡Ü 0.001)
2) Reactivity significantly increases in girls after puberty, independently of any potential confounding factors
Overall, bronchial reactivity was more severe in girls than in boys and persists after puberty . The authors suggest the role of hormonal factors (but without any hormonal study in support of their hypothesis).
This interesting work is also a long term prospective study covering puberty and whose conclusions may be useful for considering changes in asthma therapy and prevention in the adolescent.
Maternal Food diet during Pregnancy and Risk of childhood Asthma
It is known that maternal food consumption during pregnancy may affect the development of airways in the child and promote a Th2-type response to allergens during foetal life, with the risk of subsequent development of allergies or asthma during childhood.
A group of Dutch researchers has therefore carried out a longitudinal, questionnaire-based study assessing the influence of the consumption of certain foodstuffs during pregnancy on the eventual development of asthma in children followed up between 1 and 8 years of age (M. Willers et al. Maternal food consumption during pregnancy and the longitudinal development of childhood asthma. Am. J. Respir. Crit. Care Med. 2008; 178 : 124-131). 4146 pregnant women (1327 atopic and 2819 non atopic) were submitted to a questionnaire about the frequency of their consumption of 1 to 8 principal food categories, particularly during the last month of pregnancy : fruits, vegetables fish, eggs, milk, nuts (including peanut), and peanut butter (commonly used in northern countries and which was included within the nuts group, in this study).
2832 children were followed up and the obtained data were complete.
The authors did not find any significant association between maternal food consumption and asthma in children. Nevertheless, consumption of fresh fruits seemed to protect children against the risks of asthma or allergies (borderline statistical significance), whereas daily ingestion of nuts increased the risk of asthma in comparison with an intermittent consumption.
The limitations of this study derive from the difficulties in the statistical interpretation of the data as well as from the various confounding factors such as life style, socio-professional class and region or country concerned. Thus, the study does not allow professionals to advise a precise food diet for the pregnant woman, apart from a diversified diet avoiding regular ingestion of a single food, particularly nuts.
Wheezing, Atopy and Bronchial Pathology
Various studies have shown that, in the atopic child, wheezing tends to persist into the adulthood, occasionally becoming asthma, whereas they generally regress during adolescence in non-atopic children.
In order to assess whether bronchial histology is different in these 2 types of individuals, the Italian authors from the Universities of Padua and Modena performed bronchial biopsies in 38 wheezing children, who had repetitive multitrigger episodes of cough, dyspnoea and wheezing, apart cold periods (18 were non atopic and aged between de 2 and 10 years, 20 were atopic and aged between 2 and 15 years, and 17 were healthy controls between 2 and 14 years old. (G.Turato et al. Non atopic children with multi-trigger wheezing have airway pathology comparable to atopic asthma. Am. J. Respir. Crit. Care Med. 2008 ; 178 : 476-482).
All pathological and histochemical criteria were similar in the 2 groups of children. When compared to healthy controls, patients had a statistically significant thickening of the basal membrane (p=0.0001), with an increased loss of the epithelium (p= 0.03 and p = 0.002, respectively). In the mucosa, there was also an increase of respectively angiogenesis, number of eosinophils, and expression of IL-4, all criteria statistically significant (only borderline significant for IL-5).
As in adults, a tendency towards the presence of more severe symptoms with a clearer decrease in FEV1 was observed in non atopic patients.
Thus, histological and histochemical changes were identical in wheezing children responsive to bronchodilators, and whose symptoms persisted, whether the child was atopic or not. So, when suggestive symptoms such multitrigger wheezing occur in non atopic children, the pathology is typical of asthma.
Hypersensitivity to Chemotherapy : desensitisation technique
In the presence of a hypersensitivity reaction to a chemotherapy drug, the doctor
faces a cruel dilemma : either to risk an anaphylactic reaction upon reintroduction of the product or to stop the treatment and use a less efficacious or ill tolerated drug.
A Boston university team (M.C. Castells et al. Hypersensitivity reactions to chemotherapy. J. Allergy Clin. Immunol. 2008 ; 122 : 574-580 ) developed a rapid and standardised desensitisation protocol in order to obtain at least temporary tolerance to 7 different drugs : carboplatin, cisplatin, oxaliplatin, paclixatel, liposomal doxorubicin, doxorubicin and, which is original in this work, a monoclonal antibody: rituximab.
98 patients were thus treated using a rapid 12-step protocol, administered intravenously or peritoneally. The first injections were performed at an Intensive Care Unit and subsequent injections were given in an outpatient setting.
Safety and efficacy of the protocol were proven in all the cases.
In fact, out of 413 desensitisations performed, 94% were concluded without any side-effects or only with minimal reactions. There were no anaphylactic reactions or deaths and all the patients received the full target dose.
Reactions were more commonly reported during the final steps of the procedure.
Intravenous and peritoneal routes were equally effective.
Such a type of protocol had already been utilised for desensitisation to platin in some isolated cases as we had mentioned in our December 2004 Allergy Newsletter (www.egora.fr).
The interest of this study lies in the extension of this technique to a large number of patients and its application to several chemotherapy drugs including a monoclonal antibody.
Arginine metabolism and Asthma
As unique donor of a N ion in the synthesis of Nitric Oxyde (NO) as well as key participant in the urea cycle, Arginin (Arg) and its metabolites namely ornithin and citrullin are linked to cell respiration and inflammation.
Physicians involved in the Severe Asthma research programme of the NHLBI, USA, put forward the hypothesis that bioavailability of Arg might be associated to the inflammation and bronchial problems in asthma and also account for its severity.
Such bioavailability was therefore assessed by plasma Arg. dosage, relative to its metabolites and to NO synthase inhibitors and by the arginase activity in serum. This was performed in 258 patients : 232 asthmatic patients out of which 84 were severe and 148 who were moderate as well as 26 controls Simultaneously, were also studied lung function and inflammation parameters, including the fraction of expired NO (FE NO), but also IgE, skin prick tests to allergens, blood eosinophilia, and eventually broncho-alveolar lavage fluid. (A. Lara. Alterations of the Arginine metabolome in Asthma Am. J. Respir. Crit. Care Med. 2008; 178 : 673-681).
Results were the following
Asthmatic patients had higher levels of Arg. bioavailability than healthy controls, but also an increased catabolism of Arg as shown by serum arginase activity and elevated levels of FE NO.
Inflammation parameters were related to bronchial obstruction, in a paradoxical way, in patients with moderate asthma but not in severe cases. By contrast, Arg bioavailability was related to bronchial obstruction in severe asthma, but not in moderate cases. This means that bioavailability of Arg is not a surrogate measure for inflammation (in contrast with FE NO) but it is strongly associated ,like arginase activity, with airflow abnormalities in severe asthma, and particularly with bronchial remodelling.
These results are all the more important that Arginase inhibitors are studied as protection against allergen induced bronchospasm in a experimental model of asthma in the guinea pig (H. Maarsing. Am. J. Respir. Crit. Care Med. 2008 ; 178 565-573) thereby opening new therapeutic avenues.
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Claude MOLINA and Franz MARRACHE
- «Inflammometry» in the treatment of Asthma
- Determining factors for pet ownership: their relationship with Asthma & Allergy
- Allergists face to Primary Immune Deficiencies (PID)
- Genetic approach to Primary Immune Deficiencies
- Genetics, Asthma, and Passive Smoking
« Inflammometry » in the treatment of Asthma
Bronchial inflammation is, with more or less variable obstruction, one of the components of asthma. Its assessment entitled « Inflammometry » (I.D. Pavord et al. Lancet 2008; 372: 1017-1018) cannot be performed either clinically, apart from exacerbation periods, or by spirometry even when associated with multiple daily peak flow recordings. Thus, these authors tried to found eosinophils in spontaneous or induced sputum as well as to measure the fraction of nitric oxide (NO) in exhaled air (FE NO) which is currently facilitated by practical and cheap monitoring devices. Association of these 2 techniques allow ascertaining indication for therapy as well as appreciating the efficacy of anti-inflammatory treatment with corticoïds. Indeed, the authors acknowledge that induced sputum is a demanding technique and cannot always be easily performed in asthmatic patients whose expectoration is often scarce.
In addition, even if FE NO concentration (between 25 and 50 ppm) correlates well with the presence of eosinophils and justifies the indication for and maintenance of corticotherapy, its validity is far from being unanimous. Thus, S.J. Szefler et al (Management of Asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner city adolescents and young adults : a randomised controlled trial : Lancet 2008; 372: 1065-1072)think it does not bring any benefit and rather may induce an unwarranted increase of inhaled corticosteroid doses.
Similarly, de De Jongste et al (Daily telemonitoring of exhaled NO and symptoms in the treatment of childhood asthma. Am. J. Respir. Crit. Care Med. 17 October 2008) note that a sophisticated equipment do not have any advantage over the standard technique.
In conclusion in the treatment and monitoring of asthma, the assessment of airway inflammation is an interesting complement to clinical aspects and lung function testing. However, the former cannot replace the latter and vice-versa.
Determining factors for pet ownership : their relationship with Asthma and Allergy
It is known that the presence of a pet (cats and dogs, in particular) is regarded by some authors as a risk factor for asthma and allergy, whereas others assign them a protective role. Such divergence of opinion might be due to a wrong interpretation in epidemiologic studies which do not take into account all confounding factors.
This highlights the interest in this meta-analysis of factors determining ownership of a cat or a dog. This study involved the monitoring of 12 European cohorts from 7 different countries, each one including between 485 and 4089 allergic (rhinitis, eczema) or asthmatic children, in a total of 25056 families.
Questionnaires used included questions on previous history of allergies and Asthma in the children and their parents, parental educational level, the number of children in the family, access to residence (ground floor) the presence of one or many pets (E. Eller et al. Meta-analysis of determinants for pet ownership in 12 European birth cohorts on asthma and allergies: A GA²LEN initiative. Allergy 2008; 63: 1491-1498).
In this study, 14.9% of the families had at least one cat, and 12% at least one dog. A family history of allergy significantly decreased the opportunity of owning a cat (OR 0.91; CI 95% 0.85-0.99) or a dog (OR 0.90 ; 0.86-0.94).
A high level of parental education also decreased such opportunity, which was more evident for cats than for dogs.
Apart from this, the older the children are, the lower the chances are for a family to own a cat. That was not seen in the case of dogs.
Finally, the convenience of ground access is a factor which favours owning a pet, whereas the number of children is not associated with its presence.
Thus, socio-demographic factors such as family history of allergy, a high parental educational level, home ground access, must be taken into consideration in all european statistical study that may wish to analyse the influence of pets on allergy or asthma in children.
Allergists face to Primary Immune Deficiencies (PID)
PID include approximately150 identified diseases, 120 of which are due to genetic defects. They are relatively rare, and their diagnosis depends upon the sagacity of the doctor and the laboratory support in the area or region concerned.
This highlights the interest of the general review dedicated to « Common variable immunodeficiency » by English-speaking authors (M. A. Park et al. Lancet 2008: 372 ; 489-502) corresponding to Hypo- or Agammaglobulinemia or Humoral PID of the French litterature. It represents 65% of PID and is characterised by repetitive bouts of sinus and pulmonary infections, affecting the young adult, male or female, and in whom one detects a clear decrease of serum levels of at least two immunoglobulins: IgA , IgG or IgM.
The allergist or pulmonologist may therefore have to face these patients with upper (sinusitis) or lower (pneumonia) airway infections which mimic asthma or chronic bronchitis, and which are due to Hemophilus influenzae or Mycoplasma and may justify antibiotics in primary care .
However, the association with other symptoms may draws attention :
Auto-immune manifestations : thrombocytopenic purpura or haemolytic anemia, Pulmonary complications such as bronchectasis or granulomatosis resembling sarcoidosis, or Gastro-intestinal problems similar to Crohn’s disease or coeliac disease, or Non-hodgkin Lymphoma.
The diagnosis comprises 3 steps :
1st step : F.B.C. (Full blood count) and determination of serum Immunoglobulins, as well as search for proteins in the urine (to exclude a nephrotic syndrome)
2nd step : Determination of serum levels of IgG sub-classes (IgG1 to IgG 4), anti-diphteria and anti-tetanus antibodies and haemagglutinins as well as an antibody response to Streptococcus Pneumoniae type polysaccharide vaccination.
In fact, the absence of antibodies requires replacement treatment with intravenous or sub-cutaneous Immunoglobulins, as suggested by M.L. Moore and J.M. Quinn (Annals of Allergy 2008; 101: 114-121).
It is also relevant at this stage to quantify, by flow cytometry, B and T Lymphocytes as well as Natural Killer cells, whereas the study of B sub-populations will be part of the 3rd step.
3rd step : essentially genetic studies (which will be discussed next)
Genetic approach to Primary Immune Deficiencies
In the case of PID described beforehand, genetic studies are rarely indicated since corresponding mutations are rare and not always clinically relevant. In 15% of the cases, particularly when Agammaglobulinemia is associated with an absence or a very low percentage of B Lymphocytes, involved genes have been described : ICOS (Inducible T cell Costimulator) in 9 patients, TNF superfamily : 13 B in 17 patients and 13 C in one patient, and CD19 in 4 patients. As for the other PID, mainly seen in infants and children, their prognosis is often severe, and they present with different clinical phenotypes.
When a phagocytic deficit or a chronic septic granulomatosis are suspected, one should do a neutrophil count, study their chemotactic response and their phagocytic capacity using a Nitro-Blue Tetrazolium or a Dihydro-Rhodamine stain and flow cytometry for detection of expression of CD11/CD18 before studying the gene.
When one suspects that cell Immunity is affected, analysis should initially include a flow cytometry study of the percentage of T lymphocytes, and Natural Killer cell subpopulations as well as an in vivo and in vitro analysis of T cell function.
Several detailed tables of the most frequent PID and implicated genes are published in the paper by H.K. Lehman et al (The use of commercially available genetic tests in immunodeficiency disorders. Ann. Allergy Asthma Immunol. 2008; 212-218) and include the addresses of Laboratories specializing in the study of these diseases in the US.
Such genetic studies must be performed after having obtained a written informed consent from the patients and/or their families. They are carried out in the blood or in oral scrapings, particularly in severely leucopenic patients (in whom the amount of necessary DNA may be insufficient in the blood) or in the case where a bone marrow transfer must be performed (which may contain donor blood cells).
In France, it is mainly at Hôpital Necker, in Paris, that after the internationally acknowledged contribution by C. Nezelof, the remarkable work by Alain Fischer on SCID (Severe Combined Immune Deficiencies, which are most often X-linked and potentially lethal) has applied gene therapy which has proven to be very efficacious, thanks to the introduction of genes using retroviral vectors(Thérapie génique des Déficits immunitaires Sévères. A. Fischer et al. Bull.Acad. Nat. Med. 2005; 189: 779-788)
Genetics , Asthma, and Passive Smoking
In a study involving the human genome, a group of French researchers had shown the association between certain genetic variations in chromosome 17q21 and an increased risk of Asthma. In order to elucidate this association, a larger study was performed involving various clinical phenotypes of the disease (Effect of 17q21 variants and smoking exposure in early onset asthma. E. Bouzigon et al. N. Eng. J. Med. 2008 359 19 November 6 1985-1994 ).
The methodology involved testing for 36 SNP (single nucleotide polymorphism) in the 17q21 region in 1511 asthmatic patients from 372 families. The age at onset of asthma and early passive exposure to tobacco smoke (from parents) were also taken into consideration.
11 SNP were significantly associated with Asthma, of which 3 were very strongly and 4 were strongly associated with an early-onset asthma (4 years old or younger). By contrast, no association was observed with late-onset asthma.
Furthermore, a very strong association was seen between 6 SNP and early-onset asthma when the children had been early exposed, to passive smoking. A specific genetic variant (re8069176) was associated with a 3-fold higher risk of asthma than other genotypes.
Therefore this excellent study shows the joint effect of genetic (chromosome 17q21, in this case) and environmental factors (here tobacco-smoke) upon the pathophysiology of asthma, in the context of passive smoking by the young child.
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Claude MOLINA and Franz MARRACHE
- Therapeutic innovation in Asthma
- The beekeeper : a model of immunologic tolerance
- Is anti-fungal treatment useful in Severe Asthma with sensitisation to Fungi ?
- Mediterranean diet: Protective role for Wheezing in pre-school children ?
Therapeutic innovations in Asthma
1) Improvement of usual treatments
This excellent and comprehensive review (I. M. Adcock et al. New targets for drug development in Asthma. Lancet 2008; 372: 1073-1087) starts by highlighting that 90% of Asthma cases respond favourably to conventional therapy based upon inhaled corticosteroids and â2-agonists. Thus, the remainder consists of 5 to 10% of cases of severe Asthma, which are responsible for 50% of the costs associated with the disease and for which novel targets and new therapeutic approaches have to be developed. Monoclonal antibodies (mAb) have entered the therapeutic arsenal, with the anti-IgE Omalizumab which is successfully used in the severe allergic forms of asthma. However, research must understand the cellular and molecular mechanisms of these severe forms of Asthma, thereby suggesting the possibility of several different phenotypes of the disease.
The authors analyse the development of the ultra long acting â2-agonist, which may act rapidly, their effects lasting longer than 24h (carmoterol, indacaterol) and may be only taken once-a-day. Another approach is the attempt to avoid the side- effects of corticosteroids via the use of a pro-drug.
These ways include:
a) using the pro-drug which is only activated in the airways (ciclesonide)
b) dissociating corticosteroids from their different effects by modifying the activation of their receptor (transrepression)
c) by addition of a biochemical NO-donor group , which has been experimentally efficient
d) through utilisation of novel inhalers which deliver mono-dispersed particles with sparing effect, and equivalent efficacy.
One may also mention the anti-lipid mediator drugs such as anti-leucotrienes (Montelukast, Zileuton), not very effective but may eventually be tested in « neutrophilic » cases of Asthma since they inhibit neutrophil chemotaxis. Likewise,anti-prostaglandin PGD2 or anti-PAF drugs, are still at an experimental stage or at phase II of clinical trials. In any case, it is known that the inhibitory action upon a single mediator or receptor has little chances of being effective.
2) Therapeutic innovation in Asthma
The novel targets :
These are chemokines and their receptors, Th2-derived cytokines, transcription factors, enzymes and several immune cells. Chemokines are responsible for the recruitment of inflammatory cells into the airways. There are 4 families classified according to their cysteine radicals. Several receptors exist and one of them, CCR3 which recruits eosinophils is a preferential target .Their levels are increased in Asthma and inhibitory anti-sense oligonucleotides have already shown their efficacy in inhibiting eosinophil inflammation and bronchial hyperreactivity ( it is the case of TPI ASM8 from Topigen analysed in our February 2008 BUA).
However, other chemokines (CCL17, CCL22, CXCL8) may be important and their respective inhibitors are at an experimental stage or in phase II clinical trials.
Th2-derived cytokines have a role in chronic inflammation and airway modelling. If anti-IL-5 mAb have not been shown to be effective, blocking IL-4 and its á–subunit and IL-13 by Pitakinra (already mentioned in our BUA) has been shown to be an interesting approach, whereas anti-IL-13 as well as anti-IL-10 and anti-IL-12 mAb are currently being studied. Curiously, TNF-á has been shown to be a pro-inflammatory cytokine but its blockage was not associated with any clinical improvement of Asthma.
The authors also mention Suplatast tosilate which may inhibit IL-4 and IL-5 and has been slightly effective in a small clinical trial of moderate asthma.
Among the other targets
- phosphodiesterase inhibitors such as roflumilast and cilomilast, active by oral route, have side effects ,similar to those of theophylin, with nausea and vomiting;
- kinase inhibitors such as p38 MAPK, active by inhalation;
- transcription factors such as NFêB or IKK2 inhibitors useful in insensitive to corticosteroids asthma
- other nuclear factors such as PPAR (Peroxisome proliferator activated receptor) which, in association with corticosteroids may have an important anti-inflammatory role. Finally, the development of Immunotherapy targeting regulatory T cells (Treg) and Th17 cells, in combination with D3 vitamin and corticosteroids deserves to be mentioned.
This vast number of studies on biological or synthetic drugs, can be explained by the complexity of asthma mechanisms, but we must remind that targeting only one mediator, or receptor or enzyme is ineffective and meanwhile the development of distinct handprints of different subtypes of the disease, combination of therapies is clearly mandatory.
The beekeeper : a model of immunological tolerance
In an editorial in the Journal of Experimental Medicine (Published online November 10, 2008) Nicole Lebrasseur, quoting work from F. Meiler, observed with humour that better than a murine experimental model, the beekeeper fulfils an old Immunologist’s dream, by revealing that such an intrepid honey lover, kicks into action a group of T Lymphocytes which pass successively from an aggressive mode to a suppressive mode and vice-versa, just like Dr Jekyll and Mr Hyde.
In fact, due to the nature of their work, non allergic beekeepers receive when they collect honey, repetitive injections of high doses of bee venom antigens (a mean of 13 bee stings during the first week of the season is usual). In this 7 day period, the beekeepers develop tolerance which is associated with an inhibition of T cell responses, both in the skin (absence of late phase reaction) and in the blood (suppression of venom antigen-specific proliferation).
In fact, T cells which happily proliferate, in response to antigen, relax once the season starts and, instead of secreting Interferon-ã and IL 4 , by cytokine switch, start synthesising high levels of IL-10, which dampens immune reactions. These IL-10-producing regulatory T cells (Tr1) decrease the antigen-induced proliferation of other T cells in vitro. This T cell regulation continues as long as antigen exposure persists and return to in initial levels within 2 to 3 months after the season.
Such cytokine switch may require Histamine-related pathways; in fact, just like most allergens, bee venom sets off a release of histamine by mast cells and in vitro T cell studies show that the production of IL-10 and cell lethargy require the intervention of Histamine type 2 receptor (TGF-â does not seem to play an essential role in skin tolerance, in contrast with its action in mucosal tolerance).
It should be noted that such tolerance disappears at the end of the season, indicating a relatively transitory suppression of T cell activity. Afterwards, this cycle is repeated during the following season which allows one to reassure the beekeepers, if need be.
As far as bee venom-allergic individuals (who are generally deficient in IL-10) are concerned, there is no place for great enthusiasm about this finding since it shows that the success of allergen-specific immunotherapy entails a long and persevering maintenance of therapy.
Is Anti-fungal treatment useful in Severe Asthma with sensitisation to Fungi?
This is the question asked by the English authors from the University of Manchester as they analysed, in a randomised study, the response of asthmatic patients sensitised to one or various fungi, to Itraconazole (Randomized Controlled trial of Oral Antifungal treatment for severe asthma with fungal sensitization. D.W. Denning et al. Am.J.Resp.Crit.Care Med 2008, October 23).
58 subjets with severe asthma, treated with inhaled or oral corticosteroids (41% had already been hospitalised in the previous year) and having positive skin tests and/or specific IgE to one or various fungi: Penicillium, Candida, Cladosporium, Botrytis, Trychphyton, Alternaria, and Aspergillus (with the exception of subjets having precipitins against the latter) were recruited at 4 different hospitals. All the subjects had total serum IgE levels lower than 1000UI/ml.
Patients were treated either with Itraconazole orally (200mg/day) or with Placebo for 32 weeks and were subsequently followed for 16 weeks.
A standardised questionnaire with 32 items on Quality of Life of the asthmatic patient, followed by lung function testing, calculation of a rhinitis score and determination of total serum IgE levels were performed. Results were as follows:
At 32nd week, there was a significant improvement of the Quality of Life in nearly 2/3 of the cases (60%), when compared with the Placebo group. In fact, complete data were obtained from 41 subjects who have followed the treatment until the end of the study.
The Rhinitis score also improved, whereas it deteriorated in the Placebo group.
The levels of total serum IgE decreased significantly, dropping from 187 to 136 UI/ml, whereas they increased in the Placebo group, from 245 to 275 UI/ml.
Changes in lung function were modest: only morning peak expiratory flow significantly improved.
Overall, there were only a few cases of exacerbation of asthma (similar in both groups) which required an increase in the doses of corticosteroids or hospitalisation.
There were no severe side effects, but 7 subjects (5 of which were in the anti-fungal group) had to discontinue treatment.
The authors put forward some hypotheses to explain the favourable action of antifungal therapy (which progressively disappears after suspension of the latter): action on the eventual colonisation of airways by the fungi, synergy with corticosteroids, or direct stimulation of the immune system.
Mediterranean diet : Protective factor for Wheezing in pre-school children?
The Mediterranean diet (MD) is regarded in adults as protector for atherosclerosis and its cardio-vascular consequences. It is based upon increased ingestion of fruits and vegetables (anti-oxydants), n3- (fish oils) or n-6 (vegetable oil) polyunsaturated fatty acids, and a moderate ingestion of milk, meat, and avoidance of fast-food : hamburgers, fried foods, industrial cakes, pizzas…
A group of Spanish doctors had already shown that MD was a protective factor for allergy and asthma in children aged between 6 to 7 years (L. Garcia-Marcos et al. Thorax 2007; 62 : 503-508) and that, in contrast, obesity was a risk factor, particularly in girls. The same group (A. Castro-Rodriguez et al. J. Pediatrics 2008 ; 823-828) extended their epidemiological study to young children from 3 cities in the Southeast of Spain. They hand out questionnaires to the parents of 1784 children (mean age of 4 years), in searching children wheezing (asthma equivalent) in the previous year. The authors set up a score for MD according to the intake frequency of pro- and anti-MD foods.
A potent multivariate and logistic regression statistical analysis also incorporating family history of these children showed that, ingestion of Paracetamol, eczema, rhino-conjunctivitis and paternal asthma were significant risk factors for wheezing in children. In contrast, MD and the child’s older age were protective factors.
The authors acknowledge the difficulties in interpretation of these food questionnaires and cannot give advice on the amounts of such food necessary to ensure a protective effect. Therefore, they can only suggest a balance favouring pro-MD foods and pointing towards avoidance of risk foods.
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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).
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Claude MOLINA and Franz MARRACHE
- Can paracetamol be a cause of Asthma in children ?
- Objective assessment of Cough in Asthma
- Is Helicobacter pylori (HP) a preventive factor for Allergy ?
- Parasitosis in children and Allergy
- Birch-induced allergic Rhinoconjonctivitis treated with recombinant allergens
Can paracetamol be a cause of Asthma in children?
This is the guesswork of a large European survey: ISAAC in its phase 3 (Association between paracetamol use in infancy and childhood and risk of asthma, rhinoconjunctivitis and eczema. R. Beasley et al. Lancet 2008 ; 372 : 1039-1048). Indeed, since the 80s, paracetamol (P) completely replaced aspirin as anti-pyretic and analgesic in children. This is due to risk of asthma, triggered by aspirin, particularly in atopic children but also Rye’s syndrome (encephalopathy with epileptic attacks and ocular problems.
The authors tried to find out whether exposure to P during intra-uterine life, or the first year of life in infant, as well as at the age of 6-7 years and also in adult, increased the risk of Asthma and/or Allergy. 205,487 children 6-7 years old, from 73 centres in 31 countries were included in this study (questionnaire given to parents). The results showed (multivariate analysis) that the administration of P (at least once per month) during the 1st year of life was significantly associated (OR 1.46) with an increased risk of Asthma at 6 to 7 years of age. Furthermore, usual utilisation of P was associated, in a dose-dependent fashion, with a risk of asthma (OR 1.6 to 3.23, according to moderate or high drug dose, respectively). Morover, use of P during the 1st year and at 6-7 years of age was associated with an increased risk of rhinoconjunctivitis and eczema. Although impressed by the size of the sample and its multi-nationality, the methodology and the power of this statistical analysis, one cannot exclude recall bias (in the responses given by the parents to the questionnaire, translated into various languages), or reporting bias (use of other antipyretics or viral infection).
So the doubt persists. In fact, if the association is plausible, the causal relation between P and Asthma or Allergy cannot be stated, as the authors acknowledge.
Moreover, what antipyretic or analgesic drug one should use in the young child ?. Ibuprofen suggested by some authors does not gather unanimity. Aspirin has not said its last word. Thus, we think that P at moderate doses, because its efficacy and safety profile spanning 50 years, should continue to be the first choice for the treatment of fever and pain, even in allergic or atopic children.
Objective assessment of Cough in Asthma
Few studies have focused on the prevalence of cough in Asthma, and most of those are based on subjective criteria. Some authors suggest that 61% of asthmatic patients complain of cough. Whether it occurs during the night or day, whether it is productive or not, it is not the main symptom mentioned by asthmatic patients. The interesting work reported by P.A. Marsden et al, from Manchester ( JACI 2008 ; 122: 901-907) is the first which performed comparative study between subjective and objective criteria. These latter were obtained through ambulatory monitors allowing 24 hour-long recordings with a count unit : the number of seconds of cough per hour.
The methodology is original and precise: it included a questionnaire (Leicester) with 19 questions on physical, social and psychological aspects, a thorough study of asthma involving lung function studies, a test of bronchial reactivity, an analysis of FeNO, as well as reflex sensitivity through inhalation of citric acid. The subjective scores included an analogue visual scale graded from 1 to 100 and a frequency score graded from 1 to 5. 54 asthmatic subjects were included (these patients were not selected on the basis of their cough) and were compared with a similar number of healthy control subjects. Results were thoroughly analysed statistically.
The conclusions were surprising and very interesting: It is obvious that the frequency of cough was higher in asthmatic patients than in healthy subjects of similar age.
However, the median time spent by asthmatic patients coughing was little , averaging 2.6 seconds per hour (range: 0.0 to 14.0).
In patients with asthma, Cough was more frequent during the day than at night (3.9 seconds per hour versus 0.3 Overall or daytime cough rates were not significantly different between female and male patients. However, women spent more time coughing at night than men. In addition, cough rate showed a weak but significant positive correlation with the subjects age.
Objective time spent coughing was weak to moderately associated with subjective cough scores and visual analogue scales. but was not correlated with functional tests, namely bronchial reactivity, FeNO or reflex sensitivity to citric acid.
In contrast, objective time spent coughing was strongly correlated with scores of quality of life questionnaire. These notions underline the interest of objective cough recordings for all therapeutic interventions directed towards this Asthma symptom, but also for all cough-inducing causes. In this regard let us also remember a physical discipline : strioscopy, which studies the dynamics of gas flows; its application to the study of cough has shown that its generates warm air with a mean speed around 8 metres/second.
Is Helicobacter pylori (HP) a preventive factor for Allergy?
The inverse relationship between bacterial colonisation by HP and the presence of Asthma or Allergy reported by Chen and Blaser (J. Infect. Dis. 2008 ; 198 : 553-60) led some scientists to study the mechanism accounting for this possible protective effect. Thus, an Italian team (G. Del Prete et al. Immunosuppression of Th2 response in Trichinella spiralis (TS) infection by HP neutrophil-activating protein. JACI 2008 ; 122 : 908-913) infected various murine strains with the TS parasite, which triggered eosinophilia, and increases in the serum levels of total and specific IgE, as well as those of IL-4 and IL-5. In this model, the authors showed that in animals treated with Neutrophil activating protein (NAP) there was an anti-Th2 activity with a decrease in eosinophilia and in the plasma concentrations of IgE, IL-4 and IL-4, associated with an induction of IL-12 and INFã expression.
In addition, the simultaneous administration of an anti-Toll Like receptor 2 monoclonal antibody abrogated the immunosuppressive action of HP-derived NAP on Th2 activity as well as its Th1-inducing activity.
This HP-NAP-derived immunosuppressive activity was confirmed by Codolo et al belonging to the same working group(Cell Microbiol. 2008 August 15) who showed, in a murine model of ovalbumin-induced allergic asthma, that systemic and mucosal administration of recombinant NAP abrogated pulmonary eosinophilia, and reduced the serum levels of IgE and Th2 cytokines.
Thus, the HP- NAP / asthma antagonism, suggested by clinical observations and confirmed experimentally, deserves to be considered.
In this context, recombinant NAP might represent, in the future,
a novel strategy for prevention of Allergic disorders
Parasitosis in children and Allergy
A group of doctors from Latin America (Brazil and Ecuador), in collaboration with the London School of Hygiene and Tropical Medicine, UK, has tried to find if, like Hygiene hypothesis in developed countries, intestinal helminthic infestation during early childhood might account for a lower prevalence of allergic reactions and asthma later in childhood and intervene upon the immune system, to induce a lower allergen skin test reactivity.
The investigators have, therefore, selected 1055 children whose stool examination had shown, in another previous study, intestinal infestation with an helminth : Trichuris Trichiura (TT) in early childhood. Then they performed skin prick tests in these children, a few years later, with common aeroallergens and collected information on potential confounding variables in their statistical analysis (L. C. Rodrigues et al: Early infection with Trichuris trichiura and allergen skin test reactivity in later childhood. Clin. Exp. Allergy 2008 ; 38 : 1769-1777). The results are as follow: Children with heavy infections with TT in early childhood had a significantly reduced prevalence of allergen skin test reactivity in later childhood, even in the absence of intestinal infestation at the time of skin testing.
Thus, for these authors and in emerging countries, massive infestation with TT
in early childhood seems to play a protective role against skin reactivity to aeroallergens. Novel treatments programming immune regulation in the early child by mimicking the effects of the TT parasite might offer a new research avenue for the prevention of allergic diseases.
The chapter of correlatins between Parasites and Allergy, which is quite complex and has been the subject of many but not always concordant results, , is thus enriched with an innovative study showing an unexpected positive relationship.
Birch-induced allergic Rhinoconjonctivitis treated with recombinant allergens
The European task force of Recombinant allergens, led by Gabrielle Pauli (Strasbourg) reports a randomised, multicenter, study on birch-induced allergic rhinoconjunctivitis treated by the recombinant (r) allergen (JACI 2008;122: 951-960). Three types of allergens were compared: rBet v1, a patented birch pollen extract ; nBet v1, a purified natural allergen and a placebo group. 134 adult subjects participated in this study. They were given a weekly injection of the product for 12 weeks, followed by a monthly maintenance administration of 15µ Bet v1 for 2 years (2004 and 2005). All subjects were followed up on a regular basis in clinical and biological terms : 33 subjects on rBet v1, 29 on nBet v1, 29 on Birch pollen extracts and 36 on Placebo.
Results were as follows:
A significant reduction in about 50% of symptoms, rescue medication and cutaneous sensitivities in the 3 treated groups, as compared with the placebo.
group. Clinical improvement was accompanied by an increase in the levels of Bet v1-specific IgG, which was higher in the Recombinant Bet v1 group.
No new IgE specificities were observed in the rBet v1 and nBet v1 groups, whereas there were 3 in the one treated with pollen extract. There were no severe side effects in the Recombinant group. This study thus confirmed the efficacy and safety of recombinant allergens for the treatment of birch pollinosis and the skill of genetic recombination DNA technology for the manufacture of allergen extracts for vaccines.
A novel approach for conversion of allergens as vaccines is the dissociation of allergen molecule between IgE and IgG immunologic activity. This approach was carried out in an animal model by N. Mothes-Luksch et al (Disruption of allergenic activity of the major grass pollen allergen Phl p2 by reasembly as a mosaic protein. J. Immunol. 2008 ; 181 : 4864-4873) who fragmented Phleum allergen into peptides of similar length, then re-assembled them in a different order, which lead the mosaic protein so expressed to the loss of its tridimensional structure, its capacity to bind IgE, and its allergenic activity whereas induced high levels of IgG molecules bind to Phl p2 blocks its binding to IgE.
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Claude MOLINA and Franz MARRACHE
• Severe asthma in children and bronchial remodelling
• Justification for Sub-Lingual Immunotherapy (SLIT)
• IgE, atopic eczema and food allergy
• The various facets of asthma in Olympic athletes
• Impact of stress upon asthmatic adolescents
Severe asthma in children and bronchial remodelling:
A French hospital-university team (Lille/Paris) compared structural changes in bronchi after the occurrence (or not) of a bronchial obstructive syndrome in children with severe Asthma (according to American Thoracic Society criteria). (Airway remodeling is correlated with obstruction in children with severe asthma : I.Tillie-Leblond et al Allergy 2008 63 May 533-541). For this study, 25 children aged between 5 and 14 years were recruited : 15 had bronchial obstruction (FEV1 lower than 80% of predicted and not responding to bronchodilators) and 10 did not have bronchial obstruction. A bronchial biopsy was taken and thoroughly examined using immuno-histochemistry . It was concluded that a large number of features were the same in the 2 groups : that applied to basal membrane thickening, epithelial integrity (analysed using EGF and EGF-R markers), collagen I and III deposition in the mucosa (using TGF-â as a marker), the number of eosinophils or neutrophils in the bronchi or gland thickness.In contrast, there was a statistically significant correlation between bronchial obstruction, the thickness of the smooth muscle wall (with increased expression of the MLCK: Muscular Light Chain Kinase enzyme, which reflects contractility) and the extension of the vascular network within the bronchi (as determined by expression of CD31) .Thus, the hypothesis of bronchial remodelling as a consequence of chronic inflammation remains uncertain, given that the age of Asthma in these children did not affect the results. It should also be stressed that structural changes predominantly involving smooth muscle and vascular factors develop early in the natural course of this form of asthma and explain the low efficacy of corticosteroids. It is therefore adequate to envisage a revision of classical therapeutic targets in these severe forms of asthma in children (and subsequently in adults).
Justification of Sub-Lingual Immunotherapy (SLIT):
Three recent articles dedicated to SLIT justify its definitive adoption by the European allergic community, followed by the anglo-saxon one. In a general New England Journal of Medicine review on this issue, A.J. Frew (Sublingual Immunotherapy: NEJM 2008 22 May 358 2259-2264) discusses the indications, the mode of action and the effects of such therapy with its dosage, duration of treatment, its minor secondary effects, its yearly cost, but also its uncertainties concerning, among others, allergen standardisation in line with the absence of an international consensus. Nevertheless, although FDA has not yet approved this form of therapy, the British Society for Allergy and Clinical Immunology has acknowledged, since January 2008, its efficacy and safety for the treatment of pollen-induced allergic rhinitis and asthma. This method, which was initiated in Italy, is currently widely used in Europe. Authors from Madrid have had the idea of comparing the immunological effects of 2 immunotherapy methods: SLIT (11 patients) and SCIT (sub-cutaneous: 12 patients) in 23 house dust allergic children, after a 2 year-long follow up period : Antunez C. et al…2 years follow-up of immunological response in mite-allergic children ; comparaison with sub-cutaneous administration Pediatr.Allergy Immunol 2008 19 3 210-218. Clinical improvement was similar and a decrease in specific IgE /IgG4 ratio was observed from the 1st month onwards with SCIT, after 2 years with SLIT. The authors also observed, in the long run, an increase in CD4/CD8 ratio as well as a decrease in the production of TNF-á and IL-2.
In contrast, an increase in the CD4+CD25+ subpopulation and a decrease in CD8+CD25 subpopulation were only observed with SCIT, with a slight change in the INF-ã/IL-4 ratio, reflecting a re-orientation from a Th2 response to a Th1 one.
There seems to be a slight difference in the immunological response in the peripheral blood during SCIT. In contrast, is there a mucosal protection with SLIT? That is what the authors suggest. And the recent observation by K.C. Bergmann et H. Wolf: Effect of Pollen-specific SLIT on Oral Allergy Syndrome: an observational study WAO Journal May 2008 1(5) 79-84 seems to confirm this hypothesis. For this study, 102 patients with pollen-induced allergic rhinitis, 9 out 10 had a more or less intense oral syndrome to food allergens associated with pollen allergens (such as apple-birch, Artemisia - celery, tomato – grass pollen). They were treated with SLIT for 1 year. The oral allergy syndrome improved in 3/4 of the cases concurrently with an improvement of rhinitis. According to J. Ring (journal editor) this is encouraging in terms of foreseeing a possible future treatment of food allergies by SLIT.
IgE, atopic eczema and food allergy
An international group of paediatric allergists (Early Prevention of Asthma and Allergy in Child study group) investigated IgE responses in young children with atopic eczema (IgE antibody responses in young children with atopic dermatitis U.Wahn et al Pediatr.Allergy Immunol 2008 19 332-336). In this study, 2184 infants, between 13 and 24 months of age, with atopic eczema (Scorad 5-59, representing a moderate eczema score) were tested with the 8 most common allergens. Results showed that 18.7% were sensitised to a single allergen, and 36.8% were polysensitised. The frequency of positive IgE responses to aeroallergens and foodallergens (>0.35 kU/l) correlated with the severity of the cutaneous manifestations. Among these young children, a minority had elevated food allergen-specific IgE levels, which would suggest that there is an increased risk of acute clinical reactions to these allergens (7% to egg, 3% to cow’s milk, 4% to peanut). These observations confirm classical data namely the prevalence of IgE responses to food allergens which is highest during the first year of life whereas respiratory allergens develops between 1 and 2 years of age or later. The approach of this association between atopic eczema /food allergy is discussed in the review about this issue by F. Rancé, from Toulouse (France) (Food Allergy in children suffering from atopic eczema Rancé F. Pediatr.Allergy Immunol.2008 19 279-284) ; 2 cases are discussed as an example: one of the cases is a young child with early onset and severe eczema in whom a food diet excluding suspected allergens improved cutaneous lesions; the second case is that of an older child in whom such diet might have deleterious effects on growth without any improvement of the cutaneous state.
This article is followed by a MCQ type questionnaire such as those build-up for Continuous Medical Education (CME).
The various facets of asthma in Olympic athletes
The experience of the athletes of the Finnish Olympic team was analysed in the publication by Haahtela T. et al (Mecanisms of asthma in Olympic athletes – Practical implication. Allergy. 2008 Jun;63(6):685-9).
Extreme exercise conditions among elite athletes may be the source of respiratory manifestations. So, in short duration speed and power efforts or endurance tests in swimmers and long distance skiers, hyperventilation (≥ 200 l/m) has a cooling and drying effect on the airways, and also stimulates vagal nerve endings and bronchoconstriction. Among swimmers, aspiration of a large number of droplets of water full of chemical products (chlorinated products, in particular) induces, by irritation, a vagally-mediated bronchoconstriction as well as bronchial hyperreactivity. Hyperventilation is also associated with the inhalation of important amounts of allergens, domestic aeroallergens and/or pollens depending on the environment (indoor or outdoor exercise), and constitutes, a risk factor for atopy and asthma as reflected by the increase in prevalence of IgE-dependent manifestations among young athletes. The mechanisms vary according to the sport and individual athlete, depending on the aetiology but also on clinical phenotypes. At least two phenotypes are evident, thereby reflecting the existence of distinct mechanisms : the phenotype of early onset infant asthma, which is atopic and combines hyperreactivity to metacholine and an eosinophilic inflammation of the airways with an increase in exhaled NO ; and the other phenotype which includes late onset manifestations (developing during the sports career), bronchial hyperreactivity with the isocapneic hyperventilation test, and not necessarily with metacholine challenge, and which is not associated with markers of atopy.
A mixed type of bronchial inflammation, both eosinophilic and neutrophilic seems to specifically affect swimmers, ice hockey players and long distance skiers. In this case, inflammation may be both allergic and irritant.
It should be stressed that asthma in athletes is under- or over-diagnosed and is therefore an important source of therapeutic problems.
In general, in order to assess the temporal link between asthma and competition sports practise, one must take into account individual predisposition, environmental factors, and the intensity of training.
See at www.cefcap.com the file on Allergy and Sport and the file on Asthma in 2005 Updates.
Impact of stress on asthmatic adolescents
Recent studies suggesting that psychosocial factors may have an impact on asthma, account for the work of Turyk ME et al (Stressful life events and asthma in adolescent. Pediatr. Allergy Immunol. 2008 19:255-263).
The 2026 participants, high school students from Catholic Private Schools of Chicago as well as from State public schools, were aged between 12 and 14 years. Diagnosis of asthma and information on types and number of stressful events, during the previous 12 months, were the object of an anonymous questionnaire.
This questionnaire included a 15-item stressful life events inventory that encompassed traditional items featuring in established life event instruments, family life elements, sources of ill being, relationship and school difficulties and items relating to inner city youths such as gang violence, stabbings and shootings.
Anonymity of the questionnaire, facilitated the collection of information regarding drug use. Of all the participants, there were 315 asthmatic adolescents 1711 non-asthmatic, served as a control group. Overall, asthma was significantly associated with the number of stressful events faced by urban adolescents. Similar results were observed for respiratory symptoms and the other markers of morbidity : school absenteeism, hospitalisations, and physician visits due to asthma.
These associations were independent of exposure to tobacco smoking in the family, use of inhaled substances, sociodemographic factors, or home dampness.
On their own, these results do not allow to conclude to a formal cause-effect link between asthma and stress. However, by analysing and listing the effects of stressful events, the clinician may be helped in terms of preventive and therapeutic approach to the disease among these adolescents.
These texts has been translated by L.TABORDA Covilha (Portugal).
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Claude MOLINA and Franz MARRACHE
- Occupational respiratory allergy in apprentices and Atopy
- Insight into the pathophysiology of asthma and bronchial hyperreactivity
- Asthma during pregnancy and congenital malformations
- Bêta-blockers and asthma :
- Are beta-blockers useful in Asthmatic patients ?
- Are beta-blockers a good option in elderly asthmatic patients ?
- Can all proteins become allergens ?
Occupational respiratory allergy in apprentices and Atopy :
The team of JL Malo, in Montreal, specialised in occupational allergy and asthma, has carried out a long term (8 years) study on the outcomes of 408 apprentices exposed to high molecular weight allergens, such as flour, latex, and laboratory animal allergens (Long term outcomes in a prospective cohort of apprentices exposed to high-molecular-weight agents : American J. Resp. Crit Care Medicine 20008 177 871-879 D.Gautrin et al). The objectives of the study were to assess the frequency of new and persisting sensitisation, rhino-conjunctival symptoms and bronchial hyperresponsiveness in relation with job history after ending apprenticeship and to examine characteristics significantly associated with the incidence and remission of these outcomes.
A respiratory symptom questionnaire, skin prick-tests with the suspected allergens, spirometry and metacholine challenge test were used for this study together with an appropriate statistical analysis. Within the group of individuals who, at a given time of the observation period of the study, held a job related to their apprenticeship (78% of the cases) the incidence of sensitisation, rhino-conjunctival symptoms, bronchial symptoms or bronchial hyperreactivity was, respectively, 1.3, 1.7, 0.7 and 2.0 per 100 person-years. Within the group of individuals who started a job different from that of their apprenticeship, a remission was observed respectively in 18.5, 9.6, 9.6 and 12.4 per 100 person-years. The authors stressed that allergic reactions acquired during apprenticeship did not dissuade individuals from engaging in an activity in the same field (8 out of 10) and they don’t seem to have regretted it since, overall, the incidence of allergic manifestations was lower during the work period than during their apprenticeship. In addition, a high proportion of individuals who started an activity different from the one they had during their apprenticeship had a remission of symptoms. This is a particularly interesting result for atopic individuals who are normally advised to avoid careers where they may be exposed to the inhalation of high molecular weight particles (Laboratory Animal Caretaker or Dental Hygienist or Baker). As mentioned in the editorial of the review, this may be the “end of the tunnel” in this context for atopic individuals.
Insight into pathophysiology of asthma and bronchial hyperreactivity
In a previously work GL. Chupp et al, observed that the serum and pulmonary levels of a component of human cartilage, YKL-40 protein, also known as chitinase 3-like 1 protein, was correlated with asthma severity and bronchial remodeling.
The genetic aspects of this finding is related in a recent publication (Ober et al : Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma and lung function ( NEJM 2008; 358 : 1682-91,).
The study involves 1893 individuals from various populations: 753 Hutterite farmers, a sect of German descent living in South Dakota, Two control groups of European descent, with one including 638 children living in Freiburg, and the other 296 adults and children living in Chicago, as well as 206 children from Wisconsin, of European descent at high risk of asthma, belonging to COAST (Childhood Origins of Asthma Cohort Study),.
Links between the genetic polymorphism found at the CHIL3 (SNP – 131 C→G) susceptibility locus and the serum levels of chitinase-3 like 1 (YKL-40) protein were investigated.
Within the Hutterite population, increased YKL-40 levels were conditioned by the – 131 C allele (found in CC and CG genotypes) which was correlated with asthma, bronchial hyperreactivity, and lung function changes, in contrast with the protection afforded by the -131G allele. The -131C allele also allowed the prediction of asthma within the two control cohorts at Freiburg and Chicago.
In addition, within the group of children from the COAST study, analysis of CHI3L1 SNPs allowed to predict the levels of YKL-40 in the cord blood and as well as in peripheral blood, until children were 5 years old.
Given the proliferation of genetic studies in asthma, these findings need for large epidemiological studies to be confirmed. However it may be observed that the switch at a single amino acid within the terminal portion of the CHI3L1 gene is associated to disease or to protection against asthma.
In spite of absence of correlation between the levels of YKL-40 and asthma beyond 6 years of age, or between YKL 40 and atopy, this work opens the way to research projects on pathophysiology of asthma and bronchial hyperreactivity.
Are beta-blockers useful in Asthmatic patients ?
This is an apparently paradoxical question since it is known that they are clinically contra-indicated in asthmatic patients where they may cause acute bronchospasm.
However, the concept of such antagonism as defined by Sir James Black (Medicine Nobel Prize 1972) between â2-agonists such as Salbutamol and Beta-blockers (Bbls) has been discarded by a recent experimental study (L.P.Nguyen et al :Chronic exposure to beta-blockers attenuates inflammation and mucin content in a murine asthma model Am.J.Cell.Mol.Biol 2008 38 256-262).
Chronic administration of beta-blockers for 7 to 28 days, in a mouse model of ovalbumin-induced asthma, decreased bronchial hyperreactivity, reduced eosinophilic inflammation, decreased IL-13, IL-10, IL-5 and TGF-â1 secretion and reduced mucin content within the bronchial epithelium. This was achieved using 2 types of Bbls : a non selective one : Nadolol (Corgard®) and a selective one : ICI 118551 (not yet sold in pharmacy) .
Can we extrapolate these results to humans?
Various recent studies on the effects of Propranolol (®) and Metoprolol (®) in asthmatic or COPD patients with heart failure have shown deleterious side-effects on their respiratory status. Only Celiprolol (Celectol(®)) and, possibly Nadolol would be relatively tolerated by asthmatic patients, maybe at low doses in mild asthma and in prolonged administration. However, in any case, it is necessary to assess benefit/risk ratios. This implies a close collaboration between allergo-pulmonology and cardiology specialists. In practical terms it is still advisable to avoid Bbls in asthmatic patients, even by ocular route (as one of us had the opportunity to note in a patient). The taboo is still valid!
Are beta-blockers a good option in elderly asthmatic patients ?
In order to try and answer this other question, a meta-analysis including 29 prospective studies was performed in 2002 by Salpeter SR et al (Cardioselective beta-blockers in patients with reactive airway disease. a meta-analysis : Ann intern Med. 2002 ;137 :715-725). These authors did not observe any changes in FEV1, or in the clinical status, after the administration of beta-blockers (Bbls) in individuals with bronchial hyperreactivity. However beta-blocker administration did not exceed 4 weeks and the study only involved a limited number of patients 40 to 51 years old.
Another retrospective study (M.A. Rank et al: â blockers prescription in elderly patients with asthma. J Allergy Clin Immunol. 2008 Apr;121(4):1061-2.) included 390 individuals between 65 and 85 years of age, who were selected by randomisation between 2004 and 2006. All had asthma and coronary disease . 200 patients with isolated coronary disease, and similar age range, form the control group.
The authors aimed at answering four questions :
- Are Bbls prescriptions on the increase ?
- Are Bbls less frequently prescribed in elderly asthmatic patients ?
- Are doses prescribed to this type of patients lower ?
- Does the degree of asthma severity influence Bbls prescription ?
Taking as a reference the pilot study by Gottlieb et al, ((Effect of Beta-Blockade on Mortality among High-Risk and Low-Risk Patients after Myocardial Infarction….NEJM 1998339 :489-497), we can observe, , a clear increase in the rate of Bbls prescriptions, which went from 34% to 56%. Such prescriptions were, however, less frequent in the group of patients who had both coronary disease and asthma (45% versus 75%). In contrast, Bbls doses prescribed are equivalent in both groups, and prescription rates are independent of asthma severity degree, which allows to think that the elderly patients tolerates Bbls more than is currently accepted.
However the results of this study should be confirmed by prospective studies.
Asthma during pregnancy and congenital malformations
Are asthma exacerbations during the first trimester of pregnancy associated with congenital malformations? This has been the object of a study involving a cohort of 4344 pregnant asthmatic patients (Lucie Blais et al : Asthma exacerbations during the first trimester of pregnancy and the risk of congenital malformations among asthmatic women, JACI 2008 Apr 12; [Epub ahead of print] ). Clinical episodes were recorded on the basis of corticosteroid prescriptions, visits to emergency departments and hospitalisations due to asthma, whereas the presence of malformations was assessed at birth and during the first year of life. Thus, within this cohort of asthmatic patients, 398 (9.2%) newborns had at least one malformation and the latter had a major feature in 261 of them. The prevalence of these congenital malformations was 12.8% and 8.9%, respectively in pregnant women that had had asthma exacerbations during the first trimester of their pregnancy or not, with an adjusted odds ratio (OR) for malformations of 1.48 (95% IC, 1.04-2.09) in favour of the former. If applied to major malformations, OR would be 1.32. These statistically significant results demonstrate, according to the authors of this study, the risk of fetal congenital malformations in case of asthma inadequately controlled in early pregnancy and suggest that increased surveillance of the respiratory status of asthmatic pregnant women should be increased during the first trimester.
(Cf Consequences of asthma on pregnancy)
Can all proteins become allergens ?
We know that allergens are most frequently proteins. The question is to know whether allergenic proteins have features that are different from those that are not allergenic and whether the sensitisation to the former depends upon their concentration, their source and/or exposure route (respiratory, cutaneous or digestive) . The usual classification between aero-allergens and food allergens had allowed the realisation that there were common features between some protein families (Profilins, Tropomyosin, Bet v1) .
In a recent study based on the fusion of european (Allergome) and international (Allfam) databases, a group of Austrian and Italian authors have put forward a new classification based on sequence, structure and functions of proteins.
Allergens are distributed into few protein families and possess a restricted number of biochemical functions C. Radaeur et al JACI 2008 124 847-52.
Thus it seems that out of 3012 known families of proteins, only 5% of them contain allergens and most can be grouped into some functional classes such as : hydrolytic enzymes, metal-, lipid- or polysaccharide-linked proteins, storage proteins and proteins of cytological skeleton. For instance, the Der p1 major allergen of house dust is a cystine protease which directly acts on immune system cells, particularly on dendritic cells, by cleaving surface proteins. Food allergens are characterised by their high content in dissulphide bridges which ensure their stability and allow them to resist to heat and digestive secretions.
Thus, structural and functional features that turn a restricted group of proteins into allergens, allow a better understanding of the molecular mechanisms of allergen sensitisation and open the way to novel therapeutic targets, at the onset of such allergic process.
These texts have been translated by L. Taborda, Covilha (Portugal).
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Claude MOLINA and Franz MARRACHE
- Anaphylaxis to Monoclonal Antibody : Cetuximab
Eosinophil markers and corticosteroid tapering in Asthmatic patients
Classical Alternaria Alternata-specific immunotherapy: Randomised study
Mepolizumab and Hypereosinophilic Syndrome
Geohelminthiasis and anti-IgE treatments : potential risks
Anaphylaxis to a Monoclonal Antibody : Cetuximab
Monoclonal antibodies are the therapeutic innovations of the beginning of the 21st century, successfully used in Allergy (Omalizumab) and in Oncology.
Cetuximab (Erbitux® or Mabthera® ) is a chimeric mouse-human IgG1 Monoclonal antibody_ against the Epidermal Growth Factor Receptor or EGFR. It is approved for the treatment of - colo-rectal cancers and squamous tumors of the head and neck . In some areas of the US hypersensitivity reactions have been reported with a high frequency (prevalence of 22% of cases in Tennessee and North Carolina but of 1% in the Northeast, and - an average 3%, as mentioned by drug company leaflets).
That is - why the group of Prof. Platts-Mills analyzed serum samples for anti-Cetuximab IgE antibody, particularly in individuals who had had severe allergic reactions anaphylaxis-type at the beginning of Monoclonal antibody perfusions (Cetuximab-induced anaphylaxis and IgE specific for Galactose-á-1,3-Galactose : C.H. Chung et al NEJM 2008 158 1109-1117).Then they extended their study to 76 individuals who had been on Cetuximab treatment (in Tennessee, Arkansas and North Carolina) and 72 controls in Tennessee, 49 individuals with head and neck cancers in California and 341 female control individuals in Boston. Among 76 treated individuals, 25 had hypersensitivity reactions to drug and 17 of these had Cetuximab-specific IgE antibodies, before treatment. In contrast, there was only one individual with Cetuximab-specific IgE among the remaining 51 individuals . Within the the 2nd group (control), 15 out of 72 had IgE antibodies against Cetuximab (20.8%). In the 3rd group, there were 3 Cetuximab-specific IgE+ individuals out of 49 (6.1%). Within the 4th group, there were 2 Cetuximab-specific IgE+ individuals out of 341 (0.6%). These IgE antibodies were shown to be specific for an oligosaccharide which is present on the F(ab’)2 region of Cetuximab heavy chain : Galactose-á-1,3-Galactose. They are not anti-murine protein antibodies (there is no connection with the other monoclonal antibodies such as Rituximab or Infliximab); in contrast, there is a clear correlation with antibodies against non-primate mammalian proteins : cat, dog and cow, but not against mites or pollens. The authors cannot explain the regional differences observed, but they draw attention to the need for detection of anti-Cetuximab IgE prior to treatment with this monoclonal antibody since in most subjects who had ractions to the drug, IgE antibodies were present before therapy. One may also ask whether this notion also applies to other monoclonal antibodies.
Eosinophil markers and tapering of corticosteroids in Asthmatic patients
It is known that the association of Long acting beta-agonists (LABA) to corticosteroids is more efficient than isolated drugs, and allows corticosteroid tapering. A group of Danish authors has tried to evaluate the risk associated with corticosteroid tapering, based on eosinophil markers (EM) which are regarded as signs of bronchial inflammation. 61 patients recruited in 5 Danish hospitals, and efficiently treated with doses between 750 and 1000mcg/day of Corticosteroids were randomised into 2 groups : one of the groups received the minimal dose of 500mcg Fluticasone® + 50mcg Salmeterol ®, and the other group were given 500mcg Fluticasone alone. Once Asthma was well controlled, corticosteroid doses were reduced every 6 weeks, as clinical parameters and EM were monitored, until asthma symptoms eventually reappeared or patients kept on placebo (Asthmatics able to step down from inhaled corticosteroid treatment without loss of asthma control have low serum eotaxin/CCL11 : H. J. Hoffmann et al, Clinical Respiratory Journal 2008; DOI:10.1111/j.1752-699X.2008.00054.x.)
9 patients could be kept on placebo for 6 weeks, 36 patients developed mild Asthma symptoms , 16 had severe symptoms . EM were monitored in 39 cases (blood eosinophils, EPO, ECP, and chemokines : eotaxin/CCL11, eotaxin 2/CCL24, eotaxin 3/CCL26) and Th2 cytokines : IL1-â, IL-4, IL-5, TNF-á, INF-ã. Among the EM, eotaxin/CCL 11 seemed to be the most discriminating variable : patients who were able to be kept on placebo without developing severe symptoms had noticeably lower eotaxin levels than those who developed moderate or severe Asthma.
Thus, eosinophilic chemokines are, according to the authors, a useful guide for the tapering of corticosteroids in Asthmatic patients.
Alternaria Alternata-specific classical immunotherapy : Randomised study
Fungi are, after house dust mites and pollens, the 3rd most important cause of respiratory allergies. Among allergy-inducing fungi, besides Aspergillus and Penicillium,Cladosporium is the most frequent one in the North of Europe whereas Alternaria seems to predominate in Mediterranean regions. In any case, desensitisation to fungi does not have a great reputation of efficacy or tolerance induction. Spanish authors carried out a treatment with a metabolic extract -previously standardised and controlled, (by skin prick testing and immuno-enzymology) in a randomised, double blind, placebo-controlled study, involving 28 patients between 7 and 29 years of age (of which 14 were controls) who had Rhinitis with or without associated Asthma and were monosensitised to Alternaria . (Double-blind, placebo-controlled study of Alternaria alternataAna I. Tabar et al Pediatric Allergy and Immunology, February 2008 Volume 19 Issue 1 Page 76-81). immunotherapy: Clinical efficacy and safety
The protocol followed was a classical one, performed in accordance with the criteria of the EAACI. : one injection per week of a progressively higher dose of allergen extract until a maintenance dose was achieved (or the maximal tolerated dose), then once monthly for 6 to 12 months ( 1670 BE Units, corresponding to 0.167mg of lyophilised extract containing 0.1µg Alt a 1 ).
23 patients were able to complete the treatment with only 2 developing minimal side effects such as cutaneous pruritus.
It took 6 months to observe a significant improvement in all respiratory symptoms (measured clinically and with daily clinical scores) in the treated group. FEV1 was also significantly increased, but not in the placebo group. Asthma severity was decreased only in the treated group, but the symptoms of rhinitis or rhino-conjunctivitis were decreased in both after one year of treatment .
Thus, in this randomised study involving a limited number of patients and including a regular count of Alternaria spores in the environment of both randomised groups of patients, desensitisation, which was well tolerated, was efficacious at decreasing respiratory symptoms and function, but its effects were less clear upon rhino-conjunctivitis .
It is nevertheless a kind of rehabilitation of specific immunotherapy at a time where its efficacy is doubtful, even among allergists.
Mepolizumab and hypereosinophilic Syndrome
Hypereosinophilic syndrome (HES) includes a group of illnesses that are associated with blood eosinophilia > 1000 eosinophils/ml and eosinophil tissue influx into affected organs. Manifestations may be variable and may include respiratory, cardiac, gastro-intestinal, muscle and skeletal, cutaneous and neurological symptoms. Efficacy of corticosteroids in most HES cases is acknowledged, but is associated with side effects that may involve an important morbidity.
Taking into consideration the involvement of interleukin-5 (IL-5) in the development of eosinophils from their bone marrow precursors, as well as its role in the maturation, differentiation, mobilisation, activation and survival of this cell type, it was thus logical to ask whether using a humanised anti-IL-5 monoclonal antibody might be associated with corticosteroid-sparing effects in HES.
An international, multicentre, double blind study was performed between March 2004 and March 2006 by the Mepolizumab Group. NEJM published the results in a recent article (M.E. Rothenberg et al , Treatment of Patients with theEosinophilic Syndrome with Mepolizumab. NEJM march 20, 2008 vol. 358 no. 12)
Out of 107 recruited patients who were negative for the FIP1L1–PDGFRA fusion gene (which allows exclusion of cases of myeloproliferative HES, which usually require treatment by Imatinib) 87 individuals were selected and randomised into 2 goups : Mepolizumab group (MG) and placebo group (PG). All selected patients were clinically stabilised on a daily dose of 20 to 60 mg prednisone or prednisone equivalent, and their blood eosinophilia was < 1000/ml. Mepolizumab at a dose of 750mg or placebo were given as intravenous perfusion every 4 weeks for the duration of the study (36 weeks). The main objective of the study was to decrease prednisone or prednisone- equivalent to 10mg/day or even less for 8 consecutive weeks or even longer.
Within the MG group, 36/43 participants (84%) were able to achieve the protocol until its conclusion whereas in the PG only 36% of patients were able to do so. The clearly more frequent patient dropouts within the PG group were particularly linked to the re-occurrence of symptoms due to the decrease in corticosteroid dose.
The objective was attained in 84% of patients of the MG group versus 43% within the PG group. A reduction in corticosteroid doses to < 10 mg/day without destabilisation of the clinical status or an increase in eosinophilia was possible for a period of 8 weeks in almost all MG patients whereas it was only possible in 41% of PG patients.
Severe reactions, not associated with the drug, were observed with a similar frequency in both groups (5 to 7 patients). Drug-related side-effects were varied, not severe and were not more frequent in any of the groups.
In conclusion, Mepolizumab, which targets eosinophils, seems to allow a steroid-sparing effect in HES patients that are negative for the FIP1L1–PDGFRA fusion gene.
Geohelminthiases and Omalizumab : potential risks
If the role of IgE antibodies in anti-parasite defense is not denied, their place deserves to be clarified as mentioned byP.J. Cooper et al, (Geohelminth infections: a review of the role of IgE and assessment of potential risks of anti-IgE treatment, Allergy 2008: 63: 409–417).
In order to try and assess the potential role of IgE responses against helminths in humans and the possible risk associated with treatment by Omalizumab, the authors cite the study carried out by Cruz AA et al (Safety of antiimmunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection. Clin Exp Allergy2007;37:197–20).
In this study, 137 Brazilian patients, with a high risk of parasitic infection, aged between 12 and 30 years, with asthma or perennial allergic rhinitis were selected. Before the beginning of the study, an adequate anti-helminthic treatment was given to the patients in order to free them from any parasitic infection. In this double blind, placebo-controlled, 52 week-long study, participants included in the active group were given one sub-cutaneous injection of Omalizumab every 2 to 4 weeks.
At the end of the study, the rate of parasitic infections was practically identical in both groups. There was a slightly higher, but not significant, morbidity within the actively treated group, with a more relevant propensity of these individuals for re-infection.
Overall, risks that allergic patients on Omalizumab treatment face depend upon the type of population, the degree of exposure and the nature of the parasitic infection :
- negligible risk for populations who live in the European Union or the US, in case of minimal exposure, and very low risk in case of short exposure, as when on holidays, for instance;
- low risk for prolonged stays such as those involving volunteers that work in missions abroad (risk that depends upon the nature of the parasite);
- low to moderate risk for migrants originating from endemic areas;
- in contrast, increased vigilance is necessary for individuals having had previous infection with Strongyloides, given the ubiquitous feature of this parasite.
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