Claude MOLINA and Franz MARRACHE

• Improvement in Air Pollution and decrease in respiratory morbidity
• Aspirin desensitisation :  which daily dose ?
• Immunopathology of Allergic Alveolitis (A.A.)
• House Dust control measures for Allergic patients : the debate
• Â-blockers and asthma : a dogma to be revisited
  

Improvement in Air Pollution and decrease in respiratory morbidity
The SAPALDIA study carried out by Swiss authors has brought out an  important insight in the relationship between Pollution and Respiratory health. Although the short and long term effects of  air pollution are well known, very few studies have focused on the outcome of respiratory symptoms once the external conditions are modified.  The follow-up of a cohort of 7019 adults recruited in 1991 and monitored until 2002 has shown in a preliminary analyze, that during these 11 years, there was a decrease in air pollution, as reflected upon a decreasing in PM10 particles, which was associated with a slowing down of lung function decline. What this new study highlights is the possible reversibility of respiratory symptoms resulting to a reduction in the atmospheric concentration of PM10 (C. Schindler et al : Improvement in PM10-Exposure and reduced rates of respiratory symptoms in a cohort of Swiss adults A.J.R.C.C.M 2009; January 16). The mean reduction in exposure to PM 10 particles (strongly correlated with concentration in PM 2.5),during the 12 months preceding the 2002 analysis (with regard to 1991), was associated with a statistically significant decrease in regular coughing in 259 subjects, in chronic cough with phlegm in 179 subjects and in dyspnoea with wheezing in 137. Possible biases and the limitations and confounding factors for the statistical analysis of this study are acknowledged (age, tobacco smoking, fluctuations in particle concentration, geographic variations of exposure, etc.) However these encouraging results should be analysed together with a recent study showing that the reduction in exposure to fine particles in the ambient air was associated with an increase in life expectancy in USA (C.A Pope et al. NEJM 2009; 360 : 376-386). These considerations greatly justify the measures carried out by public authorities in the struggle against outdoor and indoor pollution, a struggle in which Allergists are in the front row, together with their patients as environmental sentinels.

Aspirin desensitisation :  which daily dose ?
Among individuals who are allergic to aspirin and have nasal polyposis and asthma, it is the daily intake of a single dose of aspirin which is usually recommended  for desensitisation. Doses > 325 mg, at around 500 mg per day or even higher, administered twice daily have shown their efficacy, but such doses were not consensual and, in practical terms, it is the daily intake of the minimal efficacious dose (MED) that has been the choice. However, MED is difficult to determine.
A. Rozsasi et al have focused on this issue in a small study involving 14 patients who had a positive response to the aspirin provocation test (Long-term treatment with aspirin desensitization : a prospective clinical trial comparing 100 and 300 mg aspirin daily. Allergy 2008: 63; 1228-1234). These authors compared the effects between a single intake of 100 (G1) and 300 (G2) mg of aspirin in two groups (G1 and G2) of 7 paired individuals, who were followed up for one year. Within G1, polyposis recurred, and the medication score as well as lung function changes remained the same.
By contrast, in G2, polyposis did not recur, the medication score improved in 3 patients and lung function improved in 5 patients. After this preliminary study, a prospective study was performed in a group of 39 patients receiving 300 mg/day of aspirin. It confirmed that polyposis did not recur after one year of treatment and there was a significant improvement in olfaction. According to the authors of this study, the dose of 300 mg seems to be equivalent to MED, given inefficiency observed in G1. The low power of this open study limits the impact of these results which should be confirmed by other studies. The tolerability of aspirin in a larger sample of patients followed up for a longer period also needs to be better elucidated, given the risk of adverse reactions associated with prolonged administration of aspirin.

Immunopathology of Allergic Alveolitis (A.A.)
An experimental study carried out in the mouse, by authors, from the University of Michigan, USA (IL-17-mediated Immunopathogenesis in Experimental Hypersensitivity Pneumonitis. A.D. Joshi et al. AJRCCM 2009 ; ahead of print  January 16) has reported new information on the pathogenesis of the disease.
Upon oropharyngeal instillation of the main Thermo-actinomycetes responsible for Farmer’s lung (Saccharopolyspora rectivirgula (SR)) a large number of neutrophils (reflecting innate immunity) is observed in the Bronchoalveolar lavage fluid. This was followed by the classical peribronchial and interstitial granulomatous inflammation which includes a T1-type immune response involving CD4+ and CD8+ Lymphocytes. Neutrophils and T lymphocytes secrete INFã, which may be essential for the development of lesions (inhibited by its blockage ) and also other cytokines and chemokines involved in Th1-type response :such as IL-12 and CCL3.
However, Th2-type lymphocytes and their mediators (IL-4, IL-13, IL-5) are also involved in the chronic process of fibrosis, which has a bad prognosis since it is insensitive to corticotherapy. The originality of this study stems from the observation of other cell types in the lesions, particularly Th17 cells. These cells were found in significant amounts in the lungs of mice exposed to SR (as compared with controls) and they are one of the sources of the cytokine IL-17, which is involved in the activation and expansion of neutrophils. Instillation of SR in the airways of mice which are deficient in  IL-17 gene, induces a decrease in the inflammatory cell infiltrate. In another series of experiments, the authors used anti-IL-17 antibodies and showed that the neutralisation of this cytokine was associated with a decrease in inflammation. Overall, the authors confirmed that Th1 cells play a crucial role in the pathogenesis of Allergic Alveolitis (Hypersensitivity Pneumonitis of the american authors), and that the lesions showed a hyperexpression of genes associated with Th17 lymphocytes.
Besides that, the genetic deletion and the neutralisation of IL-17 protected animal from the development of histological lesions associated with A.A.
This cytokine, whose persistence may contribute to the chronicity of the disease, should represent the preferential target of medication used for avoiding the chronic evolution and the irreversibility of lesions.
In a Canadian review, Girard et al ( Allergy 2009 64 3 322-334)confirm the release of pro-inflammatory cytokines and the decrease of immune control via surfactant, and dendritic and T regulatory cells, in the mechanism of the disease

House Dust control measures for Allergic patients : the debate
Allergy (2009 ; 64 : 187-190) published 2 letters criticizing articles by P.C.Gotzche and H.K. Johansen who, at first in 2004, then in 2008, refuted usefulness of Control Measures (CM) for house dust (HD) in Asthma, based on two meta-analyses which included 54 randomised studies involving 3002 patients. These authors concluded that chemical and physical methods (impermeable bed covers) have not demonstrated their efficacy and therefore, should not be recommended.
M.V. Kopp and collaborators, from Friburg have re-analysed the most important studies mentioned, and showed their limitations (presence of a subgroup of sensitised but symptom-free patients, low concentration of house dust in the environment, more or less efficient CM, absence of stratification among children and adults). These authors therefore suggested that CM should be recommended for asthmatic and house dust mite-allergic patients if there is a confirmed exposure to these allergens. Another criticism was put forward by De Blay and collaborators, from Strasbourg, who also refuted the statements by Gotzche and Johansen. De Blay et al highlighted the studies published in 2004 (W.J. Morgan. NEJM 2004 ; 351 : 1068-1080), in children, which showed that a reduction in allergen exposure to Dermatophagoides farinae in beds and to Dermatophagoides Pteronyssimus as well as cockroach allergens on the floor, significantly reduced asthma complications. Along the same lines, J.W. Krieger (Am. J. Public Health 2005; 95: 652-65) stressed the interest of global CM carried out by Environmental technicians. 

De Blay et al. acknowledged that CM focusing only on bedding were obviously inadequate and pointed out the need to involve Indoor Environmental specialists to implement such CM (Allergy 2003; 58: 27-33). Nevertheless, Gotzche and Johansen still maintained the notion that CM directed against house dust mites do not work and should not even be included in the global measures which focus on exposure to passive smoking, cockroach allergens and other environmental factors, which are outside the scope of their study. What to conclude at the end of such a debate?  The foundations of allergology namely eviction of the allergens responsible for diseases such as asthma, rhinitis or eczema cannot be refuted. The common sense of clinician must do the rest and direct the subsequent approach to each particular case, always bearing in mind that the discovery of the role of mites in house dust was an important step forward in the diagnosis and treatment of house dust Allergy, which is the most frequent of allergic manifestations.

Â-blockers and asthma : a dogma to be revisited
In the Asthma section of our Bibliographic Updates (ABA) from April 2008, we elaborated some comments on two publications which concerned a population of elderly patients affected by asthma and coronary disease
- Are Beta-blockers (BB) useful in these asthmatic patients ?
- Are asthma and BB a good combination for asthmatic patient ?
The joint treatment of coronary disease with BB did not trigger bronchial constriction in these patients. In a recent paper, Lipworth BJ and Williamson PA, attempt to re-analyse the paradoxical actions of BB, in an article with a provocative title : â blockers for asthma : a double-edged sword. Lancet 2009; 373: 104-59.
These authors mention previous work showing that regular administration of BB had a beneficial effect upon the regulation of â2 receptors, in contrast with excess intake of â2 agonists, which is a well known factor for the worsening of asthma, namely status asthmaticus. Similar observations were made in mice sensitised to ovalbumin. In fact, the mode of administration of BB conditioned the regulation of â2 adrenergic receptors in these animals with effects that were associated with either protection or worsening of asthma. Such results motivate the performance of methodologically rigorous studies that may take into account ethical problems related to patient safety, since the risk of non-reversible bronchial constriction remains always present in spite of the administration of salbutamol, even with â1 adrenoreceptor-specific BB.

Overall, this new view upon BB has the merit of underlining the practical interest of a good evaluation of the benefit/risk ratio of this class of drugs in individuals who have asthma and cardiovascular disease, given the broad consensus of their positive actions for the treatment of coronary disease, in particular. N the same Was this not the objective of the presentation of the clinical case published by U. Muller and G. Haeberli (Use of beta-blockers during immunotherapy for hymenoptera venom allergy. JACI 2005: 115: 606-610)? which reported the death of a patient suffering from dilated cardiomyopathy with ventricular arrythmia and vespula venom allergy. His death was due the stop of  BB rather than immunotherapy.

Source: CEFCAP