MAbs constitute a new and in rapid expansion therapeutic class which, like any drug, is likely to provoke Hypersensitivity Reactions (HSRs).Let us remember that, contrary to small molecules such as antibiotics, aspirin or chemotherapy agents, mAbs are proteins, fairly large molecules, and divided into 4 types according to their origin : murine, chimeric (of which 30% murine), humanised (5% murine) or entirely human. The American Boston group (P.J.Brennan et al JACI 124 6 1259-1266) reports on its experience in rapid desensitisation (RD), performed in 105 cases concerning 23 patients having presented an HSR to one of the 3 mAbs : Rituximab (R) or Mabthera®, Infliximab(I) or Remicade®, both chimeric mAbs, and Trastuzumab(T) or Herceptin® which is a humanised mAb. (N.B.: Omalizumab Xolair ® is a humanised mAb). In all those cases, RD was undertaken for lack of other reasonable alternative to treat the causal affection, such haematological malignancies, mainly lymphoma for R, rheumatic diseases for I, breast cancer for T.
Initial HSR had been mild in 26% of the cases, moderate in 48% and severe in 26% :anaphylaxis or immediate reactions Gell & Coombs type 1 evoking atopy in spite of absence of IgE to mAbs The RD was preceded by a skin test whose positive result justified the standardised 12 steps 6 hours protocol with a graded dosage being modified according to the reactions. In the case of a negative skin test the RD was undertaken in relation with the severity of the initial reaction and the clinical data 104 out of 105 desensitisations were successfully completed, and allowed the mABs later delivery. A few side effects were noted during the RD, always less severe than the initial HSR.
This is a promising method at a time when new mAbs are being developed for affections like Crohn disease, cancers or graft rejection and when allergists’ experience in the field of RD can prove valuable.
Exhaled Breath Profiling in Asthma
Two Dutch groups based in Amsterdam and Maastricht have analysed the exhaled breath of adult and child asthmatics by detecting the volatile organic compounds (VOCs) thanks to an “electronic nose”.
In dults this nose allowed N.Fens’ team (AJRCCM 2009 180 1076-1082) to discriminate with high statistical accuracy, within a group of 90 patients, 20 with asthma and a characteristic profile, 30 with chronic obstructive pulmonary disease (COPD), 20 non-smoking control subjects and 20 smoking control subjects. Although the individual identification of each VOC cannot be performed with this sole technique, it constitutes a non-invasive, reliable, reproducible, and easy diagnosis method, allowing the production of an asthmatic patient’s typical ‘molecular print’. Indeed, as noted by R.Machado in his humoristic titled paper (Does the e-nose knows ?), patients with COPD and smokers are not significantly discriminated. Proof that the electronic nose, even improved, is not able to replacing clinical and functional data in the discrimination between asthma and COPD. It can nevertheless reinforce a diagnosis of asthma in an adult patient.
With children, the Maastricht group of paediatricians using the same technique complemented by analysing VOCs in gas chromatography and mass spectrometry, showed that it was possible to identify among the high number of VOCs a group of 8 elements leading to the discrimination of 63 asthmatic children from 57 healthy children with a 89% sensitivity and a 95% specificity (J.W.Dallinga et al Clin & Exper.Allergy 2009 40 1 68-76)
Going further, the same group (C.M.H.H.T Robroeks et al : id pp77-84) using the exhaled breath condensate showed that it was possible to detect by immunologic dosages all the biomarkers of the allergic inflammation, that is cytokines, chemokines and adhersion molecules, all significantly increased with asthmatic patients (31 cases) as opposed to control subjects.
These are state of the art techniques, reserved for highly equipped laboratories, but which also show the advanced state of European research in this field
Occupational asthma (OA) : a diagnostic confirmation
The Canadian team at the Hopital du Sacre-C?ur of Montreal, observing that sputum eosinophil counts , useful to confirm a diagnosis of asthma, particularly in a child, was a tedious and time-consuming process, attempted to replace it by measuring the fractional concentration of exhaled nitric oxide (FeNO).
The comparison of the two techniques was jointly undertaken by Canadians and Belgians ( C.Lemierre et al Chest 2009 December 1ahead of print 09/2009). 67 workers with possible OA were enrolled in the survey, both in Canada and in Europe, and submitted to a specific inhalation challenge (SIC) of their occupation’s offending agent. Cell counts and measurement of FeNO concentration were performed immediately after the test, then 7 and 24 hours later. 41 subjects showed a negative SIC. 26 subjects had OA proven by a positive SIC, and a significant increase in sputum eosinophils at 7 and 24 hours after exposure, while the FeNO concentration was only increased after 24 hours. In comparison, a 2.2% increase in the eosinophil count showed a greater sensitivity than a 10 ppb increase in FeNO with a better positive predictive value, whereas the specificity of the 2 examinations was similar and negative predictive value for predicting a 20% decrease in FEV during SIC.
As a whole, for the authors, sputum eosinophil counts represent a more reliable tool than the exhaled breath FeNO concentration, to distinguish between a positive and a negative SIC in diagnosing an OA
Sensitization (S) and peanut Allergy (PA)
3 publications, 2 in the United Kingdom and one in Sweden, present recent developments on the issue :
One of them, monitoring 3 cohorts of children aged 3-4 years, between 1994 and 2004, all living in the same limited geographic area (the Isle of White), confirms a trend to a stabilisation if not a decrease in the prevalence of S and PA (C.Venter et al : Allergy 2010 50 103-108). The other publication, by the Manchester team, attempted to define accurately, in a cohort of 933 children 8-year old ,monitored since birth and sensitized to peanut ( as shown by positive skin tests and high rates of specific IgE), the proportion of those who present with clinical manifestations of PA when exposed to the allergen. In a particularly accurate and detailed study (N.Nicolaou et al JACI 2010 125 1pp 191-197 e13), the authors, after having identified 110 children, perform with 79 of them oral challenge tests, either open with 45 of them, or double-blind placebo-controlled (35 cases) and they compare biological profiles of two categories of subjects : subjects only sensitized and subjects with clinical manifestations of PA. For this they used a microspot multiplex, technique looking for specific IgE related to a 12-component panel : those of peanuts (Arah 1-3 and 8), those of grass allergens (Phl p1,4,5 7 12) and potentially cross-reactive components (Bet v1 pru p3) as well as carbohydrate determinants. The result of careful statistical study is that 1 child in 10 in the United Kingdom is sensitised to peanut but 1 in 50 only runs the risk of clinical manifestations. The latter indeed present a specific biological profile : their response to the allergen Arah 1-3, but mostly Arah 2, is very high, while subjects only sensitised show positive responses to all to other components. The authors thus prove that current methods of detecting sensitization to peanut (that is skin and blood tests with total extracts) cannot predict allergy itself, and that only the IgE response to Arah 2 is a discriminating predictive factor.
These conclusions go along with those of A.Asarnoj from the Karolinska Institute de Stockholm (Allergy 2009 65 2 213-219) who notes in a 1928 cohort of 4 to 8 year-olds that those who are sensitised to both peanut and birch pollen present fewer clinical manifestations than those only sensitized to peanut.
Air filters, air cleaners, individual air-conditioners and allergy
It is well known that the allergic patient is an “environmental sentry “.Thus allergists ,generally recognized as possessing the greatest expertise in relating airborne contaminants are frequently consulted for the best strategies to improve their patients’ respiratory air quality, particularly indoor. A whole series of devices are proposed in order to reduce gas concentrations and outdoor pollution particles but mostly address indoor airborne allergens, and even smells and tobacco smoke. The American Academy of Allergy and Clinical Immunology has just organised a forum around one of these problems (JACI 2010 125 1 32-38) in conjunction with air-conditioning engineers (ASHRAE). It is immediately obvious that one single method is not sufficient. As far as allergens, we must take into account their physical properties (size, density, persistence in the atmosphere) ; thus dog allergens have a diameter of 5-7µm, cat ones between 5 and 30, Hous-dust mites 28µm on average and tend to fall on the ground, whereas cockroaches, pollens, or fungi, are even larger, However Penicillium and Aspergillus being able to stay for a long time in air
Moreover, before recommending air cleaning options in residential buildings or individual devices (ionizers, room air cleaners , powered electronic filters or HEPA Air Conditioners), it is necessary to assess their efficacy, and their safety (some devices give off ozone which have harmful effects on the respiratory tract).
The quality of filters, which is often proportional to their cost, and above all the regular maintenance in order to prevent clogging, must be considered seriously. We insisted on that in the years 2000 at the French Society of Allergy. A certain number of publications, quoted in this article, report modest reductions in pet allergen concentration thanks to HEPA filters installed in bedrooms, but often without obvious clinical impact. In any case, a long observation period is needed (at least several months), possibly with placebo-control study, before concluding on the optimal choice of such cleaning devices . but it is a daily problem that allergists must take into consideration
