Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

1. Children’s non-atopic asthma (A) and molds (M) in rural and urban dwellings
2. Sun exposure and atopy
3. Recent advances on blood and sputum eosinophils (E)
4. Are eosinophils (E) essential ? Consequences of their absence
5. Recent advances on the Churg-Strauss (CS) syndrome

1. Children’s non-atopic asthma (A) and  exposure to molds (M) in rural and urban dwellings

Theme: Asthma - Allergens
Key words: Asthma – Molds – Rural environment – Urban environment

The role of Ms in A is well known but disputed. The originality of the study reviewed here (M. Flamand Hulin et al  Péd. Allergy.Immunol. 2013 24 345-351) lies in the assessment of exposure to Ms no longer visually or by spore count,  but by emission of microbial volatile organic compounds (MVOCs). The Fungal Index (FI) established and validated by the CSTB (Centre Scientifique et Technique du Bâtiment), is the result of emission of MVOCs ranked by their synthetic origin and on the basis of 19 different chemical markers.

The study of A in children from the Clermont-Ferrand area and diagnosed at least one year before included : detailed questionnaire, history, clinical examination and skin tests according to the ISAAC protocol (International Study of Asthma and Allergies in Childhood) with respiratory function tests and assessment of  FI at home in apartments or farms during one week in spring.

In all, 95 children living in an urban (U) or rural (R) environment were moitored: 44 asthmatics (51 controls), with roughly the same proportion of boys and girls, and an average age of 12.                   46% of the urban children were atopic, with sensitization to home allergens. In the rural environment only 20.8% were atopic, and only 1 with sensitization to Alternaria.

The results were as follows :
-    60% of homes were contaminated by Ms (19% through the naked eye, 58.5% through the FI); 65% of rural homes were contaminated vs 50% of urban ones.
-    Exposure to Ms was observed in 70.5% of A children vs 49% in controls; The risk was higher in R than in U areas (p=0.1077) but the relationship between  exposure to M and A was only significant in non-atopic children (10 times higher risk than in atopic: p=0.0581);        Moreover asthmatic children living in  urban contaminated dwellings, screened at hospitals, had  a higher proportion of blood neutrophils and a slightly reduced FEV1 (17.8%) than non exposed ones.

These findings:
1)    Confirm the correlation between exposure to Ms (attested by FI) and A, particularly in rural-dwelling living children.
2)    Suggest a non-atopic mechanism, which is not in contradiction with the common concept of rural environment protection from allergy and A.
3)    Are based on a small number of cases and therefore need to be confirmed by further research

2. Sun exposure and atopy

Theme: Atopy
Key words: Atopy – Eczema – Rhinitis – Sun exposure – Vit.D

A group of Australian paediatricians and epidemiologists (A.S.Kemp  Péd. Allergy . Immunol 2013. 24 5 493-500) who have been following a cohort of children since birth, attempted to specify the role of ultraviolet ray exposure in childhood or in adolescence on occurrence of allergic diseases.

In 415 subjects followed since 1988 up to the age of 16 (Tasmanian cohort), sun exposure duration was recorded through parental reports: first at the age of 1 month, then in summer holidays and week-ends, at the age of 8 and 16, then discriminated into 3 categories of daily durations : low, average, high (over 4 hours per day).

At the same time levels of vitamin D25(OH)D were measured and melanin density was checked by spectrophotometer.

An ISAAC type questionnaire (International Study of Asthma and Allergies in Childhood) recorded clinical manifestations of eczema, asthma or pollinosis (which in Australia concerns rye grass pollen), whereas sensitization to other respiratory allergens was detected by specific IgEs.

The findings were as follows:
Firstly a good correlation appeared between the 3 estimations of daily duration of sun exposure in childhood and adolescence.
Besides, it was observed that:
1)    Daily sun exposure of 4 hours and more in adolescence, especially during summer holidays and to a lesser extent on summer week-ends, is associated with significantly reduced eczema.
2)    The same can be said of pollen rhinitis the incidence of which is significantly lower, more so during holidays than at week-ends.
3)    On the contrary, this exposure at 8 or 16 years of age had no effect on sensitization to inhalant allergens.
4)    There is no association between serum vitamin D levels and allergen sensitization

On the whole increased sun exposure during summer holidays in adolescence is associated with reduced eczema and rhinitis risk, independently of measured vitamin D levels. But there is no difference in inhalant allergen sensitization or asthma. However, the authors do not recommend this practice, (not without risks), for the improvement of incidence or prevalence of allergic diseases.

3. Recent advances on blood and sputum eosinophils (E)

Theme: Cytology - Physiopathology
Key words: Eosinophil –Eosinophil peroxidase(EPX)

Eosinophils are key-cells in allergic reaction; several interesting papers on the subject can be found in the journal Allergy of July 2013 vol.7. Among others, we selected that written by the Brazilian team of M. I. Muniz-Junqueira (911-920) which studies the correlation between the morphological modifications of blood Es and the severity of childhood asthma.

55 asthmatics aged 2-13 were monitored, 40 exacerbations, 15 symptom-free asthma and 15 healthy controls. The changes observed were isolated or associated: pseudopods, cytoplasmic vacuoles, release of a small moderate or large quantity of granules, cell spreading, free granules. It appears that such modifications are statistically more frequent in asthma exacerbations.

Reduced cell density should be added to this list, as already revealed in the 1980-90s by the works of A. and M. Capron’s team who stressed the interest of these modifications, hypodense E. being an activation marker.

A Canadian-American study (P.Nair et al Allergy August 2013 early view) brings to our attention the development of an ELISA-type technique to detect sputum EPX (Eosinophil peroxidase), another eosinophilia marker, which will prevent tedious cell counts.

Thus, in 30 asthmatics tested, EPX levels statistically correlated with sputum E percentage (rs=0.84  P≥0.001). Moreover, whereas other granular proteins (ECP and EDN) could be detected even in neutrophilic asthmas or COPDs, EPX, which did not increase in such cases, seemed specific to eosinophilic airway.

In addition, EPX was detected in the course of allergenic provocative tests (10 cases) whereas counts decreased dramatically after anti-IL5 treatment (Mepolizumab) for hyper-eosinophilic manifestations

Finally, as for technical aspect, EPX levels obtained by simple noncentrifuged filtration correlated perfectly with those measured in cytocentrifuged prepared sputum supernatants (rs=0.94).

The authors consider then that this is a reliable, reproducible, simple marker of Es, specific to sputum and eosinophilic asthma airways.

4. Are eosinophils (E) essential ? Consequences of their absence

Theme: Cytology - Physiopathology
Key words: Eosinophil – Monoclonal antibodies

An apparently incongruous question, which G.J.Gleich et al. (Allergy vol 68 n°7 July 2013 829-835) attempt to answer on the basis of several clinical observations and  experimental studied.

Attention was first drawn to the subject in 1955 following the observation of a 50-year old man suffering from a benign thymoma associated with agammaglobulinemia and in whom medullar biopsies and circulating blood tests had shown the total lack of Es but the presence of basophils. Except for infectious episodes due to immunoglobulin deficiency, the lack of Es was not accompanied by any specific symptoms. Such was also the case in other similar observations in the 1960-70s. The mechanism of this anomaly was never elucidated.

Whether due to a deficiency with dysgammaglobulinemia or in allergic diseases (severe asthma, urticaria, rhinitis), the lack of Es which is clinically not very frequent (a Pittsburg University study in the 1980s only detected 24 cases out of 24 300 patients) does not seem responsible for the risk of malignant tumours nor for auto-immunity.

The same was true in experimental studies of guinea pigs (treated by E anti-serum) or mice treated by anti-IL5 monoclonal antibodies (MAs). Even in animals infected by parasites such as Schistosoma, Strongyloides or Trichinella, defence mechanisms are not affected and E does not then appear necessary for animals’ maintenance of homeostasis, health or longevity.

In these conditions, the authors are not surprised by the fact that MAs are well tolerated. Such is the case of Mepolizumab in some observations even over 6 years. This is less obvious with Relizumab and Benralizumab (anti- α chain of the IL5 receptor).

In fact these conclusions should be tempered by the small number of clinical observations of eosipenia. They must not forget the fundamental role played by E in parasitosis and as effective cells in allergic reactions, through the cytotoxic mediators released by the granules.

The interest of this paper resides essentially in the confirmation of a good tolerance of MA in hyper-eosinophilia syndromes where collapsing E levels are no longer to be feared.

5. Recent advances on the Churg-Strauss (CS) syndrome

Theme: Severe Asthma
Key words : Asthma, Churg-Strauss syndrome, ANCA, Hypereosinophilia, Vasculitis

CS syndrome is an eosinophilic granulomatosis associated systemic necrotising vasculitis clinically characterized by severe asthma and eosinophilia. Manuéla Latorre, of the Junior Members group (JMA) of EAACI Milano 2013 points out the two principal clinical aspects of the disease :
1)    Eosinophilia prominence, in adolescents,
2)    Vasculitis prominence, in older patients.

Both cases are characterised by  a difficult to treat asthma , nasal polyposis with chronic rhinitis, high proportion of blood eosinophilia, (commonly over 10%), and in sputum (which appears to be an excellent monitoring marker)

On Biologic point of view, neutrophilic anti-cytoplasmic antibodies (ANCA) are found more frequently in adults, mainly if musculoskeletal or multiorganic manifestations exist

Histologically, all cases present necrotising vasculitis and eosinophil-rich granulomatosis, involving upper airways and peripheral nervous system, less frequently involving heart, skin or digestive tract.

Regarding pathogenesis, the disease seems triggered in some cases by exposure to allergens or drugs, but a genetic factor of predisposition is  recognized; a Th2 response is also observed (IL4, IL5, IL13 cytokines). As to eosinophils, they are activated, have a prolonged lifespan, which is probably the cause of tissue damage by release of their granule proteins.

Anyway, CS syndrome is a severe disease which is often complicated with thromboembolism. Average life expectancy was estimated at  8-9 years in a small study group of Australian patients (AF. Whyte et al Intern.Med 2013 43 7 784-90).

The treatments hitherto proposed are above all glucocorticoids and immunosuppressants  such as cyclophosphamide or azathioprine, but some trials with anti-IL5 monoclonal antibodies, namely mepolizumab, supplemented with the B-cell-depleting agent rituximab, have lead to symptom regression, but with no definite conclusion regarding their long term effects (A.Vaglio et al Allergy2013 68 3 261-73).

Comments and questions welcome:
Pr. Claude Molina
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Dr Jacques Gayraud
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Last updated 15 October 2014