Bibliographic updates

Claude MOLINA* and Jacques GAYRAUD**

1. Role of long-acting anticholinergics in complementary Asthma treatment
2. Lung CT scan in asthmatics – A new approach to bronchial remodeling
3. Herpes and atopy
4. IgE-based anti-cancer immunotherapy (IT)
5. Recent findings in Hereditary Angioedema (HAE)

1. Role of long-acting anticholinergics in complementary Asthma treatment

Theme: Asthma
Key words: Beta 2 mimetics – Inhaled corticosteroids - Anticholinergics

Although asthma in adults is often treated by inhaled corticosteroids (IC) associated with long-acting sympathomimetics salmeterol type (S), the exact role of anticholinergics, also long-acting bronchodilators, type tiotropium (T), remains unclear (currently contested in COPD treatment).
This is what a group of researchers (SP Peters et al du NIHLBI JACI 2013 132 5 1068 1074) sought to clarify, with a view to defining the interest of T (Spiriva ®) as an alternative to S when added to ICs. Their aim was to describe the different responses of asthmatics to each of the two products and to pinpoint the predictors of a positive clinical response.
The classical methodology included a double-blind three-way crossover trial, randomized in 3 groups, on 210 adults whose symptoms where inadequately controlled on a low dose of inhaled corticosteroids (80 µg beclometasone, twice a day). Three groups were identified: one with a double dose (160 µg), a second associating IC and S (50 µg twice a day) and a third group with IC+T (18 µg each morning via Handihaler). Each treatment covered 14 weeks preceded by a 2-week trial period.
In these 210 patients, aged an average 42 years, 32% male, 87% atopic, with an asthma history of roughly 14 years (FEV1 approximately 70% +/- 15% of the predicted level), the clinical efficiency was assessed according to the classical main criteria: morning Peak Expiratory Flow (PEF), number of symptom-free days, FEV1 response to a short-acting bronchodilator (albuterol or ipratropium, I), and lastly cholinergic tone measured by the lower resting heart rate

Overall, results revealed that, while approximately equal numbers of patients showed a differential response to S and T in terms of morning PEF (90 and 78 respectively) and of symptom-free days (49 and 53 respectively), a greater number of subjects showed a positive response with an FEV1 higher for T (104) than for S (62). Besides, paradoxically it is an acute response to a short acting bronchodilator : albuterol (Salbutamol ®) rather than to I , which made it possible to predict significantly a positive clinical response to T, for both FEV1 and PEF. The same is true for the ‘bronchial obstruction’ factor as revealed by the FEV1/Forced Vital Capacity ratio. As for the cholinergic tone, a high level is also a predictor of positive action of T.
Conversely, ethnicity, sex, atopy, IGE level, sputum eosinophil count, FeNO, asthma duration, and body mass index were not statistically predictive factors.
In conclusion, these findings show that the clinical response to T associated with IC in the treatment of moderate asthma may be favourable, and represents a worthwhile alternative to S; Among predictive factors, the role of the short-acting β2 mimetic and the presence of a confirmed airway obstruction deserve to be mentioned.

2. Lung CT scan in asthmatics – A new approach to bronchial remodeling

Theme: Asthma
Key words: CT scan – Asthma – Airway remodeling - Trapping

A group of English radiologists and pneumologists led by S.Gupta (JACI 2013 Nov in press) studied the computed tomography (CT) of asthmatics’ proximal airways through analysis of their quantitative clinical, functional, and radiological data, and also using new statistical tools (cluster analysis and ‘fractal geometry’).
The aim of the study was to explore the notion of airway remodeling and air trapping, and to try to determine new asthmatic phenotypes according to airway structure.
65 asthmatics – 48 with severe and 17 with moderate asthma – were compared to 30 healthy subjects through usual tests. Demographic data were similar as regards age, sex, asthma duration, and socio-professional factors.
CT scanning and detailed statistical analysis, together with careful study of the structures, was carried out on the lung right upper lobe (RUL) considered by the authors to be surrogate of the whole bronchial tree.
The table of findings and detailed radiological illustrations revealed:

1. Compared to controls, all asthmatics, however severe their asthma, showed a significant decrease in the RUL lumen volume but with no systematic modification of wall volume. This means that it may be a simple bronchial change in calibration, not necessarily with thickening of wall or smooth muscle.
2.Air trapping measured by lung density expiratory/inspiratory ratio was statistically greater in asthmatics than in controls. There was no evidence of emphysema.

Moreover, comprehensive analysis revealed three asthma phenotypes:
- Cluster 1 is characterised, as always in asthmatics, by an increase in lung volume with lumen dilation, but associated with severe air trapping and notable wall thickening (11 cases); this is a severe form.

- In cluster 2 there is no proximal airway remodeling, nor air trapping; this group (34 subjects) corresponds clinically to moderate asthma.

- Finally, cluster 3 associates severe air trapping and bronchial lumen narrowing (17 patients); this is a severe asthma with poorer lung function.

As a conclusion, quantitative CT scanning appears to be an interesting diagnostic tool discriminating asthma phenotypes through lung structure figures, and offers new therapeutic possibilities.

3. Herpes and atopy

Theme: Atopy - Infectiology
Key words: a,β,y herpes virus - Cytomegalovirus - Eczema
In a recent article (JACI 132 6 1278-12 86) D.Dreyfuss, a paediatrician at Yale University USA, recalls that herpes family viruses are indisputable components of the human microbiome. The persistence and latency of the infection act on the genome, and are consequently able to modulate immune response, particularly atopic predisposition. There are three groups of these double stranded DNA virus:

α) Essentially HSV1, HSV2 and HSV3 or Zoster, responsible for skin or mucous lesions of the herpes Zoster type, usually benign, and latent mostly in neurones.
β) Cytomegalovirus, HSV5, V6 or V7, latent mostly in macrophages and lymphocytes.
γ) Epstein-Barr Virus (EPV), latent in lymphocytes and coding for a protein resembling to IL10 but with Th2 type action; it should be noted that when the virus infects pre-existing atopic lesions there is a risk of severe eczema; conversely, an early infection may have a protective effect

With examples of his personal experience, the author demonstrates the various aspects observed during viral infection which may modify the clinical picture in an atopic subject. One case describes an adult with history of allergy, where contact with a necklace was assumed to be the cause of a vesicular skin rash. In fact the presence of hemidermatome lesions revealed that this was a reactivation of herpes Zoster which resolved spontaneously.

In a second case; an adolescent suffered from eczema herpeticum which could be taken for an atopic dermatitis or contact allergy, but which, due to simultaneous mouth and eye mucous symptoms, led to the diagnosis of virus reactivation, and required rapid acyclovir treatment in order to avoid complications such as corneal scarring or vision loss.

As concerns cytomegalovirus, whose ocular and skin manifestations may suggest the severe drug-induced syndrome known as DRESS (Drug Réaction Eosinophil Systemic Symptoms), an early infection should be sought with high virus IgM levels, or a reinfection with high IgG levels. Antiviral therapy is indicated.

Finally, in the case of maculopapular skin rash, which would point to atopic dermatitis or a reaction to antibiotics, a recent EBV infection (early high IgG and IgM levels with EB nuclear antigen negativity) should be suspected. These lesions may resorb spontaneously, or more rarely call for corticosteroid and anti-viral therapy.

Finally, it should be remembered that the Kaposi sarcoma virus (HSV8), mostly observed in immunodeficient or AIDS patients, is responsible for severe skin lesions.

In conclusion, the author draws attention of allergists to the atypical presentation of these viral lesions in the atopic patient.

Also known as Hereditary Quincke Oedema, HAE is a autosomal dominant disorder characterized by repeated attacks of swelling of the skin (not itching), gastrointestinal tract, genital organs and above all larynx (with risks of asphyxiation), due to a hereditary absence or low levels of the complement C1 esterase inhibitor (C1 INH) which also plays an important role in regulating the fibrinolysis and triggers the release of bradykinin.

Although a rare disorder, it has been the subject of many recent publications including A.Banerji Annals of Allergy, Asthma Immunol. 2013 111329-336, JA.Bernstein and Jonathan American Journal of Rhinology and Allergy 2013 27 6522-527, as well as the American Guidelines ( JACI 2013 131 6 1491e by BL.Zuraw and JA. Bernstein).

Three varieties can be differentiated according to C1 INH level and activity:

- Type 1: total absence of C1 INH (roughly 50% of diagnosed patients, usually between 10 and 20 years of age);
- Type 2: C1 INH present in plasma but non functional (15%) ; these two types are caused by a mutation of SERPIN G1 gene;
- Type 3: merely symptomatic, but ill-defined, present in the family history, and often affecting women; it should be distinguished from drug-induced HAE ( angiotensin –converting enzymes).

Among factors which trigger these attacks, one should note traumatism (even benign) and surgical operations (on the airways in particular), which should be preceded by short-term prophylaxis. The use of IV plasma-derived C1 INH concentrated extracts is recommended at least 6 hours before the operation.
As for long-term prophylaxis, it is obvious that danazol type androgens are the best treatment for these patients, in terms of efficacy, cost and easy administration (to be avoided however in children and pregnant women).
As for other products such as bradykinin antagonist icatibant, or kallicrein inhibiting ecallantide, these may reduce the duration or severity of attacks; they may be of use in acute cases, but are very costly and likely to entail side effects.
In Europe and France, where the disease is extremely rare, there is a risk of diagnosis failure, but its frequency is likely to increase with the mixing of populations.
Comments and questions welcome:

Pr. Claude Molina

*This email address is being protected from spambots. You need JavaScript enabled to view it.

Dr Jacques Gayraud

**This email address is being protected from spambots. You need JavaScript enabled to view it.
Last updated 29 October 2014