• Acute Irritant-induced Asthma ( AIA). Long-term outcomes
• Advances in diagnosis and therapeutic of Aspergillosis
• Towards a molecular classification of asthma
• Zinc and allergic reactions

Acute Irritant-induced Asthma ( AIA). Long-term outcomes
Caused by inhalational accident, AIA is a condition that can happen at work but also in a general environment, by inhalation of gas or irritating products, the most typical example is the World Trade Centre catastrophe on September 11th, 2001,where fire fighters were exposed to various contaminants.
AIA is characterized by an immediate predominant coughing followed by a bronchial obstruction which does not respond to bronchodilators .It is somewhat different from Occupational Asthma (OA) induced by specific sensitization to a work place agent, although it can be itself accidental as in the case of inhalation of chlorine.
Jean-Luc Malo of Montreal, a top name in the field of OA, give his judicious contribution to this form of Asthma (Long term outcomes of acute irritant – induced Asthma: JL Malo and al, AJRCCM 2009 179 923-928). The survey concerns 68 subjects but only 35 agreed to participate, 29 men and 6 women  45 +/-11years old,  who were followed from 13 to 18 years after the acute accident. They all were assessed and recognized by the “Commission de la Santé et Sécurité au Travail de Quebec”: (20 cases are due to inhalation of chlorine) and receive full compensation, suggesting that the accident was severe.
The purpose of the work was to clarify the long-term outcome of these subjects on respiratory, biological and psychological point of view and to compare these findings with those of allergic OA.
At the end of the study, only 6 subjects (17 %) had normal airway caliber and responsiveness, compared with  28 out of 103 cured patients (27% ) with OA
Moreover they all still presented with respiratory symptoms and 24 were using  inhaled corticoids;
A lot of data obtained from induced sputum, showed a very high proportion of inflammatory and remodeling mediators such  ECP, MPO, IL8, TGF ß etc ,  a profile not significantly different in AIA and subjects with OA . 6 patients had increased levels of eosinophils.
Finally questionnaires on quality of life and psychological parameters revealed a generalized anxiety and a depression in 12 subjects
In conclusion, although it is likely that accident was severe in all these 35 patients, the long-term prognosis AAI is as bad as that of OA . The authors remind us that clinical and functional recovery is only observed in 1/3 in/4 of cases of OA, with a persistent bronchial inflammation even in absence of symptoms.

Advances in diagnosis and therapeutic of Aspergillosis
Aspergillus is an ubiquitous fungus well known by Allergists and Immunologists acting, in man, as well as saprophytic, parasite or allergen.
The focus of this comprehensive review, by B.H.Segal (NEJM 2009 360 1870-1884) is Invasive Aspergillosis (IA) which is presently the most frequent Aspergillus-related diseases , It is typical of immunocompromised subjects and a leading cause of death in patients with AIDS, Leukemias, Allogenic hematopoietic stem cell or solid organs transplantations, all  disorders treated by chemotherapy, more rarely  of chronic granulomatosis. Inflammatory fungal pneumonia and sinusitis are the main symptoms in acute or chronic forms leading to lung necrotizing histological features.
The author takes advantage of this text to remind us the large spectrum of Aspergillosis which go from Aspergilloma (compact mass inside preexisting lung cavity) to Allergic Asthma, and Allergic Broncho-Pulmonary Aspergillosis observed in Asthma of long duration, with transient pulmonary infiltration, high eosinophilia, bronchiectasis and presence in the serum of precipitating antibodies to Aspergillus.
On immunological point of view: two types of immunity may be involved according to host response: Innate Immunity based on Toll-like receptors, with activation of Th1cells and INF gamma (of good prognosis when increased in IA) or Adaptive Immunity Th2 type, characteristic of allergic reactions.
Antigen-based diagnosis relies on serum detection of 2 constituents of the fungal wall: galactomannan very specific and beta-D-glucan, which may be found in other mycoses. Galactomannan detection in broncho-alveolar fluid is even more sensitive than in serum.
Although allergists rather use for their diagnosis, skin tests and specific IgE, and bearing in mind the role of molds (suchTrichophyton, Alternaria) in the worsening of certain forms of Asthma, these techniques and the new antifungal treatments, even if they address especially IA, deserve mention.
We already know Amphotericine ® and Itroconazole ®; but among the new azoles, we must quote Voriconazole ® (Intravenous)) the most efficient and Posaconazole or Noxafil ® (per os) rather prophylactic.
In the group of Amphotericine there are new formulations B (lipid or liposomal for instance).
In a third group:  Echinocandines: antifungal agents acting on fungus cell wall  and inhibiting beta-glucan synthesis, let us quote Capsofungine (Cancidas ®), only drug presently approved  by  FDA, Mycafungine (Mycamine ®) and Anidulafungine (Ecalta ®) more useful for Candidiasis .
That is to say that this plentiful research, associated to a better understanding of pathogen characteristics, fungus reproduction cycle and host genetic factors pave the way to novel therapeutic strategies. 

Towards a molecular classification of asthma
The heterogeneity of asthma is well established and physicians had successively to distinguish, over the years, between extrinsic and intrinsic Asthma,  Atopic and not allergic Asthma, eosinophilic and not eosinophilic forms;
Introduction of genetics and molecular biology allows today to consider different mechanisms underlying the variety of clinical phenotypes.
The American group of San Francisco (Prescott.G Woodruff and al: Th2-driven inflammation defines major sub-phenotypes of Asthma AJRCCM 2009 May 29 1-48) bearing in mind that Th2 inflammation mediated by cytokines IL4, IL5, IL13 is considered as the central mechanism of asthma,  tried to determine  whether this inflammation reflects the clinical heterogeneity of the disease.
In 42 cases of moderate asthma (compared with 28 controls) a study is carried out from airway epithelial brushings using microarray and PCR analyses;
42 asthmatics are classified according high or low expression of IL13  inducible genes (POSTN, Serpin B2 among others) This classification was validated  by its clinical implication  through analyses of markers of Th2 inflammation and bronchial remodeling (serum IgE, and serum, tissular, broncho-alveolar lavage eosinophilia), through cytokine expression in bronchial biopsies(IL4, IL5, IL 13)  bronchial responsiveness  to  inhaled corticosteroids and finally by  reproducibility of these variables during repeated examinations.
It emerges from this considerable amount of documents, illustrated by many very suggestive tables, that Asthma, in this survey, can be divided into 2 different and evenly sized molecular phenotypes.
Asthma with high expression of Th2, characterized by a bronchial hyperreactivity, markers at high rates (IgE, eosinophilia), positive skin tests  to house dust mites and dogs, a net answer to inhaled corticoids, improvement of  FEV 1, a sub-epithelial bronchial fibrosis and an important storage of mucin.

As for Asthmas with low expression of Th2, they are not very different, taking into account severity, demography or bronchial obstruction of the disease, but they differ statistically for almost all other criteria and tend to come closer to the control group; the authors suggest for them, a possible neutrophilic or viral inflammation  of Th1 type.
Their conclusion, is that cytokine Th2 is a therapeutic target only for a subgroup of asthmatics and that there is an important group of Asthma which do not depend (or not enough) on inflammation Th2 and in which corticoids or usual treatments are not very efficient.
Although this conclusion is, in fact, based on a small group of patients, we must, once more underline the huge work of these authors.

Zinc and allergic reactions
Zinc is an essential nutrient and ubiquitous element (atomic number 30) welded into various metabolic neurological and immunological pathways. Its deficiency, observed in populations of many developing countries, but also in subjects who follow a strict vegetarian diet, (without meat, fishes nor shellfishes), results in  immune deficiency, source of infections, growth retardation, skin lesions, and alopecia.
In a recent experimental work (J. of Experimental Medicine 2009 published on line 18 May, K.Nishida and al: Zn transporter Zn5/Slc30a5 is required for the mast cell mediated delayed type allergy but not the immediate type reaction) a group of Japanese researchers was interested in the role of Zn in mast cells and consequently on allergic reactions after allergenic provocation test.
They showed in mice, that Zinc transporter: Znt5, shuttles Zn inside the cell, from the cytosol into the Golgi apparatus, and removing it from mast cells disrupts their activation and inhibits allergic responses.
But while Znt5 is dispensable for immediate allergic reaction which is governed by mast cell degranulation, it is needed for late phase allergic response which rely on cytokine production
So in mast cells deprived of Znt5, the release of cytokines induced by the receptor of IgE : Fc€RI is decreased, but degranulation was intact.
So it is not the immediate passive cutaneous anaphylaxis, requiring mastocyte degranulation which is inhibited, but as shown by the authors, the mast cell mediated delayed-type response, and contact hypersentivity
Going farther in their investigations, they reveal the role in this cell process of Protein kinase C and nuclear factor NF kappa B, their activation being necessary to release of cytokines.
Finally, Zn appears as a new actor of delayed allergic response, by activation of mast cells, without mastocyte degranulation.

Héréditary Angioedema ( HAE)  Therapeutic options
HAE is a rare but serious disorder, characterized by recurrent episodes of non pruritic, subcutaneous and submucosal edema, involving arms, feet, hands bowels and sometimes tongue and larynx with risk of airways compromise. It is due to an hereditary deficiency of C1 esterase Inhibitor: C1 INH, which leads to activation of complement cascade and release of vaso-active substances, mainly  bradykinin which is the predominant mediator of vascular permeability.
The only valid treatment of these acute episodes rely on  injection of concentrated C1 INH  available in France and in Europe since 1970, while  antifibrinolytics ( eg.amino-caproic acid and tranexamic acid) have never  proved their efficiency and now more rarely used because of their adverse effects
Prophylaxis is mainly based on "attenuated" androgens such  Danazol ® successfully used for more than 40 years,  particularly before scheduled surgical or dental procedure, but difficult to use for a long time in children or in pregnant women.
In an objective study of the present situation in USA, similar to that observed in Europe , in the early 1970s,  T.Craig and al: When is prophylaxis for Hereditary Angioedema necessary: Annals of  Allergy Asthma Immunology 2009 102 5 366-372) and B.L.Zuraw (NEJM  2008 359 10 1027 1036) remind us new therapeutic and prophylactic options of HAE.
So,  Ecallantide, small protein kallikrein inhibitor, presently evaluated in a trial for treatment of acute episodes, did not receive approval of FDA.
Likewise Icatibant, synthetic peptide acting as bradykinin receptor antagonist which has been approved for use in Europe under the name of Fyrazir, but received a non approvable letter of FDA because the primary outcome did not reach statistical significance.
As for purified C1 INH,  known as “Cinryze”, it used in Europe and quite recently approved by the FDA ( IV injection 1000 U. every 3 to 7 days)  as well as Berinert P: available in Europe for more than 20 years ,delivered in France in hospital environment.
Finally recombinant C1 INH ( Rhucin), has not yet obtained agreement of  European Medical Agency ( EMEA) and presently evaluated in a  randomised trial in USA.
In conclusion,  in spite of this  plentiful research for new drugs, it is necessary to stick  to classical treatment,  tested for decades, taking into account every individual case, frequency and severity of acute episodes, as well as age of  patient and his(her) physiological state.

Source: CEFCAP

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