[Biologicals in the Treatment of Bronchial Asthma]. / Biologika in der Behandlung des Asthma bronchiale.

Biologicals are a therapeutic option for patients with severe asthma. Difficult asthma in patients with untreated comorbidities or persistent trigger factors is much more common than severe refractory asthma. Optimized medical treatment, adherence to medication, elimination of trigger factors and treatment of comorbidities are essential before escalating the therapy with a biological. A careful phenotyping of patient with severe asthma is necessary because all available biological are only effective in certain phenotypes of the disease. For patients with severe allergic asthma an antibody against IgE (Omalizumab) is available. For patients with severe asthma and eosinophilic inflammation the Interleukin (IL)-5 Antibodies Mepolizumab and Reslizumab have recently been approved. The most prominent effect of biological treatment is the reduction of acute exacerbations in these patients. Further antibodies against IL-5 receptor (Benralizumab) or against the IL-4 receptor alpha chain (Dupilumab) are in advanced clinical development.

Collaboration between specialties for respiratory allergies in the International Classification of Diseases (ICD)-11.

BACKGROUND: The International Classification of Diseases (ICD) has been grouping the allergic and hypersensitivity disorders involving the respiratory tract under topographic distribution, regardless of the underlying mechanisms, triggers or concepts currently in use for allergic and hypersensitivity conditions. In order to strengthen awareness and deliberate the creation of the new "Allergic or hypersensitivity disorders involving the respiratory tract" section of the ICD-11, we here propose make the building process public. METHODS: The new frame has been constructed to cover the gaps previously identified and was based on consensus academic reports and ICD-11 principles. Constant and bilateral discussion was kept with relevant groups representing specialties and resulted in proposals submission into the ICD-11 online platform. RESULTS: The "Allergic or hypersensitivity disorders involving the respiratory tract" section covers 64 entities distributed across five main categories. All the 79 proposals submitted resulted from an intensive collaboration of the Allergy working group, relevant Expert working groups and the WHO ICD governance. CONCLUSION: The establishment of the ICD-11 "Allergic or hypersensitivity disorders involving the respiratory tract" section will allow the dissemination of the updated concepts to be used in clinical practice by many different specialties and health professionals.

Proposed ICDRG Classification of the Clinical Presentation of Contact Allergy.

The International Contact Dermatitis Research Group proposes a classification for the clinical presentation of contact allergy. The classification is based primarily on the mode of clinical presentation. The categories are direct exposure/contact dermatitis, mimicking or exacerbation of preexisting eczema, multifactorial dermatitis including allergic contact dermatitis, by proxy, mimicking angioedema, airborne contact dermatitis, photo-induced contact dermatitis, systemic contact dermatitis, noneczematous contact dermatitis, contact urticaria, protein contact dermatitis, respiratory/mucosal symptoms, oral contact dermatitis, erythroderma/exfoliative dermatitis, minor forms of presentation, and extracutaneous manifestations.

IL-25 and IL-33 induce Type 2 inflammation in basophils from subjects with allergic asthma.

BACKGROUND: The alarmin cytokines IL-25 and IL-33 are key promoters of type 2 inflammation. Basophils respond to alarmin cytokines, however the relationship of these cytokines with basophil activation and recruitment in human studies of allergic asthma has not been well characterized. This study investigated the effect of IL-25 and IL-33 on basophils in a model of allergic asthma. METHODS: 10 mild allergic asthmatics underwent allergen and diluent inhalation challenges. Bone marrow aspirates were collected at pre-challenge and 24 h (h) post challenge. Peripheral blood and sputum samples were collected at pre-challenge, 7 h, and 24 h post-challenge to measure basophil expression of IL-17RB, ST2, and intracellular IL-25. Freshly isolated peripheral blood basophils from allergic donors were incubated overnight with IL-25 and IL-33, or sputum supernatant collected post-allergen to assess pro-inflammatory effects of mediators released in the airways. RESULTS: There were increased percentage of basophils expressing IL-17RB, ST2, and intracellular IL-25 collected from bone marrow, peripheral blood, and sputum after allergen inhalation challenge. In vitro stimulation with IL-25 and IL-33 increased the percentage of basophils expressing intracellular type 2 cytokines and surface activation markers, and primed eotaxin-induced migratory potential of basophils, which was mediated directly through IL-17RB and ST2, respectively. Stimulation of basophils with sputum supernatants collected post-allergen challenge up-regulated the percentage of basophils expressing markers of activation and intracellular type 2 cytokines, which was reversed following blockade of the common ß chain (ßc). CONCLUSIONS: Our findings indicate that the alarmin cytokines IL-33 and IL-25 increase basophil activation and migratory potential, and may pose as a novel therapeutic targets for the treatment of allergic asthma.

The additional values of microarray allergen assay in the management of polysensitized patients with respiratory allergy.

BACKGROUND: The IgE response is directed against specific components from an allergenic source. The traditional diagnostic methods use whole extracts, containing allergenic, nonallergenic and cross-reactive molecules. This may pose diagnostic challenges in polysensitized patients. Microarray techniques detect specific IgE against multiple molecules, but their value in term of additional information and economic saving has not been yet defined. OBJECTIVE: We assessed the additional diagnostic information provided by an allergen microarray in a large population of polysensitized subjects. METHODS: In this multicentre study, allergists were required to carefully record diagnosis and treatment of consecutive patients referred for asthma/rhinitis, using the standard methodology (history, skin prick test, IgE assay). Then, a microarray allergen assay was carried out. Clinicians were required to review their diagnosis/treatment according to microarray results. RESULTS: 318 allergic patients (30% reporting also nonrespiratory symptoms) and 91 controls were enrolled. The clinicians reported at least one additional information from the microarray in about 60% of patients, this resulting in therapeutic adjustments. In 66% of patients IgE to pan-allergens were detectable, being this clinically relevant in 38% of patients with polysensitization to pollens. CONCLUSION: Microarray IgE assay represents an advancement in allergy diagnosis, as a third-level approach in polysensitized subjects, when the traditional diagnosis may be problematic.

Cough hypersensitivity syndrome: a distinct clinical entity.

We postulate that most patients with chronic cough have a single discrete clinical entity: cough hypersensitivity syndrome. We constructed a questionnaire that elicits the major components of the syndrome. Here we describe the validation of this questionnaire. Following iterative development, the Hull Airway Reflux Questionnaire (HARQ) was administered to patients and normal volunteers. It is self-administered and comprises 14 items with a maximum score of 70. Unselected patients were recruited sequentially from the Hull Cough Clinic. Preclinic questionnaires were compared with those obtained at the clinic. Responsiveness was assessed 2 months after the clinic visit. One hundred eighty-five patients and 70 normal volunteers were included in this study. There was a marked difference in HARQ scores between patients with chronic cough and normal volunteers. The sensitivity (94%) and specificity (95%) of the HARQ was high, with an area under the ROC curve of 0.99. All items of the scale significantly correlated positively with others in the scale and with the total score. On repeatability testing using Cohen's kappa with quadratic weights, significant agreement was noted for all items. Good correlation was observed between the total scores (r = 0.78). The questionnaire was also responsive to treatment; the minimum clinically significant change was estimated to be 16 points. We have demonstrated the HARQ to have good construct and criterion validity. It is both reproducible and responsive to change. It can be used as a diagnostic instrument and demonstrates that chronic cough represents a single coherent entity: cough hypersensitivity syndrome.

[Nasal allergy and asthma: one or two diseases?]. / Allergie nasale et asthme: maladies uniques ou différentes?

Epidemiological studies have shown that rhinitis and asthma are associated. At least four out of five asthmatics suffer from rhinitis and one out of four rhinitic subjects develop asthma. Recent progress in cellular and molecular biology confirms that the same inflammatory cells and similar mechanisms participate in the pathophysiology of the two diseases. Histological findings show that although nasal inflammation resembles bronchial inflammation, specific remodelling features that are present in asthma are lacking in rhinitis. This may be due to the different embryologic origin of the two organs. These similarities explain certain clinical interactions and are the basis of the ARIA (Allergic Rhinitis and its Impact on Asthma)--WHO guidelines recommending that symptoms of rhinitis be sought in asthmatic subjects and symptoms of asthma in rhinitic subjects.

[Classification of chronic inflammation of the upper respiratory tract based on allergy status]. / Klasifikacija hronicnih inflamacija gornjih disajnih puteva na bazi alergijskog statusa.

Almost one third to one half of all patients in otorhinolaryngologic practice experience some kind of inflammation of the upper respiratory tract out of which allergic mechanisms, either as primary factors or secondary ones, appear in 30-40% of adults and 60-80% of children and adolescents. The objective of this study was to analyse inflammatory conditions of the upper airways on the basis of allergic state of the patient and to establish the classification that will respect the actual immunological alteration level (subclinical allergy, clinical allergy) and spreading (localized allergy, generalized allergy). Inclusion criteria for all sixty nine patients were the diagnosis of chronic upper airway inflammation and their exposition just to ubiquitous allergens. Diagnostic procedure included anamnesis, physical examination and allergic in vivo testing of the skin and nasal mucosa to inhalant allergens. The certain categories of results were established for the skin prick-test (positive, negative, indefinite), specific nasal provocation test (positive, negative, hyperreactive) and nasal symptoms (present, absent). By using a strictly determined combination of results, we were able to define the six groups in our classification: nasal clinical allergy (30% of patients), non-nasal clinical allergy (19% of patients), localized nasal allergy (11% of patients), latent allergy (3% of patient), nonspecific nasal hyperreactivity (12% of patient) and non-allergic inflammation (25% of patients). Our classification takes into consideration the modern knowledge in the field of allergology and may bring an additional quality in respect to selection of therapy options, long-term follow-up of allergy status evolution in the individual person as well as intragroup and intergroup analysis of parameters important to evaluate the effects of antiallergic prevention or therapy.

Quantification of IgE antibodies simplifies the classification of allergic diseases in 4-year-old children. A report from the prospective birth cohort study--BAMSE.

Allergic diseases are common among small children, but it is still unclear how immunoglobulin E (IgE) antibodies to ambient allergens are distributed in a population-based prospective material of children at 4 years of age. The study is based on 75% (n = 4089) of all eligible children from northern Stockholm, born between 1994 and 1996 in pre-defined geographical areas. Data on exposure and outcome were obtained by parental questionnaires when the child was 3 months and 4 years of age. Of the 92% who responded to the 4 years of age questionnaire, serum was obtained in 88% of these children for analysis of IgE antibodies performed with Pharmacia CAP system (Phadiatop and food mix fx5). An antibody level > or =0.35 kUA/l was considered as positive. A positive Phadiatop or fx5 was found in 24% of the 4 years old children. A rather poor correlation was found between the two tests (r = 0.39). Occurrence of IgE antibodies > or =3.5 kU/l for both Phadiatop and fx5 in combination could predict any suspected allergic disease [asthma, rhinitis, atopic eczema dermatitis syndrome (AEDS) and allergic reaction to food] to 97.4%. However, the presence of > or =3.5 kUA/l of Phadiatop or fx5 used as single tests only, was far less efficient to predict any allergic disease. The two mixes of airborne and food allergens were also associated, not only to the severity of the allergic disease in terms of number of organ involved, but also to the severity of recurrent wheeze, in particular in boys with a positive Phadiatop who exhibited significantly limited peak flows compared to those with a negative test. Already at the age of 4, one child in four is sensitized to an allergen as assessed by Phadiatop or food mix (fx5). The presence of IgE antibodies seems not only to predict allergic diseases in this age group, but also relates to severity of such diseases, in particular to asthma. Notable, there was a poor correlation between Phadiatop and fx5 that needs to be considered when identifying allergic diseases in young children. The study demonstrates that quantification of IgE antibodies in blood may be beneficial, not only to diagnose allergic diseases in young children, but especially to serve as a marker of severity of asthma.

An epidemiological survey on the allergological importance of some emerging pollens in Italy.

Epidemiological studies on the pollens responsible for allergic diseases throughout Italy are lacking. Routine diagnostic panels consist prevalently of grass, Parietaria, weeds, birch, olive and mugwort. Considering the great variety of Italian geographical areas and the observation of the growing allergological importance of new botanical species (e.g., ambrosia), a survey on pollen species considered "minor" was necessary. A panel of "emerging" pollens (birch, hazelnut, alder, hornbeam, cypress, ragweed) and a routine panel were used to skin prick test 2,934 consecutive outpatients with respiratory pathology of suspected allergic origin, in 21 centers across Italy. A specific questionnaire was compiled. It was found that 20.1% of patients did not react to allergens tested, 28.2% were positive for at least one emerging pollen and 51.7% did not react to emerging pollens but tested positive for at least one allergen from the routine panel. The prevalence of single pollen species was related to geographical areas. Ragweed pollen was shown to provoke asthma much more frequently than other pollens. Hitherto scarcely considered pollens play a considerable role in causing allergic diseases in Italy. In the great majority of patients, positivity for these pollens was associated with positivity to the better recognized group of pollen allergens, although in some cases they were the primary pathogenic agent. We suggest that these more recently considered allergens be included in routine diagnostic panels.

Comparison of three definitions of asthma: a longitudinal perspective.

In epidemiological studies, defining "current asthma" as the presence of both wheeze in the last year and airway hyperresponsiveness (AHR) identifies children with more severe abnormality compared with children with either measure alone. The predictive value of this definition of asthma and other commonly used definitions have not been compared. In 1982, we enrolled a random sample of 718 schoolchildren aged 8-10 years, and in 1992, we restudied a representative sample of 407. On both occasions, we measured wheeze, medication use, morbidity, AHR, and atopy. We compared three asthma definitions-"current asthma," recent wheeze, and doctor-diagnosed asthma. Approximately 70% of subjects classified by each definition remained consistently classified in 1992. However, the current asthma definition distinguished a group with more severe illness after 10 years than did the other asthma definitions. The current asthma definition not only differentiates children with more severe asthma, but also differentiates those with a more severe prognosis.

Is reactive airways dysfunction syndrome a variant of occupational asthma?

BACKGROUND: Reactive airways dysfunction syndrome (RADS) or irritant-induced asthma is a syndrome that leaves subjects with asthma-like symptoms after one or more exposures to a high concentration of an irritant substance. The degree of reversibility of airway obstruction in subjects with RADS is nevertheless unknown, as is the degree of associated lesions at the airway level. METHODS: We compared the acute reversibility of forced expiratory volume in 1 second (FEV1) after inhalation of albuterol (200 micrograms) in 15 subjects with RADS (12 cases caused by chlorine inhalation) with that of 30 subjects with occupational asthma (OA) caused by various agents. They were paired according to baseline airway obstruction (61% and 63% of predicted value in the RADS and OA groups), requirement for medication (bronchodilator only--7 of 15 subjects with RADS and 14 of 30 subjects with OA--as compared with bronchodilator + inhaled steroids in 8 of 15 subjects with RADS and 16 of 30 subjects with OA, respectively), and interval since removal from exposure (means of 30 and 24 months in the RADS and OA groups). In addition, five nonsmokers with RADS who had not received inhaled steroids underwent bronchoscopy with lavage and bronchial biopsies less than 2 years after the exposure. RESULTS: The percentage increase in FEV1 over baseline after inhalation of albuterol was 10% +/- 9% in the RADS group and 19% +/- 16% in the OA group (p = 0.005). Only 2 of 15 subjects (13%) with RADS and 12 of 30 subjects (40%) with OA showed an improvement in FEV1 of 20% or greater after inhalation of albuterol. Bronchoalveolar lavage showed an increased number of cells with a predominance of lymphocytes, and biopsy specimens showed increased basement membrane thickness in the five subjects with RADS who underwent bronchoscopy. CONCLUSION: Subjects with RADS are generally left with less airway reversibility than those with OA. We suggest that this difference is secondary to distinct pathologic changes.

Clearance of Pseudomonas aeruginosa in different rat lung models.

Chronic pulmonary infections with Pseudomonas aeruginosa remain a serious problem in patients with cystic fibrosis. Structurally altered lung mucosa and local inflammation may impair bacterial clearance from the airways. This hypothesis was investigated in (1) the reserpinized rat, (2) proteinase-pretreated rat lungs, and (3) Type III hypersensitivity rat lung models. Reserpine treatment led to surface alterations of Type I epithelial lung cells and diminished food uptake. Significantly enhanced P. aeruginosa colony-forming units (CFU) were found in all (12 of 12) rat lungs 48 h after challenge compared to partially starved rats (p less than 0.025) or untreated rats (p less than 10(-6)). Pretreatment of normal rat lungs with elastase from polymorphonuclear leukocytes (PMN-elastase) resulted in extensive tissue damage, and 48 h after bacterial challenge the mean P. aeruginosa CFU of 12 animals was significantly higher 1.1 X 10(4) +/- 1.0 X 10(4) CFU; p less than 0.01) than in the reserpinized rat lungs. P. aeruginosa organisms were also found in PMN-elastase-treated rat lungs not challenged with bacteria (five of 12 animals), suggesting cross infection from infected animals in the same cage. In immunized rats that were challenged with aerosolized antigen (bovine serum albumin) and P. aeruginosa, bacterial CFU after 10 h were significantly higher than in nonimmune animals (p less than 0.005), and highest after 48 h when P. aeruginosa alkaline proteinase was used as the antigen (1.2 X 10(5) +/- 1.4 X 10(5) CFU). These data provide new evidence that clearance of P. aeruginosa from lung tissue is impaired after malnutrition, epithelial cell alteration, or epithelial cell damage.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of 2 therapeutic protocols in minor forms of respiratory allergy]. / Effet de deux protocoles thérapeutiques dans les formes mineures d'allergies respiratoires.

The purpose of this prospective study was to determine in 261 children whether the "minor" allergic respiratory diseases (MARD) (chronic cough, bronchitis asthmatic, rhinopharyngitis, recurrent otitis media, croup) are due to inhalants allergens and, if so, whether they can be treated with two therapeutic protocols. First protocol (B) included nonspecific immunotherapy with bacterial vaccines aerosols + Fusafungin sprays and Ketotifen were employed in 103 children; and the second protocol (C) included specific immunotherapy with D. Pteronyssinus, in 64 children. This two formula were compared with a control group (67 children). The children were previous tested by PRIST, prick test with house dust, mite, pollens, moulds and by RAST to house dust and mite allergens (56.5% positive results). The follow up study was conducted over 1 to 4 years periods (mean = 1.95 years). Each child's behaviour was monitored regularly by parents and doctor. 54 children drop out this study. Specific hyposensitized children (C) had significant higher improvement (83.6% - p less than 0.01) than B protocol (52.4%) and than control group (16.4%) in overall population. During this study, 51 children with previous MARD go on to more serious obstructive lung disease - asthma: 37.3% in the control group, 23.3% in B group and 6% in hyposensitized group. The results suggest that it is important in children with MARD to monitor the levels of the total and specific Ig E and cutaneous reactions with prick test to common allergens; specific immunotherapy is highly indicated in atopic MARD; in non-atopic MARD children, ketotifen and nonspecific immunotherapy have satisfactory results. Total and specific Ig E levels and prick test must be repeated once a year in this non-atopic children in order to find the specific allergens.

[Routine treatment methods in respiratory allergy]. / Hiérarchie du traitement dans l'allergie respiratoire.

Drug therapy of asthma chiefly relies on beta 2-mimetics, corticosteroids, theophyllines and disodium cromoglycate. In recent years, experience has improved our knowledge of these drug therapies, but it is worth recalling some useful concepts: - Sympathicomimetic bronchodilators are not as dangerous as was previously thought. There is now less reluctance to increase dosage when their efficacy becomes inadequate. - Inhaled corticosteroids have definitely improved many chronic asthmatics. It is known that these drugs must be administered in fairly high doses, at any rate in the initial stages of treatment. - Theophyllines are difficult to use in the acute stage of asthma. On the other hand, the delayed action tablets allow the physician to attain and maintain, with precautions, adequate serum levels. - The new inhalation forms and devices developed for some drugs have improved their therapeutic action and are worth prescribing for many patients. The treatment of the various types of asthma is described. The treatment of various forms of allergic rhinitis is discussed with respect to the indications for DSCG, inhaled steroids, antihistamines and immunotherapy.