Valentina Garelli

Sublingual immunotherapy for allergic rhinitis and conjunctivitis

Sublingual immunotherapy (SLIT) for allergic respiratory diseases was first described in 1986 and immediately appeared as a viable alternative to the traditional subcutaneous route. Since then, more than 60 randomized controlled trials have been published, almost all with very favorable results. The average improvement over placebo in symptom score and medication use was always greater than 20%. The results of the clinical trials were pooled in several meta-analyses, which consistently confirmed the efficacy of the treatment. SLIT is characterized by a satisfactory safety profile, its side effects being mainly limited to oral discomfort. Only six anaphylaxes and no fatalities have been so far reported. Due to the good risk:benefit ratio, SLIT is currently being investigated in diseases other than respiratory allergy, such as food allergy and atopic dermatitis.

The administration of a polyvalent mechanical bacterial lysate in elderly patients with COPD results in serological signs of an efficient immune response associated with a reduced number of acute episodes

The administration of a polyvalent mechanical bacterial lysate (PMBL) in elderly patients with COPD has been shown to reduce the number of exacerbation. This is largely related to the involvement of cells belonging to the innate and the adaptive immune system (including dendritic cells, granulocytes, T and B lymphocytes and NK cells) that actively cooperate inducing the production of specific opsonizing antibodies directed to the antigens of PMBL. We have evaluated the production of antibodies directed to respiratory and systemic pathogens in a group of elderly COPD patients, recruited in a clinical trial, ancillary to a larger multicenter double blind, placebo-controlled, parallel-designed clinical trial in which patients were randomized to daily receive either PMBL or placebo. The treated group not only experienced a reduced number of seroconversion, but also, better controlled the number of infectious episodes and COPD exacerbations. It was thus evident that the administration of PMBL resulted not only effective in inducing the secretion of specific antibodies, but also effective in reducing the infectious episodes trough the potentiation of the antibody-mediated arm of the immune response.

Administration of a polyvalent mechanical bacterial lysate to elderly patients with COPD: Effects on circulating T, B and NK cells.

The modifications of the subsets of circulating lymphocytes were evaluated in a group of patients with COPD undergoing treatment with a polyvalent mechanical bacterial lysate (PMBL), a drug that is able to significantly modify the natural history of these patients. Using multicolor immune-florescence and flow cytometry, T, B subsets and NK cells were extensively studied both in the group of treated patients and in a disease and age matched controls. Despite the age, in treated patients, T and NK cells were significantly increased in numbers of circulating cells, but not in percentages, while B cells remained unmodified. CD3+4+T cells were increased in treated patients, while CD3+CD8T cells were unmodified by the treatment. Activated T cells were increased but Treg, resulted reduced both in percentage than in absolute numbers. Transitional B cells resulted increased (in percentage and in absolute numbers) in their late maturation step (T3), while only early Naïve B cells were increased by the treatment, while other naïve subpopulations were unmodified. Memory B cells were reduced in percentage (but remained unmodified as absolute numbers), while the most immature form of memory B cells was significantly increased. Finally, both switch memory B cells and plasma cells resulted unmodified by the PMBL treatment. These results clearly indicated that the administration of the PMBL, even in elderly patients with COPD, was able to induce a significant immune-stimulation and these results, at cellular level, clearly support the evidence that the mechanism of action of PMBL is strictly related to a direct effect on immune-competent cells.

COPD treatment: Real life and experimental effects on peripheral NK cells, their receptors expression and their IFN-γ secretion

A role in pulmonary immunity has been ascribed to Natural Killer (NK) cells and several in vitro studies have shown a corticosteroid-induced inhibition of NK cells mediated cytotoxicity. Several clinical trials on chronic obstructive pulmonary disease (COPD) have suggested a relationship between COPD treatment and occurrence of respiratory infections. Aims of our study were to investigate if real life COPD treatment affects peripheral blood NK cells total count and their receptors expression and to assess if different doses of formoterol and budesonide, administered alone or in combination, are able to modulate the surface expression of activating (NKp30, NKp44, NKp46 and NKG2D) and inhibitory (KIR2DL2/L3, KIR3DL1 and NKG2A) receptors on peripheral blood NK cells of COPD patients. Moreover, we evaluated the potential effect of treatment with budesonide and/or formoterol on IFN-γ secretion in vitro. NK cells were isolated from peripheral blood of 7 healthy volunteers, 9 chronic bronchitis (CB) and 11 COPD patients. Total NK cells count and activating and inhibitory receptors expression were evaluated. NK cells were cultured for 20h in 96-well plates with IL-2 (100IU/ml)+IL-12 (2.5ng/ml), with or without budesonide (Bud; 1 and 0.01μM) and formoterol (For; 30 and 0.3nM) alone or in combination. Cells were analyzed by flow cytometry and IFN-γ was measured in cell supernatants by ELISA test. No difference between real life treated COPD, CB and healthy subjects was found concerning NK total count and NK cell receptors expression. When cells were stimulated over night with cytokines and treated with drugs, only NKG2D receptor was modulated. Its expression was significantly downregulated by budesonide alone and in combination with formoterol in COPD patients. IFN-γ production induced by stimulation with IL-2+IL-12 was decreased in a highly significant way (p<0.01) by all treatments in all groups. Even if in vitro experiments with budesonide, alone or in combination with formoterol, showed a modulation of NKG2D receptor expression and IFN-γ production, our ex vivo results show that real life LABA and ICS treatment does not influence peripheral NK cells count and their receptors phenotype.

Persistent Allergic Rhinitis and the XPERT Study

Allergic rhinitis (AR) is a chronic disease with an increasing trend in most of the Western Countries. It may significantly impair the individual quality of life (QoL) and also represents a social burden for its economic costs. Levocetirizine (XYZAL; UCB Pharma) as a second generation, nonsedating H1-antihistamine, has been shown to be clinically effective in patients with AR in different randomized controlled trials. The XPERT (XYZAL in Persistent Rhinitis Trial) is the first large, long-term clinical study involving patients with persistent rhinitis as defined by ARIA (Allergic Rhinitis and its Impact on Asthma). The XPERT was a 6-month double-blind, placebo-controlled, multicenter, multinational trial in 551 subjects. Adults with persistent rhinitis sensitized to both grass pollen and house dust mites were randomized to receive levocetirizine 5 mg/d or placebo. Two primary objectives were considered: comparison of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) overall score and Total 5 Symptoms Score (rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) (T5SS) between active and control group over a period of 4 weeks. As secondary endpoints, similar evaluations at 1 week and 3, 4, 5, and 6 months, summary scores for a general health status questionnaire (Medical Outcomes Survey Short Form 36), comorbidities, pharmacoeconomic and safety evaluations. Levocetirizine significantly improved both the RQLQ overall score and the T5SS from week 1 to 6 months (P < .001). Medical Outcomes Survey Short Form 36 summary scores were also improved in the group treated with levocetirizine with respect to placebo. Treatment cessation because of lack of efficacy, comorbidities, and overall costs of disease, and comorbidities per working patient per month (160.27 vs 108.18) were lower in the levocetirizine group. In conclusion, levocetirizine resulted to improve the quality of life and the symptoms related to AR and also to reduce the overall costs of the disease after 6 months treatment.

May we strengthen the human natural defenses with bacterial lysates

During the last twenty years bacterial lysates have gained a new interest and their use has obtained a progressively larger consensus in the medical practice. They are commonly used as immunomodulators, in order to up-regulate immune responses against infectious damages. As a matter of fact, the role of these lysate seems relevant in upper and lower respiratory tract infections prevention, frequently observed both in paediatric and elder ages, and which represent a relevant problem also in terms of socio-economical implications. The effects of bacterial lysates as immunostimulatory agents have become the central point of many studies. The aim of those in vivo and in vitro studies was to understand and evaluate the capacity of this kind of treatments to create a better answer of the immune system against microbial infections, eventually leading to a reduction in their number. All the in vivo and in vitro findings analyzed support the evidence that bacterial lysates are powerful inducers of a specific immune response against bacterial infections. Both in paediatric and adult clinical trials, a positive trend has been found in terms of overall reduction of infection rates and duration, beneficial effect on symptoms, reduction in antibiotics use and possibility to improve the patients quality of life in several diseases. Further well-designed trials in terms of blinding and randomization procedures and including a higher number of patients, selected according to the disease and its severity, are needed.

The bacterial lysate Lantigen B reduces the number of acute episodes in patients with recurrent infections of the respiratory tract: the results of a double blind, placebo controlled, multicenter clinical trial.

Abstract Studies in the 1970s and 1980s reported that bacterial lysates (BL) had a prophylactic effect on recurrent respiratory tract infections (RRTI). However, controlled clinical study procedures have evolved substantially since then. We performed a trial using updated methods to evaluate the efficacy of Lantigen B®, a chemical BL. This double blind, placebo controlled, multi-center clinical trial had the primary objective of assessing the capacity of Lantigen B to significantly reduce the total number of infectious episodes in patients with RRTI. Secondary aims were the RRTI duration, the frequency and the severity of the acute episodes, the use of drugs and the number of missed workdays. In the subgroup of allergic patients with RRTI, the number of allergic episodes (AE) and the use of anti-allergic drugs were also evaluated. One hundred and sixty patients, 79 allocated to the treated group (TG) and 81 to the placebo group (PG), were enrolled; 30 were lost during the study and 120 (79 females and 38 males) were evaluated. The PG had 1.43 episodes in the 8-months of follow-up while the TG had 0.86 episodes (p =0.036). A similar result was observed in the allergic patients (1.80 and 0.86 episodes for the PG and the TG, respectively, p =0.047). The use of antibiotics was reduced (mean 1.24 and 2.83 days of treatment for the TG and the PG). Logistic regression analysis indicated that the estimated risk of needing antibiotics and NSAIDs was reduced by 52.1 and 30.6%, respectively. With regard to the number of AE, no significant difference was observed between the two groups, but bronchodilators, antihistamines and local corticosteroids were reduced by 25.7%, 56.2% and 41.6%, respectively, in the TG. Lantigen B significantly reduced the number of infectious episodes in patients with RRTI. This finding suggests a first line use of this drug for the prophylaxis of infectious episodes in these patients.

Immunotherapy – 2082. Long term prevention of asthma and rhinitis in children with atopic dermatitis four year after discontinuation of sublingual immunotherapy

Background Atopic Dermatitis is a disease with high prevalence in Italy (about 15% of the population). As known, Atopic Dermatitis is often associated with respiratory allergy to mite.We previously showed that sublingual immunotherapy (SLIT) to mite has a beneficial clinical effect in patients with allergic extrinsic Atopic Dermatititis (AD). To investigate the long term effects, we performed a 4-year follow up after the termination of SLIT. Methods 46 children with AD, aged 5-16 years and allergic to mite were re-assessed 4 years after discontinuation of a 2-year course of SLIT (or placebo). Methacholine provocation tests were carried out at baseline, after 2 years (when SLIT was stopped) and after 4 years. The development of asthma and rhinitis was assessed by clinical evaluations. Results The children who previously had received SLIT had significantly less asthma after 6 years as evaluated by clinical symptoms: odd ratio 3.73 (0.130 vs 0.511; P=0.02) as compared to the former placebo group. In addition, significantly less patients reported an increase in asthma scores P=0.003. A significant difference in bronchial methacholine responsiveness was found between the two groups (P=0.03), with an overall lower bronchial hyperreactivity in children who previously received active SLIT. Conclusions A 2-year course of SLIT to mite provided a long term clinical effect and prevented the development of asthma in children with allergic extrinsic form of Atopic Dermatitis.

Open access bronchoscopy atlas: An online educational tool for pulmonologists

Introduction: Bronchoscopy is a basic procedure for pulmonologists. Familiarization with endoscopic aspects requires visual educational support. Aims: To create a thorough online atlas, including extensive photographic material and educational links. Methods: Gallery ® was used for the online platform. An extensive literature research was conducted to indentify relevant educational resources. Thematic files were created in an exhaustive organizational tree format. After approval of the ethics committee, anonymized photos were collected by the bronchoscopists and the endoscopy department archive. Educational resources were selected by two bronchoscopists from internet research. Quality control was done by the project coordinator and three dedicated site reviewers. Results: Out of more than 2000 bronchoscopies conducted each year in our division and from the electronic archive used since 2012, more than 400 photos were selected. Two bronchoscopists screened approximately 700 articles and websites to choose the educational links. Photographs and links were grouped in the following thematic items: materials/techniques, normal anatomy, anatomical variations, terminology, specific diseases, post-operative bronchoscopy, trauma-foreign bodies-inhalation injuries, pediatric bronchoscopy and quiz. Specific subjects can be retrieved using the 9search function9 and 9popular tags9. Users can leave a comment. Conclusions: The created online bronchoscopy atlas (www.chuv.ch/bronchoscopyatlas) is constantly updated and completed to cover the wide spectrum of techniques and pathologies relevant to bronchoscopy. It is expected to become an invaluable educational tool for pulmonologists.