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Supplemental material, Author_Response_1 for Switching from omalizumab to mepolizumab: real-life experience from Southern Italy by Giovanna Elisiana Carpagnano, Corrado Pelaia, Maria D’Amato, Nunzio Crimi, Nicola Scichilone, Giulia Scioscia, Onofrio Resta, Cecilia Calabrese, Girolamo Pelaia, Carla Maria Irene Quarato and Maria Pia Foschino Barbaro in Therapeutic Advances in Respiratory Disease

Supplemental material, Reviewer_1_v.1 for Switching from omalizumab to mepolizumab: real-life experience from Southern Italy by Giovanna Elisiana Carpagnano, Corrado Pelaia, Maria D’Amato, Nunzio Crimi, Nicola Scichilone, Giulia Scioscia, Onofrio Resta, Cecilia Calabrese, Girolamo Pelaia, Carla Maria Irene Quarato and Maria Pia Foschino Barbaro in Therapeutic Advances in Respiratory Disease

Asthma is a very frequent chronic airway disease that includes many different clinical phenotypes and inflammatory patterns. In particular, eosinophilic bronchial inflammation is often associated with allergic as well as nonallergic asthma. The most important cytokine involved in the induction, maintenance, and amplification of airway eosinophilia in asthma is interleukin-5 (IL-5), released by both T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2). Hence, IL-5 and its receptor are suitable targets for selective biologic drugs which can play a key role in add-on treatment of severe eosinophilic asthma refractory to corticosteroids. Within such a context, the anti-IL-5 monoclonal antibodies mepolizumab and reslizumab have been developed and approved for biological therapy of uncontrolled eosinophilic asthma. In this regard, on the basis of several successful randomized controlled trials, the anti-IL-5 receptor benralizumab has also recently obtained the approval from US Food and Drug Administration (FDA).

Post-infectious bronchiolitis obliterans (PIBO) is a small airways disease characterized by fixed airflow limitation. Therefore, inhaled bronchodilators and corticosteroids are not recommended as maintenance therapy options. The management of PIBO currently consists only of close monitoring of affected patients, aimed at the prevention and early treatment of pulmonary infections. In recent years, there has been an increase in the incidence of PIBO in the pediatric population. Patients with PIBO are characterized by a progressive decline in lung function, accompanied by a decrease in overall functional capacity. Here, we report the case of a relatively young man diagnosed with PIBO and followed for three years. After short- and long-term therapy with an inhaled corticosteroid/long-acting 2 agonist combination, together with an inhaled long-acting antimuscarinic, the patient showed relevant improvement of airway obstruction that had been irreversible at the time of the bronchodilator test. The lung function of the patient worsened when he interrupted the triple inhaled therapy. In addition, a 3-week pulmonary rehabilitation program markedly improved his physical performance. RESUMO A bronquiolite obliterante pós-infecciosa (BOPI) é uma doença das pequenas vias aéreas caracterizada por limitação fixa do fluxo aéreo. Portanto, os broncodilatadores e os corticosteroides inalatórios não são recomendados como opções de terapia de manutenção. Atualmente, o manejo da BOPI consiste apenas de um acompanhamento rigoroso dos pacientes afetados, visando à prevenção e ao tratamento precoce de infecções pulmonares. A incidência de BOPI tem aumentado na população pediátrica nos últimos anos. Os pacientes com BOPI caracterizam-se por um declínio progressivo da função pulmonar, associado a uma diminuição da capacidade funcional global. Relatamos aqui o caso de um homem relativamente jovem diagnosticado com BOPI, acompanhado por três anos. Após terapia de curto e de longo prazo com uma combinação de corticosteroide/2-agonista de longa duração inalatórios, associada a um agente antimuscarínico de longa duração inalatório, o paciente apresentou uma melhora relevante da obstrução das vias aéreas, a qual fora irreversível durante o teste de broncodilatação. A função pulmonar do paciente piorou quando ele interrompeu a terapia inalatória tripla. Além disso, um programa de reabilitação pulmonar de três semanas significativamente melhorou seu desempenho físico.

Girolamo Pelaia,1 Alessandro Vatrella,2 Maria Teresa Busceti,1 Luca Gallelli,3 Cecilia Calabrese,4 Rosa Terracciano,3 Nicola Lombardo,1 Rosario Maselli11Department of Medical and Surgical Sciences, Magna Græcia University of Catanzaro, Catanzaro, 2Departmentof Medicine and Surgery, University of Salerno, Salerno, 3Department of Health Science, Magna Græcia University of Catanzaro, Catanzaro, 4Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, ItalyAbstract: Bronchodilators are the most important drugs used for the treatment of chronic obstructive pulmonary disease (COPD). In particular, these therapeutic agents are mostly long-acting compounds utilized via inhalation, and include LAMA (long-acting muscarinic receptor antagonists) and LABA (long-acting β2-adrenoceptor agonists). Because LAMA and LABA induce bronchodilation by distinct mechanisms of action, LABA/LAMA combinations provide a reciprocal potentiation of the pharmacological effects caused by each component. Hence, many COPD patients who do not achieve a satisfactory control of their symptoms using a single, either LAMA or LABA bronchodilator, can experience relevant benefits with the use of LAMA/LABA fixed combinations. Many different LAMA/LABA combinations have been recently developed and evaluated in randomized clinical trials. In this context, our review focuses on the pharmacological mechanisms underpinning the bronchodilation elicited by the LAMA tiotropium bromide and the LABA olodaterol. We also discuss the results of the most important clinical studies carried out in COPD patients to assess the efficacy and safety of tiotropium/olodaterol combinations.Keywords: LAMA, LABA, tiotropium, olodaterol, dual bronchodilation, tiotropium/olodaterol combinations

Background Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo. Methods In this randomized, double-blind, parallel-group trial involving 17,135 patients with COPD, we evaluated the safety and efficacy of tiotropium Respimat at a oncedaily dose of 2.5 μg or 5 μg, as compared with tiotropium HandiHaler at a oncedaily dose of 18 μg. Primary end points were the risk of death (noninferiority study, Respimat at a dose of 5 μg or 2.5 μg vs. HandiHaler) and the risk of the first COPD exacerbation (superiority study, Respimat at a dose of 5 μg vs. HandiHaler). We also assessed cardiovascular safety, including safety in patients with stable cardiac disease. Results During a mean follow-up of 2.3 years, Respimat was noninferior to HandiHaler with respect to the risk of death (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.96; 95% confidence interval [CI], 0.84 to 1.09; Respimat at a dose of 2.5 μg vs. HandiHaler: hazard ratio, 1.00; 95% CI, 0.87 to 1.14) and not superior to HandiHaler with respect to the risk of the first exacerbation (Respimat at a dose of 5 μg vs. HandiHaler: hazard ratio, 0.98; 95% CI, 0.93 to 1.03). Causes of death and incidences of major cardiovascular adverse events were similar in the three groups. Conclusions Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium HandiHaler at a dose of 18 μg in patients with COPD. (Funded by Boehringer Ingelheim; TIOSPIR ClinicalTrials.gov number, NCT01126437.)

Asthma is a phenotypically heterogeneous chronic disease of the airways, characterized by either predominant eosinophilic or neutrophilic, or even mixed eosinophilic/neutrophilic inflammatory patterns. Eosinophilic inflammation can be associated with the whole spectrum of asthma severity, ranging from mild-to-moderate to severe uncontrolled disease, whereas neutrophilic inflammation occurs mostly in more severe asthma. Eosinophilic asthma includes either allergic or nonallergic phenotypes underlying immune responses mediated by T helper (Th)2 cell-derived cytokines, whilst neutrophilic asthma is mostly dependent on Th17 cell-induced mechanisms. These immune-inflammatory profiles develop as a consequence of a functional impairment of T regulatory (Treg) lymphocytes, which promotes the activation of dendritic cells directing the differentiation of distinct Th cell subsets. The recent advances in the knowledge of the cellular and molecular mechanisms underlying asthmatic inflammation are contributing to the identification of novel therapeutic targets, potentially suitable for the implementation of future improvements in antiasthma pharmacologic treatments.

In CF patients, Glutathione (GSH), the first-line defence of lungs against oxidative stress, is severely reduced. A randomized, single blind controlled trial of inhaled GSH vs placebo (NCT01450267) is underway to evaluate the effect of GSH in a cohort of CF patients. 94 CF patients (48 F, median age 20.8 years) in regular follow up at the Regional Pediatric and Adult CF Center of Naples, were enrolled, 50 patients (23 F) were randomly assigned to the GSH group and 44 (25 F) to the placebo group. The inclusion criteria were: CF diagnosis by sweat test and/or two CF causing mutations, age of patients >6yrs, FEV1% >40% of the predicted value, negative culture for Burkholderia Cepacia. Spirometry was performed before, 10 and 60 minutes after GSH inhalation test (10 mg/Kg, maximum dosage 600mg/dose) in order to assess tolerability. Follow-up visits including spirometry took place one, three, six, nine months and after the end of treatments. No patients showed a decrease in FEV1% >15% after GSH inhalation. In the subgroup of CF patients (n=27) with an obstructive ventilatory defect (FEV1/FVC

Obiettivi: Nei pazienti con Fibrosi Cistica (FC), malattia genetica sistemica ad interessamento multiorgano, la difesa antiossidante é ridotta e contribuisce alla comparsa di stress ossidativo, riducendo la capacità di risposta alle infezioni delle vie aeree. E’ stato dimostrato che in FC il Glutatione (GSH), prima linea di difesa dei polmoni nei confronti del danno cellulare indotto dai radicali liberi, è notevolmente ridotto e la sua somministrazione esogena potrebbe controbilanciare lo stress ossidativo. È in corso uno studio randomizzato controllato in singolo cieco con GSH inalatorio versus placebo (NCT01450267) per valutare l’effetto del GSH in una coorte di pazienti FC. Riportiamo i dati preliminari sulla tollerabilità al GSH nel gruppo di pazienti arruolati. Metodi: Dei 94 pazienti FC (48 F, 46 M, età M 20,8 anni ) in regolare follow up presso il Centro di Riferimento Regionale Pediatrico e Adulti di Napoli, 50 (23 F) sono stati assegnati mediante randomizzazione al gruppo GSH e 44 (25 F) al gruppo placebo. I principali criteri di inclusione erano: diagnosi di FC mediante test del sudore e/o due mutazioni causanti malattia, età del paziente >6 anni, FEV1%>40% del predetto; coltura negativa per Burkholderia Cepacia. Per valutare la tollerabilità del farmaco è stata effettuata una spirometria prima, 10 e 60 minuti dopo il test di inalazione del GSH (10 mg/Kg, dosaggio massimo 600mg/dose). Una riduzione del FEV1%>15% rispetto al valore basale è criterio di esclusione dallo studio. Risultati: Nessun paziente ha mostrato una diminuzione del FEV1% >15% dopo l’inalazione di GSH. I risultati preliminari mostrano che in un sottogruppo di pazienti con un FEV≤ 80% (n=27), dopo sei mesi di trattamento, il FEV1% è aumentato in maniera statisticamente significativa (58.3 ± 13.2 vs 62.6 ± 15.1 p =0.048) a differenza di quanto osservato nel gruppo di pazienti (n= 20) trattati con placebo (59.3 ± 14.9 vs 56.8 ± 18.4). Conclusioni: Il GSH inalatorio è tollerato in tutti i pazienti trattati. Risultati preliminari suggeriscono che la terapia con GSH inalatorio determina un miglioramento della funzione polmonare. È in corso di valutazione l’efficacia del GSH inalatorio su parametri clinici e funzionali e sui livelli degli indici di infiammazione nel corso dei 12 mesi di terapia.

A twenty-one year old female with a history of recurrent pneumonia and airway infections since infancy, chronic cough, gastroesophageal reflux symptoms, and persistent allergic rhinitis was referred to our asthmatic centre. She exhibited a normal sweat test, skin prick test positive to common allergens, and gastroscopy showing hiatal hernia and reflux esophagitis. We performed spirometry for the first time. The flow-volume curve showed a plateau of forced expiratory flow suggesting a variable intrathoracic airway obstruction. We then carried out bronchoscopy that showed a compression of the distal trachea. A computed tomography angiogram revealed a vascular ring consisting of a double aortic arch with right-arch dominance compressing the trachea and esophagus. Echocardiography confirmed the presence of the vascular ring. The patient has been referred for surgery. This report underscores the importance of spirometry and the analysis of the flow-volume curve.

Tre gruppi di donne di età media simile superiore ai 35 anni affette rispettivamente da asma bronchiale cronico di grado severo, moderato e lieve, sono state sottoposte a valutazione anamnestica, clinica e funzionale al fine di individuare caratteristiche distintive di esordio ed evoluzione della patologia asmatica nei suoi differenti gradi di severità. Tutte le pazienti affette da asma bronchiale di grado severo rispondevano ai criteri ATS di asma refrattario. Le pazienti afferenti ai tre gruppi sono state esaminate nel periodo di migliore controllo della sintomatologia asmatica come da asma control test. Sono stati valutati: 1) anamnesi personale e familiare di atopia, asma ed intolleranza a farmaci; 2) esposizioni professionali e/o a fumo di sigarette; 3) età, modalità di esordio ed inizio del trattamento regolare dell’asma; 4) comorbidità quali rinite, malattia dei seni paranasali, MRGE, obesità, distiroidismo, bronchiectasie e disturbi psichiatrici. Le pazienti sono state sottoposte ad esame spirometrico pre e post-broncodilatatore e alla misurazione dei livelli di NO nell’aria esalata (FENO). Nelle pazienti affette da asma severo, rispetto a quelle con asma moderato e lieve, abbiamo riscontrato, in accordo con i dati della letteratura, un più frequente esordio tardivo della patologia e una maggiore prevalenza di comorbidità, in particolare sinusiti e MRGE. In aggiunta, nel gruppo di donne affette da asma cronico refrattario, abbiamo osservato un più frequente esordio della malattia in concomitanza o dopo una gravidanza e un ritardo nell’inizio di un trattamento regolare di fondo dell’asma. Nei tre gruppi di pazienti i livelli di FENO erano molto variabili; tuttavia in alcune pazienti che riferivano un buon controllo della sintomatologia asmatica abbiamo riscontro alti livelli di FENO (>35 ppb), che hanno suggerito un incremento della dose giornaliera di steroidi inalatori con ulteriore beneficio per le pazienti.

Alessandro Vatrella,1 Immacolata Fabozzi,1 Cecilia Calabrese,2 Rosario Maselli,3 Girolamo Pelaia3 1Department of Medicine and Surgery, University of Salerno, Salerno, 2Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, Naples, 3Department of Medical and Surgical Sciences, University Magna Græcia, Catanzaro, Italy Abstract: Simultaneously with the steady progress towards a better knowledge of the pathobiology of asthma, the potential usefulness of anticytokine therapies is emerging as one of the key concepts in the newly developing treatments of this widespread airway disease. In particular, given the key role played by interleukin (IL)-4 and IL-13 in the pathophysiology of the most typical aspects of asthma, such as chronic airway inflammation, tissue remodeling, and bronchial hyperresponsiveness, these pleiotropic cytokines are now considered as suitable therapeutic targets. Among the recently developed antiasthma biologic drugs, the monoclonal antibody dupilumab is very promising because of its ability to inhibit the biological effects of both IL-4 and IL-13. Indeed, dupilumab prevents IL-4/13 interactions with the α-subunit of the IL-4 receptor complex. A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab. Keywords: Th2-high asthma, interleukin-4, interleukin-13, dupilumab

Chronic obstructive pulmonary disease (COPD) is a complex disorder involving both airways and lung parenchyma, usually associated with progressive and poorly reversible airflow limitation. In order to better characterize the phenotypic heterogeneity and the prognosis of patients with COPD, there is currently an urgent need for discovery and validation of reliable disease biomarkers. Within this context, proteomic and peptidomic techniques are emerging as very valuable tools that can be applied to both systemic and pulmonary samples, including peripheral blood, induced sputum, exhaled breath condensate, bronchoalveolar lavage fluid, and lung tissues. Identification of COPD biomarkers by means of proteomic and peptidomic approaches can thus also lead to discovery of new molecular targets potentially useful to improve and personalize the therapeutic management of this widespread respiratory disease.

Pathological angiogenesis has been demonstrated in lung cancer and in chronic airway inflammatory diseases such as asthma, chronic bronchitis, and COPD. The aim of the present study was to evaluate whether the degree of bronchial angiogenesis in non-neoplastic mucosa of sympthomatic cigarette smokers could be influenced by the presence of a concomitant lung cancer. An immunohistochemical study was performed on GMA embedded bronchial biopsies obtained from 37 smokers: 17 without lung cancer (9 with chronic bronchitis, 8 with COPD), 20 with a contralateral non-small cell lung cancer (10 with chronic bronchitis, 10 with COPD). The number of vessels and the percentage of vascular area in the lamina propria were assessed using monoclonal antibody against CD31. An image processing and analysis system was used to quantify the immunohistochemical data. The study was conformed to the declaration of Helsinki and all patients gave their written informed consent. Our data show that the number of vessels and the percentage of vascular area in the lamina propria are not significantly different in smokers with and without contralateral lung cancer (p = 0.341 and 0.534 respectively). The results of the study suggest that the presence of lung cancer does not influence the degree of bronchial angiogenesis in non-neoplastic airways of smokers with chronic bronchitis or COPD.

The role played by bronchial vasculature in the remodelling process occurring in the airways of smokers with and without COPD has been poorly investigated.Vascular endothelial growth factor (VEGF) is the most potent and widely distributed angiogenic factor known to date. αvβ3 integrin, an adhesion molecule expressed only at low levels on resting endothelium, is upregulated in new capillaries proliferating in response to angiogenic stimuli. We performed an immunohistochemical study on bronchial biopsies taken from 8 non-smokers, 9 smokers with normal lung function (GOLD 0) and 9 smokers with moderate COPD (GOLD 2). We evaluated in the lamina propria: 1) the number of vessels and the percentage of vascular area 2) the cellular expression of VEGF and 3) the vascular expression of αvβ3. Results did show that the number of vessels, the vascular area, the cellular expression of VEGF, the number and percentage of αvβ3 positive vessels were significantly higher in both GOLD 0 and GOLD 2 smokers than in non-smokers. The comparison between GOLD 0 and GOLD 2 smokers did show a weak but significantly lower number of vessels in GOLD 2, while the vascular area and the percentage of αvβ3 positive vessels did not differ between the two groups. A higher VEGF expression was detected in the GOLD 2 than in the GOLD 0 group. Our data suggest that angiogenesis of bronchial vessels is a significant component of the airway remodelling occurring in symptomatic smokers with normal lung function and with COPD.

Epithelioid hemangioendothelioma (EHE) is an uncommon vascular tumor characterized by epithelioid or histiocytoid cells exhibiting primitive vascular differentiation. This lesion may involve lung, soft tissue, bone, liver, breast, brain andlymphnodes. The pulmonary EHE is of “borderline malignancy”, the prognosis is unpredictable (mean survival 4.6 years) and death usually occurs for a progressive respiratory failure. About 50 cases have been reported in literature. In February 2000 a 20-year-old woman with a one year history of dry cough had a HRCT scan showing multiple bilateral nodules in the lungs. The patient underwent thoracoscopic lung biopsy and an interstitial lung disease was suspected. After a nine months course of corticosteroid therapy a remission of symptoms was obtained and the HRCT scan periodically perfomed for three years did not show a progression of the disease. In September 2004 she was admitted to our Department for a suspected pneumonia and a bronchoscopy was performed. The histological examen of bronchial biopsies revealed a poorly differentiated neoplasm immunohistochemically positive for vimentin and endothelial markers (factor VIII-related antigen and CD34). A diagnosis of angiosarcoma (malignant hemangioendothelioma) was made. Chemotherapy with paclitaxel (80 mg/mq 1, 8, 15 every 28 days for three cycles) was admnistered but after six months from the diagnosis the patient died. The revision of the former CT scan and histological examen suggested a diagnosis of pulmonary EHE (intravascular bronchiolo-alveolar tumor- IVBAT). At our knowledge, this is the first reported case of EHE, a low grade neoplasm, transformed into a very high grade angiosarcoma.