Brunilda Marku

University of Ferrara, Ferrare, Emilia-Romagna, Italy

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Publications (11)50.96 Total impact

  • No preview · Article · Sep 2015 · European Respiratory Journal
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    ABSTRACT: Asthma and other Th2 inflammatory conditions have been associated with increased susceptibility to viral infections. The mechanisms by which Th2 cytokines can influence immune responses to infections are largely unknown. We measured the effects of Th2 cytokines (IL-4 and IL-13) on bronchial epithelial cell innate immune antiviral responses by assessing interferon (IFN-β and IFN-λ1) induction following rhinovirus (RV)-16 infection. We also investigated the modulatory effects of Th2 cytokines on Toll-like receptor (TLR)-3, interferon-responsive factor (IRF)-3, and nuclear factor (NF)-kB, i.e. key molecules and transcription factors involved in the rhinovirus-induced interferon production and inflammatory cascade. Pharmacological and redox modulation of these pathways was also assessed. Th2 cytokines impaired RV16-induced interferon production, increased rhinovirus replication and impaired TLR3 expression in bronchial epithelial cells. These results were replicated in vivo: we found increased IL-4 mRNA levels in nasal epithelial cells from nasal brushing of atopic rhinitis patients and a parallel reduction of TLR3 expression and increased RV16 replication compared to non-atopic subjects. Mechanistically, Th2 cytokines impaired RV-16 induced activation of IRF3, but had no effects on RV16-induced NF-kB activation in bronchial epithelial cell cultures. N-acetylcysteine and phosphoinositide 3-kinase (PI3k) inhibitor restored the inhibitory effects of Th2 cytokines over RV-16 induced activation of IRF3. IL-4 and IL-13, through inhibition of TLR3 expression and signalling (IRF-3), impair immune response to RV-16 infection. These data suggest that Th2 conditions increase susceptibility to infections and identify pharmacological approaches with potential to restore impaired immune response in these conditions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    No preview · Article · Apr 2015 · Allergy
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    ABSTRACT: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting β2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 μg budesonide and 4·5 μg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 μg budesonide and 4·5 μg formoterol combination plus symptom-driven 500 μg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with, number NCT00849095. Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. Italian Medicines Agency. Copyright © 2014 Elsevier Ltd. All rights reserved.
    No preview · Article · Dec 2014 · The Lancet Respiratory Medicine
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    ABSTRACT: Background. Inhalation of thermal water with antioxidant properties is empirically used for COPD. Aims. To evaluate the effects of sulphurous thermal water (reducing agents) on airway oxidant stress and clinical outcomes in COPD. Methods. Forty moderate-to-severe COPD patients were randomly assigned to receive 12-day inhalation with sulphurous thermal water or isotonic saline. Patients were assessed for superoxide anion (O2 (-)) production in the exhaled breath condensate and clinical outcomes at recruitment, the day after the conclusion of the 12-day inhalation treatment, and one month after the end of the inhalation treatment. Results. Inhalation of reducing agents resulted in a significant reduction of O2 (-) production in exhaled breath condensate of COPD patients at the end of the inhalatory treatment and at followup compared to baseline. A significant improvement in the COPD assessment test (CAT) questionnaire was shown one month after the end of the inhalatory treatment only in patients receiving sulphurous water. Conclusion. Thermal water inhalation produced an in vivo antioxidant effect and improvement in health status in COPD patients. Larger studies are required in order to evaluate whether inhalation of thermal water is able to modify relevant clinical outcomes of the disease (the study was registered at NCT01664767).
    Preview · Article · Dec 2013 · The Scientific World Journal
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    ABSTRACT: A standardised definition of infective exacerbation of chronic obstructive pulmonary disease (COPD) still represents an unmet need in respiratory medicine because it relies on clinical empiricism with little evidence-based scientific support. Infective exacerbations of COPD are certainly clear events in the mind of practising physicians. However, there is little consensus on their definition and relevance of different infective aetiologies. Indeed, the efforts to assess the efficacy of new therapies in the treatment and prevention of COPD exacerbations have been hampered by the lack of a widely agreed and consistently used definition. There is a strong need for greater investment in research on infective exacerbations of COPD in order to promote a better understanding and clinical approach of this event in the natural history of COPD. Herein we will review the current concepts, definitions and aetiology of the infective exacerbations of COPD, underlining their strength and limitations.
    No preview · Chapter · Jun 2013
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    ABSTRACT: BACKGROUND: Impaired immune response to viral infections in atopic asthmatic patients has been recently reported and debated. Whether this condition is present in childhood and whether it is affected by atopy per se deserves further investigation. OBJECTIVE: We sought to investigate airway interferon production in response to rhinovirus infection in children who are asthmatic, atopic, or both and its correlation with the airway inflammatory profile. METHODS: Bronchial biopsy specimens and epithelial cells were obtained from 47 children (mean age, 5 ± 0.5 years) undergoing bronchoscopy. The study population included asthmatic children who were either atopic or nonatopic, atopic children without asthma, and children without atopy or asthma. Rhinovirus type 16 induction of IFN-λ and IFN-β mRNA and protein levels was assessed in bronchial epithelial cell cultures. The immunoinflammatory profile was evaluated by means of immunohistochemistry in bronchial biopsy specimens. RESULTS: Rhinovirus type 16-induced interferon production was significantly reduced in atopic asthmatic, nonatopic asthmatic, and atopic nonasthmatic children compared with that seen in nonatopic nonasthmatic children (all P < .05). Increased rhinovirus viral RNA levels paralleled this deficient interferon induction. Additionally, IFN-λ and IFN-β induction correlated inversely with the airway T(H)2 immunopathologic profile (eosinophilia and IL-4 positivity: P < .05 and r = -0.38 and P < .05 and r = -0.58, respectively) and with epithelial damage (P < .05 and r = -0.55). Furthermore, total serum IgE levels correlated negatively with rhinovirus-induced IFN-λ mRNA levels (P < .05 and r = -0.41) and positively with rhinovirus viral RNA levels (P < .05 and r = 0.44). CONCLUSIONS: Deficient interferon responses to rhinovirus infection are present in childhood in asthmatic subjects irrespective of their atopic status and in atopic patients without asthma. These findings suggest that deficient immune responses to viral infections are not limited to patients with atopic asthma but are present in those with other T(H)2-oriented conditions.
    No preview · Article · Sep 2012 · The Journal of allergy and clinical immunology
  • Article: Asthma
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    ABSTRACT: There are increasing data to support the "hygiene" and "microbiota" hypotheses of a protective role of infections in modulating the risk of subsequent development of asthma. There is less evidence that respiratory infections can actually cause the development of asthma. There is some evidence that rhinovirus respiratory infections are associated with the development of asthma, particularly in childhood, whereas these infections in later life seem to have a weaker association with the development of asthma. The role of bacterial infections in chronic asthma remains unclear. This article reviews the available evidence indicating that asthma may be considered as a chronic infectious disease.
    No preview · Article · Sep 2012 · Clinics in chest medicine
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    ABSTRACT: The natural history of chronic obstructive pulmonary disease (COPD) is characterized by recurrent episodes of increased symptoms and airflow obstruction, named exacerbations. Exacerbations contribute to disease progression and increased morbidity and mortality related to COPD. Bacterial and/or viral infections of the respiratory tract are the most important causes of COPD exacerbations. The comprehension of the inflammatory and immunological mechanisms that pave the way to an exacerbation, following respiratory tract infection, will identify new pharmacological targets able to modify the natural history of the disease. The purpose of this review is to evaluate the role of viral and bacterial infections in COPD exacerbations and to review the pharmacological approaches able to prevent COPD exacerbations.
    No preview · Article · Jan 2012 · Rassegna di Patologia dell'Apparato Respiratorio

  • No preview · Conference Paper · May 2010
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    ABSTRACT: Both smokers and patients with asthma can experience fixed airflow obstruction, which is associated with distinctive patterns of airway pathology. The influence of fixed airflow obstruction on the prognosis of these patients is unknown. We sought to investigate lung function decline and exacerbations in a 5-year prospective study of subjects with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease (COPD). We also sought to explore correlations between functional, pathological, and clinical features. Patients with fixed airflow obstruction due to asthma (n = 16) or COPD (n = 21) and a control group of asthmatic patients with fully reversible airflow obstruction (n = 15) were followed for 5 years. The rates of decline in FEV(1) were similar in patients with fixed airflow obstruction caused by asthma (-49.7 +/- 10.6 mL/y) or COPD (-51.4 +/- 9.8 mL/y) and were higher than in asthmatic patients with reversible airflow obstruction (-18.1 +/- 10.1 mL/y, P < .01). Exacerbation rates were also higher in patients with fixed airflow obstruction caused by asthma (1.41 +/- 0.26 per patient-year) or COPD (1.98 +/- 0.3 per patient-year) compared with those seen in asthmatic patients with reversible airflow obstruction (0.53 +/- 0.11 per patient-year, P < .01). Baseline exhaled nitric oxide levels and sputum eosinophil counts correlated with the FEV(1) decline in asthmatic patients with fixed airflow obstruction. By contrast, baseline sputum neutrophil counts, emphysema scores, comorbidities, and exacerbation frequency correlated directly and pulmonary diffusion capacity correlated inversely with the FEV(1) decline in patients with COPD. In both patients with asthma and those with COPD, fixed airflow obstruction is associated with increased lung function decline and frequency of exacerbations. Nevertheless, the decline in lung function entails the specific pathological and clinical features of the underlying diseases.
    No preview · Article · Mar 2010 · The Journal of allergy and clinical immunology
  • M Contoli · B Marku · V Conti · S Saturni · G Caramori · A Papi
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    ABSTRACT: Respiratory viral infections are recognized as the most frequent cause of asthma and chronic obstructive pulmonary disease (COPD) exacerbations with rhinovirus (i.e. the virus of the common cold) being the most frequent identified virus. The recent development of human experimental models of rhinovirus-induced asthma and COPD exacerbations represent innovative tools with the potential to increase our understanding in this field. Moreover this models will provide the opportunity to test, in a carefully controlled setting, novel pharmacological compounds. In this review we will provide an overview of the role of viral infections in asthma and COPD exacerbations and in particular we will summarize the inflammatory and immunological mechanisms that can pave the way to exacerbation following respiratory viral infection in these patients.
    No preview · Article · Dec 2009 · Minerva medica