Background: The clinical and pathological presentation of COPD is heterogeneous. ‘Chronic bronchitis’ is a phenotype of COPD, which is a clinical diagnosis of a productive cough of ≥ 3 months for ≥ 2 consecutive years. Chronic bronchitis is associated with worse lung function, frequent exacerbations, recurrent hospitalisations and premature death in patients with COPD. Chronic bronchitis sufferers can be further subphenotyped into those who produce sputum during exacerbation or during winter months only and those who are ‘persistent sputum producers,’ who experience mucous hypersecretion throughout the year. An improved understanding of persistent sputum producers is the object of this thesis. Aims: 1) To compare the clinical characteristics and airway inflammatory biomarker profile of COPD persistent sputum producers to that of COPD sputum non-producers 2) To investigate the short term repeatability of sputum parameters in COPD persistent sputum producers 3) To study the expression and relationship of mucins, hypoxia inducible factor (HIF-1α) and carbonic anhydrase IX (CAIX) in COPD persistent sputum producers. Methods: 1) Lung physiology, health status, sputum inflammatory biomarkers and sputum culture results were compared between COPD persistent sputum producers and sputum non-producers 2) Repeatability of spontaneous and induced sputum parameters at 8 weeks was assessed in COPD persistent sputum producers 3) Immunohistochemistry was performed on bronchial biopsies of COPD persistent sputum producers and control groups (COPD sputum non-producers, smokers with normal lung function and lifelong healthy non-smokers with normal lung function) to study the expression of MUC5AC, MUC5B, HIF-1α and CAIX 4) The association between HIF-1α and MUC5B expression was investigated in vitro. Results and Conclusions: The findings suggest that 1) COPD persistent sputum producers have clinically more severe disease, increased airway inflammation, increased impact on health status, increased rate of bacterial colonization and higher number of exacerbations compared to COPD sputum non-producers 2) Induced sputum is repeatable over short term in COPD persistent sputum producers 3) Expression of MUC5B, HIF-1α and CAIX is increased in COPD persistent sputum producers compared to COPD sputum non-producers, smokers with normal lung function and healthy non-smokers 4) HIF-1α can potentially cause increased MUC5B expression. This work reveals potential targets for the development of novel therapies to limit mucous hypersecretion in COPD.

Submitted by JOSÉ WILLIAM ZUCCHI null (jwzucchi@hotmail.com) on 2018-04-02T23:13:39Z No. of bitstreams: 1 Dissertação Mestrado José W. Zucchi.pdf: 2342865 bytes, checksum: 860bbd3c7b2672c61b7ca6b121b0e8f9 (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2018-04-03T12:55:11Z (GMT) No. of bitstreams: 1 zucchi_jw_me_bot.pdf: 2342865 bytes, checksum: 860bbd3c7b2672c61b7ca6b121b0e8f9 (MD5) / Made available in DSpace on 2018-04-03T12:55:11Z (GMT). No. of bitstreams: 1 zucchi_jw_me_bot.pdf: 2342865 bytes, checksum: 860bbd3c7b2672c61b7ca6b121b0e8f9 (MD5) Previous issue date: 2018-02-28 / Introdução: Os pacientes com doença pulmonar obstrutiva crônica (DPOC) exibem características clínicas heterogêneas que estão associados a diferentes respostas a tratamentos e prognósticos. A complexidade da doença faz com que sejam buscadas ferramentas alternativas como o agrupamento de cluster para a identificação de características específicas e que possam tratadas diferentemente dentro da mesma doença. Entretanto, ainda são escassos dados da América Latina em relação aos possíveis clusters da DPOC. Objetivo: Avaliar os possíveis clusters na DPOC em dois centros de estudo no Brasil. Métodos: Os pacientes foram submetidos à avaliação composta por doenças associadas, Índice de Charlson, composição corporal, fármacos atuais, história de tabagismo (anos/maço), monóxido de carbono exalado, histórico de exacerbações/ hospitalizações no último ano, espirometria, teste de caminhada de seis minutos, questionários de qualidade de vida, dispneia e escala hospitalar de ansiedade e depressão. Também foram coletadas amostras de sangue para dosagens de proteína C reativa (PCR), gases sanguíneos, análise laboratorial e hemograma. Resultados: Foram avaliados 334 pacientes portadores de sintomas respiratórios e fator de risco para DPOC. Desse total, 13 pacientes foram excluídos do estudo por não terminarem o protocolo, 20 pacientes sem diagnóstico de DPOC e 10 por não terem sido classificados em nenhum cluster. Assim, foram incluídos 291 pacientes [53,6% homem, 67,5 ± 9,6 anos e volume expiratório forçado no primeiro segundo (VEF1) = 45,5 ± 17,9]. Para a construção dos clusters foram selecionadas 13 variáveis continuas e realizado análise com o método de Ward e método K means que determinaram quatro clusters. O primeiro cluster foi caracterizado por menor gravidade sintomática e funcional da doença, o segundo grupo por maior valor de eosinófilos periféricos, o terceiro grupo por serem mais inflamados sistemicamente e o quarto grupo por serem com maior gravidade obstrutiva e pior troca gasosa. O cluster 2 apresentou média de 959± 3 eosinófilos periféricos, cluster 3 apresentou maior prevalência de depleção nutricional (46,1%) e o cluster 4 apresentou maior índice BODE. Em relação as comorbidades associadas identificamos que apenas a síndrome de apneia obstrutiva do sono e o tromboembolismo pulmonar foram mais prevalentes no cluster 4. Conclusão: As manifestações clínicas e comorbidades associadas da DPOC identificadas nos quatros diferentes clusters deste estudo mostram as características heterogêneas da doença e isso pode estar relacionado à desfechos prognósticos diferentes em cada cluster podem diferenciar o tratamento em cada agrupamento com maior efetividade. / Introduction: Patients with chronic obstructive pulmonary disease (COPD) exhibit heterogeneous clinical features that are associated with different responses to treatments and prognoses. The complexity of the disease causes alternative tools such as clustering to identify specific characteristics and that can be treated differently within the same disease. However, there are still little data from Latin America regarding possible clusters in COPD. Objective: To evaluate possible clusters in COPD in two Brazilian centers. Methods: We assesses the comorbidities, Charlson's index, body composition, pharmacological treatment, smoking history (pack-years), exhaled carbon monoxide, exacerbations/hospitalizations rate in the last year, spirometry, six-minute walk test, quality of life questionnaires, dyspnea and hospital anxiety and depression scale. We also collected blood gases, laboratory and blood counts. Results: A total of 334 patients with respiratory symptoms and a risk factor for COPD were evaluated. From the total, 13 patients were excluded from the study because they didn’t complete the protocol, 20 patients without a diagnosis of COPD and 10 because they were not classified in any cluster. Thus, 291 patients were included [53.6% male, 67.5 ± 9.6 years and forced expiratory volume in the first second (FEV1) = 45.5 ± 17.9]. For the construction of the clusters, 13 continuous variables were selected and an analysis was performed with the Ward method and K method, which determined four clusters. The first cluster was characterized by lower symptomatic and mild COPD. The second cluster was characterized by higher value of peripheral eosinophils, the third cluster with systemic inflammation and the fourth cluster had severe COPD and worst gas exchange. Cluster 2 presented a mean of 959 ± 3 peripheral eosinophils, cluster 3 presented a higher prevalence of nutritional depletion (46.1%) and cluster 4 presented higher BODE index. In relation to the associated comorbidities, we identified that only obstructive sleep apnea syndrome and pulmonary thromboembolism were more prevalent in cluster 4. Conclusion: The clinical manifestations and associated comorbidities of COPD identified in the four different clusters of this study show the heterogeneous characteristics of the disease and this may be related to different outcomes and treatment.

Orientador: Suzana Erico Tanni Minamoto / Resumo: Introdução: Os pacientes com doença pulmonar obstrutiva crônica (DPOC) exibem características clínicas heterogêneas que estão associados a diferentes respostas a tratamentos e prognósticos. A complexidade da doença faz com que sejam buscadas ferramentas alternativas como o agrupamento de cluster para a identificação de características específicas e que possam tratadas diferentemente dentro da mesma doença. Entretanto, ainda são escassos dados da América Latina em relação aos possíveis clusters da DPOC. Objetivo: Avaliar os possíveis clusters na DPOC em dois centros de estudo no Brasil. Métodos: Os pacientes foram submetidos à avaliação composta por doenças associadas, Índice de Charlson, composição corporal, fármacos atuais, história de tabagismo (anos/maço), monóxido de carbono exalado, histórico de exacerbações/ hospitalizações no último ano, espirometria, teste de caminhada de seis minutos, questionários de qualidade de vida, dispneia e escala hospitalar de ansiedade e depressão. Também foram coletadas amostras de sangue para dosagens de proteína C reativa (PCR), gases sanguíneos, análise laboratorial e hemograma. Resultados: Foram avaliados 334 pacientes portadores de sintomas respiratórios e fator de risco para DPOC. Desse total, 13 pacientes foram excluídos do estudo por não terminarem o protocolo, 20 pacientes sem diagnóstico de DPOC e 10 por não terem sido classificados em nenhum cluster. Assim, foram incluídos 291 pacientes [53,6% homem, 67,5 ± 9,6 anos e volume expi... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Patients with chronic obstructive pulmonary disease (COPD) exhibit heterogeneous clinical features that are associated with different responses to treatments and prognoses. The complexity of the disease causes alternative tools such as clustering to identify specific characteristics and that can be treated differently within the same disease. However, there are still little data from Latin America regarding possible clusters in COPD. Objective: To evaluate possible clusters in COPD in two Brazilian centers. Methods: We assesses the comorbidities, Charlson's index, body composition, pharmacological treatment, smoking history (pack-years), exhaled carbon monoxide, exacerbations/hospitalizations rate in the last year, spirometry, six-minute walk test, quality of life questionnaires, dyspnea and hospital anxiety and depression scale. We also collected blood gases, laboratory and blood counts. Results: A total of 334 patients with respiratory symptoms and a risk factor for COPD were evaluated. From the total, 13 patients were excluded from the study because they didn’t complete the protocol, 20 patients without a diagnosis of COPD and 10 because they were not classified in any cluster. Thus, 291 patients were included [53.6% male, 67.5 ± 9.6 years and forced expiratory volume in the first second (FEV1) = 45.5 ± 17.9]. For the construction of the clusters, 13 continuous variables were selected and an analysis was performed with the Ward method and K method, which dete... (Complete abstract click electronic access below) / Mestre