Master of Science / Department of Clinical Sciences / Daniel U. Thomson / Acute Interstitial Pneumonia (AIP) is a costly issue that affects feedlot cattle, especially during hot and dry summers. Research has yet to elucidate the exact etiology of AIP; therefore this study was conducted to determine possible factors that contribute to AIP in feedlot cattle. During the summer of 2011 in a 55,000 head feedyard in southwest Kansas, animals exhibiting clinical signs of AIP were selected for ante-mortem examination and data collection. The animal population within the feedlot consisted of 75% heifers and 25% steers. Approximately 50% of the animal population was black hided animals. Ante-mortem data consisted of rumen gas cap measurement for NH3 and H2S, rumen pH, serum chemistry, rectal temperature, and body weight. Post-mortem cases with and without ante-mortem evaluations were also selected for an additional examination. Postmortem examination included similar data as ante-mortem examination with addition of visual and histological examination of lung tissue. There were 31 ante-mortem cases of clinical AIP with the following observations (mean ± SD): rectal temperature 105.3 ± 0.7 °F, weight 1098 ± 123 lbs., H2S 136 ± 133.3 ppm, and rumen pH 6.4 ± 0.5. Twenty-five healthy cohorts were selected from identical pens to serve as controls. Observations from control animals were: rectal temperature 103.7 ± 1.1 °F, weight 1113 ± 133.3lbs, H2S 269.8 ± 311.6 ppm and rumen pH 6.2 ± 0.6. A total of 61 post-mortem cases with a preliminary diagnosis of AIP were analyzed and displayed the following values: H2S 1279.7 ± 1569 ppm, and rumen pH 6.3 ± 0.36. Fifty-three of these postmortem cases had diffuse, focal and /or patchy AIP confirmed by histology.

Abstract Antioxidants function as blockers of radical processes and eliminate harmful reactive oxygen species (ROS) produced during normal cellular metabolism. A complex antioxidant defence system has evolved to protect the cellular homeostasis. This system includes antioxidant enzymes (AOEs), such as superoxide dismutases (SODs), which are intracellular MnSOD and CuZnSOD and extracellular ECSOD, H2O2 scavenging enzymes catalase and glutathione peroxidase, and hemeoxygenase-1 (HO-1), an important enzyme in heme metabolism, which has also been suggested to have antioxidant capacities. ROS play an important role in the pathogenesis of interstitial lung diseases. These diseases represent a group of disorders with different etiology, histopathology, treatment and prognosis. Sarcoidosis, extrinsic allergic alveolitis and two different forms of idiopathic pulmonary fibrosis, usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) were included in this study. The purpose of this research was to evaluate the expressions of inducible nitric oxide synthase (i-NOS), endothelial nitric oxide synthase (e-NOS) and xanthine oxidase (XAO), oxidant generating enzymes commonly associated with tissue injury, and, on the other hand, the expressions of AOEs suggested to be involved in the defence of lung tissue against oxidant stress. The methods included immunohistochemistry on lung biopsies (n=48) and Western blotting, Northern blotting or reverse polymerase chain reaction (RT-PCR) on human inflammatory cells and cells obtained from bronchoalveolar lavage. I-NOS was intensively expressed in inflammatory, but not in fibrotic lesions, similar e-NOS expression was found in control lung and in all interstitial lung diseases, while XAO was mainly negative. MnSOD and HO-1 were highly expressed in the granulomas of sarcoidosis. In contrast the expressions of MnSOD and HO-1 in late fibrotic lesions of UIP were low or undetectable by immunohistochemistry. CuZnSOD and catalase showed similar immunoreactivity in healthy and diseased lung. A cell specific expression and regulation of various enzymes may play an important role during acute inflammatory diseases and also in the progression of lung fibrogenesis.

Pneumonia intersticial familiar (PIF) é definida como a ocorrência de pelo menos dois casos de pneumonia intersticial fibrosante em uma mesma família biológica. Apesar do avanço sobre o tema em anos recentes, ainda não há estudos brasileiros nessa área. O objetivo deste estudo foi caracterizar uma amostra de pacientes brasileiros com PIF quanto aos aspectos clínicos, radiológicos, anatomopatológicos e genéticos, bem como analisar os respectivos comprimentos teloméricos (CT). Entre março de 2014 e novembro de 2017 foi realizada uma busca ativa por casos de PIF. Os pacientes identificados foram submetidos a testes de função pulmonar; tomografia computadorizada de alta resolução (TCAR) de tórax e a coleta de amostras de sangue. Ainda foram realizadas avaliações empregando ficha clínica padronizada. Amostras de tecido pulmonar foram obtidas e revisadas em seis casos. Empregando-se um kit apropriado, DNA genômico foi extraído de células brancas do sangue periférico. A avaliação do CT foi feita pelo método de Southern blot. Um painel envolvendo 154 genes de interesse foi desenvolvido pelo grupo de pesquisa e construído pela empresa Agilent Technologies. A pesquisa desses genes foi realizada empregando-se técnicas de sequenciamento de nova geração (NGS-Illumina). Foram selecionados 35 pacientes, com idade mediana de 66 (35,5-89,3) anos. Tabagismo e outras exposições ambientais estiveram presentes em 45,7% e 80% dos casos, respectivamente. Estertores finos foram identificados em 91,4% dos pacientes e baqueteamento digital em 20%. Os testes de função pulmonar foram classificados como restritivos em 20 (57,1%), normais em 10 (28,6%), inespecíficos em 4 (11,45) e obstrutivo leve em 1 (2,9%). A DCO esteve reduzida nos 30 pacientes em que foi possível pesquisá-la. Padrão típico de PIU na TCAR foi detectado em 6 (17,1%) pacientes e padrão indeterminado para PIU em outros 4 (11,4%). A maioria dos casos, 25 (71,4%), exibiu padrão tomográficoinconsistente com PIU. A revisão do material anatomopatológico revelou pneumonite intersticial com acentuação bronquiolocêntrica em quatro indivíduos. A grande maioria (85,7%) mostrou CTs inferiores ao percentil 50%. Quatro indivíduos exibiram CTs curtos e um muito curto. Foram identificadas variantes genéticas comuns no promotor do gene MUC5B (rs35705950), nos genes TOLLIP (rs111521887, rs5743894 e rs5743890) ou TERT (rs2736100) em 90% dos casos. Detectaram-se ainda sete variantes raras distintas. As alterações c.2594G>A e c.2146G>A do gene TERT, e c.394C>T do gene RTEL1, previamente descritas e associadas a telomeropatias. Uma anormalidade de TERT (c.1730G>A) e outra de RTEL1 (c.2299C>T) inéditas. Duas outras variantes raras encontradas já conhecidas, ainda não haviam sido associadas a doenças pulmonares: gene SHQ1 (c.828_831del) e gene WRAP53 (c.1558dupG). Em conclusão, pacientes brasileiros com PIF demonstram acentuada heterogeneidade fenotípica e genotípica. Este estudo identificou ainda duas novas variantes genéticas raras associadas a PIF e dois possíveis novos genes implicados na patogênese dessa doença. / Familial interstitial pneumonia (FIP) is defined as the occurrence of at least two cases of interstitial fibrosing pneumonias in the same biological family. Despite advances in the field in recent years, there are no Brazilian studies in this area. The aim of this study was to characterize a sample of Brazilian patients with PIF regarding clinical, radiological, histological and genetic aspects, as well as to analyze the respective telomeric lengths (TL). Between March 2014 and November 2017 an active search was conducted for FIP cases. The patients identified were submitted to pulmonary function tests, high resolution computed tomography (HRCT) of the chest and the collection of blood samples. In addition, a standardized clinical file was also fulfilled. Pulmonary tissue samples were obtained and reviewed in six cases. Using a suitable kit, genomic DNA was extracted from white peripheral blood cells. The TL measurements were done by Southern blot method. A panel of 154 genes of interest was developed by the research group and built by Agilent Technologies. Research on these genes was carried out using next generation sequencing techniques (NGSIllumina). Thirty-five patients were selected, with a median age of 66 (35.5-89.3) years. Smoking and other environmental exposures were present in, respectively, 45.7% and 80% of the cases. Fine crackles were identified in 91.4% of patients and digital clubbing in 20%. Pulmonary function tests were classified as restrictive in 20 (57.1%), normal in 10 (28.6%), non-specific in 4 (11.45) and mild obstructive in 1 (2.9%). The DLCO was reduced in the 30 patients in whom it was possible to investigate it. Typical pattern of UIP in HRCT was detected in 6 (17.1%) patients and undetermined pattern for UIP in another 4 (11.4%). The majority of cases, 25 (71.4%), showed a tomographic pattern inconsistent with UIP. The review of histological material revealed interstitial pneumonitis with bronchiolocentric accentuation in four individuals. The vast majority (85.7%) showed TL lower than the 50th percentile. Four individuals had short TL and one a very short TL. Commongenetic variants were identified in the MUC5B gene promoter (rs35705950), in the TOLLIP genes (rs111521887, rs5743894 and rs5743890) or TERT (rs2736100) in 90% of the cases. Seven different rare variants were also detected: the changes c.2594G> A and c.2146G> A of the TERT gene, and c.394C> T of the RTEL1 gene, previously described and associated with telomeropathy; one previously unknown abnormality of TERT (c.1730G> A) and another of RTEL1 (c.2299C> T); two additional rare genetic variants, had not yet been associated with pulmonary diseases: SHQ1 gene (c.828_831del) and WRAP53 gene (c.1558dupG). In conclusion, FIP Brazilian patients demonstrate marked phenotypic and genotypic heterogeneity. This study also identified two new rare genetic variants associated with FIP and two other possible new genes implicated in the pathogenesis of this disease.

Pneumonia intersticial familiar (PIF) é definida como a ocorrência de pelo menos dois casos de pneumonia intersticial fibrosante em uma mesma família biológica. Apesar do avanço sobre o tema em anos recentes, ainda não há estudos brasileiros nessa área. O objetivo deste estudo foi caracterizar uma amostra de pacientes brasileiros com PIF quanto aos aspectos clínicos, radiológicos, anatomopatológicos e genéticos, bem como analisar os respectivos comprimentos teloméricos (CT). Entre março de 2014 e novembro de 2017 foi realizada uma busca ativa por casos de PIF. Os pacientes identificados foram submetidos a testes de função pulmonar; tomografia computadorizada de alta resolução (TCAR) de tórax e a coleta de amostras de sangue. Ainda foram realizadas avaliações empregando ficha clínica padronizada. Amostras de tecido pulmonar foram obtidas e revisadas em seis casos. Empregando-se um kit apropriado, DNA genômico foi extraído de células brancas do sangue periférico. A avaliação do CT foi feita pelo método de Southern blot. Um painel envolvendo 154 genes de interesse foi desenvolvido pelo grupo de pesquisa e construído pela empresa Agilent Technologies. A pesquisa desses genes foi realizada empregando-se técnicas de sequenciamento de nova geração (NGS-Illumina). Foram selecionados 35 pacientes, com idade mediana de 66 (35,5-89,3) anos. Tabagismo e outras exposições ambientais estiveram presentes em 45,7% e 80% dos casos, respectivamente. Estertores finos foram identificados em 91,4% dos pacientes e baqueteamento digital em 20%. Os testes de função pulmonar foram classificados como restritivos em 20 (57,1%), normais em 10 (28,6%), inespecíficos em 4 (11,45) e obstrutivo leve em 1 (2,9%). A DCO esteve reduzida nos 30 pacientes em que foi possível pesquisá-la. Padrão típico de PIU na TCAR foi detectado em 6 (17,1%) pacientes e padrão indeterminado para PIU em outros 4 (11,4%). A maioria dos casos, 25 (71,4%), exibiu padrão tomográficoinconsistente com PIU. A revisão do material anatomopatológico revelou pneumonite intersticial com acentuação bronquiolocêntrica em quatro indivíduos. A grande maioria (85,7%) mostrou CTs inferiores ao percentil 50%. Quatro indivíduos exibiram CTs curtos e um muito curto. Foram identificadas variantes genéticas comuns no promotor do gene MUC5B (rs35705950), nos genes TOLLIP (rs111521887, rs5743894 e rs5743890) ou TERT (rs2736100) em 90% dos casos. Detectaram-se ainda sete variantes raras distintas. As alterações c.2594G>A e c.2146G>A do gene TERT, e c.394C>T do gene RTEL1, previamente descritas e associadas a telomeropatias. Uma anormalidade de TERT (c.1730G>A) e outra de RTEL1 (c.2299C>T) inéditas. Duas outras variantes raras encontradas já conhecidas, ainda não haviam sido associadas a doenças pulmonares: gene SHQ1 (c.828_831del) e gene WRAP53 (c.1558dupG). Em conclusão, pacientes brasileiros com PIF demonstram acentuada heterogeneidade fenotípica e genotípica. Este estudo identificou ainda duas novas variantes genéticas raras associadas a PIF e dois possíveis novos genes implicados na patogênese dessa doença. / Familial interstitial pneumonia (FIP) is defined as the occurrence of at least two cases of interstitial fibrosing pneumonias in the same biological family. Despite advances in the field in recent years, there are no Brazilian studies in this area. The aim of this study was to characterize a sample of Brazilian patients with PIF regarding clinical, radiological, histological and genetic aspects, as well as to analyze the respective telomeric lengths (TL). Between March 2014 and November 2017 an active search was conducted for FIP cases. The patients identified were submitted to pulmonary function tests, high resolution computed tomography (HRCT) of the chest and the collection of blood samples. In addition, a standardized clinical file was also fulfilled. Pulmonary tissue samples were obtained and reviewed in six cases. Using a suitable kit, genomic DNA was extracted from white peripheral blood cells. The TL measurements were done by Southern blot method. A panel of 154 genes of interest was developed by the research group and built by Agilent Technologies. Research on these genes was carried out using next generation sequencing techniques (NGSIllumina). Thirty-five patients were selected, with a median age of 66 (35.5-89.3) years. Smoking and other environmental exposures were present in, respectively, 45.7% and 80% of the cases. Fine crackles were identified in 91.4% of patients and digital clubbing in 20%. Pulmonary function tests were classified as restrictive in 20 (57.1%), normal in 10 (28.6%), non-specific in 4 (11.45) and mild obstructive in 1 (2.9%). The DLCO was reduced in the 30 patients in whom it was possible to investigate it. Typical pattern of UIP in HRCT was detected in 6 (17.1%) patients and undetermined pattern for UIP in another 4 (11.4%). The majority of cases, 25 (71.4%), showed a tomographic pattern inconsistent with UIP. The review of histological material revealed interstitial pneumonitis with bronchiolocentric accentuation in four individuals. The vast majority (85.7%) showed TL lower than the 50th percentile. Four individuals had short TL and one a very short TL. Commongenetic variants were identified in the MUC5B gene promoter (rs35705950), in the TOLLIP genes (rs111521887, rs5743894 and rs5743890) or TERT (rs2736100) in 90% of the cases. Seven different rare variants were also detected: the changes c.2594G> A and c.2146G> A of the TERT gene, and c.394C> T of the RTEL1 gene, previously described and associated with telomeropathy; one previously unknown abnormality of TERT (c.1730G> A) and another of RTEL1 (c.2299C> T); two additional rare genetic variants, had not yet been associated with pulmonary diseases: SHQ1 gene (c.828_831del) and WRAP53 gene (c.1558dupG). In conclusion, FIP Brazilian patients demonstrate marked phenotypic and genotypic heterogeneity. This study also identified two new rare genetic variants associated with FIP and two other possible new genes implicated in the pathogenesis of this disease.

Abstract Interstitial lung diseases (ILD), including interstitial pneumonias (IP), represent disorders with variable degrees of parenchymal inflammation and/or fibrosis offer an ideal model to investigate the histopathological features in relation to the course of these diseases. The most common IP is idiopathic pulmonary fibrosis (IPF) with the histological pattern of usual interstitial pneumonia (UIP) exhibiting the histological hallmark of fibroblast foci (FF). Surgical lung biopsy (SLB) is not usually needed for diagnosis of IPF, but the lung biopsy samples taken by SLB confers the diagnosis in atypical cases. The safety of SLB in IPF/UIP has been a controversial issue. The acute exacerbation occasionally occurs during the course of IPF/UIP, but pathological features related to this event are poorly understood. Recent studies suggest that one important determinant in the pathogenesis of ILDs, as in IPF, is oxidant stress and an imbalance of the redox-state in the lung. Thiol containing redox-regulated proteins which paticipate in the antioxidant defence of the lung include thiorexin (Trx) and gamma-glutamylcysteine synthetase (γGCS), also called glutamate-cysteine ligase (GLCL), the rate-limiting enzyme of glutathione (GSH) synthesis. The goal of this research was to evaluate the safety of SLB and the relationships between the histological findings and the course of IPF/UIP, and to investigate the above mentioned defense mechanisms in a variety of ILDs by means of immmunohistochemical analyses, Western Blotting and immunoelectronmicroscopy. No deaths occurred in the following 30 days after 34 video-assisted thoracoscopic lung biopsy (VATS). The number of FF in the lung sample predicted the survival, but it was not associated with acute exacerbation of IPF/UIP before death. Diffuse alveolar damage was a common feature in autopsy samples. The studied redox regulated defense enzymes were expressed in bronchial epithelium, metaplastic alveolar epithelium and alveolar macrophages, but the fibrotic areas generally showed no expression. In IPF/UIP VATS is a safe diagnostic method and counting the number of FF represents a reproducible and reliable method for predicting patient survival. Alterations in the redox regulated defense enzymes further point to the importance of oxidant burden in the fibrotic lung.

Introdução: A doença intersticial pulmonar (DIP) é uma forma de acometimento visceral grave pela esclerose sistêmica (ES), correspondendo na atualidade à principal causa de mortalidade pela doença. Atualmente, a tomografia computadorizada de alta resolução pulmonar (TCAR) é considerada o padrão-ouro no seu diagnóstico. Estudos recentes têm proposto diversos algoritmos clínicos para a predição diagnóstica e prognóstica da DIP-ES, objetivando ampliar sua detecção precoce e auxiliar na determinação de sua evolução e prognóstico. Objetivo: Testar os algoritmos clínicos propostos na literatura na predição diagnóstica e prognóstica na DIP-ES, estimar sua prevalência e avaliar a associação da extensão do acometimento pulmonar na TCAR com mortalidade em uma coorte de pacientes com ES. Métodos: Estudo de coorte prospectivo, incluindo 177 pacientes com ES recrutados no período de abril de 2000 a abril de 2009, avaliados através de entrevista, exame físico, exames laboratoriais, provas de função pulmonar e TCAR. Algoritmos clínicos (A, B e C), combinando dados da ausculta pulmonar, radiografia de tórax e capacidade vital forçada (CVF), foram aplicados para o diagnóstico de diferentes extensões da pneumopatia intersticial na TCAR. Curvas de Kaplan-Meier e Regressão de Cox uni e multivariada foram utilizadas para analisar a associação dos algoritmos e da extensão de DIP na TCAR com a mortalidade. Resultados: A prevalência estimada de DIP na TCAR do baseline foi de 57,1% e 79 pacientes (44,6%) morreram em uma mediana de 11,1 anos de seguimento. Para identificação de DIP com extensão ≥10 e ≥20% na TCAR, todos os algoritmos apresentaram uma alta sensibilidade (>89%) e um likelihoodratio negativo muito baixo (<0,16). Para fins prognósticos, sobrevida foi reduzida para todos os algoritmos, com destaque para o algoritmo C, o qual identifica DIP considerando a presença de crepitantes na ausculta pulmonar, alterações na radiografia de tórax ou CVF <80% (HR 3,47; IC 95% 1,62-7,42). Pacientes com doença extensa como proposto por Goh e Wells (extensão >20% na TCAR ou, em casos indeterminados, CVF <70%) apresentam uma significativa redução na sobrevida (HR 3,42; IC 95% 2,12-5,52). Sobrevida não foi diferente entre pacientes com extensão ≥10 ou ≥20% na TCAR e análise de mortalidade em 10 anos sugere que extensão >10% na TCAR apresenta uma boa capacidade preditiva para mortalidade, embora não haja um ponto de corte claro a partir do qual ocorra um maior incremento na mortalidade. Conclusão: Algoritmos clínicos apresentam uma alta sensibilidade e um likelihood ratio negativo muito baixo para o diagnóstico de extensões de DIP com relevância clínica e prognóstica (≥10 e ≥20%) e foram fortemente associados com mortalidade. Assim sendo, a utilização desses algoritmos pode evitar a necessidade de realização de TCAR em alguns casos. / Introduction: Interstitial lung disease (ILD) is a form of severe visceral involvement by systemic sclerosis (SSc) and currently is the primary cause of death by disease. Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis of SSc-ILD, aiming to expand its early detection and estimate prognosis. Objective: To test the clinical algorithms to predict the presence and prognosis of SSc-ILD, to estimate the prevalence of SSc-ILD, and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients. Methods: Prospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Clinical algorithms, combining lung auscultation, chest radiography and % predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR). Results: The prevalence of ILD was 57.1% on baseline HRCT and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10 and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR 3.47, 95% CI 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray or FVC <80%. Extensive disease as proposed by Goh and Wells (extent of ILD >20% on HRCT or, in indeterminate cases, FVC <70%) had a significantly higher risk of death (HR 3.42, 95% CI 2.12 to 5.52). Survival was not different between patients with extent of 10 or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased. Conclusion: Clinical algorithms had a good diagnostic performance for extent of SSc-ILD on HRCT with clinical and prognostic relevance (≥10 and ≥20%), and were also strongly related to mortality. Therefore, they probably could be used to obviate the requirement of HRCT in some cases.

Introdução: A doença intersticial pulmonar (DIP) é uma forma de acometimento visceral grave pela esclerose sistêmica (ES), correspondendo na atualidade à principal causa de mortalidade pela doença. Atualmente, a tomografia computadorizada de alta resolução pulmonar (TCAR) é considerada o padrão-ouro no seu diagnóstico. Estudos recentes têm proposto diversos algoritmos clínicos para a predição diagnóstica e prognóstica da DIP-ES, objetivando ampliar sua detecção precoce e auxiliar na determinação de sua evolução e prognóstico. Objetivo: Testar os algoritmos clínicos propostos na literatura na predição diagnóstica e prognóstica na DIP-ES, estimar sua prevalência e avaliar a associação da extensão do acometimento pulmonar na TCAR com mortalidade em uma coorte de pacientes com ES. Métodos: Estudo de coorte prospectivo, incluindo 177 pacientes com ES recrutados no período de abril de 2000 a abril de 2009, avaliados através de entrevista, exame físico, exames laboratoriais, provas de função pulmonar e TCAR. Algoritmos clínicos (A, B e C), combinando dados da ausculta pulmonar, radiografia de tórax e capacidade vital forçada (CVF), foram aplicados para o diagnóstico de diferentes extensões da pneumopatia intersticial na TCAR. Curvas de Kaplan-Meier e Regressão de Cox uni e multivariada foram utilizadas para analisar a associação dos algoritmos e da extensão de DIP na TCAR com a mortalidade. Resultados: A prevalência estimada de DIP na TCAR do baseline foi de 57,1% e 79 pacientes (44,6%) morreram em uma mediana de 11,1 anos de seguimento. Para identificação de DIP com extensão ≥10 e ≥20% na TCAR, todos os algoritmos apresentaram uma alta sensibilidade (>89%) e um likelihoodratio negativo muito baixo (<0,16). Para fins prognósticos, sobrevida foi reduzida para todos os algoritmos, com destaque para o algoritmo C, o qual identifica DIP considerando a presença de crepitantes na ausculta pulmonar, alterações na radiografia de tórax ou CVF <80% (HR 3,47; IC 95% 1,62-7,42). Pacientes com doença extensa como proposto por Goh e Wells (extensão >20% na TCAR ou, em casos indeterminados, CVF <70%) apresentam uma significativa redução na sobrevida (HR 3,42; IC 95% 2,12-5,52). Sobrevida não foi diferente entre pacientes com extensão ≥10 ou ≥20% na TCAR e análise de mortalidade em 10 anos sugere que extensão >10% na TCAR apresenta uma boa capacidade preditiva para mortalidade, embora não haja um ponto de corte claro a partir do qual ocorra um maior incremento na mortalidade. Conclusão: Algoritmos clínicos apresentam uma alta sensibilidade e um likelihood ratio negativo muito baixo para o diagnóstico de extensões de DIP com relevância clínica e prognóstica (≥10 e ≥20%) e foram fortemente associados com mortalidade. Assim sendo, a utilização desses algoritmos pode evitar a necessidade de realização de TCAR em alguns casos. / Introduction: Interstitial lung disease (ILD) is a form of severe visceral involvement by systemic sclerosis (SSc) and currently is the primary cause of death by disease. Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis of SSc-ILD, aiming to expand its early detection and estimate prognosis. Objective: To test the clinical algorithms to predict the presence and prognosis of SSc-ILD, to estimate the prevalence of SSc-ILD, and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients. Methods: Prospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Clinical algorithms, combining lung auscultation, chest radiography and % predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR). Results: The prevalence of ILD was 57.1% on baseline HRCT and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10 and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR 3.47, 95% CI 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray or FVC <80%. Extensive disease as proposed by Goh and Wells (extent of ILD >20% on HRCT or, in indeterminate cases, FVC <70%) had a significantly higher risk of death (HR 3.42, 95% CI 2.12 to 5.52). Survival was not different between patients with extent of 10 or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased. Conclusion: Clinical algorithms had a good diagnostic performance for extent of SSc-ILD on HRCT with clinical and prognostic relevance (≥10 and ≥20%), and were also strongly related to mortality. Therefore, they probably could be used to obviate the requirement of HRCT in some cases.

Introdução: A doença intersticial pulmonar (DIP) é uma forma de acometimento visceral grave pela esclerose sistêmica (ES), correspondendo na atualidade à principal causa de mortalidade pela doença. Atualmente, a tomografia computadorizada de alta resolução pulmonar (TCAR) é considerada o padrão-ouro no seu diagnóstico. Estudos recentes têm proposto diversos algoritmos clínicos para a predição diagnóstica e prognóstica da DIP-ES, objetivando ampliar sua detecção precoce e auxiliar na determinação de sua evolução e prognóstico. Objetivo: Testar os algoritmos clínicos propostos na literatura na predição diagnóstica e prognóstica na DIP-ES, estimar sua prevalência e avaliar a associação da extensão do acometimento pulmonar na TCAR com mortalidade em uma coorte de pacientes com ES. Métodos: Estudo de coorte prospectivo, incluindo 177 pacientes com ES recrutados no período de abril de 2000 a abril de 2009, avaliados através de entrevista, exame físico, exames laboratoriais, provas de função pulmonar e TCAR. Algoritmos clínicos (A, B e C), combinando dados da ausculta pulmonar, radiografia de tórax e capacidade vital forçada (CVF), foram aplicados para o diagnóstico de diferentes extensões da pneumopatia intersticial na TCAR. Curvas de Kaplan-Meier e Regressão de Cox uni e multivariada foram utilizadas para analisar a associação dos algoritmos e da extensão de DIP na TCAR com a mortalidade. Resultados: A prevalência estimada de DIP na TCAR do baseline foi de 57,1% e 79 pacientes (44,6%) morreram em uma mediana de 11,1 anos de seguimento. Para identificação de DIP com extensão ≥10 e ≥20% na TCAR, todos os algoritmos apresentaram uma alta sensibilidade (>89%) e um likelihoodratio negativo muito baixo (<0,16). Para fins prognósticos, sobrevida foi reduzida para todos os algoritmos, com destaque para o algoritmo C, o qual identifica DIP considerando a presença de crepitantes na ausculta pulmonar, alterações na radiografia de tórax ou CVF <80% (HR 3,47; IC 95% 1,62-7,42). Pacientes com doença extensa como proposto por Goh e Wells (extensão >20% na TCAR ou, em casos indeterminados, CVF <70%) apresentam uma significativa redução na sobrevida (HR 3,42; IC 95% 2,12-5,52). Sobrevida não foi diferente entre pacientes com extensão ≥10 ou ≥20% na TCAR e análise de mortalidade em 10 anos sugere que extensão >10% na TCAR apresenta uma boa capacidade preditiva para mortalidade, embora não haja um ponto de corte claro a partir do qual ocorra um maior incremento na mortalidade. Conclusão: Algoritmos clínicos apresentam uma alta sensibilidade e um likelihood ratio negativo muito baixo para o diagnóstico de extensões de DIP com relevância clínica e prognóstica (≥10 e ≥20%) e foram fortemente associados com mortalidade. Assim sendo, a utilização desses algoritmos pode evitar a necessidade de realização de TCAR em alguns casos. / Introduction: Interstitial lung disease (ILD) is a form of severe visceral involvement by systemic sclerosis (SSc) and currently is the primary cause of death by disease. Thoracic high-resolution computed tomography (HRCT) is considered the gold standard for diagnosis. Recent studies have proposed several clinical algorithms to predict the diagnosis of SSc-ILD, aiming to expand its early detection and estimate prognosis. Objective: To test the clinical algorithms to predict the presence and prognosis of SSc-ILD, to estimate the prevalence of SSc-ILD, and to evaluate the association of extent of ILD with mortality in a cohort of SSc patients. Methods: Prospective cohort study, including 177 SSc patients assessed by clinical evaluation, laboratory tests, pulmonary function tests, and HRCT. Clinical algorithms, combining lung auscultation, chest radiography and % predicted forced vital capacity (FVC), were applied for the diagnosis of different extents of ILD on HRCT. Univariate and multivariate Cox proportional models were used to analyze the association of algorithms and the extent of ILD on HRCT with the risk of death using hazard ratios (HR). Results: The prevalence of ILD was 57.1% on baseline HRCT and 79 patients died (44.6%) in a median follow-up of 11.1 years. For identification of ILD with extent ≥10 and ≥20% on HRCT, all algorithms presented a high sensitivity (>89%) and a very low negative likelihood ratio (<0.16). For prognosis, survival was decreased for all algorithms, especially the algorithm C (HR 3.47, 95% CI 1.62-7.42), which identified the presence of ILD based on crackles on lung auscultation, findings on chest X-ray or FVC <80%. Extensive disease as proposed by Goh and Wells (extent of ILD >20% on HRCT or, in indeterminate cases, FVC <70%) had a significantly higher risk of death (HR 3.42, 95% CI 2.12 to 5.52). Survival was not different between patients with extent of 10 or 20% of ILD on HRCT, and analysis of 10-year mortality suggested that a threshold of 10% may also have a good predictive value for mortality. However, there is no clear cutoff above which mortality is sharply increased. Conclusion: Clinical algorithms had a good diagnostic performance for extent of SSc-ILD on HRCT with clinical and prognostic relevance (≥10 and ≥20%), and were also strongly related to mortality. Therefore, they probably could be used to obviate the requirement of HRCT in some cases.

Introduction : Les pneumopathies interstitielles diffuses (PID), incluant les fibroses pulmonaires idiopathiques (FPI), sont des pathologies rares et sévères. Dans moins de 20% des cas, un défaut moléculaire d'un gène du complexe des télomérases ou du surfactant est identifié. L'objectif de ce travail a été de documenter, dans une cohorte de patients pédiatriques et adultes présentant une PID sans cause identifiée, des variations des gènes codant les protéines du surfactant (SP), en particulier SP-A1, SP-A2 et SP-D. Méthodes : Les gènes SFTPA1, SFTPA2 et SFTPD, ont été séquencés et les variations identifiées ont été étudiées par des analyses fonctionnelles et tissulaires. Résultats : Dans une cohorte de 345 patients, une mutation hétérozygote du gène SFTPA1 (p.Trp211Arg) a été identifiée dans une large famille. Les patients présentaient des PID de l'enfant et des PID/FPI l'adulte, associées pour certains à des adénocarcinomes pulmonaires. La mutation W211R concernait un acide aminé invariant au cours de l'évolution et altérait la sécrétion de SP-A1 et l'expression tissulaire de SP-A. Cinq nouvelles variations de SFTPA2 ont aussi été identifiées. Au total, une variation de l'un des gènes du complexe du surfactant a été retrouvée pour 7,5% des patients. Conclusion : Cette étude a permis d'impliquer pour la première fois le gène SFTPA1 dans les PID de l'enfant et de l'adulte. L'association entre les mutations de SFTPA1 et SFTPA2 et un risque plus élevé de cancers pulmonaire soulève la question d'un conseil génétique complexe, et ouvre des hypothèses physiopathologiques nouvelles ciblant, entre autres, les anomalies de prolifération et de réparation de la surface alvéolaire. / Background: Idiopathic interstitial pneumonias (IIP) comprise a heterogeneous group of rare lung parenchyma disorders with high morbidity and mortality. In adults, the most common form of IIP is idiopathic pulmonary fibrosis (IPF). A genetic cause is identified in up to 20% of cases, telomerase and surfactant genes mutations being the first etiologies. This study aims to investigate the implication of the genes encoding the surfactant protein (SP), in particular SP-A1, SP-A2, and SP-D, in pediatric and adult patients with unexplained IIP.Methods: Surfactant genes, in particular SFTPA1, SFTPA2 and SFTPD, were sequenced. New variations were studied with functional and tissues experimentations. Results: The study involved 345 patients. A heterozygous missense mutation (p.Trp211Arg) in SFTPA1 was identified in a large family. The IIP were isolated or associated with an adenocarcinoma of the lung in patients with IPF. The W211R mutation involves an amino-acid that is invariant throughout evolution, impairs SP-A1 secretion, and is associated with an abnormal tissue expression of SP-A. Five new SFTPA2 mutations were also identified, and all together, a surfactant gene variation was described for 7.5% of the patients.Conclusion: This study has involved for the first time SFTPA1 in pediatric and adult IIP. The association of SFTPA1 and SFTPA2 mutations with an increased risk of lung cancer raises the issue of a complex genetic counseling in the involved families. It also brings out new pathophysiologic hypothesis such as aberrant proliferation and epithelial repair of the alveolar surface.

Orientador: Maria Marluce dos Santos Vilela / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T20:47:23Z (GMT). No. of bitstreams: 1 Toro_AdyleiaAparecidaDalboContrera_D.pdf: 3459466 bytes, checksum: a2a86bc660c9851dab70414f47dc5420 (MD5) Previous issue date: 2008 / Resumo: INTRODUÇÃO: A infecção pelo HIV desencadeia diversificadas e extensas alterações no mecanismo de defesa do pulmão, o que se traduz em maior número de infecções por germes habituais ou oportunistas e processos imunológicos diversos como a pneumonia intersticial linfocítica (PIL), a hiperplasia linfóide (HLP) ou neoplasias. A infecção simultânea do HIV e do EBV pode aumentar o risco de HLP/ PIL. OBS.: O resumo na integra poderá ser visualizado no link ou texto completo da tese digital / Abstract: BACKGROUND: Pulmonary Lymphoid Hyperplasia (PLH) / Lymphoid Interstitial Pneumonitis (LIP) complex is common in HIV infected children. It may reflect a particular response to HIV from a developing immune system, and is also related to exposure to Epstein-Barr virus (EBV). Note: the complete abstract is avaiable with the link or full eletronic digital theses or dissertations / Doutorado / Pediatria / Doutor em Saude da Criança e do Adolescente