Tendencia de la mortalidad por fibrosis pulmonar idiopática en Chile / Trend in idiopathic pulmonary fibrosis in Chile

INTRODUCCIÓN: La Fibrosis Pulmonar Idiopática (FPI) es una de las enfermedades respiratorias crónicas del adulto de mayor impacto y letalidad, diversos estudios epidemiológicos muestran tendencias progresivas al aumento de las tasas de mortalidad por FPI. En Chile no existen reportes sobre las tendencias de las tasas de mortalidad por FPI. El objetivo del presente estudio es determinar las tendencias de la mortalidad por FPI en Chile entre los años 2002 y 2015. MÉTODO: Estudio descriptivo de diseño ecológico, a partir de la información de bases de datos secundarias de libre disposición de las estadísticas vitales del Departamento de Estadísticas e Información de Salud (DEIS) y del Instituto Nacional de Estadísticas (INE) de Ministerio de Salud de Chile entre los años 2002 y 2015 se obtuvieron las tasas crudas de mortalidad por fibrosis pulmonar idiopática en población de 45 años y más en ambos sexos y las tasas ajustadas por sexo y edad por regiones, se calculó también la frecuencia mensual de las muertes por FPI y se compararon las tasas medias de mortalidad por regiones. RESULTADOS: Se observó un incremento progresivo de la tasa nacional cruda de mortalidad por FPI entre los años 2002 a 2015, la que fue de 18,5 fallecidos por 100.000 habitantes en el año 2002 hasta 24,6 fallecidos por 100.000 habitantes en el año 2015 con una pendiente de ascenso por año de +0,27 por 100.000 habitantes (p = 0,013). En las mujeres las tasas fueron más altas que en los hombres, pero las pendientes de ascenso no presentaron diferencias entre sexos. En la gran mayoría de las regiones las tasas ajustadas presentaron tendencias significativas al ascenso y las tasas medias más altas se presentaron en las regiones del norte de Chile. Se observó un comportamiento estacional de las muertes siendo las frecuencias más altas en los meses de invierno. CONCLUSIONES: Las tasas de mortalidad por FPI en Chile presentan una tendencia progresiva al aumento, con marcadas diferencias regionales lo que lleva a considerar, entre otros factores, influencia ambiental y contaminación del aire y de suelos que se debieran investigar para poder realizar intervenciones de salud pública que permitan reducir la mortalidad de esta enfermedad en nuestro país.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is one of the chronic respiratory diseases in adults with the greatest impact and high case fatality rate. Various epidemiological studies show progressive trends towards increasing IPF mortality rates. In Chile there are no national reports on country and regional trends in IPF mortality rates. The objective of this study is to determine trends in mortality due to IPF in Chile from year 2002 to 2015. METHOD: Epidemiological study of ecological design based on information from public databases of vital statistics of the Department of Health Statistics and Information (DEIS) and the National Institute of Statistics (INE) of the Ministry of Health of Chile. Crude mortality rates due to IPF in the population aged 45 years and over in both sexes were obtained from years 2002 to 2015. Besides the adjusted mortality rates for sex and age by region, the monthly frequency of IPF deaths during the same period and the average mortality rates by Chilean regions were calculated. RESULTS: A progressive increasing trend in the crude national IPF mortality rate was observed between years 2002 to 2015, which went from 18.5 deaths per 100,000 inhabitants in 2002 to 24.6 deaths per 100,000 inhabitants in 2015 with a slope of ascent per year of +0.27 per 100,000 inhabitants (p = 0.013); female rates were higher than men rates, but without differences in the slopes between sexes; in the vast majority of the regions the rates showed significant upward trends with the higher ones in the northern regions of Chile. A seasonal behavior of the death's frequency was observed being the highest in the winter term. CONCLUSIONS: Mortality rates due to IPF in Chile show a progressive upward trend, with marked regional differences which leads to consider, among other factors, environmental influence and air and soil contamination that should be investigated to carry out public health interventions that allow reducing the mortality of this disease in our country.

Six-minute walk distance and survival time in patients with idiopathic pulmonary fibrosis in Brazil / Distância no teste de caminhada de seis minutos e sobrevida na fibrose pulmonar idiopática no Brasil

ABSTRACT Objective: To determine the cut-off point for the six-minute walk distance (6MWD) that indicates lower survival time in patients with idiopathic pulmonary fibrosis (IPF) in Brazil. Methods: This was retrospective study carried out in two referral centers for IPF. The 6MWT was performed twice, considering the highest value of the 6MWD. Various cut-off points were estimated, in absolute values and in percentage of predicted values, using ROC curves, the Kaplan-Meier method, and data from other studies. Results: The sample comprised 70 patients with IPF. The mean age was 71.9 ± 6.4 years, and 50 patients (71.4%) were male. The mean FVC was 76.6 ± 18.2% of predicted value. The mean SpO2 at rest before and after 6MWT were 93.8 ± 2.5% and 85.3 ± 6.5%, respectively. The median survival time was 44 months (95% CI: 37-51 months). The mean 6MWD was 381 ± 115 m (79.2 ± 24.0% of predicted). After the analyses, the best cut-off points for estimating survival were 6MWD < 330 m and < 70% of predicted. The median survival time of patients with a 6MWD < 330 m was 24 months (95% CI: 3-45 months), whereas that of those with a 6MWD ≥ 330 m was 59 months (95% CI: 41-77 months; p = 0.009). Similarly, the median survival times of those with a 6MWD < 70% and ≥ 70% of predicted, respectively, were 24 months (95% CI: 13-35 months) and 59 months (95% CI: 38-80 months; p = 0.013). Cox multivariate regression models including age, sex, smoking status, SpO2 at the end of the 6MWT, and FVC% showed that 6MWD remained significantly associated with survival (p = 0.003). Conclusions: Values of 6MWD < 330 m and < 70% of predicted value were associated with lower survival time in IPF patients in Brazil.

RESUMO Objetivo: Determinar o ponto de corte da distância no teste de caminhada de seis minutos (DTC6) em relação à menor sobrevida em pacientes com fibrose pulmonar idiopática (FPI) no Brasil. Métodos: Estudo retrospectivo realizado em dois centros de referência para FPI. O TC6 foi realizado em duplicata, considerando-se o maior valor da DTC6. Vários pontos de corte foram estimados, em valores absolutos e em percentual do previsto, utilizando curvas ROC, método de Kaplan-Meier e dados de outros estudos. Resultados: A amostra envolveu 70 pacientes com FPI, com média de idade de 71,9 ± 6.4 anos, sendo 50 homens (71,4%). A média de CVF foi de 76,6 ± 18.2% do previsto. As médias de SpO2 em repouso antes e depois do TC6 foram de 93,8 ± 2,5% e 85,3 ± 6,5%, respectivamente. A mediana de sobrevida foi de 44 meses (IC95%: 37-51 meses). A média da DTC6 foi 381 ± 115 m (79,2 ± 24,0% do previsto). Após as análises, os melhores pontos de corte para estimar a sobrevida foram de DTC6 < 330 m e < 70% do previsto. A mediana de sobrevida foi de 24 meses (IC95%: 3-45 meses) para aqueles com DTC6 < 330 m comparada a 59 meses (IC95%: 41-77 meses) para aqueles com DTC6 ≥ 330 m (p = 0,009). Similarmente, a mediana de sobrevida foi de 24 meses (IC95%: 13-35 meses) para pacientes com DTC6 < 70% do previsto e de 59 meses (IC95%: 38-80 meses) para aqueles com DTC6 ≥ 70% do previsto (p = 0,013). Modelos de regressão multivariada de Cox incluindo idade, sexo, tabagismo, SpO2 ao final do TC6 e CVF% mostraram que a DTC6 permaneceu significativamente associada à sobrevida (p = 0,003). Conclusões: Valores de DTC6 < 330 m e < 70% do valor previsto associaram-se à menor sobrevida em pacientes com FPI no Brasil.

Mortality from idiopathic pulmonary fibrosis: a temporal trend analysis in Brazil, 1979-2014 / Mortalidade por fibrose pulmonar idiopática: análise temporal no Brasil, 1979-2014

ABSTRACT Objective: To analyze mortality from idiopathic pulmonary fibrosis (IPF) in Brazil over the period 1979-2014. Methods: Microdata were extracted from the Brazilian National Ministry of Health Mortality Database. Only deaths for which the underlying cause was coded as International Classification of Diseases version 9 (ICD-9) 515 or 516.3 (until 1995) or as ICD version 10 (ICD-10) J84.1 (from 1996 onward) were included in our analysis. Standardized mortality rates were calculated for the 2010 Brazilian population. The annual trend in mortality rates was analyzed by joinpoint regression. We calculated risk ratios (RRs) by age group, time period of death, and gender, using a person-years denominator. Results: A total of 32,092 deaths were recorded in the study period. Standardized mortality rates trended upward, rising from 0.24/100,000 population in 1979 to 1.10/100,000 population in 2014. The annual upward trend in mortality rates had two inflection points, in 1992 and 2008, separating three distinct time segments with an annual growth of 2.2%, 6.8%, and 2.4%, respectively. The comparison of RRs for the age groups, using the 50- to 54-year age group as a reference, and for the study period, using 1979-1984 as a reference, were 16.14 (14.44-16.36) and 6.71 (6.34-7.12), respectively. Men compared with women had higher standardized mortality rates (per 100,000 person-years) in all age groups. Conclusion: Brazilian IPF mortality rates are lower than those of other countries, suggesting underdiagnosis or underreporting. The temporal trend is similar to those reported in the literature and is not explained solely by population aging.

RESUMO Objetivo: Analisar a mortalidade por fibrose pulmonar idiopática (FPI) no Brasil no período de 1979-2014. Métodos: Foram extraídos microdados do Sistema de Informações de Mortalidade do Ministério da Saúde cuja causa básica de óbito tenha sido codificada conforme a Classificação Internacional das Doenças, 9ª edição, códigos 515 ou 516.3 (até 1995), e 10ª versão, código J84.1 (a partir de 1996). Os coeficientes de mortalidade padronizados foram calculados para a população brasileira de 2010. A tendência anual da mortalidade foi analisada pelo método de regressão por pontos de inflexão. Foram calculadas as razões de risco (RR) por faixa etária, período analisado e gênero, utilizando-se como denominador pessoas-ano. Resultados: Foram registrados 32.092 óbitos no período estudado. O coeficiente de mortalidade padronizado mostrou-se ascendente, passando de 0,24/100.000 habitantes em 1979 para 1,10/100.000 em 2014. A tendência anual de crescimento identificou dois pontos de inflexão, em 1992 e 2008, gerando três retas com crescimento anual percentual de 2,2%, 6,8% e 2,4%, respectivamente. As RR (IC95%) por faixa etária, elegendo a faixa de 50-54 anos como referência, e por período estudado, elegendo o período de 1979-1984 como referência, foram de 16,14 (14,44-16,36) e de 6,71 (6,34-7,12), respectivamente. Homens, comparados a mulheres, apresentaram taxas de mortalidade padronizadas (por 100.000 pessoas-ano) superiores em todas as faixas etárias. Conclusões: Os coeficientes de mortalidade brasileiros por FPI são inferiores aos de outros países, podendo indicar subdiagnóstico ou subnotificação. A tendência temporal é semelhante à descrita na literatura e não é justificada apenas pelo envelhecimento populacional.

Functional improvement in patients with idiopathic pulmonary fibrosis undergoing single lung transplantation / Melhora funcional em portadores de fibrose pulmonar idiopática submetidos a transplante pulmonar unilateral

AbstractObjective: To evaluate the changes in lung function in the first year after single lung transplantation in patients with idiopathic pulmonary fibrosis (IPF).Methods: We retrospectively evaluated patients with IPF who underwent single lung transplantation between January of 2006 and December of 2012, reviewing the changes in the lung function occurring during the first year after the procedure.Results: Of the 218 patients undergoing lung transplantation during the study period, 79 (36.2%) had IPF. Of those 79 patients, 24 (30%) died, and 11 (14%) did not undergo spirometry at the end of the first year. Of the 44 patients included in the study, 29 (66%) were men. The mean age of the patients was 57 years. Before transplantation, mean FVC, FEV1, and FEV1/FVC ratio were 1.78 L (50% of predicted), 1.48 L (52% of predicted), and 83%, respectively. In the first month after transplantation, there was a mean increase of 12% in FVC (400 mL) and FEV1 (350 mL). In the third month after transplantation, there were additional increases, of 5% (170 mL) in FVC and 1% (50 mL) in FEV1. At the end of the first year, the functional improvement persisted, with a mean gain of 19% (620 mL) in FVC and 16% (430 mL) in FEV1.Conclusions: Single lung transplantation in IPF patients who survive for at least one year provides significant and progressive benefits in lung function during the first year. This procedure is an important therapeutic alternative in the management of IPF.

ResumoObjetivo: Avaliar as alterações de função pulmonar no primeiro ano após transplante de pulmão unilateral em pacientes portadores de fibrose pulmonar idiopática (FPI).Métodos: Foi avaliada retrospectivamente a variação da função pulmonar de portadores de FPI submetidos a transplante pulmonar unilateral entre janeiro de 2006 e dezembro de 2012 no decorrer do primeiro ano após o procedimento.Resultados: Dos 218 pacientes submetidos a transplante pulmonar durante o período do estudo, 79 (36,2%) eram portadores de FPI. Desses 79 pacientes, 24 (30%) foram a óbito e 11 (14%) não realizaram espirometria ao final do primeiro ano. Dos 44 pacientes incluídos no estudo, 29 (66%) eram homens. A média de idade dos pacientes foi de 57 anos.Antes do transplante, as médias de CVF, VEF1 e relação VEF1/CVF foram de 1,78 l (50% do previsto), 1,48 l (52% do previsto) e 83%, respectivamente. No primeiro mês após o transplante, houve um aumento médio de 12% tanto na CVF (400 ml) como no VEF1 (350 ml). No terceiro mês após o transplante, houve um aumento adicional médio de 5% (170 ml) na CVF e de 1% (50 ml) no VEF1. Ao final do primeiro ano, a melhora funcional foi persistente, com um ganho médio de 19% (620 ml) na CVF e de 16% (430 ml) no VEF1.Conclusões: O transplante pulmonar unilateral em portadores de FPI que sobrevivam por pelo menos um ano proporciona importante e progressivo benefício na sua função pulmonar no decorrer do primeiro ano. Este procedimento é uma importante alternativa terapêutica no manejo da FPI.

Fibrosis pulmonar idiopática / Idiopathic pulmonary fibrosis

La FPI predomina en el sexo masculino, en edades avanzadas, con tos y/o disnea progresivas. Un 5% se presenta como una forma familiar. La tomografía axial computarizada de tórax, fundamental en el diagnóstico, en al menos un 50% hace innecesaria la biopsia. El diagnóstico es conjunto con clínicos, radiólogos y patólogos. La sobrevivencia media es de tres a cinco años desde el diagnóstico. La historia natural es un deterioro progresivo, pero hay formas rápidas y también pueden aparecer exacerbaciones que ensombrecen el pronóstico. Diversas comorbilidades se han descrito como la hipertensión pulmonar, la asociación con enfisema y el reflujo gastroesofágico. Sólo recientemente aparecen fármacos útiles, que son la Pirfenidona y el Nintedanib. El clásico esquema de prednisona, azatriopina y N-acetil cisteina, se ha demostrado ineficaz. Otros recursos que pueden utilizarse como complementos útiles en la enfermedad son el oxígeno, la rehabilitación, las terapias antirreflujo y el manejo sintomático de la tos.

PF appears mainly in aged males, with progressive cough and dyspnea. In 5% of the cases the disease presents as a familial form. CT scan is key in diagnosis of the disease. In no less than 50% biopsy is unnecessary but diagnosis must be made in conjunction with clinician, radiologist and pathologist. Median survival is 3 to 5 years from diagnosis. Natural history is a progressive deterioration but there are fast evolution cases and exacerbation of the disease that make worse the prognosis. Pulmonary hypertension, the association with emphysema and gastroesophageal reflux has been described as comorbidities of the disease. Last year has been published the positive results of therapeuticall trials with two new drugs, Pirfenidone and Nintedanib. The classical regime for IPF with Prednisone, Azathriopine and Acetylcysteine has been showed as useless. Oxygen, Pulmonary rehabilitation, gastroesophageal reflux and cough management are complementary treatment for the disease.

Supervivencia de pacientes con fibrosis pulmonar idiopática diagnosticados por biopsia quirúrgica de pulmón: experiencia del Instituto Nacional del Tórax / Survival of patients with biopsy-proven idiopathic pulmonary fibrosis: Chilean National Thorax Institute experience

Background: Idiopathic Pulmonary Fibrosis (IPF) is the most prevalent of all interstitial lung diseases. The usual underlying pathological picture is an interstitial pneumonia (UIP). Aim: To describe the evolution of a Chilean cohort of patients with IPF. Material and Methods: Patients with the disease were identified at the pathology registry of National Institute of Thoracic Diseases, Santiago, Chile. Patients were included if they had surgical biopsy of UIP and compatible clinical and radiological characteristics. The medical records of included patients were reviewed, recording clinical information and lung function test results. Survival was analyzed obtaining death records from the Chilean National Identification Service. Results: Data from 142 patients with a mean age of 58 years (42% men), were analyzed. Mean initial lung function showed a forced vital capacity (FVC) of 73%, carbon monoxide diffusing capacity (DLCO) of 57% and a distance covered in 6-minute walk (6MWT) of 95% of expected normal values. The median survival was 80 months. Predictors of survival were a DLCO of less than 40% and an oxygen saturation at the end of the 6MWT of less than 89%. Conclusions: Survival in this group of patients was higher than the figures reported elsewhere. DLCO and the fall of oxygen saturation after walking were predictors of mortality, as previously described in other populations.

Immunohistochemical and morphometric evaluation of COX 1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis / Avaliacao imuno-histoquimica e morfometrica de COX-1 e COX-2 no remodelamento pulmonar na fibrose pulmonar idiopatica e na esclerose sistemica

OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc-NSIP lung tissue than in the control tissue. No difference was found between IPF-UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. .

OBJETIVO: Estudar a expressão de COX-1 e COX-2 em áreas pulmonares remodeladas em pacientes com esclerose sistêmica (ES) ou fibrose pulmonar idiopática (FPI) e correlacioná-la com a sobrevida desses pacientes. MÉTODOS: Examinamos espécimes de biópsia pulmonar a céu aberto de 24 pacientes com ES e de 30 pacientes com FPI, utilizando-se tecido pulmonar normal como controle. Os padrões histológicos incluíram pneumonia intersticial não específica (PINE) fibrótica em pacientes com ES e pneumonia intersticial usual (PIU) nos pacientes com FPI. Imuno-histoquímica e histomorfometria foram usadas para avaliar a expressão celular de COX-1 e COX-2 em septos alveolares, vasos e bronquíolos, sua correlação com provas de função pulmonar e seu impacto na sobrevida. RESULTADOS: A expressão de COX-1 e COX-2 em septos alveolares foi significativamente maior em FPI-PIU e ES-PINE do que no tecido controle. Não houve diferença entre FPI-PIU e ES-PINE quanto à expressão de COX-1 e COX-2. A análise multivariada baseada no modelo de regressão de Cox mostrou que os fatores associados a baixo risco de morte foram ter idade menor, valores elevados de DLCO/volume alveolar, FPI, e alta expressão de COX-1 em septos alveolares, ao passo que os fatores associados a alto risco de morte foram ter idade maior, valores baixos de DLCO/volume alveolar, ES (com PINE) e baixa expressão de COX-1 em septos alveolares. CONCLUSÕES: Nossos resultados sugerem que estratégias de prevenção de baixa síntese de COX-1 terão maior impacto sobre a ES, ao passo que as de prevenção de alta síntese de COX-2 terão maior impacto sobre a FPI. Porém, são necessários ensaios clínicos randomizados prospectivos para confirmar essa hipótese. .

Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance

In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1) and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP) using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF). Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci), severe (mural) fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.

Lymphatic fluctuation in the parenchymal remodeling stage of acute interstitial pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis

Because the superficial lymphatics in the lungs are distributed in the subpleural, interlobular and peribroncovascular interstitium, lymphatic impairment may occur in the lungs of patients with idiopathic interstitial pneumonias (IIPs) and increase their severity. We investigated the distribution of lymphatics in different remodeling stages of IIPs by immunohistochemistry using the D2-40 antibody. Pulmonary tissue was obtained from 69 patients with acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD, N = 24), cryptogenic organizing pneumonia/organizing pneumonia (COP/OP, N = 6), nonspecific interstitial pneumonia (NSIP/NSIP, N = 20), and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP, N = 19). D2-40+ lymphatic in the lesions was quantitatively determined and associated with remodeling stage score. We observed an increase in the D2-40+ percent from DAD (6.66 ± 1.11) to UIP (23.45 ± 5.24, P = 0.008) with the advanced process of remodeling stage of the lesions. Kaplan-Meier survival curves showed a better survival for patients with higher lymphatic D2-40+ expression than 9.3%. Lymphatic impairment occurs in the lungs of IIPs and its severity increases according to remodeling stage. The results suggest that disruption of the superficial lymphatics may impair alveolar clearance, delay organ repair and cause severe disease progress mainly in patients with AIP/DAD. Therefore, lymphatic distribution may serve as a surrogate marker for the identification of patients at greatest risk for death due to IIPs.