ABSTRACT
Beyond the acute infection of coronavirus disease (COVID-19), concern has arisen about long-term effects of SARS-CoV-2 infection. The aim of our study was to analyze if there is any biomarker of fibrogenesis in COVID-19 pneumonia patients capable of predicting post-COVID pulmonary sequelae. We conducted a multicenter, prospective, observational cohort study of patients admitted to hospital with bilateral COVID-19 pneumonia. We classified patients in two groups according to severity, and blood samples to measure MMP1, MMP7, periostin and VEGF, respiratory function tests and HRCT imaging were obtained at 2 and 12 months after hospital discharge. A total of 135 patients were evaluated at 12 months. Median age was 61 (IQR: 19) years and 58.5% were men. We found between-group differences in age, radiological involvement, length of hospital stay and inflammatory laboratory parameters. Differences were found between 2 and 12 months in all functional tests, including improvements in FVC% (98.0 vs. 103.9; p=0.001) and DLCO<80% (60.9% vs. 39.7%; p=0.001). At 12 months, 63% of patients had complete HRTC resolution, but fibrotic changes persisted in 29.4%. Biomarker analysis demonstrated differences at 2 months in periostin (ng/mL) (0.8893 vs. 1.437; p<0.001) and MMP-7 (ng/mL) (8.7249 vs. 15.2181; p<0.001). No differences were found at 12 months. In multivariable analysis, only 2-month periostin was associated with 12-month fibrotic changes (OR: 1.0013 95% CI: 1.0006-1.00231; p=0.003) and 12-month DLCO impairment (OR: 1.0006 95% CI: 1.0000-1.0013; p=0.047). Our data suggest that early periostin post-discharge could predict the presence of fibrotic pulmonary changes.
ABSTRACT
INTRODUCTION: Impairment in pulmonary function tests and radiological abnormalities are a major concern in COVID-19 survivors. Our aim is to evaluate functional respiratory parameters, changes in chest CT, and correlation with peripheral blood biomarkers involved in lung fibrosis at two and six months after SARS-CoV-2 pneumonia. METHODS: COVID-FIBROTIC (clinicaltrials.gov NCT04409275) is a multicenter prospective observational cohort study aimed to evaluate discharged patients. Pulmonary function tests, circulating serum biomarkers, chest radiography and chest CT were performed at outpatient visits. RESULTS: In total, 313, aged 61.12 ± 12.26 years, out of 481 included patients were available. The proportion of patients with DLCO < 80% was 54.6% and 47% at 60 and 180 days. Associated factors with diffusion impairment at 6 months were female sex (OR: 2.97, 95%CI 1.74-5.06, p = 0.001), age (OR: 1.03, 95% CI: 1.01-1.05, p = 0.005), and peak RALE score (OR: 1.22, 95% CI 1.06-1.40, p = 0.005). Patients with altered lung diffusion showed higher levels of MMP-7 (11.54 ± 8.96 vs 6.71 ± 4.25, p = 0.001), and periostin (1.11 ± 0.07 vs 0.84 ± 0.40, p = 0.001). 226 patients underwent CT scan, of whom 149 (66%) had radiological sequelae of COVID-19. In severe patients, 68.35% had ground glass opacities and 38.46% had parenchymal bands. Early fibrotic changes were associated with higher levels of MMP7 (13.20 ± 9.20 vs 7.92 ± 6.32, p = 0.001), MMP1 (10.40 ± 8.21 vs 6.97 ± 8.89, p = 0.023), and periostin (1.36 ± 0.93 vs 0.87 ± 0.39, p = 0.001). CONCLUSION: Almost half of patients with moderate or severe COVID-19 pneumonia had impaired pulmonary diffusion six months after discharge. Severe patients showed fibrotic lesions in CT scan and elevated serum biomarkers involved in pulmonary fibrosis.
INTRODUCCIÓN: El deterioro de la función pulmonar en las pruebas correspondientes y las alteraciones radiológicas son las preocupaciones principales en los supervivientes de la COVID-19. Nuestro objetivo fue evaluar los parámetros de la función respiratoria, los cambios en la TC de tórax y la correlación con los biomarcadores en sangre periférica involucrados en la fibrosis pulmonar a los 2 y a los 6 meses tras la neumonía por SARS-CoV-2. MÉTODOS: El ensayo COVID-FIBROTIC (clinicaltrials.gov NCT04409275) es un estudio de cohortes multicéntrico, prospectivo y observacional cuyo objetivo fue evaluar los pacientes dados de alta. Se realizaron pruebas de función pulmonar, detección de biomarcadores en plasma circulante y radiografía y TC de tórax durante las visitas ambulatorias. RESULTADOS: En total 313 pacientes, de 61,12 ± 12,26 años, de los 481 incluidos estuvieron disponibles.La proporción de pacientes con DLCO < 80% fue del 54,6 y del 47% a los 60 y 180 días.Los factores que se asociaron a la alteración de la difusión a los 6 meses fueron el sexo femenino (OR: 2,97; IC del 95%: 1,74-5,06; p = 0,001), la edad (OR: 1,03; IC del 95%: 1,01-1,05; p = 0,005) y la puntuación RALE más alta (OR: 1,22; IC del 95%: 1,06-1,40; p = 0,005). Los pacientes con alteración de la difusión pulmonar mostraron niveles más altos de MMP-7 (11,54 ± 8,96 frente a 6,71 ± 4,25; p = 0,001) y periostina (1,11 ± 0.07 frente a 0,84 ± 0,40; p = 0,001). Se le realizó una TC a 226 pacientes de los cuales 149 (66%) presentaban secuelas radiológicas de la COVID-19. En los pacientes graves, el 68,35% mostraban opacidades en vidrio esmerilado y el 38,46%, bandas parenquimatosas. Los cambios fibróticos tempranos se asociaron a niveles más altos de MMP7 (13,20 ± 9,20 frente a 7,92 ± 6,32; p = 0,001), MMP1 (10,40 ± 8,21 frente a 6,97 ± 8,89; p = 0,023), y periostina (1,36 ± 0,93 frente a 0,87 ± 0,39; p = 0,001). CONCLUSIÓN: Casi la mitad de los pacientes con neumonía moderada o grave por COVID-19 presentaba alteración de la difusión pulmonar 6 meses después del alta. Los pacientes graves mostraban lesiones fibróticas en laTC y un aumento de los biomarcadores séricos relacionados con la fibrosis pulmonar.