Biomarkers of Fibrosis in Patients with COVID-19 One Year After Hospital Discharge: A Prospective Cohort Study.

Beyond the acute infection of coronavirus disease (COVID-19), concern has arisen about long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The aim of our study was to analyze if there is any biomarker of fibrogenesis in patients with COVID-19 pneumonia capable of predicting post-COVID-19 pulmonary sequelae. We conducted a multicenter, prospective, observational cohort study of patients admitted to a hospital with bilateral COVID-19 pneumonia. We classified patients into two groups according to severity, and blood sampling to measure matrix metalloproteinase 1 (MMP-1), MMP-7, periostin, and VEGF and respiratory function tests and high-resolution computed tomography were performed at 2 and 12 months after hospital discharge. A total of 135 patients were evaluated at 12 months. Their median age was 61 (interquartile range, 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 predicted forced vital capacity (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 high-resolution computed tomography resolution, but fibrotic changes persisted in 29.4%. Biomarker analysis demonstrated differences at 2 months in periostin (0.8893 vs. 1.437 ng/ml; P < 0.001) and MMP-7 (8.7249 vs. 15.2181 ng/ml; P < 0.001). No differences were found at 12 months. In multivariable analysis, only 2-month periostin was associated with 12-month fibrotic changes (odds ratio, 1.0013; 95% confidence interval, 1.0006-1.00231; P = 0.003) and 12-month DlCO impairment (odds ratio, 1.0006; 95% confidence interval, 1.0000-1.0013; P = 0.047). Our data suggest that early periostin postdischarge could predict the presence of fibrotic pulmonary changes.

Lung Function, Radiological Findings and Biomarkers of Fibrogenesis in a Cohort of COVID-19 Patients Six Months After Hospital Discharge / Función pulmonar, hallazgos radiológicos y biomarcadores de la fibrogénesis en una cohorte de pacientes de COVID-19 seis meses después del alta

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 sociaron 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

Lung Function, Radiological Findings and Biomarkers of Fibrogenesis in a Cohort of COVID-19 Patients Six Months After Hospital Discharge.

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.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Hyperamylasaemia and gastrointestinal bleeding as the first manifestation of jejunal ectopic páncreas / Hiperamilasemia y hemorragia digestiva como primera manifestación de páncreas ectópico yeyunal

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[Multiple comorbidities from the perspective of primary care health professionals]. / La multimorbilidad vista desde la perspectiva de los profesionales de atención primaria.

OBJECTIVE: To explore the perception of primary care health professionals in the Basque Country (Spain) of multiple comorbidities and their influence on clinical practice and the organization of health services. DESIGN: Qualitative study based on interviews, a storytelling workshop and cocreation. SETTING: The autonomous community of the Basque Country. Primary care in the Basque health system. PARTICIPANTS: Fourteen health professionals: 6 specialists in family medicine, 3 hospital specialists (internal medicine, pneumology, and geriatrics), 4 nurses, and 1 community pharmacist. METHODS: A qualitative, exploratory study was carried out, based on a cocreation workshop (12 participants) and 10 interviews with health professionals. The research was performed between February and June 2013. All interviews and the group workshop were audio recorded and some were video recorded. RESULTS: The emerging dominant themes were as follows: a) the challenges posed by multiple comorbidities for a "disease-centered" health system; b) the manifestation of these challenges in daily clinical practice in aspects such as the patient-health professional relationship, clinical decision-making, polypharmacy management, and coordination between healthcare settings; c) the barriers to the appropriate care of these patients: training, decision-making tools, lack of time, etc.; and d) the question of the most appropriate professional competencies and profiles. CONCLUSIONS: The increase in multiple comorbidities is a reality that worries primary care professionals, who express the need for adequate training, decision-making tools and support in daily clinical practice dealing with the most frequent situations and combinations of multiple comorbidities. The most effective approach to these problems requires a shift in the healthcare model toward an integrated view of the patient, a transition from a paternalist approach to a more proactive approach, and the development of healthcare integration.

La multimorbilidad vista desde la perspectiva de los profesionales de atención primaria / Multiple comorbidities from the perspective of primary care health professionals

OBJETIVO: Explorar la percepción de profesionales clínicos de atención primaria del País Vasco sobre la multimorbilidad y su influencia en la práctica clínica y en la organización de la prestación sanitaria. DISEÑO: Estudio cualitativo basado en entrevistas, taller de storytelling y cocreación. Emplazamiento: Comunidad autónoma del País Vasco. Atención primaria de Osakidetza. Participantes: Participaron 14 profesionales clínicos: 6 especialistas de medicina de familia, 3 especialistas hospitalarios (medicina interna, neumología y geriatría), 4 profesionales de enfermería, y una profesional de farmacia comunitaria. MÉTODOS: Estudio de carácter cualitativo, exploratorio, basado en un taller de cocreación (12 participantes) y 10 entrevistas con profesionales sanitarios. La investigación se llevó a cabo entre los meses de febrero a junio de 2013. Todas las entrevistas y el taller grupal se grabaron en formato audio y algunas de ellas en formato vídeo. RESULTADOS: Los temas emergentes dominantes fueron: a) los retos que plantea la multimorbilidad para un sistema sanitario "centrado en la enfermedad"; b) la manifestación de esos retos en la práctica clínica cotidiana en aspectos como la relación professional-paciente, la toma de decisiones clínicas, el manejo de la polifarmacia y la coordinación entre ámbitos asistenciales; c) las barreras existentes para un manejo apropiado de estos pacientes: formación, herramientas de ayuda a la decisión, falta de tiempo, etc., y d) la cuestión de las competencias y perfiles profesionales más adecuados. CONCLUSIONES: El aumento de la multimorbilidad es una realidad que preocupa a los profesionales de atención primaria. Los profesionales manifiestan la necesidad de disponer formación adecuada y de sistemas de ayuda a la decisión y de soporte de la práctica diaria que contemplen las situaciones y combinaciones de multimorbilidad más frecuentes. Un abordaje más efectivo de esta problemática requiere un cambio en el modelo sanitario que privilegie una visión integral del paciente, la transición de un enfoque paternalista a uno más proactivo y el desarrollo de la integración asistencial

OBJECTIVE: To explore the perception of primary care health professionals in the Basque Country (Spain) of multiple comorbidities and their influence on clinical practice and the organization of health services. DESIGN: Qualitative study based on interviews, a storytelling workshop and cocreation. Setting: The autonomous community of the Basque Country. Primary care in the Basque health system. Participants: Fourteen health professionals: 6 specialists in family medicine, 3 hospital specialists(internal medicine, pneumology, and geriatrics), 4 nurses, and 1 community pharmacist. METHODS: A qualitative, exploratory study was carried out, based on a cocreation workshop (12 participants) and 10 interviews with health professionals. The research was performed between February and June 2013. All interviews and the group workshop were audio recorded and some were video recorded. RESULTS: The emerging dominant themes were as follows: a) the challenges posed by multiple comorbidities for a "disease-centered" health system; b) the manifestation of these challenges in daily clinical practice in aspects such as the patient-health professional relationship, clinical decision-making, polypharmacy management, and coordination between healthcare settings; c) the barriers to the appropriate care of these patients: training, decision-making tools, lack of time, etc.; and d) the question of the most appropriate professional competencies and profiles. CONCLUSIONS: The increase in multiple comorbidities is a reality that worries primary care professionals, who express the need for adequate training, decision-making tools and support in daily clinical practice dealing with the most frequent situations and combinations of multiple comorbidities. The most effective approach to these problems requires a shift in the healthcare model toward an integrated view of the patient, a transition from a paternalist approach to a more proactive approach, and the development of healthcare integration

Clinical and myopathological evaluation of early- and late-onset subtypes of myofibrillar myopathy.

Myofibrillar myopathies (MFM) are a group of disorders associated with mutations in DES, CRYAB, MYOT, ZASP, FLNC, or BAG3 genes and characterized by disintegration of myofibrils and accumulation of degradation products into intracellular inclusions. We retrospectively evaluated 53 MFM patients from 35 Spanish families. Studies included neurologic exam, muscle imaging, light and electron microscopic analysis of muscle biopsy, respiratory function testing and cardiologic work-up. Search for pathogenic mutations was accomplished by sequencing of coding regions of the six genes known to cause MFM. Mutations in MYOT were the predominant cause of MFM in Spain affecting 18 of 35 families, followed by DES in 11 and ZASP in 3; in 3 families the cause of MFM remains undetermined. Comparative analysis of DES, MYOT and ZASP associated phenotypes demonstrates substantial phenotypic distinctions that should be considered in studies of disease pathogenesis, for optimization of subtype-specific treatments and management, and directing molecular analysis.

Reversible splenial lesion syndrome (RESLES): what's in a name?

BACKGROUND: The presence of transient lesions involving the splenium of the corpus callosum (SCC) has been described in patients with encephalitis or encephalopathy of varied etiology. We have termed it RESLES (reversible splenial lesion syndrome). PURPOSE: To describe 3 additional patients (2 encephalitis, 1 hypoglycemia) and review the literature to define this syndrome, its etiology, presentation, prognosis, and possible pathophysiological mechanisms. METHODS: Search of the MEDLINE database from 1966 through 2007. English language article titles and abstracts were screened and the appropriate articles reviewed. Additional articles cited by original references were also reviewed. RESULTS: RESLES is caused by antiepileptic drug withdrawal, infection, high-altitude cerebral edema (HACE), or metabolic disorders (hypoglycemia and hypernatremia). Complete resolution after a variable lapse is the rule. Clinical presentation is nonspecific, without evidence of callosal disconnection syndromes. Neuroimaging shows a nonenhancing, round-shaped lesion centered in the SCC that disappears after a variable lapse. Diffusion studies reveal DW hypersignal with low ADC values, suggestive of cytotoxic edema. Only HACE-related cases and 1 patient with pregabalin withdrawal showed high ADC values, consistent with vasogenic edema. CONCLUSION: RESLES is a distinct clinicoradiological syndrome of varied etiology and benign course except in those patients with an underlying severe disorder.

Isolated and reversible lesions of the corpus callosum: a distinct entity.

The Reversible Splenial Lesion Syndrome represents a distinct clinicoradiological syndrome, associated with several disorders, including infection, high altitude cerebral edema, antiepileptic drug withdrawal, and severe metabolic disturbances (hypoglycemia and hypernatremia). Clinical presentation is nonspecific, most frequently as an encephalopathy or encephalitis. Outcome is favorable in most patients unless there is a severe underlying disorder. Magnetic resonance imaging findings are restricted to the splenium and consist of a nonenhancing oval lesion, hyperintense on T2-weighted images, including FLAIR. Findings on diffusion-weighted imaging are consistent with cytotoxic edema except for high-altitude cerebral edema, where vasogenic edema is present. Resolution after weeks or months is the rule.