Respiratory consequences after COVID-19: outcome and treatment.

The SARS-CoV-2 (COVID-19) pandemic represents the infection with the highest lethality, but also the one that has caused the most sequelae and multi-organ consequences, especially respiratory, in the last century. Several actions have been required in the field of respiratory and intensive care medicine to reduce mortality and chronicity. The consequences of COVID-19 are multiple and encompass different physical, emotional, organizing, and economic aspects, which will require a multidisciplinary, transversal, and collaborative approach. This review includes the observations and results of published retrospective and prospective studies on post-COVID19 respiratory sequelae, especially after severe pneumonia with associated adult respiratory distress syndrome (ARDS).

A prospective study of lung disease in a cohort of early rheumatoid arthritis patients.

Lung disease is common in patients with rheumatoid arthritis (RA). The onset of lung involvement in RA is not well known. The objective is to describe the features and evolution of lung involvement in early RA, its relationship with disease activity parameters, smoking and treatments. Consecutive patients with early RA without respiratory symptoms were included and tracked for 5 years. Lung assessment included clinical, radiological and pulmonary function tests at diagnosis and during follow-up. Peripheral blood parameters (erythrocyte sedimentation rate, C reactive protein, rheumatoid factor and anti-citrullinated peptide autoantibodies) and scales of articular involvement, such as DAS28-CRP, were evaluated. 40 patients were included and 32 completed the 5-year follow up. 13 patients presented lung involvement in the initial 5 years after RA diagnosis, 3 of them interstitial lung disease. Significant decrease of diffusion lung transfer capacity of carbon monoxide over time was observed in six patients, 2 of them developed interstitial lung disease. DLCO decrease was correlated with higher values of CRP and ESR at diagnosis. Methotrexate was not associated with DLCO deterioration or lung disease development. Subclinical progressive lung disease correlates with RA activity parameters. Smoking status and methotrexate were not associated with development or progression of lung disease.

Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells.

BACKGROUND: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. METHODS: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor ß1 (TGF-ß). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and α-smooth muscle actin [α-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-ß-containing media was performed. RESULTS: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-ß. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. CONCLUSIONS: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach.

A haplotype of cyclooxygenase-2 gene is associated with idiopathic pulmonary fibrosis.

BACKGROUND: Cyclooxygenase-2, a key regulatory enzyme in the synthesis of the antifibrotic agent prostaglandin E2, is downregulated in lung tissue from patients with idiopathic pulmonary fibrosis. OBJECTIVE: To investigate the association between COX2.3050 (G --> C), COX2.8473 (C --> T) and COX2.926 (G --> C) single nucleotide polymorphisms (SNP) and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. DESIGN: Genetic polymorphisms were analyzed in 121 out of 225 available control subjects and in all of 174 patients with idiopathic pulmonary fibrosis by real time polymerase chain reaction. Logistic regression analysis of covariance and chi-squares test were used for statistical analysis. RESULTS: While analysis of disease development did not find any significant association with single SNP genotype, a haplotype analysis revealed a strong association between the disease development and one haplotype [GC] at loci COX2.3050 and COX2.8473, and suggested a recessive genetic effect of this haplotype. Further analysis concluded that subjects having two copies of [GC] haplotype, or equivalently (GG/CC) genotype at the two SNPs, had an increased risk after adjusting for age and sex. Due to the interaction, this elevated risk increased slowly with age, and the estimated odds ratio (OR) decreased with age from OR = 1.4 at age 30 to OR = 1 at age 74 and OR = 0.96 at age SO. The OR was significantly greater than 1 up to age 66, and not significant for age older than 66. Therefore, the recessive effect of [GC] haplotype increased the risk of IPF of subjects younger than 66 years, but its effect diminished for seniors older than 66. One hundred and forty-nine patients with idiopathic pulmonary fibrosis were followed up for 33.7 +/- 2.1 months. Further analysis of disease progressions, defined by the changes in pulmonary function tests, did not reveal any association with either SNP genotypes or haplotypes. CONCLUSIONS: The carriage of double homozygote (GG/CC) at the SNP loci of COX2.3050 and COX2.8473 polymorphisms may increase the susceptibility to idiopathic pulmonary fibrosis, by approximately 1.4 folds at age 30 and by a smaller fold greater than 1 up to age 66 years, but not the progression of the disease. These findings may help to improve our understanding of idiopathic pulmonary fibrosis pathogenesis and may lead to the development of new therapeutic strategies.

Fe de errores de “Implicación de la alteración en la regulación de la ciclooxigenasa-2 sobre la formación de miofibroblastos en la fibrogénesis pulmonar” / No disponible

Introducción: Se ha descrito la existencia de una disminución en la expresión de ciclooxigenasa 2 (COX-2) y de prostaglandina-E2 (PGE-2) en la fibrogénesis pulmonar. La PGE-2 es un mediador antifibrótico. Los miofibroblastos desempeñan un importante papel en la fibrogénesis. Los miofibroblastos pueden formarse a partir de fibroblastos (transición fibroblasto-miofibroblasto) y de células epiteliales (transición epitelio-mesenquimal). El objetivo es estudiar la expresión de COX-2 y la síntesis de PGE2 en la inducción de la formación de miofibroblastos.Métodos: Mediante biopsia pulmonar se obtuvieron fibroblastos normales de sujetos con neumotórax (n=5) y fibroblastos de pacientes con fibrosis pulmonar idiopática (FPI) (n=5). Para el estudio de la función epitelial se utilizaron células epiteliales inmortales A549. Se realizó inmunohistoquímica (IHC) y Western blot para la determinación de COX-2 y α-SMA (marcador de miofibroblastos). Mediante ELISA se estudio la síntesis de PGE2. La proliferación celular se valoró mediante la incorporación nuclear de un análogo de nucleósido.Resultados: Los fibroblastos de la FPI presentan mayores niveles de ß-SMA comparados con los fibroblastos control. Ambos presentan una expresión indetectable de COX-2. Después de la estimulación con interleucina 1ß (IL-1ß), los fibroblastos control expresan mayores niveles de COX-2 que los fibroblastos fibróticos. Los miofibroblastos detectados mediante IHC no expresaron COX-2. Los fibroblastos tratados con TGF-ß1 expresan α-SMA, en forma, dosis y tiempo dependiente, tanto en fibroblastos fibróticos como en controles. A549 tratadas con TGF-ß1 cambian su fenotipo, expresando fibras de estrés relacionadas con la formación de miofibroblastos (α-SMA+). Los miofibroblastos obtenidos de tratar fibroblatos o A549 con TGF-ß1 muestran un descenso de los niveles de COX-2 y PGE-2 tras estimulación con IL-1ß. No hubo variaciones en la proliferación celular(AU)

Conclusiones: Los miofibroblastos se caracterizan por una alteración en la regulación de la expresión de COX-2 y en la síntesis de PGE-2, tanto en los transformados a partir de fibroblastos como de células epiteliales(AU)

Lymphangioleiomyomatosis: a study of 72 patients from the Spanish registry.

BACKGROUND: Pulmonary lymphangioleiomyomatosis (LAM) is a rare lung disease that almost exclusively affects young women of childbearing age. The true incidence and prevalence of LAM are unknown. This study was conducted to evaluate the characteristics of lymphangioleiomyomatosis in Spain. METHODS: Over a 2-year period, a questionnaire designed for this study was collected. This questionnaire included sociodemograhic, clinical, radiological and functional data. Information about the study and this questionnaire were both sent by e-mail to all the participants of the interstitial disease registry of 2004. RESULTS: Seventy-two patients, all of whom were women, were included in the registry, with a mean age of 44.56 +/- 11.1 yr. Sixty-three patients (87.5%) presented the sporadic LAM and 9 (12.5%) presented LAM associated with tuberous sclerosis (LAM-TS). LAM diagnosis was confirmed with an open lung biopsy in 57 patients (79.2%) and was performed with thoracic HRCT compatible with LAM diagnosis in the other 15 cases. The most frequent symptom was dyspnoea (90%) followed by cough (44.4%). Almost 40% of patients presented renal angiomyolipomas in the study and the most frequent spirometric pattern was obstructive in more than half of the patients. Most patients with LAM-TS (88.8%) had renal angiomyolipomas compared with 31.7% in the sporadic LAM group. CONCLUSION: The characteristics of the Spanish population affected with LAM are similar to those of other countries. Most patients were symptomatic, had a history of previous pneumothorax and presented abnormal radiological findings and pulmonary function tests.

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression.

Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate. In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects. The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37+/-0.7 mmHg (0.049+/-0.093 kPa) per month) compared to GA genotype (0.12+/-1 mmHg (0.016+/-0.133 kPa) per month) and GG genotype (0.2+/-0.6 mmHg (0.027+/-0.080 kPa) per month). G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis.

BACKGROUND: The angiotensin system has a role in the pathogenesis of pulmonary fibrosis. This study examines the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in bleomycin induced lung fibrosis and its possible implication in the regulation of prostaglandin E(2) (PGE(2)) synthesis and cyclooxygenase-2 (COX-2) expression. METHODS: Rats were given a single intratracheal instillation of bleomycin (2.5 U/kg). Losartan (50 mg/kg/day) was administrated orally starting one day before induction of lung fibrosis and continuing to the conclusion of each experiment. RESULTS: Losartan reduced the inflammation induced by bleomycin, as indicated by lower myeloperoxidase activity and protein content in the bronchoalveolar lavage fluid. Collagen deposition induced by bleomycin was inhibited by losartan, as shown by a reduction in the hydroxyproline content and the amelioration of morphological changes. PGE(2) levels were lower in fibrotic lungs than in normal lungs. Losartan significantly increased PGE(2) levels at both 3 and 15 days. A reduction in COX-2 expression by bleomycin was seen at 3 days which was relieved by losartan. CONCLUSIONS: The antifibrotic effect of losartan appears to be mediated by its ability to stimulate the production of PGE(2). Losartan, which is already widely used clinically, could be assessed as a new treatment in lung fibrosis.

Violencia doméstica y profesionales sanitarios: conocimientos, opiniones y barreras para la infradetección / Domestic violence and sanitaries professionals: knowledge, opinions and barriers for the low detection

Objetivos: A pesar de las mejoras de coordinación entre los servicios de salud, más del 70 por ciento de los casos de Violencia Doméstica (VD) siguen siendo invisibles a ojos de los sanitarios. Pretendemos conocer el grado de formación que sobre el tema tienen los profesionales sanitarios, detectar barreras de actitud, barreras organizativas de los servicios y analizar opiniones de mejora frente al problema de la infradetección. Métodos: Encuesta anónima dirigida a 116 profesionales de un servicio de urgencias hospitalario (médicos, enfermeras y auxiliares), valorando los objetivos propuestos. Resultados: La participación fue del 74 por ciento. En un test de conocimientos solo se obtuvo un 51,1 por ciento de respuestas correctas. Las principales barreras de actitud fueron la desmotivación y desconocimiento. Hasta un 66 por ciento de los profesionales no suelen plantearse la VD como un diagnóstico diferencial más en su actividad diaria y más del 50 por ciento de los sanitarios no plantea soluciones al problema. Como barreras organizativas destacan una creciente presión asistencial que limita el tiempo de asistencia y la ausencia de personal experto durante las 24 horas de trabajo. Conclusiones: La VD sigue siendo una auténtica desconocida para los sanitarios de urgencias, considerándola más como un problema social que sanitario. Elaborar planes formativos periódicos es una buena medida pero insuficiente para paliar la infradetección. Es necesario además, controlar la presión asistencial, formar un "grupo de expertos en VD" que asesoren, supervisen y participen en la actividad clínica diaria y crear un sistema de vigilancia activa que monitorice y detecte problemas de mejora (AU)