Imbalance of SARS-CoV-2-specific CCR6+ and CXCR3+ CD4+ T cells and IFN-γ + CD8+ T cells in patients with Long-COVID.

Long-COVID (LC) is characterised by persistent symptoms for at least 3 months after acute infection. A dysregulation of the immune system and a persistent hyperinflammatory state may cause LC. LC patients present differences in activation and exhaustion states of innate and adaptive compartments. Different T CD4+ cell subsets can be identified by differential expression of chemokine receptors (CCR). However, changes in T cells with expression of CCRs such as CCR6 and CXCR3 and their relationship with CD8+ T cells remains unexplored in LC. Here, we performed unsupervised analysis and found CCR6+ CD4+ subpopulations enriched in COVID-19 convalescent individuals upon activation with SARS-CoV-2 peptides. SARS-CoV-2 specific CCR6+ CD4+ are decreased in LC patients, whereas CXCR3+ CCR6- and CCR4+ CCR6- CD4+ T cells are increased. LC patients showed lower IFN-γ-secreting CD8+ T cells after stimulation with SARS-CoV-2 Spike protein. This work underscores the role of CCR6 in the pathophysiology of LC.

Cystic fibrosis with liver involvement in adults has a benign course. Results from a tertiary referral center cohort.

BACKGROUND: Cystic Fibrosis Liver Disease is a poorly understood entity, especially in adults, in terms of its real prevalence, natural history and diagnostic criteria, despite being the most important extrapulmonary cause of mortality. The aim was to evaluate the prevalence, characteristics and potential risk factors of liver disease in adults with cystic fibrosis, according to two diagnostic criteria accepted in the scientific literature. METHODS: Patients were recruited in a tertiary referral hospital, and laboratory, ultrasound, non-invasive liver fibrosis tests (AST to Platelet Ratio Index; Fibrosis-4 Index) and transient elastography (Fibroscan) were performed. The proportion of patients with liver disease according to the Debray and Koh criteria were evaluated. RESULTS: 95 patients were included, 48 (50.5%) females, with a mean age of 30.4 (28.6-32.2) years. According to the Debray criteria, 6 (6.3%) patients presented liver disease. According to the Koh criteria, prevalence increased up to 8.4%, being statistically different from the 25% value described in other published series (p = 0.005). Seven (7.5%) presented ultrasonographic chronic liver disease. Eleven (13%) presented liver fibrosis according to the APRI score; 95 (100%) had a normal FIB-4 value. Mean liver stiffness value was 4.4 (4.1-4.7) kPa. FEV1 (OR=0.16, p 0.05), meconium ileus (OR=14.16, p 0.002), platelets (Pearson coefficient -0.25, p 0.05) and younger age (Pearson coefficient -0.19, p 0.05) were risk factors. CONCLUSIONS: Prevalence and severity of liver disease in adult cystic fibrosis patients were lower than expected. Meconium ileus, platelets, age and respiratory function were confirmed as risk factors associated to cystic fibrosis liver disease.

A prospective study to assess the impact of a novel CFTR therapy combination on body composition in patients with cystic fibrosis with F508del mutation.

BACKGROUND & AIM: Malnutrition is a prevalent condition in Cystic Fibrosis (CF) and can result in worsening of pulmonary function and other comorbidities. Cystic fibrosis transmembrane regulator (CFTR) modulator therapies are improving the CF-related care and outcomes. Body Mass Index (BMI) is the most commonly used parameter to assess nutritional status, albeit it is a very unspecific indicator. Hence, current guidelines recommend body composition analysis as a part of nutritional assessment. The aim of our study was to evaluate the impact of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) treatment on body composition and respiratory function. METHODS: We recruited patients with CF from University Hospital La Princesa, with follow-up in the Adult Cystic Fibrosis Unit. All patients were eligible to initiate ELX/TEZ/IVA therapy. Body composition was assessed with a Bioelectrical Impedance Analysis (BIA) and spirometry data were obtained before and after 6 months of treatment. RESULTS: Our study sample was composed of 36 patients with CF. We observed a significant increase in BMI after 6 months of treatment (p < 0.001), as well as an increase in fat mass (p = 0.008) and visceral fat area (p = 0.026). The other body composition parameters did not yield significant changes. Overall, %FEV1 increased from 72.67 % (±17.39) to 84.74 % (±18.18) after 6 months of treatment. Interestingly, we found an inverse correlation between %FEV1 and fat mass (r = -0,476; p = 0,0058), %FEV1 and age (r = -0,411; p = 0,0196) and between %FEV1 and visceral fat area (r = -0,515; p = 0,0025). On the contrary, we found a direct correlation between %FEV1 and body cell mass (r = 0,367; p = 0,038). CONCLUSIONS: Novel CFTR modulators are emerging for the treatment of CF. Specifically, triple combination with ELX/TEZ/IVA has shown to effectively improve both pulmonary and nutritional status in patients with CF with F508del mutation. Body composition should be a part of the routine assessment for patients with CF.

Cystic fibrosis with liver involvement in adults has a benign course. Results from a tertiary referral center cohort

Background: Cystic Fibrosis Liver Disease is a poorly understood entity, especially in adults, in terms of its real prevalence, natural history and diagnostic criteria, despite being the most important extrapulmonary cause of mortality. The aim was to evaluate the prevalence, characteristics and potential risk factors of liver disease in adults with cystic fibrosis, according to two diagnostic criteria accepted in the scientific literature. Methods: Patients were recruited in a tertiary referral hospital, and laboratory, ultrasound, non-invasive liver fibrosis tests (AST to Platelet Ratio Index; Fibrosis-4 Index) and transient elastography (Fibroscan) were performed. The proportion of patients with liver disease according to the Debray and Koh criteria were evaluated. Results: 95 patients were included, 48 (50.5%) females, with a mean age of 30.4 (28.6-32.2) years. According to the Debray criteria, 6 (6.3%) patients presented liver disease. According to the Koh criteria, prevalence increased up to 8.4%, being statistically different from the 25% value described in other published series (p = 0.005). Seven (7.5%) presented ultrasonographic chronic liver disease. Eleven (13%) presented liver fibrosis according to the APRI score; 95 (100%) had a normal FIB-4 value. Mean liver stiffness value was 4.4 (4.1-4.7) kPa. FEV1 (OR=0.16, p 0.05), meconium ileus (OR=14.16, p 0.002), platelets (Pearson coefficient -0.25, p 0.05) and younger age (Pearson coefficient -0.19, p 0.05) were risk factors. Conclusions: Prevalence and severity of liver disease in adult cystic fibrosis patients were lower than expected. Meconium ileus, platelets, age and respiratory function were confirmed as risk factors associated to cystic fibrosis liver disease (AU)

Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review.

Cystic fibrosis (CF) is a genetic disease that causes absence or dysfunction of a protein named transmembrane conductance regulatory protein (CFTR) that works as an anion channel. As a result, the secretions of the organs where CFTR is expressed are very viscous, so their functionality is altered. The main cause of morbidity is due to the involvement of the respiratory system as a result of recurrent respiratory infections by different pathogens. In recent decades, survival has been increasing, rising by around age 50. This is due to the monitoring of patients in multidisciplinary units, early diagnosis with neonatal screening, and advances in treatments. In this chapter, we will approach the different therapies used in CF for the treatment of symptoms, obstruction, inflammation, and infection. Moreover, we will discuss specific and personalized treatments to correct the defective gene and repair the altered protein CFTR. The obstacle for personalized CF treatment is to predict the drug response of patients due to genetic complexity and heterogeneity of uncommon mutations.

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study / Efecto de las diferencias de sexo en los hallazgos en la tomografía axial computerizada en adultos con fibrosis quística: un estudio multicentro

Background: The survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings.Material and methods: We performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables.Results: Of the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean±SD global score on the modified Bhalla score was 13.7±3.8 in women and 15.2±3.8 in men (p=0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV1, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations.Conclusions: This is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage. (AU)

Introducción: La supervivencia de las mujeres con fibrosis quística (FQ) es menor que la de los varones, en aproximadamente 5 años. Si bien se han presentado varios factores para explicar esta discrepancia, no se han establecido razones específicas. Nuestra hipótesis fue que el compromiso anatómico-estructural es más pronunciado en las mujeres con FQ que en los varones, y que esto se refleja en los hallazgos de la TCAR torácica.Materiales y métodos: Realizamos un estudio prospectivo multicéntrico, en el que los pacientes adultos se fueron incluyendo consecutivamente durante 18 meses. Se realizó un TCAR de tórax, y 2 radiólogos torácicos evaluaron los hallazgos utilizando la escala de Bhalla modificada. También estudiamos la función respiratoria, aplicamos el cuestionario CFQR 14+ y recogimos ciertas variables clínicas.Resultados: De los 360 pacientes en seguimiento en las unidades participantes, finalmente se incluyeron 160. La edad media fue de 28 años, y el 47,5% eran mujeres. La puntuación global media±DE en la escala de Bhalla modificada fue de 13,7±3,8 en mujeres y de 15,2±3,8 en varones (p=0,024). Las puntuaciones más altas se observaron para las saculaciones o abscesos, las generaciones bronquiales y el atrapamiento de aire en mujeres. Las mujeres tenían un IMC, % FEV1, % FVC y % DLCO más bajos. Del mismo modo, los resultados para el dominio respiratorio en el CFQR 14+ fueron peores en las mujeres, que también tenían más exacerbaciones anuales.Conclusiones: Este es el primer estudio que proporciona evidencia de la implicación de las diferencias de sexo en los hallazgos de la TCAR en pacientes con FQ. Las mujeres con FQ presentan una forma más grave de la enfermedad que resulta en exacerbaciones más frecuentes, peores resultados funcionales y nutricionales, deterioro de la calidad de vida y mayor daño estructural. (AU)

Personalized approaches to bronchiectasis.

Introduction: Interest in bronchiectasis is increasing due to its rising prevalence, associated with aging populations and the extended use of high-resolution chest tomography (HRCT), and the resulting high morbidity, mortality, and demand for resources.Areas covered: This article provides an extensive review of bronchiectasis as a complex and heterogeneous disease, as well as examining the difficulty of establishing useful clinical phenotypes. In keeping with the aims of 'precision medicine', we address the disease of bronchiectasis from three specific perspectives: severity, activity, and impact. We used PubMed to search the literature for articles including the following keywords: personalized medicine, bronchiectasis, biomarkers, phenotypes, precision medicine, treatable traits. We reviewed the most relevant articles published over the last 5 years.Expert opinion: This article reflects on the usefulness of these three dimensions in 'control panels' and clinical fingerprinting, as well as approaches to personalized medicine and the treatable features of bronchiectasis non-cystic fibrosis.

Effect of Sex Differences on Computed Tomography Findings in Adults With Cystic Fibrosis: A Multicenter Study.

BACKGROUND: The survival of women with cystic fibrosis (CF) is lower than that of men by approximately 5 years. While various factors have been put forward to account for this discrepancy, no specific reasons have been established. Our hypothesis was that anatomical-structural involvement is more pronounced in women with CF than in men and that this is reflected in thoracic HRCT findings. MATERIAL AND METHODS: We performed a prospective multicentre study, in which adult patients were consecutively included over 18 months. Chest HRCT was performed, and findings were scored by 2 thoracic radiologists using the modified Bhalla system. We also studied respiratory function, applied the CFQR 14+ questionnaire, and collected clinical variables. RESULTS: Of the 360 patients followed up in the participating units, 160 were eventually included. Mean age was 28 years, and 47.5% were women. The mean±SD global score on the modified Bhalla score was 13.7±3.8 in women and 15.2±3.8 in men (p=0.024). The highest scores were observed for sacculations, bronchial generations, and air trapping in women. Women had lower BMI, %FEV1, %FVC, and %DLCO. Similarly, the results for the respiratory domain in CFQR 14+ were worse in women, who also had more annual exacerbations. CONCLUSIONS: This is the first study to provide evidence of the implication of sex differences in HRCT findings in patients with CF. Women with CF present a more severe form of the disease that results in more frequent exacerbations, poorer functional and nutritional outcomes, deterioration of quality of life, and greater structural damage.

Predictive value of the modified Bhalla score for assessment of pulmonary exacerbations in adults with cystic fibrosis.

OBJECTIVES: The objective of this study was to analyze the predictive value of the modified Bhalla score in high-resolution computed tomography (HRCT) for assessment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) patients. We also describe the relationship between this score and pulmonary function test results. METHODS: We performed a multicenter and prospective study where adult patients with CF were included consecutively over 18 months. All patients underwent HRCT with acquisition in inspiration and expiration. The results were analyzed by an expert radiologist who assigned a modified Bhalla score value. Lung function was also assessed, and clinical variables were collected. Follow-up lasted approximately 1 year, and PEx were registered. RESULTS: The study population comprised 160 subjects selected from 360 CF patients monitored in the participating CF units. The mean age was 28 years, 47.5% were women, and mean forced expiratory volume in 1 s (FEV1) was 67.5%. The mean global modified Bhalla score was 14.5 ± 0.31 points. Pulmonary function test (PFT) results and the modified Bhalla score correlated well, mainly forced vital capacity (FVC) and FEV1. We constructed a statistical model based on the overall Bhalla score to predict the number of PEx. CONCLUSIONS: The overall modified Bhalla score can predict future PEx in CF patients. This useful tool can help to prevent PEx in higher risk patients. KEY POINTS: • Pulmonary function test results and the modified Bhalla score correlated well with FVC and FEV1. • The total modified Bhalla score can predict the number of exacerbations in adult CF patients. • Our findings highlight the need to establish a unified protocol for chest HRCT during the follow-up of adult patients with CF in order to anticipate possible complications and determine their impact on pulmonary function.

COPD Assessment Test in Bronchiectasis: Minimum Clinically Important Difference and Psychometric Validation: A Prospective Study.

BACKGROUND: Health-related quality of life (QoL) is one of the most important end points in bronchiectasis (BE). However, the majority of health-related QoL questionnaires are time-consuming or not validated in BE. The COPD Assessment Test (CAT) is an easy-to-use questionnaire. The objective of this study was to perform a complete validation of the CAT in BE. METHODS: This was an observational, multicenter, prospective study in patients with BE. Psychometric properties of the CAT were measured: internal consistency (Cronbach α), repeatability (test-retest; intraclass correlation coefficient), discriminant validity (correlation with severity scores), convergent validity (correlation with some validated QoL questionnaire and other clinical variables of interest), longitudinal validity (measuring before and after each exacerbation during follow-up to determine the sensitivity to change and responsiveness), predictive validity to future exacerbations, and finally minimum clinically important difference. RESULTS: Ninety-six patients were included and followed up for 1 year. Their mean age was 62.2 (15.6) years (79.2% women). The CAT showed excellent internal consistency (α, 0.95) and repeatability (intraclass correlation coefficient, 0.95). The validity of the CAT was excellent in all the measures (almost all with a Pearson coefficient > 0.40) except for the correlations with severity scores (Pearson coefficient between 0.22 and 0.26). Sensitivity to change before and after exacerbations was set at between 5.4 and 5.8 points. A CAT value ≥ 10 points showed prognostic value for patients with more than one exacerbation, and finally the minimum clinically important difference was set at 3 points. CONCLUSIONS: The CAT presented excellent psychometric properties and is a questionnaire that is easy to use and interpret in patients with BE.

Estudio de una cohorte de paciente con fibrosis quística y Scedosporium spp / Study of a Cohort of Patients With Cystic Fibrosis and Isolation of Scedosporium spp

Introducción: En los últimos años se observa un aumento de la prevalencia de colonización e infección por Scedosporium spp. en pacientes con fibrosis quística (FQ). En el presente estudio se registra la frecuencia de aislamiento de Scedosporium spp. en una Unidad de FQ de adultos, analizándose las características de los pacientes y los factores predisponentes. Métodos: Se realizó un estudio observacional retrospectivo en 87 pacientes adultos con FQ en los que se valoró la presencia de cultivo positivo para Scedosporium spp. durante 5 años (enero de 2012-julio de 2017). Se recogieron las siguientes variables clínicas: edad, sexo, índice de masa corporal, genotipo, presencia de insuficiencia pancreática, colonizaciones bacterianas, función pulmonar, complicaciones, exacerbaciones y tratamiento, así como puntuación Bhalla modificada de la última tomografía computarizada axial de alta resolución. Los resultados se analizaron con el paquete estadístico IBM SPSS Statistics Version 22.0. Resultados: En un 25,3% de los pacientes se aisló Scedosporium spp. En el análisis bivariante se observó en estos enfermos más frecuencia de Pseudomonas aeruginosa, peor puntuación en la clasificación de Bhalla (destacando los ítems presencia de bronquiectasias, tapones mucosos y generaciones bronquiales), un descenso leve en la capacidad de difusión pulmonar (DLCO) y que recibían con más frecuencia antibioterapia inhalada. En el análisis multivariante de regresión logística únicamente el ítem generaciones bronquiales fue significativo. Conclusiones: Scedosporium spp. debe considerarse un patógeno oportunista emergente en pacientes con FQ del que se desconoce su implicación clínica, factores de riesgo o necesidad de tratamiento

Introduction: In recent years an increase in the prevalence of colonization and infection by Scedosporium spp. in patients with cystic fibrosis (CF) has been observed. In this article, we study the frequency of isolation of Scedosporium spp. in an adult CF Unit, analyzing characteristics of the patients and predisposing factors. Methods: A retrospective observational study was conducted in 87 adult CF patients in whom the presence of positive culture for Scedosporium spp. was tested for a 5-year period (January 2012-July 2017). We recorded the following clinical variables: age, sex, body mass index, genotype, presence of pancreatic insufficiency, bacterial colonization, lung function, other complications, exacerbations and treatment, and the modified Bhalla score from the last high-resolution computed tomography. Results were analyzed with IBM SPSS Statistics Version 22.0 software. Results: Scedosporium spp. was isolated in 25.3% of patients. In the bivariate analysis, these patients showed a higher rate of Pseudomonas aeruginosa infection, worse score in the Bhalla classification (highlighting the following items: bronchiectasis, mucus plugs and bronchial generations), a slight decrease in the lung diffusion capacity and more frequently received inhaled antibiotics. In the logistic regression multivariate analysis, only the bronchial generations item was significant. Conclusion: Scedosporium spp. must be considered an emerging opportunistic pathogen in patients with CF whose clinical involvement, risk factors or need for treatment is unknown