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.

The cardiomyopathy of cystic fibrosis: a modern form of Keshan disease.

Introduction: We conducted a study to determine the prevalence of structural heart disease in patients with CF, the characteristics of a cardiomyopathy not previously described in this population, and its possible relationship with nutritional deficiencies in CF. Methods: We studied 3 CMP CF patients referred for heart-lung transplantation and a prospective series of 120 adult CF patients. All patients underwent a clinical examination, blood tests including levels of vitamins and trace elements, and echocardiography with evaluation of myocardial strain. Cardiac magnetic resonance imaging (CMR) was performed in patients with CMP and in a control group. Histopathological study was performed on hearts obtained in transplant or necropsy. Results: We found a prevalence of 10% (CI 4.6%-15.4%) of left ventricular (LV) dysfunction in the prospective cohort. Myocardial strain parameters were already altered in CF patients with otherwise normal hearts. Histopathological examination of 4 hearts from CF CMP patients showed a unique histological pattern of multifocal myocardial fibrosis similar to Keshan disease. Four of the five CF CMP patients undergoing CMR showed late gadolinium uptake, with a characteristic patchy pattern in 3 cases (p < 0.001 vs. CF controls). Selenium deficiency (Se < 60 µg/L) was associated with more severe LV dysfunction, higher prevalence of CF CMP, higher NTproBNP levels, and more severe pulmonary and digestive involvement. Conclusion: 10% of adults with CF showed significant cardiac involvement, with histological and imaging features resembling Keshan disease. Selenium deficiency was associated with the presence and severity of LV dysfunction in these patients.

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease

Introduction: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. Methodology: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. Results: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. Conclusions: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug. (AU)

Mycobacterial infection after COVID-19 pneumonia / Infección por micobacterias tras neumonía por COVID-19

A 69-year-old man with a history of hypertrophic cardiomyopathy and major depressive disorder was admitted to the Emergency Department with fever, weakness, and shortness of breath. He was diagnosed with acute respiratory distress syndrome due to COVID-19 and received oxygen and steroids during a one-month hospital stay. After discharge, he continued steroids and home oxygen therapy for nearly two years. CT scans revealed bronchiectasis and ground glass opacities related to COVID-19. He developed pulmonary nodules and M. intracellulare infection, which were treated with rifampicin, ethambutol, and azithromycin. After six months of treatment, the patient showed clinical and radiological improvement (AU)

Un hombre de 69 años con antecedentes de miocardiopatía hipertrófica y trastorno depresivo mayor acudió a urgencias por fiebre, debilidad y dificultad respiratoria. Se le diagnosticó síndrome de distrés respiratorio agudo debido a COVID-19 y fue ingresado en planta de neumología, donde recibió oxígeno y esteroides durante 1 mes. Después del alta continuó con esteroides y oxigenoterapia domiciliaria durante casi 2 años. Las tomografías objetivaron bronquiectasias y opacidades en vidrio deslustrado relacionadas con la COVID-19. Desarrolló nódulos pulmonares e infección por Mycobacterium intracellulare, siendo tratado con rifampicina, etambutol y azitromicina. Después de 6 meses de tratamiento, el paciente mostró mejoría clínica y radiológica (AU)

Experience With Elexacaftor/Tezacaftor/Ivacaftor in Patients With Cystic Fibrosis and Advanced Disease.

INTRODUCTION: Elexacaftor/tezacaftor/ivacaftor (ETI) was used through the early access programme in Spain from December 2019 in cystic fibrosis (CF) patients with homozygous or heterozygous F508del mutation with advanced lung disease. METHODOLOGY: Multicentre, ambispective, observational, study in which 114 patients in follow-up in 16 national CF units were recruited. Clinical data, functional tests, nutritional parameters, quality of life questionnaires, microbiological isolates, number of exacerbations, antibiotic treatments and side effects were collected. The study also compared patients with homozygous and heterozygous F508del mutations. RESULTS: Of the 114 patients, 85 (74.6%) were heterozygous for F508del mutation, and the mean age was 32.2±9.96 years. After 30 months of treatment, lung function measured by FEV1% showed improvement from 37.5 to 48.6 (p<0.001), BMI increased from 20.5 to 22.3 (p<0.001), and all isolated microorganisms decreased significantly. The total number of exacerbations was also significantly reduced from 3.9 (±2.9) to 0.9 (±1.1) (p<0.001). All items in the CFQ-R questionnaire showed improvement, except for the digestive domain. Oxygen therapy use decreased by 40%, and only 20% of patients referred for lung transplantation remained on the active transplant list. ETI was well-tolerated, with only 4 patients discontinuing treatment due to hypertransaminemia. CONCLUSIONS: ETI decreases the number of exacerbations, increases lung function and nutritional parameters, decrease in all isolated microorganisms, for 30 months of treatment. There is an improvement in the CFQ-R questionnaire score except for the digestive item. It is a safe and well-tolerated drug.

Genitourinary tract symptoms in patients admitted with COVID-19: Exploring changes in frequency by determinants and pandemic waves.

Background: Urothelial cells exhibit increased expression of angiotensin-converting enzyme-2 receptor, which is the binding site of severe acute respiratory syndrome coronavirus 2 to cells. The frequency and distribution of genitourinary tract symptoms in patients diagnosed with coronavirus disease 2019 (COVID-19) is unknown. Objective: We explored trends in genitourinary tract symptoms by gender and each of six pandemic waves in patients admitted for COVID-19, and related them with severity, death and length of hospitalization. Design Setting and Participants: A retrospective study took place in our institution of COVID-19 admitted patients. Only patients with RT-PCR or antigen test confirmed SARS-CoV-2 infection were included. Demographic, clinical, and genitourinary symptoms were explored. Outcome Measurements and Statistical Analysis: COVID-19 patients with genitourinary tract symptoms were compared with those without. Statistical comparisons were conducted by parametric and nonparametric tests for quantitative variables, and χ 2 test for qualitative variables. Results and limitations: Out of a total of 4,661 COVID-19 patients, genitourinary symptoms were found in 21,1%. These symptoms were more frequent in patients admitted for longer than 30 days, except for urinary incontinence (UI) and erectile dysfunction (ED). Acute kidney injury (AKI) and urinary tract infections (UTI) had a higher presence in the 5th (16.7%; 12.8% respectively) and 3rd wave (13.3%; 12.6% respectively). Genitourinary symptoms were higher for those patients admitted in critical care units. Frequency of AKI, UI, UTI and acute urinary retention (AUR) were higher for patients who were finally deceased (26.2%; 3.5%; 13.6% and 3.6% respectively). Conclusions: A high frequency of genitourinary symptoms in patients admitted for COVID-19 was observed, whose frequency and distribution varied according to pandemic waves. Specific genitourinary conditions were associated with worse outcomes and poorer prognosis.

Fungal microbiota dynamics and its geographic, age and gender variability in patients with cystic fibrosis.

OBJECTIVES: In cystic fibrosis (CF), there is a predisposition to bronchial colonization by potentially pathogenic microorganisms, such as fungi. Our aims were to describe the dynamics of respiratory mycobiota in patients with CF and to evaluate the geographic, age and gender variability in its distribution. METHODS: Cohort study in which 45 patients with CF from four hospitals in three Spanish cities were followed up during a 1-year period, obtaining spontaneous sputum samples every 3 to 6 months. Fungal microbiota were characterized by Internal Transcribed Spacer sequencing and Pneumocystis jirovecii was identified by nested PCR in a total of 180 samples. RESULTS: The presence of fungi were detected in 119 (66.11%) of the 180 samples and in 44 (97.8%) of the 45 patients: 19 were positive and 1 negative throughout all follow-ups and the remaining 25 presented alternation between positive and negative results. A total of 16 different genera were identified, with Candida spp. (50/180, 27.78%) and Pneumocystis spp. (44/180, 24.44%) being the most prevalent ones. The distribution of fungal genera was different among the evaluated centres (p < 0.05), by age (non-adults aged 6-17 years vs. adults aged ≥18 years) (p < 0.05) and by gender (p < 0.05). DISCUSSION: A high prevalence of fungal respiratory microbiota in patients with CF was observed, whose dynamics are characterized by the existence of multiple cycles of clearance and colonization, reporting the existence of geographic, age and gender variability in the distribution of fungal genera in this disease.

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)

Real Life With Tezacaftor and Ivacaftor in Adult Patients With Cystic Fibrosis: Spanish Multicenter Study

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Impact of the SARS-CoV-2 Virus Pandemic on Patients with Bronchiectasis: A Multicenter Study.

BACKGROUND: Infection by SARS-CoV-2 has unquestionably had an impact on the health of patients with chronic respiratory airway diseases, such as COPD and asthma, but little information is available about its impact on patients with bronchiectasis. The objective of the present study was to analyze the effect of the SARS-CoV-2 pandemic on the state of health, characteristics, and clinical severity (including the number and severity of exacerbations) of patients with non-cystic fibrosis bronchiectasis. METHODS: This study was multicenter, observational, and ambispective (with data collected before and during the SARS-CoV-2 pandemic), and included 150 patients diagnosed with non-cystic fibrosis bronchiectasis. RESULTS: A significant drop was observed in the number and severity of the exacerbations (57% in all exacerbations and 50% in severe exacerbations) in the E-FACED and BSI multidimensional scores, in the pandemic, compared with the pre-pandemic period. There was also a drop in the percentage of sputum samples positive for pathogenic microorganisms in general (from 58% to 44.7%) and, more specifically, Pseudomonas aeruginosa (from 23.3% to 13.3%) and Haemophilus influenzae (from 21.3% to 14%). CONCLUSIONS: During the SARS-CoV-2 period, a significant reduction was observed in the exacerbations, severity, and isolations of pathogenic microorganisms in patients with bronchiectasis.

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.