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OBJECTIVES: Physical activity is reduced in patients with interstitial lung disease (ILD) and physical inactivity is related to poor health outcomes. We investigated the effect of a telecoaching intervention to improve physical activity in patients with ILD. METHODS: Eighty patients with ILD were randomized into the intervention or control group. Patients in the intervention group received a 12-week telecoaching program including a step counter, a patient-tailored smartphone application, and coaching calls. Patients in the control group received usual care. Physical activity (primary outcome), physical fitness and quality of life were measured at baseline and 12 weeks later with an accelerometer, 6-min walking test and quadriceps muscle force and the King's Brief Interstitial Lung Disease questionnaire (K-BILD). RESULTS: Participation in telecoaching did not improve physical activity: between-group differences for step count: 386 ± 590 steps/day, p = .52; sedentary time: 4 ± 18 min/day, p = .81; movement intensity: 0.04 ± 0.05 m/s2, p = .45). Between-group differences for the 6-min walking test, quadriceps muscle force and K-BILD were 14 ± 10 m, p = .16; 2 ± 3% predicted, p = .61; 0.8 ± 1.7 points, p = .62 respectively. CONCLUSIONS: Twelve weeks of telecoaching did not improve physical activity, physical fitness or quality of life in patients with ILD. Future physical or behavioural interventions are needed for these patients to improve physical activity.
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Doenças Pulmonares Intersticiais , Tutoria , Humanos , Qualidade de Vida , Doenças Pulmonares Intersticiais/terapia , Exercício Físico , Inquéritos e QuestionáriosRESUMO
INTRODUCTION: Physical activity (PA) is reduced in patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Evidence about the PA pattern of patients with ILD is scarce. If PA of patients with ILD would be comparable to COPD, it is tempting to speculate that existing interventions focusing on enhancing PA could be as effective in ILD as already shown in COPD. Therefore, we aimed to compare PA and the correlates with PA in matched patients with ILD, COPD, and healthy subjects. MATERIALS AND METHODS: Patients with ILD (n = 45), COPD (n = 45) and healthy subjects (n = 30) were propensity matched. PA level, pattern, and PA correlations with lung function and physical performance (6-minute walking distance and quadriceps force) were compared between groups. RESULTS: Daily number of steps was similar in both patient groups (mean±SE: 5631±459 for ILD, 5544±547 for COPD, p = 0.900), but significantly lower compared to healthy subjects (10031±536, p<0.001 for both). Mean intensity of PA tended to be lower in the ILD group (mean±SE metabolic equivalents of task per day: 1.41±0.04) compared to COPD (1.52±0.05, p = 0.074) and healthy individuals (1.67±0.04, p<0.001). The pattern of PA over one day was found to be similar between the three groups. Lastly, the correlation between PA and 6-minute walking distance was significantly weaker in patients with ILD compared to patients with COPD (respectively r = 0.348 and r = 0.739; p<0.05 for both). CONCLUSIONS: For a given functional reserve, patients with ILD perform an equal amount of steps but perform PA at lower intensity compared to patients with COPD. Both groups are less active compared to healthy control subjects. Functional exercise capacity was shown to be only moderately related to PA. This can potentially influence the effectiveness of PA interventions that can be expected.
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Doenças Pulmonares Intersticiais , Doença Pulmonar Obstrutiva Crônica , Humanos , Exercício Físico , Nível de SaúdeRESUMO
BACKGROUND: Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets. METHODS: In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed. RESULTS: We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of TBX21 (encoding T-bet) and RORC (ROR-γ), IFN-G (IFN-γ), IL-17A, CSF2 (GM-CSF), and cytotoxicity genes. Type 1 regulatory T cells and naïve-like CD4+ T cells were also enriched. Within the CD8+ T-cell compartment, mainly effector memory T cells were increased. Correspondingly, myeloid cells in ICI-pneumonitis bronchoalveolar lavage fluid were relatively depleted of anti-inflammatory resident alveolar macrophages while pro-inflammatory 'M1-like' monocytes (expressing TNF, IL-1B, IL-6, IL-23A, and GM-CSF receptor CSF2RA, CSF2RB) were enriched compared with control samples. Importantly, a feedforward loop, in which GM-CSF production by pathogenic T-helper 17.1 cells promotes tissue inflammation and IL-23 production by pro-inflammatory monocytes and vice versa, has been well characterized in multiple autoimmune disorders but has never been identified in ICI-related pneumonitis. CONCLUSIONS: Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.
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Fator Estimulador de Colônias de Granulócitos e Macrófagos , Pneumonia , Anti-Inflamatórios , Proteínas Reguladoras de Apoptose , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Interleucina-17 , Interleucina-6 , Monócitos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , RNA , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , TranscriptomaRESUMO
The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome.
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Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Predisposição Genética para Doença , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/cirurgia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/cirurgia , Mucina-5B/genética , Polimorfismo Genético , Regiões Promotoras GenéticasRESUMO
BACKGROUND: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another. RESEARCH QUESTION: Do IPF endotypes exist and are they associated with outcome? STUDY DESIGN AND METHODS: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples. RESULTS: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score-corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotype-specific survival-associated genes. INTERPRETATION: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.
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Fibrose Pulmonar Idiopática , Humanos , Pulmão/metabolismo , Prognóstico , Fatores de Transcrição/metabolismo , TranscriptomaRESUMO
BACKGROUND: Sarcoidosis is a non-caseating granulomatous disease, mostly affecting previously healthy persons in their fourth and fifth decade. In Belgium, there is a paucity of epidemiological data concerning sarcoidosis and it is unknown to what respect national data on sarcoidosis relates to the global epidemiology of the disease. OBJECTIVES: In this cohort study we describe the patient population in an academic center of reference, serving both as a regional care center and a center for a tertiary referral. METHODS: We collected epidemiological data among 234 consecutive patients consulting the outpatient sarcoidosis clinic during a two-year time period. We manually explored the electronic patient file for data retrieval. RESULTS: Out of the 234 patients, 140 are male (60%) and 94 are female (40%) patients. Forced vital capacity showed a median decline of 2% during follow-up, whereas median diffusion capacity increased with 4% over the same period of time. Within our study cohort, we observed a preponderance in employment as construction workers (14%), the chemical industry (6%) and in the metal processing industry (6%). CONCLUSION: The current study reports on epidemiological findings among the largest cohort of sarcoidosis patients in Belgium published to date.Graphical abstract [Figure: see text].
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Sarcoidose , Bélgica/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Sarcoidose/epidemiologiaRESUMO
Randomized placebo-controlled trials demonstrated the efficacy of antifibrotic treatment in non-IPF progressive fibrosing ILD (fILD). Currently, there is no consensus on how progression should be defined and clinical data of non-IPF fILD patients in a real-world setting are scarce. Non-IPF fILD patients presenting at the University Hospitals Leuven between 2012 and 2016 were included. Different definitions of progression according to the selection criteria of the INBUILD, RELIEF and the uILD study were retrospectively evaluated at every hospital visit. Univariate and multivariate analyses were performed to identify predictors of progression and mortality. The study cohort comprised 120 patients; 68.3%, 54.2% and 65.8% had progressive disease based on the INBUILD, RELIEF and uILD study, respectively. A large overlap of progressive fILD patients according to the different clinical trials was observed. Median transplant-free survival time of progressive fILD patients was 3.9, 3.9, 3.8 years and the median time-to-progression after diagnosis was 2.0, 3.1 and 2.3 years according to the INBUILD, RELIEF and uILD study, respectively. We identified several predictors of mortality, but only an underlying diagnosis of HP and uILD was independently associated with progression. Our data show a high prevalence of progressive fibrosis among non-IPF fILD patients and a discrepancy between predictors of mortality and progression. Mortality rate in fILD is high and the identification of progressive disease is only made late during the disease course. Moreover, future treatment decisions will be based upon disease behavior. Therefore, more predictors of progressive disease are needed to guide treatment decisions in the future.
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Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/fisiopatologia , Idoso , Bélgica/epidemiologia , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Sarcoidosis most commonly affects lungs and intrathoracic lymph nodes, but any other organ can be involved. In epidemiological studies, many occupational and environmental exposures have been linked to sarcoidosis but their relationship with the disease phenotype has barely been studied. OBJECTIVE: To investigate how occupational and environmental exposures prior to diagnosis relate to organ involvement in patients with sarcoidosis METHODS: We retrospectively studied patients seen at a sarcoidosis clinic between 2017 and 2020. Patients were included if they had a clinical presentation consistent with sarcoidosis and histologically confirmed epithelioid granulomas or had Löfgren syndrome. In a case-case analysis using multivariable logistic regression we calculated odds ratios (OR) of prespecified exposure categories (based on expert ascertainment) for cases with a given organ involvement versus cases without this organ involvement. RESULTS: We included 238 sarcoidosis patients. Sarcoidosis limited to pulmonary involvement was associated with exposure to inorganic dust prior to diagnosis (OR 2.11; 95% confidence interval [CI] 1.11-4.17). Patients with liver involvement had higher odds of contact with livestock (OR 3.68; 95% CI 0.91-12.7) or having jobs with close human contact (OR 4.33; 95% CI 1.57-11.3) than patients without liver involvement. Similar associations were found for splenic involvement (livestock: OR 4.94, 95% CI 1.46-16.1; close human contact: OR 3.78; 95% CI 1.47-9.46). Cardiac sarcoidosis was associated with exposure to reactive chemicals (OR 5.08; 95% CI 1.28-19.2) or livestock (OR 9.86; 95% CI 1.95-49.0). Active smokers had more ocular sarcoidosis (OR 3.26; 95% CI 1.33-7.79). CONCLUSIONS: Our study indicates that, in sarcoidosis patients, different exposures might be related to different organ involvements-hereby providing support for the hypothesis that sarcoidosis has more than one cause, each of which may promote a different disease phenotype.
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Poeira , Exposição Ambiental/efeitos adversos , Pulmão/patologia , Linfonodos/patologia , Exposição Ocupacional/efeitos adversos , Sarcoidose Pulmonar/diagnóstico , Adulto , Animais , Feminino , Humanos , Gado , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sarcoidose Pulmonar/epidemiologia , Sarcoidose Pulmonar/etiologia , Fumar/efeitos adversos , Fumar/epidemiologiaRESUMO
This review aims to provide an overview of pre-transplant antifibrotic therapy on peri-transplant outcomes and to address the possible role of antifibrotics in lung transplant recipients with chronic lung allograft dysfunction.Lung transplantation is an established treatment modality for patients with various end-stage lung diseases, of which idiopathic pulmonary fibrosis and other progressive fibrosing interstitial lung diseases are growing indications. Theoretically, widespread use of antifibrotics prior to lung transplantation may increase the risk of bronchial anastomotic complications and impaired wound healing.Long-term graft and patient survival are still hampered by development of chronic lung allograft dysfunction, on which antifibrotics may have a beneficial impact.Antifibrotics until the moment of lung transplantation proved to be safe, without increasing peri-transplant complications. Currently, best practice is to continue antifibrotics until time of transplantation. In a large multicentre randomised trial, pirfenidone did not appear to have a beneficial effect on lung function decline in established bronchiolitis obliterans syndrome. The results of antifibrotic therapy in restrictive allograft syndrome are eagerly awaited, but nonrandomised data from small case reports/series are promising.
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Antifibróticos , Fibrose Pulmonar Idiopática , Transplante de Pulmão , Aloenxertos , Antifibróticos/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/cirurgia , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos RetrospectivosRESUMO
BACKGROUND: Lung transplantation (LTx) requires a calcineurin inhibitor-based immunosuppressive regimen. A once daily (QD) tacrolimus regimen was developed to increase medication adherence. However, data concerning its safety and efficacy in LTx are lacking. METHODS: In this prospective study, stable LTx patients were consecutively converted from twice daily (BID) tacrolimus to QD tacrolimus on a 1 mg:1 mg basis. Trough level (Cmin), renal function, cholesterol, fasting glucose, potassium and lung function were monitored six months before and up to one year after conversion. Adherence and its barriers were assessed by self-reported questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and Identification of Medication Adherence Barriers questionnaire (IMAB)) and blood-based assays (mean Cmin and coefficient of variation (CV)). RESULTS: We included 372 patients, in whom we observed a decrease in tacrolimus Cmin of 18.5% (p < 0.0001) post-conversion, requiring subsequent daily dose adaptations in both cystic fibrosis (CF) (nâ¯=â¯72) and non-CF patients (nâ¯=â¯300). We observed a small decrease in eGFR one year post-conversion (p = 0.024). No significant changes in blood creatinine, potassium, fasting glucose, cholesterol or rate of lung function decline were observed. In a subgroup of 166 patients, significantly fewer patients missed doses (8.4% vs. 19.3%, pâ¯=â¯0.016) or had irregular intake post-conversion (19.3% vs. 32.5%, pâ¯=â¯0.019). Mean Cmin and CV, as well as the total number of barriers, also decreased significantly post-conversion. CONCLUSIONS: In LTx, conversion from BID to QD tacrolimus (1 mg:1 mg) requires close monitoring of tacrolimus Cmin. QD tacrolimus after transplantation is safe with respect to renal function, metabolic parameters and allograft function and improves LTx recipient adherence.
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Rejeição de Enxerto/prevenção & controle , Transplante de Pulmão , Adesão à Medicação , Tacrolimo/administração & dosagem , Adulto , Aloenxertos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness of idiopathic pulmonary fibrosis (IPF). Common pathophysiological mechanisms such as a shared genetic susceptibility and a common downstream pathway-self-sustaining fibroproliferation-support the concept of a progressive fibrosing phenotype, which is applicable to a broad range of non-IPF ILDs. While antifibrotic drugs became the standard of care in IPF, immunosuppressive agents are still the mainstay of treatment in non-IPF fibrosing ILD (F-ILD). However, recently, randomized placebo-controlled trials have demonstrated the efficacy and safety of antifibrotic treatment in systemic sclerosis-associated F-ILD and a broad range of F-ILDs with a progressive phenotype. This review summarizes the current pharmacological management and highlights the unmet needs in patients with non-IPF ILD.
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BACKGROUND: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking. RESEARCH QUESTION: What is the role of the (small) airways in fibrotic sarcoidosis? STUDY DESIGN AND METHODS: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes. RESULTS: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was inversely correlated with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination. INTERPRETATION: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis.
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Bronquiectasia/patologia , Doenças Pulmonares Intersticiais/patologia , Fibrose Pulmonar/patologia , Sarcoidose Pulmonar/patologia , Idoso , Bélgica , Bronquiectasia/diagnóstico por imagem , Progressão da Doença , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Transplante de Pulmão , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/cirurgia , Sarcoidose Pulmonar/diagnóstico por imagem , Sarcoidose Pulmonar/cirurgia , Tomografia Computadorizada por Raios X , Microtomografia por Raio-XRESUMO
How the innate and adaptive host immune system miscommunicate to worsen COVID-19 immunopathology has not been fully elucidated. Here, we perform single-cell deep-immune profiling of bronchoalveolar lavage (BAL) samples from 5 patients with mild and 26 with critical COVID-19 in comparison to BALs from non-COVID-19 pneumonia and normal lung. We use pseudotime inference to build T-cell and monocyte-to-macrophage trajectories and model gene expression changes along them. In mild COVID-19, CD8+ resident-memory (TRM) and CD4+ T-helper-17 (TH17) cells undergo active (presumably antigen-driven) expansion towards the end of the trajectory, and are characterized by good effector functions, while in critical COVID-19 they remain more naïve. Vice versa, CD4+ T-cells with T-helper-1 characteristics (TH1-like) and CD8+ T-cells expressing exhaustion markers (TEX-like) are enriched halfway their trajectories in mild COVID-19, where they also exhibit good effector functions, while in critical COVID-19 they show evidence of inflammation-associated stress at the end of their trajectories. Monocyte-to-macrophage trajectories show that chronic hyperinflammatory monocytes are enriched in critical COVID-19, while alveolar macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, are depleted. In critical COVID-19, monocytes contribute to an ATP-purinergic signaling-inflammasome footprint that could enable COVID-19 associated fibrosis and worsen disease-severity. Finally, viral RNA-tracking reveals infected lung epithelial cells, and a significant proportion of neutrophils and macrophages that are involved in viral clearance.
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Imunidade Adaptativa , Lavagem Broncoalveolar , COVID-19/diagnóstico , COVID-19/imunologia , Imunidade Inata , Análise de Célula Única , Líquido da Lavagem Broncoalveolar , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Comunicação Celular , Perfilação da Expressão Gênica , Humanos , Pulmão/virologia , Macrófagos Alveolares/citologia , Monócitos/citologia , Neutrófilos/citologia , Fenótipo , Análise de Componente Principal , RNA-Seq , Células Th17/citologiaAssuntos
Broncoscopia , COVID-19 , Teste para COVID-19 , Humanos , Pandemias , RNA Viral , SARS-CoV-2RESUMO
OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood. The predominant subtypes, oligoarticular and polyarticular JIA, are traditionally considered to be autoimmune diseases with a central role for T cells and autoantibodies. Mounting evidence suggests an important role for neutrophils in JIA pathogenesis. We undertook this study to investigate the phenotypic features of neutrophils present in the blood and inflamed joints of patients. METHODS: JIA synovial fluid (SF) and parallel blood samples from JIA patients and healthy children were collected. SF-treated neutrophils from healthy donors and pleural neutrophils from patients with pleural effusion were investigated as controls for SF exposure and extravasation. Multicolor flow cytometry panels allowed for in-depth phenotypic analysis of neutrophils, focusing on the expression of adhesion molecules, activation, and maturation markers and chemoattractant receptors. Multiplex technology was used to quantify cytokines in plasma and SF. RESULTS: SF neutrophils displayed an activated, hypersegmented phenotype with decreased CD62L expression, up-regulation of adhesion molecules CD66b, CD11b, and CD15, and down-regulation of CXCR1/2. An elevated percentage of CXCR4-positive neutrophils was detected in SF from patients. Pleural neutrophils showed less pronounced maturation differences. Strikingly, significant percentages of SF neutrophils showed a profound up-regulation of atypical neutrophil markers, including CXCR3, intercellular adhesion molecule 1, and HLA-DR. CONCLUSION: Our data show that neutrophils in inflamed joints of JIA patients have an activated phenotype. This detailed molecular analysis supports the notion that a complex intertwining between these innate immune cells and adaptive immune events drives JIA.
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Artrite Juvenil/imunologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Receptores CXCR3/imunologia , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8B/imunologia , Líquido Sinovial/citologia , Imunidade Adaptativa/imunologia , Adolescente , Antígenos CD/metabolismo , Artrite Juvenil/metabolismo , Antígeno CD11b/metabolismo , Adesão Celular , Moléculas de Adesão Celular/metabolismo , Criança , Pré-Escolar , Regulação para Baixo , Feminino , Citometria de Fluxo , Proteínas Ligadas por GPI/metabolismo , Antígenos HLA-DR/imunologia , Humanos , Imunidade Inata/imunologia , Imunofenotipagem , Molécula 1 de Adesão Intercelular/metabolismo , Selectina L/imunologia , Antígenos CD15/metabolismo , Masculino , Neutrófilos/metabolismo , Derrame Pleural , Regulação para CimaRESUMO
BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial lung disease with poor prognosis despite the recent availability of two antifibrotic drugs. Patients are more susceptible to cardiovascular comorbidities. In this study, we aimed to determine the impact of concomitant cardiovascular drugs on disease progression and survival in a modern IPF cohort. METHODS: The database of a tertiary referral centre for interstitial lung diseases in Belgium was reviewed for statin, antiaggregant, anticoagulant and metformin therapy. For a study period of four years, we noted both FVC% and DLCO% trajectories along with survival as outcome measurements. RESULTS: 323 patients were included of which 45% had at least one cardiovascular comorbidity. 274 (86%) patients received antifibrotic therapy. Statin users (n = 171) displayed significantly slower annual FVC% (difference 2.9%, CI 1.6-4.4, p < 0.001) and DLCO% decline (difference 1.3%, CI 0.24-2.3, p = 0.013). Results for antiaggregant therapy (n = 152) were inconclusive: we found a trend for slower FVC decline (p = 0.098) and a numerically decrease in survival rates (HR 1.63, p = 0.074) in a multivariate Cox analysis. Anticoagulant use (n = 49) showed a trend towards worse DLCO decline (difference -1.3%, CI -2.6 - 0.02, p = 0.055).r Metformin (n = 28) therapy did not affect IPF progression in terms of pulmonary function test evolution or survival. CONCLUSION: This retrospective study demonstrated a benefit of statin therapy on IPF progression. Our observations emphasize the need for large clinical trials analysing the effect of statins, as well as other cardiovascular drugs, in the management of IPF patients.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/prevenção & controle , Idoso , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Comorbidade , Progressão da Doença , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Capacidade VitalRESUMO
Several case reports and small case series have been published on coronavirus disease 2019 infection after solid organ transplantation; however, thus far there are limited data on coronavirus disease 2019 infections in lung transplant patients. In the present single-center case series we discuss 10 lung transplant patients with a documented severe acute respiratory syndrome coronavirus 2 infection, diagnosed with nasopharyngeal swab in 8 and bronchoalveolar lavage in 2. Eight of 10 patients needed hospital admission, of whom 1 was in the intensive care unit. He died after 2 weeks from multiple organ failure. The remaining nine patients recovered. Cell cycle inhibitors were withheld in all patients, whereas the calcineurin inhibitor and corticosteroids were continued at the same dose, with an acceptable outcome.