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INTRODUCTION: Although COPD may frequently co-exist with bronchiectasis [COPD-bronchiectasis associated (CBA)], little is known regarding the clinical heterogeneity. We aimed to identify the phenotypes and compare the clinical characteristics and prognosis of CBA. METHODS: We conducted a retrospective cohort study involving 2928 bronchiectasis patients, 5158 COPD patients, and 1219 patients with CBA hospitalized between July 2017 and December 2020. We phenotyped CBA with a two-step clustering approach and validated in an independent retrospective cohort with decision-tree algorithms. RESULTS: Compared with patients with COPD or bronchiectasis alone, patients with CBA had significantly longer disease duration, greater lung function impairment, and increased use of intravenous antibiotics during hospitalization. We identified five clusters of CBA. Cluster 1 (N=120, CBA-MS) had predominantly moderate-severe bronchiectasis, Cluster 2 (N=108, CBA-FH) was characterized by frequent hospitalization within the previous year, Cluster 3 (N=163, CBA-BI) had bacterial infection, Cluster 4 (N=143, CBA-NB) had infrequent hospitalization but no bacterial infection, and Cluster 5 (N=113, CBA-NHB) had no hospitalization or bacterial infection in the past year. The decision-tree model predicted the cluster assignment in the validation cohort with 91.8% accuracy. CBA-MS, CBA-BI, and CBA-FH exhibited higher risks of hospital re-admission and intensive care unit admission compared with CBA-NHB during follow-up (all P<0.05). Of the five clusters, CBA-FH conferred the worst clinical prognosis. CONCLUSION: Bronchiectasis severity, recent hospitalizations and sputum culture findings are three defining variables accounting for most heterogeneity of CBA, the characterization of which will help refine personalized clinical management.
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Bronquiectasia , Hospitalização , Fenótipo , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Masculino , Estudos Retrospectivos , Feminino , Idoso , Pessoa de Meia-Idade , Hospitalização/estatística & dados numéricos , Prognóstico , Árvores de Decisões , Antibacterianos/uso terapêutico , Análise por ConglomeradosAssuntos
Bronquiectasia , Fosfatos de Cálcio , Escarro , Humanos , Cor , Bronquiectasia/diagnóstico , Biomarcadores , Sistema de RegistrosRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/metabolismo , Inflamação/genética , Inflamação/metabolismo , Transdução de Sinais , Células Epiteliais/metabolismo , GlucocorticoidesRESUMO
PURPOSE: Although estrogen receptors (ERs) signal pathways are involved in the pathogenesis and development of asthma, their expressions and effects remain controversial. This study aimed to investigate the expressions of ERα and ERß as well as their mechanisms in airway remodeling and mucus production in asthma. METHODS: The expressions of ERα and ERß in the airway epithelial cells of bronchial biopsies and induced sputum cells were examined by immunohistochemistry. The associations of ERs expressions with airway inflammation and remodeling were evaluated in asthmatic patients. In vitro, the regulations of ERs expressions in human bronchial epithelial cell lines were examined using western blot analysis. The epidermal growth factor (EGF)-mediated ligand-independent activation of ERα and its effect on epithelial-mesenchymal transitions (EMTs) were investigated in asthmatic epithelial cells by western blot, immunofluorescent staining, and quantitative real-time polymerase chain reaction. RESULTS: ERα and ERß were expressed on both bronchial epithelial cells and induced sputum cells, and the expressions showed no sex difference. Compared to controls, male asthmatic patients had higher levels of ERα on the bronchial epithelium, and there were cell-specific expressions of ERα and ERß in induced sputum. The expression of ERα in the airway epithelium was inversely correlated to forced expiratory volume in 1 second (FEV1) % and FEV1/forced vital capacity. Severe asthmatic patients had significantly greater levels of ERα in the airway epithelium than mild-moderate patients. ERα level was positively correlated with the thickness of the subepithelial basement membrane and airway epithelium. In vitro, co-stimulation of interleukin (IL)-4 and EGF increased the expression of ERα and promoted its nuclear translocation. EGF activated the phosphorylation of ERα via extracellular signal-regulated kinase and c-Jun N-terminal kinase pathways. ERα knockdown alleviated EGF-mediated EMTs and mucus production in airway epithelial cells of asthma. CONCLUSIONS: ERα contributes to asthmatic airway remodeling and mucus production through the EGF-mediated ligand-independent pathway.
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Background: Asthma patients potentially have impaired adaptive immunity to virus infection. The levels of SARS-CoV-2-specific adaptive immunity between COVID-19 survivors with and without asthma are presently unclear. Methods: COVID-19 survivors (patients with asthma n=11, with allergies n=8, and COVID-19 only n=17) and non-COVID-19 individuals (asthmatic patients n=10 and healthy controls n=9) were included. The COVID-19 patients were followed up at about 8 months and 16 months after discharge. The clinical characteristics, lymphocyte subsets, memory T cells, and humoral immunity including SARS-CoV-2 specific antibodies, SARS-CoV-2 pseudotyped virus neutralization assay, and memory B cells were analyzed in these subjects. Results: The strength of virus-specific T cell response in COVID-19 survivors was positively correlated with the percentage of blood eosinophils and Treg cells (r=0.4007, p=0.0188; and r=0.4435, p=0.0086 respectively) at 8-month follow-up. There were no statistical differences in the levels of SARS-CoV-2-specific T cell response between the COVID-19 survivors with, and without, asthma. Compared to those without asthma, the COVID-19 with asthma survivors had higher levels of SARS-CoV-2-specific neutralizing antibodies (NAbs) at the 8-month follow-up (p<0.05). Moreover, the level of NAbs in COVID-19 survivors was positively correlated with the percentage of Treg and cTfh2 cells (r=0.5037, p=0.002; and r=0.4846, p=0.0141), and negatively correlated with the percentage of Th1 and Th17 cells (r=-0.5701, p=0.0003; and r=-0.3656, p=0.0308), the ratio of Th1/Th2, Th17/Treg, and cTfh1/cTfh2 cell (r=-0.5356, r=-0.5947, r=-0.4485; all p<0.05). The decay rate of NAbs in the COVID-19 survivors with asthma was not significantly different from that of those without asthma at 16-month follow-up. Conclusion: The level of SARS-CoV-2-specific NAbs in COVID-19 survivors with asthma was higher than that of those without asthma at 8-month follow-up. The SARS-CoV-2-specific T cell immunity was associated with blood eosinophils and Treg percentages. The SARS-CoV-2-specific humoral immunity was closely associated with cTfh2/cTfh1 imbalance and Treg/Th17 ratio. According to the findings, asthmatic patients in COVID-19 convalescent period may benefit from an enhanced specific humoral immunity, which associates with skewed Th2/Th1 and Treg/Th17 immune.
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Asma , COVID-19 , Imunidade Adaptativa , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , SARS-CoV-2 , SobreviventesRESUMO
BACKGROUND: Neutrophilic asthmatics (NA) have less response to inhaled corticosteroids. We aimed to find out the predictor of treatment response in NA. METHODS: Asthmatics (n = 115) and healthy controls (n = 28) underwent clinical assessment during 6-month follow-up with standardized therapy. Asthmatics were categorized by sputum differential cell count. The mRNA expressions were measured by RT-qPCR for sputum cytokines (IFN-γ, IL-1ß, IL-27, FOXP3, IL-17A, and IL-5). The protein of IL-1ß in sputum supernatant was detected by ELISA. Reticular basement membranes (RBM) were measured in the biopsy samples. The role and signaling pathways of IL-1ß mediating the epithelial-mesenchymal transition (EMT) process were explored through A549 cells. RESULTS: NA had increased baseline sputum cell IL-1ß expression compared to eosinophilic asthmatics (EA). After follow-up, NA had less improvement in FEV1 compared to EA. For all asthmatics, sputum IL-1ß mRNA was positively correlated with protein expression. Sputum IL-1ß mRNA and protein levels were negatively correlated to FEV1 improvement. After subgrouping, the correlation between IL-1ß mRNA and FEV1 improvement was significant in NA but not in EA. Thickness of RBM in asthmatics was greater than that of healthy controls and positively correlated with neutrophil percentage in bronchoalveolar lavage fluid. In vitro experiments, the process of IL-1ß augmenting TGF-ß1-induced EMT cannot be abrogated by glucocorticoid or montelukast sodium, but can be reversed by MAPK inhibitors. CONCLUSIONS: IL-1ß level in baseline sputum predicts the poor lung function improvement in NA. The potential mechanism may be related to IL-1ß augmenting TGF-ß1-induced steroid-resistant EMT through MAPK signaling pathways. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (IRB ID: 20150406).
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Asma/imunologia , Transição Epitelial-Mesenquimal/imunologia , Interleucina-1beta/imunologia , Neutrófilos/imunologia , Mucosa Respiratória/imunologia , Fator de Crescimento Transformador beta/administração & dosagem , Células A549 , Adulto , Asma/genética , Asma/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Seguimentos , Humanos , Interleucina-1beta/genética , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Adulto JovemRESUMO
To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.
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COVID-19/epidemiologia , Pulmão/virologia , Transtornos Respiratórios/virologia , SARS-CoV-2/patogenicidade , Sobreviventes , Adulto , Idoso , Seguimentos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Transtornos Respiratórios/fisiopatologia , Fenômenos Fisiológicos Respiratórios , Estudos Retrospectivos , Sobreviventes/estatística & dados numéricosRESUMO
BACKGROUND: IL-27 attenuates allergic inflammation and improves lung function in mouse models of allergic asthma. However, plasma IL-27 levels of asthma patients and the association with clinical features remain poorly understood. METHODS: This study examined plasma IL-27 protein expression in untreated asthma patients and controls, analyzed its correlation with Th2 inflammation and lung function, and evaluated the effect of corticosteroids on IL-27 expression. RESULTS: Plasma IL-27 levels were lower in untreated asthma patients compared to controls. Plasma IL-27 levels were inversely correlated with sputum IL-5 mRNA expression in Th2Hi group. The Th2HiIL-27Low subgroup suffered from the highest airway hyperresponsiveness (AHR) and the worst pulmonary function. The patients in Th2LowIL-27Low subgroup were less likely to be atopic and had the worst improvement of symptoms after four weeks of standard treatment. In vitro, dexamethasone could decrease the expression of IL-27 in THP-1 cell line. The majority of asthma patients had further decreased IL-27 levels after standard treatment, whereas patients with sustained high levels of IL-27 post-treatment had more blood neutrophils at baseline compared with those without. CONCLUSIONS: The results indicate that low levels of IL-27 in peripheral blood are closely related to Th2 inflammation and lung function of asthma patients. Low IL-27 levels in combination with high Th2 inflammation identify an asthma phenotype with high AHR and substantial response to corticosteroids. Understanding of this interaction could help to elucidate the inherent inflammation heterogeneity of asthma.
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Asma/genética , Asma/fisiopatologia , Interleucinas/sangue , Pulmão/fisiopatologia , Adulto , Animais , Asma/imunologia , Feminino , Volume Expiratório Forçado , Expressão Gênica , Humanos , Inflamação , Interleucina-5/genética , Interleucina-5/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Hipersensibilidade Respiratória , Escarro/metabolismo , Células THP-1 , Células Th2/imunologia , Capacidade VitalRESUMO
BACKGROUND: The rapid outbreak of coronavirus disease 2019 (COVID-19) has turned into a public health emergency of international concern. Epidemiological research has shown that sex is associated with the severity of COVID-19, but the underlying mechanism of sex predisposition remains poorly understood. We aim to study the gendered differences in inflammation reaction, and the association with severity and mortality of COVID-19. METHODS: In this retrospective study, we enrolled 548 COVID-19 inpatients from Tongji Hospital from 26 January to 5 February 2020, and followed up to 3 March 2020. Epidemiological, demographic and clinical features, and inflammatory indexes were collected and compared between males and females. The Cox proportional hazard regression model was applied to identify the gendered effect on mortality of COVID-19 after adjusting for age, comorbidity, and smoking history. The multiple linear regression method was used to explore the influence of sex on inflammation reaction. RESULTS: Males had higher mortality than females did (22.2% vs 10.4%), with an hazard ratio of 1.923 (95% confidence interval, 1.181-3.130); elder age and comorbidity were significantly associated with decease of COVID-19 patients. Excess inflammation reaction was related to severity of COVID-19. Male patients had greater inflammation reaction, with higher levels of interleukin 10, tumor necrosis factor-α, lactose dehydrogenase, ferritin, and hyper-sensitive C-reactive protein, but a lower lymphocyte count than females adjusted by age and comorbidity. CONCLUSIONS: Sex, age, and comorbidity are critical risk factors for mortality of COVID-19. Excess innate immunity and proinflammation activity, and deficiency in adaptive immunity response promote males, especially elder males, to develop a cytokine storm, causing potential acute respiratory distressed syndrome, multiple organ failure and decease.
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COVID-19/imunologia , COVID-19/mortalidade , Síndrome da Liberação de Citocina/imunologia , Inflamação/virologia , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , China/epidemiologia , Comorbidade , Síndrome da Liberação de Citocina/virologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Adulto JovemRESUMO
BACKGROUND: In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited. OBJECTIVE: We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19. METHODS: Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients. RESULTS: We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19. CONCLUSIONS: Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.