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BACKGROUND: There are many studies on the relationship between vitamin D and coronavirus disease 2019 (COVID-19), while the results are matters of debate and the mechanisms remain unknown. The present study was performed to assess the impact of serum 25-hydroxyvitamin D [25(OH)D] levels on the severity of disease in hospitalized COVID-19 patients and identify potential mechanisms of 25(OH)D alterations. METHODS: A total of 399 hospitalized COVID-19 patients were recruited from three centers between December 19, 2022, and February 1, 2023. Medical history, laboratory examination, and radiologic data were retrospectively collected. The patients were divided into four groups based on disease severity. Serum 25(OH)D levels in the patients were determined by the electrochemiluminescence method and cytokines were detected by flow cytometry. The relationship between serum 25(OH)D status and the severity of COVID-19, and the correlation between 25(OH)D levels and cytokines in COVID-19 patients were assessed. RESULTS: Levels of 25(OH)D were significantly lower in the deceased group than in the other three groups (P < 0.05), and lower in the critical group than in the general group (P < 0.05). There were no significant differences in the 25(OH)D levels between the general and severe groups (P > 0.05). The levels of 25(OH)D (odds ratio = 0.986, 95% confidence interval: 0.973-0.998, P = 0.024) and IL-5 (odds ratio = 1.239, 95% confidence interval: 1.104-1.391, P = 0.04) were independent risk factors for the severity of COVID-19 disease upon admission. Serum 25(OH)D levels were able to predict the mortality of patients with COVID-19, and the predictive value was even higher when combined with IL-5 levels and eosinophil (Eos) count. Circulating 25(OH)D status correlated negatively with the expression of IL-5 (r=-0.262, P < 0.001) and was positively linked with CD8+ T cell counts (r=-0.121, P < 0.05) in patients with COVID-19. CONCLUSIONS: This study found that the serum 25(OH)D status combined with IL-5 levels and Eos counts could be identified as a predictive factor for recognizing the risk of COVID-19 mortality. The serum 25(OH)D status in COVID-19 patients correlated negatively with the expression of IL-5. The potential mechanism for this relationship is worth further exploration.
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COVID-19 , Interleucina-5 , Humanos , Citocinas , Gravidade do Paciente , Estudos Retrospectivos , Vitamina DRESUMO
BACKGROUND: The clinical significance of small airway dysfunction (SAD) determined with spirometry in patients with normal forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FVC) is controversial. OBJECTIVE: To determine whether SAD presents histologic abnormalities in the setting of normal computed tomography (CT) imaging and FEV1 and FEV1/FVC. METHODS: A cross-sectional study was performed in 64 patients undergoing thoracotomy for pulmonary nodules. Thoracic high-resolution CT (HRCT), bronchodilation test, and fractional exhaled nitric oxide (FENO) and its alveolar component (nitric oxide alveolar concentration [CANO]) were obtained before surgery. Lung pathology and levels of cytokines in lung tissue were measured. The patients were divided into SAD and small airway normal function groups according to forced expiratory flow at 75% and 50% of the FVC (maximal expiratory flow [MEF] 25, MEF50) and maximum midexpiratory flow. RESULTS: The MEF50, MEF25, and maximum midexpiratory flow were strongly negatively correlated with CANO (r, -0.42, -0.42, -0.40, respectively; P ≤ .001 for all). The MEFs were mildly negatively correlated with interleukin (IL)-6 and macrophages in lung tissue (r < -0.25, P < .001 for all). The CANO (P < .001), airspace size (mean linear intercept) (P = .02), macrophages (P = .003), IL-6 (P = .003), and IL-8 (P = .008) in lung tissue were higher in patients with SAD (n = 35) than those with small airway normal function (n = 29). A total of 8 patients (22.86%) with SAD and 2 (6.90%) without SAD had pneumatoceles (P = .10). CONCLUSION: Patients with pulmonary nodules and SAD were more likely to have abnormal inflammation and emphysematous destruction than patients without SAD. Thus, SAD indicates histologic abnormalities in patients with normal CT imaging and FEV1 and FEV1/FVC.
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Teste da Fração de Óxido Nítrico Exalado , Pulmão , Estudos Transversais , Volume Expiratório Forçado , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Pneumopatias , Espirometria , Capacidade VitalRESUMO
BACKGROUND: Exposure to ambient ozone (O3) increases the susceptivity to allergens and triggers exacerbations in patients with asthma. However, the detailed mechanisms of action for O3 to trigger asthma exacerbations are still unclear. METHODS: An ovalbumin (OVA)-established asthmatic mouse model was selected to expose to filtered air (OVA-model) or 1.0 ppm O3 (OVA-O3 model) during the process of OVA challenge. Next, the possible involvements of p38 MAPK and oxidative stress in the ozone actions on the asthma exacerbations were investigated on the mice of OVA-O3 model by treating them with SB239063 (a p38 MAPK inhibitor), and/or the α-tocopherol (antioxidant). Biological measurements were conducted including airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL), inflammation in the airway lumen and lung parenchyma, the phosphorylation of p38 MAPK and heat shock protein (HSP) 27 in the tracheal tissues, and the malondialdehyde (MDA) content and the glutathione peroxidase (GSH-Px) activity in lung tissues. RESULTS: In OVA-allergic mice, O3 exposure deteriorated airway hyperresponsiveness (AHR), airway resistance (Raw), lung compliance (CL) and pulmonary inflammation, accompanied by the increased oxidative stress in lung tissues and promoted p38 MAPK and HSP27 phosphorylation in tracheal tissues. Administration of SB239063 (a p38 MAPK inhibitor) on OVA-O3 model exclusively mitigated the Raw, the CL, and the BAL IL-13 content, while α-tocopherol (antioxidant) differentially reduced the BAL number of eosinophils and macrophages, the content of BAL hyaluronan, the peribronchial inflammation, as well as the mRNA expression of TNF-α and IL-5 in the lung tissues of OVA-O3 model. Administration of these two chemical inhibitors similarly inhibited the AHR, the BAL IFN-γ and IL-6 production, the perivascular lung inflammation and the lung IL-17 mRNA expression of OVA-O3 model. Interestingly, the combined treatment of both compounds together synergistically inhibited neutrophil counts in the BALF and CXCL-1 gene expression in the lung. CONCLUSIONS: O3 exposure during the OVA challenge process promoted exacerbation in asthma. Both p38 MAPK and oxidative stress were found to play a critical role in this process and simultaneous inhibition of these two pathways significantly reduced the O3-elicited detrimental effects on the asthma exacerbation.
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Asma/metabolismo , Estresse Oxidativo/fisiologia , Ozônio/toxicidade , Pneumonia/metabolismo , Hipersensibilidade Respiratória/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Asma/induzido quimicamente , Asma/fisiopatologia , Inibidores Enzimáticos/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Pneumonia/induzido quimicamente , Pneumonia/fisiopatologia , Hipersensibilidade Respiratória/induzido quimicamente , Hipersensibilidade Respiratória/fisiopatologia , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
BACKGROUND: Inflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress-induced pathology. OBJECTIVE: We sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells. METHODS: Mice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ. RESULTS: Mice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-ß-induced ASM cell proliferation and CXCL8 release. CONCLUSIONS: Mitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD.
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Antioxidantes/farmacologia , Mitocôndrias/metabolismo , Músculo Liso/metabolismo , Compostos Organofosforados/farmacologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Sistema Respiratório/metabolismo , Ubiquinona/análogos & derivados , Adulto , Idoso , Remodelação das Vias Aéreas/genética , Animais , Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/tratamento farmacológico , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/patologia , Complexo de Proteínas da Cadeia de Transporte de Elétrons/genética , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Peróxido de Hidrogênio/farmacologia , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Estresse Oxidativo/efeitos dos fármacos , Ozônio , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/genética , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/patologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Transdução de Sinais , Fumar/metabolismo , Fumar/fisiopatologia , Ubiquinona/farmacologiaRESUMO
Objective: To assess the diurnal rhythm and variability of lung function in healthy individuals, encompassing both large and small airways. Methods: A prospective study enrolled 35 healthy adults without a history of smoking. Initial spirometry and a bronchodilation test were performed using the Jaeger spirometer, followed by a seven-day continuous home monitoring using the GOSPT2000. We evaluated repeatability using the intraclass correlation coefficient and agreement through linear regression and Bland-Altman analyses. Circadian rhythm and variability in spirometric measurements were analyzed using the coefficient of variation (CV) and daily variation rate. Results: The GOSPT2000 demonstrated strong repeatability and high agreement with the Jaeger spirometer. Notable findings included a decrease in nocturnal forced expiratory volume in 1â s (FEV1), forced vital capacity (FVC), and FEV3 by 44, 59, and 53 mL, respectively. In contrast, peak expiratory flow at noon showed an increase of 0.143L/min. Small-airway variables, including forced expiratory flow at 50% and 75% of the FVC and maximum midexpiratory flow, showed no significant diurnal variation. The nocturnal CV for large-airway variables was ≤ 4%, while for small-airway variables, it was ≤ 11.89%. Conclusion: This study has established a spectrum of variability for both large and small airways in healthy populations. The variability of small-airway variables is higher than that of large-airway variables. The investigation into the diurnal rhythms and variability characteristics of both large and small airway variables in the healthy population can serve as a foundation for diagnosing asthma or assessing the efficacy of asthma treatments.
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BACKGROUND AND OBJECTIVE: Procaterol, a selective, short-acting beta-2 adrenoceptor agonist, is effective in treating 'classical' asthma, but its efficacy for cough-variant asthma (CVA) is unknown. We evaluated the efficacy and safety of procaterol combined with budesonide for CVA. METHODS: A prospective, randomized, double-blind, placebo-controlled, multicenter trial in China was conducted. One hundred and fifty-nine patients diagnosed with CVA (aged 18-75 years) were randomly divided into two groups to receive twice daily for 8 weeks, inhaled budesonide 100 µg plus either oral procaterol 25 µg or placebo. Primary and secondary efficacy variables were cough symptom severity scores and Leicester Cough Questionnaire (LCQ) life quality scores. Adverse events were also assessed. RESULTS: The budesonide/placebo and budesonide/procaterol groups contained 80 and 78 participants (one excluded for later diagnosis of eosinophilic bronchitis), respectively, with similar baseline characteristics. Daily cough score declined during treatment in both groups and was lower in the budesonide/procaterol group at 8 (0.44 vs 0.73) and 10 (0.36 vs 0.69) weeks (P < 0.05). Compared with the budesonide/placebo group, the proportion of patients with a reduction of 3 points or greater (66% vs 42%) and that of patients scoring 0 points (63% vs 51%) was higher in the budesonide/procaterol group for daily cough scores (P < 0.05). At 8 weeks, LCQ score improvement was superior in the budesonide/procaterol group (38.94 ± 19.24 vs 32.71 ± 18.92; P < 0.05). CONCLUSION: Procaterol combined with budesonide was well tolerated and effective at improving cough symptoms and quality of life in patients with CVA.
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Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Asma/tratamento farmacológico , Broncodilatadores/uso terapêutico , Budesonida/uso terapêutico , Tosse/tratamento farmacológico , Procaterol/uso terapêutico , Agonistas de Receptores Adrenérgicos beta 2/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Adulto , Asma/epidemiologia , Asma/fisiopatologia , Broncodilatadores/efeitos adversos , Broncodilatadores/farmacologia , Budesonida/efeitos adversos , Budesonida/farmacologia , China , Comorbidade , Tosse/epidemiologia , Tosse/fisiopatologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Procaterol/efeitos adversos , Procaterol/farmacologia , Estudos Prospectivos , Resultado do Tratamento , Capacidade Vital/efeitos dos fármacos , Capacidade Vital/fisiologiaRESUMO
BACKGROUND: Atopy varies in people of different ages owing to different physical conditions and exposure to allergens. We aimed to cluster ages based on atopic severity using K-means cluster analysis and identify atopic incidence, severity, as well as the association among peripheral eosinophils, IgE and sensitisation. METHODS: Consecutive patients (n = 7654) with allergic symptoms and undergoing allergen-specific IgE tests were included from 2013 to 2017. Age, sex, specific-IgE, peripheral eosinophil counts and total-IgE were collected. RESULTS: Five age categories were identified: 1-17, 18-36, 37-52, 53-69 and 70-100 years. The incidences of atopy and poly-sensitisation decreased with increasing age. Similar trend was observed for aeroallergens, egg and milk but not for peanuts, soy or seafood. Dust mites remain the crucial factor bothering patients with allergic symptoms, especially for children and adolescents. In patients aged <52 years, sensitisation to aeroallergens was more prevalent than food. In group 37-52 years, incidence of females' atopy was higher than that of males. The overlap of atopy, high eosinophils, and high total-IgE was found in only 19.18% of patients. The trend of allergen-test positivity is not parallel to total IgE and peripheral eosinophil counts. CONCLUSION: Age-grouping based on cluster analysis helps to find the changes in atopic status and distribution of sensitised allergens with age. Allergen tests are still necessary in the clinical diagnosis and treatment. An innovative exploration of the influence of age and allergens on total-IgE and eosinophil counts is helpful for the development of bio-targeted precision therapy. CLINICAL TRIAL REGISTRATION: ChiCTR2300067700.
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Introduction: Asthma is primarily divided into two categories: type 2 (T2-high) and non-type 2 (T2-low). A relationship between asthma severity and vitamin D deficiency has been identified, but its impact on each asthma endotype remains unknown. Methods: We clinically examined the influence of vitamin D on patients with T2-high (n = 60) or T2-low asthma (n = 36) compared with controls (n = 40). Serum 25(OH)D levels, inflammatory cytokines and spirometry were measured. Mouse models were then used to further analyze the effects of vitamin D on both asthmatic endotypes. BALB/c mice were fed with vitamin D-deficient (LVD), -sufficient (NVD), or -supplemented diets (HVD) throughout lactation and offspring followed the same diet after weaning. Offspring were sensitized/challenged with ovalbumin (OVA) to establish "T2-high" asthma or OVA combined with ozone exposure (OVA + ozone) to induce "T2-low" asthma. Spirometry and serum, bronchoalveolar lavage fluid (BALF), and lung tissues were analyzed. Results: Serum 25(OH)D levels were decreased in asthmatic patients compared with controls. Patients with vitamin D deficiency (Lo) had varying degrees of elevation of the pro-inflammatory cytokines IL-5, IL-6, and IL-17A, decreased expression of the anti-inflammatory cytokine IL-10, and altered forced expiratory volume in the first second as a percentage of predicted value (FEV1%pred) in both asthmatic endotypes. Vitamin D status had a stronger correlation with FEV1%pred in T2-low asthma than T2-high asthma, and 25(OH)D level was only positively linked to maximal mid-expiratory flow as a percentage of predicted value (MMEF%pred) in the T2-low group. Inflammation, hyperresponsiveness, and airway resistance (RL) was increased in both asthma models compared with controls while vitamin D deficiency further increased airway inflammation and airway obstruction. These findings were particularly prominent in T2-low asthma. Discussion: The potential function and mechanisms of vitamin D and both asthma endotypes should be studied individually, and further analysis of the potential signaling pathways involved with vitamin D on T2-low asthma is warranted.
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Obstrução das Vias Respiratórias , Asma , Ozônio , Deficiência de Vitamina D , Camundongos , Animais , Feminino , Humanos , Vitamina D , Asma/metabolismo , Citocinas , Inflamação , VitaminasRESUMO
Gefitinib, osimertinib and icotinib are the most commonly used tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) with EGFR mutation. Therapeutic drug monitoring (TDM) for these TKIs has become a standard and essential procedure. Dried plasma spots (DPS) was choosen for microsampling strategies for TDM, allowing easy and cost-effective logistics in many settings. This study developd and validated an assay for the simultaneous quantitative determination of gefitinib, osimertinib and icotinib in DPS by online solid-phase extraction-liquid chromatography-tandem mass spectrometry (online SPE-LC-MS) system. The TKIs were extracted from DPS with methanol and enriched on a Welch Polar-RP SPE column (30 × 4.6 mm, 5 µm), followed by separation on Waters X Bridge C18 analytical column(4.6 × 100 mm, 3.5 µm). The method achieved LLOQ of 2 ng mL-1 for gefitinib and osimertinib (4 ng mL-1 for icotinib), respectively (r2 > 0.99). Precision (within-run 1.54-7.41 % RSD; between-run 3.03-12.84 % RSD), accuracy (range from 81.47 % to 105.08 %; between-run bias 87.87-104.13 %). Osimertinib and icotinib were stable in DPS stored at - 40 °C for 30 days, 4 °C, 42 °C and 60 °C for 5 days and well-sealed 37 °C,75 % humidity (except gefitinib). Lastly, the assay was applied to TDM of TKIs in 46 patients and the results were compared to SALLE assisted LC-MS analysis, it could be confirmed that the developed method achieves similarly good results as the already established one and no bias could be detected. It implies that this method capable of supporting clinical follow-up TDM of TKIs in DPS from poor medical environment.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gefitinibe , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Monitoramento de Medicamentos/métodos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Background: The aim of the current study was to investigate the clinical value of cellular analysis and metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF) in differentiating pulmonary non-infectious and infectious diseases in immunocompetent patients. Methods: The present retrospective study was conducted from December 2017 to March 2020, and included immunocompetent patients with suspected pulmonary infection. High-resolution computed tomography, total cell counts and classification of BALF, conventional microbiological tests (CMTs), laboratory tests and mNGS of BALF were performed. Patients were assigned to pulmonary non-infectious disease (PNID) and pulmonary infectious disease (PID) groups based on final diagnoses. PNID-predictive values were analyzed via areas under receiver operating characteristic curves (AUCs). Optimal cutoffs were determined by maximizing the sum of sensitivity and specificity. Results: A total of 102 patients suspected of pulmonary infection were enrolled in the study, 23 (22.5%) with PNID and 79 (77.5%) with PID. The diagnostic efficiency of BALF mNGS for differentiating PID from PNID was better than that of CMTs. Neutrophil percentage (N%) and the ratio of neutrophils to lymphocytes (N/L) in BALF were significantly lower in the PNID group than in the PID group. The AUCs for distinguishing PNID and PID were 0.739 (95% confidence interval [CI] 0.636-0.825) for BALF N%, 0.727 (95% CI 0.624-0.815) for BALF N/L, and 0.799 (95% CI 0.702-0.876) for BALF mNGS, with respective cutoff values of 6.7%, 0.255, and negative. Joint models of BALF mNGS combined with BALF N/L or BALF N% increased the respective AUCs to 0.872 (95% CI 0.786-0.933) and 0.871 (95% CI 0.784-0.932), which were significantly higher than those for BALF mNGS, BALF N%, and BALF N/L alone. Conclusions: BALF N% ≤ 6.7% or BALF N/L ≤ 0.255 combined with a negative BALF mNGS result can effectively distinguish PNID from PID in immunocompetent patients with suspected pulmonary infection. BALF mNGS outperforms CMTs for identifying pathogens in immunocompetent patients, and the combination of mNGS and CMTs may be a better diagnostic strategy.
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Doenças Transmissíveis , Pneumonia , Humanos , Líquido da Lavagem Broncoalveolar , Estudos Retrospectivos , Sequenciamento de Nucleotídeos em Larga Escala , Metagenômica , Sensibilidade e EspecificidadeRESUMO
Background: The aim of the study was to investigate the possible influencing factors of the large- and small-airway function variation in healthy non-smoking adults. Methods: Healthy non-medical non-smoking adults were enrolled in this prospective cohort study. Each participant took the portable spirometer test relying only on video teaching. Then conventional spirometry and bronchodilation test were conducted using a Jaeger spirometer, followed by 7-day diurnal and nocturnal home monitoring using a portable spirometer. Results: A drop in both large- and small-airway function began at about 25 years of age, and a rapidly decline at about 50 years. The CV of FEV1 (r = 0.47, P = 0.0082) and small-airway function variables correlated with age (r ≥ 0.37, P < 0.05 for both MEFs and MEFs/FVC), especially for evening small-airway function variables. The CV of large (4.666 ± 1.946, P = 0.002 for FEV1; 4.565 ± 2.478, P = 0.017 for FEV3) and small airways (10.38 ± 3.196, P = 0.031 for MEF50 and 11.21 ± 4.178, P = 0.023 for MMEF) was higher in the 45- to 60-year subgroup than in the 30- to 45-year and 18- to 30-year subgroups. Interpretation: Age was the main influencing factor of both central and peripheral airway function variability, especially for the small-airway function in the evening. The LLN of small-airway variables varies depending on the age and circadian rhythm. People older than 45 years should pay more attention to monitoring small-airway function in the evening, which will be helpful for early clinical detection of those at high risk for asthma. Trial registration number: ChiCTR2100050355.
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Ritmo Circadiano , Eletrônica , Adulto , Humanos , Estudos Prospectivos , Espirometria , Testes de Função RespiratóriaRESUMO
Background: Many patients with cough variant asthma (CVA) are underdiagnosed and undertreated due to the atypical symptoms, low diagnostic sensitivity of bronchodilator response (BDR), and limited application of bronchial challenge test. Objective: To investigate whether airway reversibility in BDR can predict CVA diagnosis in patients with chronic cough and negative BDR. Methods: This open-label, prospective cohort study included patients with chronic cough, nearly normal chest CT scan, and negative BDR results. Inhaled corticosteroids and long-acting ß2 agonists were given for 4 weeks. The confirmed diagnosis of CVA was defined as improved symptoms and an increase of forced expiratory volume in 1 s (FEV1) by >12% and >200 mL after 4 weeks of treatment. Results: Of 155 patients recruited, 140 completed the study. Patients in the CVA positive diagnosis group had greater absolute (Δ) and percent (Δ%) improvements in FEV1 and forced expiratory flows (FEFs), and higher fractional exhaled nitric oxide (FENO) than in the CVA negative diagnosis group. The area under the receiver operating characteristic curves (AUCs) of ΔFEV1%, FEF25-75%pred (percentage of predicted forced expiratory flow at 25% to 75%) and FENO for CVA positive diagnosis was 0.825, 0.714, and 0.637, with cutoff values of 5.90%, 61.99% and 41.50 ppb, respectively. A joint model of ΔFEV1% combined with FEF25-75%pred or FENO increased the AUC to 0.848 and 0.847, respectively. Conclusion: ΔFEV1% in BDR can predict a CVA diagnosis and response to anti-asthma treatment in patients with chronic cough and negative BDR. Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2000029065].
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OBJECTIVE AND DESIGN: Ozone exposure is an important risk factor for Chronic Obstructive Pulmonary Disease (COPD) which is a global public health concern. Until now, there is no effective approach to reverse airflow limitation and accelerated loss of lung function completely. Here, we delineate the efficacy of mouse allogeneic adipose-derived mesenchymal stem cells (mASCs) in the treatment of COPD mice by intratracheal and intravenous administration. METHODS: In this study, we established ozone-exposed COPD model in mice and were administered intratracheally or intravenously with mASCs which were extracted, cultured, and identified in vitro. RESULTS: We observed that exposure to ozone resulted in a marked lung neutrophilia with high levels of inflammatory cell counts, enhanced expression of cytokines IL-1ß and TNF-α, reduced expression of IL-10, lung function and airspace enlargement. mASCs intratracheal administration rescured the lung neutrophilia, lung function and emphysema-like phenotype. Similar results were observed in mice with mASCs intravenous administration. But the altered levels of serum cytokines in mice with mASCs intratracheal administration appears more robust than those in mice with mASCs intravenous administration. CONCLUSIONS: Collectively, these data indicate that intratracheal administration of mASCs appears more effective in treating ozone-induced COPD compared to intravenous administration of mASCs, although the two approaches can be comparable in safety. mASCs are expected to become a new potential intervention strategy for COPD.
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Células-Tronco Mesenquimais , Ozônio , Doença Pulmonar Obstrutiva Crônica , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-10/metabolismo , Pulmão/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/terapia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVES: The SABINA CHINA study aimed to determine prescription data for asthma medication with a focus on SABA and ICS in a representative population of patients with asthma in China. METHODS: SABINA China was a multicentre, observational, cross-sectional study with data collected retrospectively from a convenience sample of 25 tertiary centres across China. Patients (age ⩾ 12 years) with ⩾3 consultations/year were enrolled. Data were collected on clinical characteristics, asthma severity, and symptom control (as per GINA 2017), treatment and history of severe exacerbations over the past year. SABA over-prescription was defined as ⩾3 SABA canisters/year. Descriptive statistics are presented. RESULTS: Between March and August 2020, 498 patients were included in the outcome analysis. Mean (SD) age was 48.7 (15.0) years, 57.9% were female and 91% had moderate-to-severe asthma (n = 453). Overall, 12.5% (n = 62) and 26.4% (n = 131) of patients had uncontrolled and partly controlled asthma, respectively. SABA add-on was prescribed to 20.3% (n = 101) of patients; one patient with moderate-to-severe asthma was prescribed SABA-alone. SABA over-prescription in the overall population was 4.0% (n = 20; all with moderate-to-severe asthma) and 19.8% (20/101) among those prescribed SABA add-on. In the mild asthma group, 50% (n = 22) were prescribed ICS/LABA and 43.2% (n = 19) were prescribed LTRA. Among those with moderate-to-severe asthma, 97.4% (n = 441) were prescribed ICS/LABA and 55.0% (n = 249) were prescribed LTRA. Approximately 30% of patients (n = 149) experienced ⩾1% and 6.6% (n = 33) ⩾3 severe exacerbations in the preceding year; mean annual number of severe exacerbation/patient was 0.6 (1.2). Among those prescribed SABA add-on, ICS/LABA and LTRA (non-mutually exclusive groups due to overlapping prescriptions), 54.5%, 29.9%, and 35.3% had ⩾1 severe exacerbations, respectively. CONCLUSION: Among patients with predominantly moderate-to-severe asthma managed in tertiary care and were prescribed SABA, 1 in 5 received ⩾3 canisters/year. Fewer patients who received ICS/LABA prescriptions experienced annual exacerbations than those prescribed SABA add-on.
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Antiasmáticos , Asma , Administração por Inalação , Corticosteroides/uso terapêutico , Antiasmáticos/efeitos adversos , Asma/diagnóstico , Asma/tratamento farmacológico , Asma/epidemiologia , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prescrições , Estudos RetrospectivosRESUMO
Background: Poor control of asthma results from many factors, partly due to inadequate knowledge towards asthma among patients. It is necessary to know patients' knowledge level before education. However, there is no accepted instrument to evaluate knowledge of asthma in Chinese patients with asthma. The study aims to develop a Chinese version of Patient-completed Asthma Knowledge Questionnaire (PAKQ) to assess its reliability, validity, and responsiveness for testing its clinical application in Chinese adult patients with asthma. Methods: After translation, back-translation, and cross-cultural adaptation of the PAKQ into Chinese version, a survey of patients with asthma (n=464) in China was conducted. Demographics and clinical data were collected in addition to questionnaires concerning cognition of asthma, education, history, and asthma control test score. The PAKQ was then completed. 14±4 days after the initial assessment, the participants completed the retested questionnaire and again completed the questionnaire immediately after education. The reliability and the construct validity were evaluated. The optimal cut-off points for predicting disease knowledge among asthma patients were determined using the Youden index method. Results: The Chinese version of PAKQ showed high internal consistency (Cronbach's alpha =0.888) at baseline and an acceptable 2-week test-retest reliability (ICC =0.932, r=0.874). On the basis of large modification indices (>10), this four-factor questionnaire was found to fit the data satisfactorily (χ2/df =1.695, RMSEA =0.039, GFI =0.856, CFI =0.885, and SRMR =0.058). Paired t-tests showed significant changes on pre-educational and post-educational tests (t=22.83, df=463, P<0.0001). The optimal cut-off value of the PAKQ total score for assessing patients' knowledge level was 35 points (AUC =0.757). Conclusions: The Chinese version of the PAKQ questionnaire was developed and validated in terms of reliability and validity as an effective instrument for the insight into asthma knowledge of adult patients with asthma in China. Future research will evaluate the utility of the instrument in clinical practice.
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PURPOSE: Patients with variable symptoms suggestive of asthma but with normal forced expiratory volume in 1 second (FEV1) often fail to be diagnosed without a bronchial provocation test, but the test is expensive, time-consuming, risky, and not readily available in all clinical settings. PATIENTS AND METHODS: A cross-sectional study was performed in 692 patients with FEV1≥80% predicted; normal neutrophils and chest high-resolution computed tomography; and recurrent dyspnea, cough, wheeze, and chest tightness. RESULTS: Compared with subjects negative for AHR (n=522), subjects positive for AHR (n=170) showed increased FENO values, peripheral eosinophils (EOS), and R5-R20; decreased FEV1, FEV1/Forced vital capacity (FVC), and forced expiratory flow (FEFs) (P≤.001 for all). Small-airway dysfunction was identified in 104 AHR+ patients (61.17%), and 132 AHR- patients (25.29%) (P<0.001). The areas under the curve (AUCs) of variables used singly for an AHR diagnosis were lower than 0.77. Using joint models of FEF50%, FEF75%, or FEF25%-75% with FENO increased the AUCs to 0.845, 0.824, and 0.844, respectively, significantly higher than univariate AUCs (P <0.001 for all). Patients who reported chest tightness (n=75) had lower FEFs than patients who did not (P<0.001 for all). In subjects with chest tightness, the combination of FEF50% or FEF25%-75% with EOS also increased the AUCs substantially, to 0.815 and 0.816, respectively (P <0.001 for all versus the univariate AUCs). CONCLUSION: FENO combined with FEF50% and FEF25%-75% predict AHR in patients with normal FEV1. FEF25%-75%, FEF50%, or FEF25%-75% together with EOS also can potentially suggest asthma in patients with chest tightness.
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BACKGROUND: Whether COVID-19 comorbidities and risk factors such as old age, male gender, smoking, obesity, eosinophils and blood types have direct contact with expression of ACE2 and pro-inflammation cytokines in human lung tissues were still unclear. PATIENTS AND METHODS: Sixty-four patients with normal FEV1 and FEV1/FVC underwent thoracotomy for pulmonary nodules were included. Blinded histological assessments were performed by two pathologists. Clinical features and results of the immunohistochemical staining of ACE2 were collected and analyzed. RESULTS: ACE2 expressed in alveolar macrophages (most obvious), alveolar epithelia and vascular endothelia, but not in small-airway epithelia. ACE2 expressions are positively related to age (r =0.26, P =0.040), weight (r =0.43, P<0.001), as well as BMI (r = 0.38, P =0.002), and male patients show higher expressions of ACE2 in lungs (P <0.05). ACE2 expressions are negatively related to peripheral eosinophils (r = -0.30, P =0.017). There was no correlation between ABO blood types and ACE2 expression in normal lung tissues (P > 0.05). IL-13 and IL-6R expression in lung tissue increased with age (r =0.26, P <0.05, for both). CONCLUSION: Our pathological evidences showed that the alveolar epithelia, vascular endothelia, and alveolar macrophages are susceptible in human lungs for SARS-CoV-2 infection. The risk factors such as high body weight/BMI, old age, male gender, and eosinopenia may be related to ACE2 expression in human lungs, and associated with more chance to develop the severe cases. IL-6R expression in lung tissue also increased with age. Therefore, weight control and smoking cessation are essential to reduce the susceptibility of SARS-CoV-2 infection, especially in obesity, old or male patients. Peripheral eosinophils monitor is also quite necessary to detect severe tendency in COVID-19 patients.
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BACKGROUND: There has been growing evidence of small-airway dysfunction in patients with asthma. Few studies have evaluated the mechanism of small-airway dysfunction in mouse models of asthma. PURPOSE: We explored the correlation between small-airway spirometric variables and large-airway function or inflammation in different endotypes of asthma. METHODS: Ovalbumin (OVA) sensitization/challenge was used to produce a type 2 (T2)-high asthma model, and OVA combined with ozone exposure (OVA + ozone) was used for the T2-low asthma model with increased neutrophils. Spirometry, airway responsiveness, cytokine levels in bronchoalveolar lavage fluid (BALF), and pathological analyses of lung slices stained with hematoxylin-eosin, periodic acid-Schiff, and Masson's trichrome stain were all determined. Muc5ac expression in lung tissue was evaluated by the reverse transcription-polymerase chain reaction (RT-PCR), and alpha-smooth muscle actin was measured by immunohistochemistry. RESULTS: Inflammatory cells infiltrated the lung tissue and inflammatory cytokines were increased in the BALF of both the OVA and OVA + ozone groups, compared with the control group. Peribronchial hypersecretion and collagen deposition were evident in the models. The OVA + ozone group showed greater neutrophilic infiltration and peribronchial smooth muscle proliferation than the OVA group. Large-airway obstruction, small-airway dysfunction, and airway hyperresponsiveness were confirmed in both models. Small-airway functional variables, such as MMEF (mean midexpiratory flow, average flow from 25 to 75% forced vital capacity [FVC]) and FEF50 (forced expiratory flow at 50% of FVC), were positively correlated with large-airway function and had a stronger negative correlation with airway inflammation, mucus secretion, and responsiveness than large-airway function. CONCLUSION: Small-airway dysfunction was evident in the two endotypes of asthma and was correlated with severe airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. The small airways may be an important target in asthma treatment, and further research in the role of small-airway variables in the pathogenesis of asthma is warranted.
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BACKGROUND AND OBJECTIVE: Vitamin D is involved in various physiological and pathological processes, including inflammation and autophagy. We aimed to investigate the effects of dietary vitamin D deficiency or supplementation initiated in lactation and early life on inflammation and autophagy in an ovalbumin (OVA) mouse model. METHODS: Female BALB/c were fed with vitamin D-deficient, sufficient or supplemented diets throughout lactation and their offspring followed the same diet after weaning. Offspring were then sensitized and challenged with OVA, airway resistance (RL) was measured, and their serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected. Alveolar macrophages (AMs) were isolated from lung tissue and cultured with different concentrations of 1,25(OH)2D3. The expressions of autophagy-related (ATG) proteins including light-chain 3 (LC3), Beclin-1, and ATG5, and NF-κB p65 in lung tissue and AMs were measured. RESULTS: OVA sensitization and challenge induced dramatic allergic airway inflammation and higher RL in the vitamin D-deficient group compared with vitamin D-sufficient or the supplemented group. The expression of ATGs including LC3, Beclin-1, and ATG5, and NF-κB p65 in lung tissue in the vitamin D-deficient OVA-mediated group was increased compared with vitamin D-supplemented OVA-mediated group. There was correlation between the expression of LC3 mRNA and inflammatory cell numbers and cytokines in BALF. In vitro, 1,25(OH)2D3 also regulated the expression of LC3, Beclin-1, ATG5, and NF-κB p65 mRNA in AMs in a time- and dose-dependent manner. CONCLUSION: Deficiency of vitamin D in early life may aggravate allergic airway inflammation, and maintaining sufficient vitamin D during early life is necessary for lung health. Vitamin D may modulate autophagy in lungs of OVA sensitized/challenged mice, thus playing a protective role in OVA-induced allergic airway inflammation.
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Exposure to high levels of ozone contributes to insensitivity to glucocorticoids in asthma treatment, but the underlying mechanisms are not known. We built two asthma models: a "T2-high" asthma model was established by ovalbumin (OVA) sensitization/challenge and OVA sensitization/challenge combined with ozone exposure (OVA + ozone) was used to induce airway inflammation with increased numbers of neutrophils to simulate "T2-low" asthma. The expression of T-helper (Th)1/2/17-related cytokines was measured by cytokine antibody arrays. Bronchial provocation tests were carried out to evaluate the lung resistance of mice. Hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical (IHC) analyses of alpha-smooth muscle actin were undertaken to observe morphology changes in lungs. The expression of glucocorticoid receptors (GRs) and phosphorylated-GR (p-GR) was measured by western blotting. Nr3c1 mRNA was quantified by RT-qPCR. Protein expression of proinflammatory cytokines, signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3), and CXCL1 was measured through ELISAs, western blotting, or IHC analyses. Resected lung tissue from seven asthma patients and 10 healthy controls undergoing thoracotomy for pulmonary nodules was evaluated by IHC analyses and ELISAs. In both asthma models, mucus hypersecretion, as well as inflammation, hyperresponsiveness, and remodeling of the airways, was present compared with the control group, whereas the OVA + ozone group showed severe neutrophil infiltration. The expression of Th17-related cytokines (interleukin (IL)-6, IL-17A, IL-21), GR protein, and CXCL1 increased in the OVA + ozone group, whereas the expression of p-GR decreased. Dexamethasone (Dex) could not totally reverse the expression of p-GR and histone deacetylase-2 in the OVA + ozone group. STAT3 expression increased in the OVA + ozone group and could not be completely reversed by Dex, and nor could IL-6 expression. A positive correlation between IL-6 or IL-17A and STAT3 and negative correlation between SOCS3 and STAT3 were shown, suggesting that the IL-6/STAT3 pathway may be involved in OVA + ozone-induced corticosteroid-resistant airway inflammation. In clinical samples, IL-17A expression in lung tissue was positively correlated with percent STAT3-positive area and negatively correlated with SOCS3 expression. The IL-6/STAT3 pathway may contribute to corticosteroid insensitivity in OVA + ozone-induced neutrophilic airway inflammation through regulation of Th17 cells and could provide new targets for individual treatment of corticosteroid resistance in asthma.