26例(PAH n=17;CTEPH n=9)进行增量症状受限周期运动试验。在运动过程中评估分钟通气(V'E)、呼吸模式、肺容积和呼吸困难强度。使用三项问卷(呼吸困难描述符)连续评估运动期间的呼吸困难质量。潮汐量的拐点(VT)相对于V'E为每个增量试验确定。运动时吸气量的变化分为两组患者:过度充气者(65%)和非过度充气者(35%)。运动后使用多维呼吸困难剖面对呼吸困难进行多维特征描述。< / p >
In hyperinflators, inspiratory capacity decreased progressively throughout exercise by 0.36 L, while remaining stable in non-hyperinflators. The "work/effort" descriptor was most frequently selected throughout exercise in both types of patients (65% of all responses). At the VT/V'E inflection, work/effort plateaued while "unsatisfied inspiration" descriptors became selected predominantly only in hyperinflators (77% of all responses). In the affective domain, the emotion most frequently associated with dyspnoea was anxiety.
In pulmonary hypertension patients who develop hyperinflation during exercise, dyspnoea descriptors referring to unsatisfied inspiration become predominant following the VT/V'E inflection. As these descriptors are generally associated with more negative emotional experiences, delaying or preventing the VT/V'E inflection may have important implications for symptom management in patients with pulmonary hypertension.
哮喘是一种异质性疾病，以气道慢性炎症为特征，通常用吸入支气管扩张剂和皮质类固醇治疗。在不受控制的哮喘情况下，经常处方口服皮质类固醇(OCSs)。良好的依从性和吸入技术与改善预后相关;然而，很难监测个别患者的适当药物摄入量和有效性。呼出的气含有成千上万的挥发性有机化合物(VOCs)，它们反映了人体化学物质的变化，可能对监测药物药代动力学/药效动力学有用。我们旨在研究U-BIOPRED队列中严重哮喘患者呼出的VOCs(通过气相色谱-飞行时间质谱联用)与尿液中沙丁胺醇和OCSs(通过液相色谱-高分辨率质谱联用)水平的关系。
在基线和随访12–18 月后采集样本。基于单变量和多变量建模进行统计分析，然后计算受试者工作特征曲线下面积(AUC)。结果通过纵向复制和独立验证进行验证。< / p > < /秒> Data were available for 78 patients (baseline n=48, replication n=30 and validation n=30). Baseline AUC values were 82.1% (95% CI 70.4–93.9%) for salbutamol and 78.8% (95% CI 65.8–91.8%) for OCS. These outcomes could be adequately replicated and validated. Additional regression analysis between qualified exhaled VOCs and urinary concentrations of salbutamol and prednisone showed statistically significant correlations (p<0.01). We have linked exhaled VOCs to urinary detection of salbutamol and OCSs. This merits further development of breathomics into a point-of-care tool for therapeutic drug monitoring.
哮喘和慢性阻塞性肺病(COPD)在世界范围内造成严重的发病率和死亡率。在疾病发病机制方面，哮喘和慢性阻塞性肺病都涉及肺部慢性炎症，其特征是炎症细胞因子的异常释放、免疫细胞活性失调和气道重塑。迄今为止，目前的治疗方法仍然只能治疗症状，不能逆转原发疾病的进程。在最近的工作中，白细胞介素(IL)-1& α;和IL-1β已被认为在哮喘和慢性阻塞性肺病中发挥重要作用。在这篇综述中，我们总结了il -1和α信号失调的压倒性临床前证据;和IL-1β并讨论IL-1在哮喘和COPD治疗研究中的悖论。考虑到最近完成的和正在进行的IL-1生物制剂的临床试验，这些试验作为哮喘和COPD疾病的治疗手段有不同程度的失败和成功，这一点尤为重要
The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of "within-breath" analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols (e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children.
We collected DNA from 14 patients with PAM and four relatives, and analysed the coding regions of SLC34A2 by direct DNA sequencing. To determine the phenotype characteristics, clinical data were collected and a severity score was created for each variant, based on type and localisation within the protein.
We identified eight novel allelic variants of SLC34A2 in 14 patients with PAM. Four of these were nonsense variants, three were missense and one was a splice site variant. One patient was heterozygous for two different variants and all other patients were homozygous. Four patients were asymptomatic and 10 patients were symptomatic. The severity of the disease was associated with the variant severity.
Our findings support a significant role for SLC34A2 in PAM and expand the variant spectrum of the disease. Thus, SLC34A2 variants were detected in all patients and eight novel allelic variants were discovered. An association between disease severity and the severity of the variants was found; however, this needs to be investigated in larger patient populations.
We analysed three different mouse models of asthma and assessed cytokine profiles in sputum from human patients with asthma stratified according to inflammatory phenotype. In addition, we evaluated the therapeutic efficacy of various cytokine blockades in a mouse model of neutrophilic asthma.
Among the CSFs, airway granulocyte CSF (G-CSF) contributes to airway neutrophilia by promoting neutrophil development in bone marrow and thereby distinguishes neutrophilic inflammation from eosinophilic inflammation in mouse models of asthma. G-CSF is produced by concurrent stimulation of the lung epithelium with interleukin (IL)-17A and tumour necrosis factor (TNF)-α; therefore, dual blockade of upstream stimuli using monoclonal antibodies or genetic deficiency of the cytokines in IL-17AxTNF-α double-knockout mice reduced the serum level of G-CSF, leading to alleviation of neutrophilic inflammation in the airway. In humans, the sputum level of G-CSF can be used to stratify patients with asthma with neutrophil-dominated inflammation.
Our results indicated that myelopoiesis-promoting G-CSF and cytokines as the upstream inducing factors are potential diagnostic and therapeutic targets in patients with neutrophilic asthma.
1286例T-CHEQ参与者从出生到预后(2016年3月31日)或失去随访，平均随访17年。利用地面观测、化学/气象模型、遥感和土地利用回归模型，将1999年1月1日至2012年12月31日期间的二氧化氮(NO2)、臭氧(O )和50%截止气动直径为2.5 µm的颗粒物(PM2.5)的浓度分配给参与者，根据他们出生时的邮政编码。研究结果包括医生诊断的哮喘、过敏性鼻炎和湿疹的发生率。Cox比例风险回归模型用于估计每四分位暴露范围和结果的风险比，并对潜在混杂因素进行了调整。< / p > < /秒> Hazard ratios of 1.17 (95% CI 1.05–1.31) for asthma and 1.07 (95% CI 0.99–1.15) for eczema were observed for total oxidants (O3 and NO2) at birth. No significant increase in risk was found for PM2.5. Exposures to oxidant air pollutants (O3 and NO2) but not PM2.5 were associated with an increased risk of incident asthma and eczema in children. This suggests that improving air quality may contribute to the prevention of asthma and other allergic disease in childhood and adolescence.
中度至重度OSA患者为1.6次(95% CI为1.18–2.15次;经心血管危险因素调整后，p=0.002)比无OSA的患者更容易发生升胸主动脉钙化(≥100 单位)。此外，中重度OSA与升主动脉钙化之间的相关性，较高心外膜脂肪量的患者略强于无OSA患者和最低心外膜脂肪量的患者(OR 2.11, 95% CI 1.30–3.43)。
一般人群中OSA的严重程度与亚临床系统性动脉粥样硬化独立相关。这些发现强调了严重OSA的潜在重要性，尤其是在心外膜脂肪含量较高的受试者中，它可能是全身性动脉粥样硬化和心血管疾病的预测因素
TAC的信息来自8年的食物频率调查问卷。8岁和16岁时采用肺活量测定法、脉冲振荡测定法(IOS)和16岁时呼出一氧化氮分数(FeNO)测量肺功能。低肺功能定义为用力呼气量1 s (FEV1) z-score低于25百分位。TAC与肺功能之间的纵向关联通过混合效应模型进行分析，以调整潜在的混杂因素。在8年按哮喘进行分层，以检查效果的改变。< / p >
The median TAC intake was 10 067 μmol Trolox equivalents (TE)·g–1, with males having a lower mean compared to females (9963 versus 10 819 μmol TE·g–1). In analyses of lung function change between 8 and 16 years, there were no statistically significant associations between TAC in tertiles and spirometry results for the total study population. Among children with asthma at 8 years (prevalence 7%), higher TAC was associated with higher mean FEV1 (0.46
High dietary antioxidant intake in school age may be associated with improved lung function development from school age to adolescence among children with asthma.
纤维化间质性肺疾病(ILDs)是一种慢性且经常进展的疾病，对发病率、与健康相关的生活质量(HRQoL)和卫生系统费用有重大影响。在日常活动中使用流动氧(AO)可改善运动表现，减轻症状，改善日常生活中的活动能力。英国一项前瞻性、多中心、混合方法、随机对照交叉试验(AmbOx试验:NCT02286063)对纤维化性ILD患者的日常生活影响进行了首次研究，报告称，与没有干预相比，AO治疗2周后HRQoL改善，通过King’s Brief ILD (K-BILD)问卷测量[1–3]。虽然AO用于ILD，但缺乏支持其健康-经济影响的证据。在这里，我们利用AmbOx试验收集的数据，评估了AO在ILD患者中的成本效益
Biopsies from 117 adult LCH patients, 83 with PLCH (median age 36.4 years, 56 females, 38 multisystem disease, 79 single system disease, 65 current smokers) were genotyped for the BRAFV600E mutation. In 69 cases, LCH lesions were also genotyped by whole-exome sequencing (WES) or targeted gene panel next-generation sequencing (NGS). Cox models were used to estimate the association of baseline characteristics with the hazard of LCH progression.
MAPK pathway alterations were detected in 59 out of 69 cases (86%) (BRAFV600E mutation: 36%, BRAFN486_P490 deletion: 28%, MAP2K1 mutations: 15%, isolated NRASQ61 mutations: 4%), while KRAS mutations were virtually absent in PLCH lesions. The BRAFV600E mutation was not associated with LCH presentation at diagnosis, including smoking status and lung function, in PLCH patients. BRAFV600E status did not influence the risk of LCH progression over time.
Thus, MAPK alterations are present in most lesions from adult LCH patients, particularly in PLCH. Unlike reports in paediatric LCH, BRAFV600E genotyping did not provide additional information on disease outcome. The search for alterations involved in the MAPK pathway, including BRAF deletions, is useful for guiding targeted treatment in selected patients with refractory progressive LCH.
持续哮喘和缓解哮喘之间有4个cpg位点和42个区域甲基化差异。 I n cis位点的DNA甲基化与ACKR2和DGKQ位点的基因表达相关。在缓解受试者和健康对照组之间，有1163个cpg位点和328个区域甲基化差异。DNA甲基化与一组在纤毛上皮中表达的基因的表达相关。< / p >
CpGs differentially methylated between remission and persistent asthma identify genetic loci associated with resolution of inflammation and airway responsiveness. Despite the absence of symptoms, remission subjects have a DNA methylation profile that is distinct from that of healthy controls, partly due to changes in cellular composition, with a higher gene expression signal related to ciliated epithelium in remission versus healthy controls.
Hs-TnI在2020例患者中检测到(96.9%)。中位hs-TnI浓度为3.8 ng·L–1(四分位范围2.5–6.6 ng·L–1)， 1.8%的患者的水平高于99百分位参考限值27 ng·L–1。在Cox回归分析中，包括调整气流限制、呼吸困难等级、运动能力和严重加重史，以及传统心血管危险因素、估计的肾小球滤过率、踝臂指数、n端脑钠肽前体和流行的心血管疾病，hs-TnI是全因死亡率的显著预测因子，两者都是连续变量(危险比(HR)为log hs-TnI 1.28，95% CI 1.01–1.62)，并根据6 ng·L–1 (HR 1.63, 95% CI 1.10–2.42)的截止值进行分类。< / p >
In patients with stable COPD, hs-TnI is a strong predictor of all-cause mortality beyond established COPD mortality predictors, and independent of a broad range of cardiovascular risk factors and prevalent cardiovascular diseases. Hs-TnI concentrations well below the upper reference limit provide further prognostic value for all patients with COPD when added to established risk assessments.
妊娠期哮喘加重与不良母婴健康结果之间的关系尚未得到适当的调查。我们的目的是确定哮喘孕妇哮喘加重的短期和长期代际影响。< / p >
A population cohort study was conducted using data from the Ontario asthma surveillance system and population-level health administrative data. Asthma exacerbation in pregnant women with asthma was defined as at least one of the following criteria: at least five physician visits, or one emergency department visit or one hospital admission for asthma during pregnancy. Pregnancy complications, adverse perinatal outcomes and early childhood respiratory disorders were identified using International Classification of Disease codes (9th and 10th revisions).
The cohort consisted of 103 424 singleton pregnancies in women with asthma. Asthma exacerbation in pregnant women with asthma was associated with higher odds of pre-eclampsia (OR 1.30, 95% CI 1.12–1.51) and pregnancy-induced hypertension (OR 1.17, 95% CI 1.02–1.33); babies had higher odds of low birthweight (OR 1.14, 95% CI 1.00–1.31), preterm birth (OR 1.14, 95% CI 1.01–1.29) and congenital malformations (OR 1.21, 95% CI 1.05–1.39). Children born to women with asthma exacerbation during pregnancy had elevated risk of asthma (OR 1.23, 95% CI 1.13–1.33) and pneumonia (OR 1.12, 95% CI 1.03–1.22) during the first 5 years of life.
Asthma exacerbation during pregnancy in women with asthma showed increased risk of pregnancy complications, adverse perinatal outcomes and early childhood respiratory disorders in their children, indicating that appropriate asthma management may reduce the risk of adverse health outcomes.
肺腺癌(LUADs)在放射学上表现为亚实性结节(ssn)，比实性LUADs表现出更多的惰性生物学行为。SSNs通常包括浸润前和浸润性早期腺癌，可分为纯磨玻璃状结节和部分实性结节。ssr的基因组特征仍然知之甚少。< / p > < /秒> We subjected 154 SSN samples from 120 treatment-naïve Chinese patients to whole-exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced-stage LUADs were defined. In addition, we investigated the intratumour heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis. The median somatic mutation rate across the SSN cohort was 1.12 mutations per Mb. Mutations in EGFR were the most prominent and significant variation, followed by those in RBM10, TP53, STK11 and KRAS. The differences between SSNs and advanced-stage LUADs at a genomic level were unravelled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multicentric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in EGFR, TP53, RBM10 and ARID1B, suggesting that these genes play roles in the progression of LUADs. Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.
A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.
We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80–2.01) in a multicentre case–control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92–1.24) or the secondary (ORcausal 1.09, 95% CI 0.77–1.54) MR analysis.
The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH.
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运动中肺动脉压升高的识别具有重要的诊断、预后和治疗意义。在运动测试中，压力超声心动图常用于估计肺动脉压力，但支持这种做法的数据有限。本研究检验了多普勒超声心动图在休息和运动时估计肺动脉压力的准确性。< / p > < /秒> Simultaneous cardiac catheterisation-echocardiographic studies were performed at rest and during exercise in 97 subjects with dyspnoea. Echocardiography-estimated pulmonary artery systolic pressure (ePASP) was calculated from the right ventricular (RV) to right atrial (RA) pressure gradient and estimated RA pressure (eRAP), and then compared with directly measured PASP and RAP. Estimated PASP was obtainable in 57% of subjects at rest, but feasibility decreased to 15–16% during exercise, due mainly to an inability to obtain eRAP during stress. Estimated PASP correlated well with direct PASP at rest (r=0.76, p<0.0001; bias –1 mmHg) and during exercise (r=0.76, p=0.001; bias +3 mmHg). When assuming eRAP of 10 mmHg, ePASP correlated with direct PASP (r=0.70, p<0.0001), but substantially underestimated true values (bias +9 mmHg), with the greatest underestimation among patients with severe exercise-induced pulmonary hypertension (EIPH). Estimation of eRAP during exercise from resting eRAP improved discrimination of patients with or without EIPH (area under the curve 0.81), with minimal bias (5 mmHg), but wide limits of agreement (–14–25 mmHg). The RV–RA pressure gradient can be estimated with reasonable accuracy during exercise when measurable. However, RA hypertension frequently develops in patients with EIPH, and the inability to noninvasively account for this leads to substantial underestimation of exercise pulmonary artery pressures.
在纤维化间质性肺病(ILD)患者中，运动时低氧血症频繁发生，可导致运动不耐受、运动性呼吸困难和生活质量降低[1–3]。临床上显著的运动性低氧血症通常定义为经皮动脉氧饱和度(SpO2)在6分钟行走试验(6MWT)[4]中下降至le88%，与ILD患者[5].
生存率降低相关在癌症患者中，目前的指南建议对偶发和症状性静脉血栓栓塞(VTE)进行类似的治疗，主要基于回顾性数据。我们旨在评估抗凝治疗在偶发和症状性静脉血栓栓塞的癌症患者。< / p > < /秒> The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.
吸入性皮质类固醇(ICS)被认为是肺癌潜在的化学预防手段。几项针对慢性阻塞性肺疾病(COPD)患者的观察性研究报告了不一致的结果，使用ICS后肺癌发病率显著降低或没有效果。我们评估了这种关联，使用了一种避免影响某些研究的偏见的方法。< / p > < /秒> A cohort of patients with COPD, new users of long-acting bronchodilators over 2000–2014, was formed using the Quebec healthcare databases, and followed until 2015 for a first diagnosis of lung cancer. A 1-year delay after cohort entry was used to avoid protopathic bias and a 1-year latency period was included after the initiation of ICS use. A time-dependent Cox regression model was used to estimate the hazard ratio (HR) of lung cancer associated with ICS exposure, adjusted for covariates. The cohort involved 63 276 subjects, including 63% receiving ICS, with 3743 lung cancers occurring during a mean follow-up of 5 years. The adjusted HR of lung cancer associated with any ICS exposure was 1.01 (95% CI 0.94–1.08), relative to no ICS use. The HR with longer time (>4 years) since ICS initiation was 0.92 (95% CI 0.83–1.03), while with higher mean daily ICS dose (>1000 μg fluticasone equivalents) was 1.36 (95% CI 1.03–1.81). Inhaled corticosteroid use is not associated with a reduction in lung cancer incidence in patients with COPD. Observational studies reporting such reduction may have been affected by time-related biases and the inclusion of patients with asthma. The proposition of a randomised trial warrants some caution.
全球巨大负担的肺外结核(EPTB)病例中有很大一部分是凭经验治疗的，没有准确定义疾病部位和多器官疾病累及的程度。正电子发射断层扫描(PET)在结核病中使用2-脱氧-2-(氟-18)氟- We conducted a study of HIV-negative adult patients with a new clinical diagnosis of EPTB across eight centres located in six countries: India, Pakistan, Thailand, South Africa, Serbia and Bangladesh, to assess the extent of disease and common sites involved at first presentation. 18F-FDG PET/computed tomography (CT) scans were performed within 2 weeks of presentation. 358 patients with EPTB (189 females; 169 males) were recruited over 45 months, with an age range of 18–83 years (females median 30 years; males median 38 years). 350 (98%) out of 358 patients (183 female, 167 male) had positive scans. 118 (33.7%) out of 350 had a single extrapulmonary site and 232 (66.3%) out of 350 had more than one site (organ) affected. Lymph nodes, skeleton, pleura and brain were common sites. 100 (28%) out of 358 EPTB patients had 18F-FDG PET/CT-positive sites in the lung. 110 patients were 18F-FDG PET/CT-positive in more body sites than were noted clinically at first presentation and 160 patients had the same number of positive body sites. 18F-FDG PET/CT scan has potential for further elucidating the spectrum of disease, pathogenesis of EPTB and monitoring the effects of treatment on active lesions over time, and requires longitudinal cohort studies, twinned with biopsy and molecular studies.
T
肺动脉高压(PH)描述了一组与发病率和死亡率增加相关的异质性疾病，无论病因如何[1–4]。诊断和表型PH值的金标准仍然是侵入性测量通过右心导管[5]。肺血流动力学的无创评估是一种有吸引力的替代方法，以降低手术风险，并更广泛地研究患者亚群谁没有统一进行右心导管评估PH值(，例如。多为左心PH患者)[5–7]。然而，有创测量和无创测量之间的不完全相关性限制了无创策略在PH评估中的广泛采用[8–13]
作为全球公民，我们有责任减少环境退化和气候变化对地球福祉和人口健康构成的严重威胁。现在对我们未来的这些毫无疑问的威胁是由于人口增长和人类的资源消耗模式造成的。同时，作为医疗专业人员，我们应该为患者寻求最好的治疗结果，我们需要考虑不同患者群体之间的公平。在呼吸医学专业，目前关于如何处理压力计量吸入器(pmis)中使用的推进剂在全球变暖中的作用的争论是一个非常紧迫的例子，说明这些有时相互冲突的命令如何在我们的日常实践中面对我们
Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.
Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (–89.0%, p<0.01) and impaired tracheal MCT (–29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min–1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and ciliary beat frequency were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro, and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.
Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.
本文件为严重哮喘的管理提供了临床建议。进行了全面的证据综合，包括荟萃分析，以总结与欧洲呼吸学会/美国胸科学会工作组的问题相关的所有可用证据。188bet官网地址使用GRADE(建议、评估、发展和评价的分级)方法对证据进行评价，并在证据概要中总结结果。由哮喘专家组成的多学科工作组对证据综合进行了讨论，并提出了建议，他们就六个具体问题提出了具体建议。在考虑了理想和不理想后果的平衡、证据质量、可行性和各种干预措施的可接受性后，工作组提出了以下建议:1)建议使用抗白介素(IL)-5和抗IL-5受体& α;对于严重失控的成人嗜酸性粒细胞性哮喘表型;2)建议使用血液嗜酸性粒细胞切点≥150 μL–1指导重度哮喘成人患者启动抗il -5;3)建议考虑特定的嗜酸性粒细胞(≥260 μL–1)和呼出一氧化氮分数(≥19.5 ppb)临界值，以确定抗ige治疗反应可能性最大的青少年或成人;4)建议对患有严重不受控制哮喘的青少年和成年人使用吸入噻托溴铵，尽管全球哮喘倡议(GINA)的第4步和第5步或国家哮喘教育和预防计划(NAEPP)的第5步治疗;5)建议在GINA第5步或NAEPP第5步治疗中进行慢性大环内酯治疗试验，以减少持续有症状或不受控制的患者的哮喘加重，无论哮喘表型如何; and 6) suggest using anti-IL-4/13 for adult patients with severe eosinophilic asthma and for those with severe corticosteroid-dependent asthma regardless of blood eosinophil levels. These recommendations should be reconsidered as new evidence becomes available.
本体论上不同的巨噬细胞群体通过未知的机制不同地促进器官纤维化。< / p >
We applied lineage tracing, single-cell RNA sequencing and single-molecule fluorescence in situ hybridisation to a spatially restricted model of asbestos-induced pulmonary fibrosis.
We demonstrate that tissue-resident alveolar macrophages, tissue-resident peribronchial and perivascular interstitial macrophages, and monocyte-derived alveolar macrophages are present in the fibrotic niche. Deletion of monocyte-derived alveolar macrophages but not tissue-resident alveolar macrophages ameliorated asbestos-induced lung fibrosis. Monocyte-derived alveolar macrophages were specifically localised to fibrotic regions in the proximity of fibroblasts where they expressed molecules known to drive fibroblast proliferation, including platelet-derived growth factor subunit A. Using single-cell RNA sequencing and spatial transcriptomics in both humans and mice, we identified macrophage colony-stimulating factor receptor (M-CSFR) signalling as one of the novel druggable targets controlling self-maintenance and persistence of these pathogenic monocyte-derived alveolar macrophages. Pharmacological blockade of M-CSFR signalling led to the disappearance of monocyte-derived alveolar macrophages and ameliorated fibrosis.
Our findings suggest that inhibition of M-CSFR signalling during fibrosis disrupts an essential fibrotic niche that includes monocyte-derived alveolar macrophages and fibroblasts during asbestos-induced fibrosis.
生物和功能衰老加速在纤维化间质性肺病(ILD)中很常见;然而，它们对不良健康结果的影响尚未在该人群中进行评估。< / p > < /秒> Patients were prospectively recruited from a specialised ILD clinic. Functional ageing was determined by frailty index and biological age by measurement of absolute telomere length (aTL) from patients' peripheral blood leukocytes. Adverse health outcomes included health-related quality of life (St George's Respiratory Questionnaire), number and length of respiratory and non-respiratory hospitalisations, medication tolerability and time to death or lung transplantation. Multivariable models were used to determine the risks and rates of adverse health outcomes associated with the frailty index and aTL. 540 patients with fibrotic ILD, including 100 with idiopathic pulmonary fibrosis (IPF), provided 749 frailty index assessments, with 189 patients providing blood samples. The frailty index was strongly associated with quality of life, rate of hospitalisation, time to hospital discharge and mortality, including adjustment for age, sex, disease severity and IPF diagnosis. Mortality prognostication was improved by the addition of the frailty index to commonly used clinical parameters and previously validated composite indices. Conversely, aTL was not associated with most adverse health outcomes. The effect of chronological age on outcomes was mediated primarily by the frailty index, and to a lesser extent by aTL. Functional ageing is associated with adverse health outcomes in patients with fibrotic ILD, indicating the need for consideration of the individual functional age into clinical decision-making.
肺间充质在成熟的呼吸系统中产生多种不同的细胞谱系，包括气道和血管的平滑肌细胞。然而，对人类肺的规格和间充质细胞多样性缺乏全面的了解。
我们完成了胎儿人肺组织的单细胞RNA测序分析。在Seurat中进行典型相关分析、聚类、聚类标记基因鉴定和t分布随机近邻嵌入表示。细胞群体使用ToppFun进行注释。利用免疫组化和in situ杂交验证关键标记基因的时空表达模式。< / p > < /秒> We identified molecularly distinct populations representing "committed" fetal human lung endothelial cells, pericytes and smooth muscle cells. Early endothelial lineages expressed "classic" endothelial cell markers (platelet endothelial cell adhesion molecule/CD31 and claudin 5), while pericytes expressed platelet-derived growth factor receptor-β, Thy-1 membrane glycoprotein and basement membrane molecules (collagen IV, laminin and proteoglycans). We observed a large population of "nonspecific" human lung mesenchymal progenitor cells characterised by expression of collagen I and multiple elastin fibre genes (ELN, MFAP2 and FBN1). We closely characterised the diversity of mesenchymal lineages defined by α2-smooth muscle actin (ACTA2) expression. Two cell populations, with the highest levels of ACTA2 transcriptional activity, expressed unique sets of markers associated with airway or vascular smooth muscle cells. Spatiotemporal analysis of these marker genes confirmed early and persistent spatial specification of airway (HHIP, MYLK and IGF1) and vascular (NTRK3 and MEF2C) smooth muscle cells in the developing human lung. Our data suggest that specification of distinct airway and vascular smooth muscle cell phenotypes is established early in development and can be identified using the markers we provide.
Long-term mortality in patients with NTM-PD was significantly associated with the aetiological NTM organism, cavitary disease and certain demographic characteristics.
Current research suggests that allergy is driven by genetic and epigenetic factors, in concert with environmental factors such as microbiome and diet, leading to early-life disturbance in immunological development and disruption of balance within key immuno-inflammatory pathways. Variation in inherited susceptibility and exposures causes heterogeneity in manifestations of asthma and other allergic diseases. Machine learning approaches are being used to explore this heterogeneity, and to probe the pathophysiological patterns or "endotypes" that correlate with subphenotypes of asthma and allergy. Mathematical models are being built based on genomic, transcriptomic and proteomic data to predict or discriminate disease phenotypes, and to describe the biomolecular networks behind asthma.
The use of systems biology in allergy and asthma research is rapidly growing, and has so far yielded fruitful results. However, the scale and multidisciplinary nature of this research means that it is accompanied by new challenges. Ultimately, it is hoped that systems medicine, with its integration of omics data into clinical practice, can pave the way to more precise, personalised and effective management of asthma.
较短的外周血白细胞(PBL)端粒长度(TL)与各种慢性肺部疾病的不良预后相关。本研究检验了PBL-TL是否与重症生存率相关。< / p >
We analysed data from a prospective observational cohort study of 937 critically ill patients at Vanderbilt University Medical Center (VUMC). PBL-TL was measured using quantitative PCR of DNA isolated from PBLs. Findings were validated in an independent cohort of 394 critically ill patients with sepsis admitted to the University of California San Francisco (UCSF).
In the VUMC cohort, shorter PBL-TL was associated with worse 90-day survival (adjusted hazard ratio (aHR) 1.3, 95% CI 1.1–1.6 per 1 kb TL decrease; p=0.004); in subgroup analyses, shorter PBL-TL was associated with worse 90-day survival for patients with sepsis (aHR 1.5, 95% CI 1.2–2.0 per 1 kb TL decrease; p=0.001), but not trauma. Although not associated with development of acute respiratory distress syndrome (ARDS), among ARDS subjects, shorter PBL-TL was associated with more severe ARDS (OR 1.7, 95% CI 1.2–2.5 per 1 kb TL decrease; p=0.006). The associations of PBL-TL with survival (adjusted HR 1.6, 95% CI 1.2–2.1 per 1 kb TL decrease; p=0.003) and risk for developing severe ARDS (OR 2.5, 95% CI 1.1–6.3 per 1 kb TL decrease; p=0.044) were validated in the UCSF cohort.
Short PBL-TL is strongly associated with worse survival and more severe ARDS in critically ill patients, especially patients with sepsis. These findings suggest that telomere dysfunction may contribute to outcomes from critical illness.
阻塞性睡眠呼吸暂停(OSA)会增加不降24小时血压异常的风险，这是心血管疾病(CVD)的独立危险因素。我们检测了未治疗的正常浸入式血压(NDBP)和反浸入式血压(RDBP)(一种极端的不浸入式血压)OSA患者的差异外泌体microRNA (miRNA)表达，以了解OSA中不浸入式血压的机制。
46例患者(15 RDBP vs 31 NDBP)匹配OSA严重程度(呼吸事件指数32.6±22.5 vs 32.2±18.1 events·h–1;p=0.9)，年龄(54.8±12.9 versus 49±9.9 岁;p=0.09)和身体质量指数(36.2±6.6 vs 34.4±6.8 kg·m–2;P =0.4)。用流式细胞术鉴定血浆外泌体，对培养的内皮细胞进行体外 报告细胞功能测定。外泌体miRNA货物用微阵列进行分析，随后进行生物信息学分析。< / p > < /秒> Exosomes from RDBP patients increased the permeability of endothelial cell tight junctions and adhesion molecule expression. Principal component analyses of miRNA array data showed strict separation and identification of the two groups. A restricted and validated signature of exosomal miRNAs was identified in the RDBP versus NDBP group. Their predicted target genes involved phosphatidylinositol 3-kinase-Akt (p=0.004), Ras (p=3.42E-05), Wnt (p=0.003) and hypoxia inducible factor-1 signalling (p=0.04), inflammatory mediator regulation of transient receptor potential channels (p=0.01), and several cancer-related pathways. Patients with RDBP have altered miRNA cargoes in circulating exosomes that invoke in vitro endothelial dysfunction. A selected number of circulating exosomal miRNAs play an important role in abnormal circadian regulation of blood pressure and may provide prognostic biomarkers of CVD risk in OSA.
大剂量吸入皮质类固醇(ICS)治疗口服皮质类固醇依赖哮喘中由于全身效应而产生的疗效比例尚不确定。本研究旨在评估口服皮质激素依赖性哮喘患者口服皮质激素保留效应的ICS剂量反应关系，并基于ICS 与口服皮质激素对肾上腺抑制的比较剂量反应关系，确定口服皮质激素保留效应因其全身效应所占的比例。
报告口服高剂量ICS对口服皮质激素依赖性哮喘的皮质激素保留作用的随机对照试验的系统回顾和荟萃分析。此外，还检索了口服皮质类固醇与ICS在肾上腺抑制方面剂量等效的报告。主要结果是口服ICS的皮质激素保留效应可归因于全身吸收的比例，每增加1000微克ICS，以比率表示。这一比率估计了ICS由于全身效应而产生的口服皮质类固醇保留效应。< / p > < /秒> 11 studies including 1283 participants reporting oral corticosteroid-sparing effects of ICS were identified. The prednisone dose decrease per 1000 µg increase in ICS varied from 2.1 mg to 4.9 mg, depending on the type of ICS. The ratio of the prednisone-sparing effect due to the systemic effects per 1000 µg of fluticasone propionate was 1.02 (95% CI 0.68–2.08) and for budesonide was 0.93 (95% CI 0.63–1.89). In patients with oral corticosteroid-dependent asthma, the limited available evidence suggests that the majority of the oral corticosteroid-sparing effect of high-dose ICS is likely to be due to systemic effects.
This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.
Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m–2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day–1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day–1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.
The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.
We prospectively followed up 122 South African patients (52.5% HIV-infected) with DR-TB and poor prognostic features between 2014 and 2018. We examined outcomes and safety in those who received a bedaquiline-based regimen (n=82) compared to those who received a bedaquiline–delamanid combination regimen (n=40).
There was no significant difference in 6-month culture conversion (92.5% versus 81.8%; p=0.26) and 18-month favourable outcome rate (63.4% versus 67.5%; p=0.66) in the bedaquiline versus the bedaquiline–delamanid combination group, despite the latter having more advanced drug resistance (3.7% versus 22.5% resistant to at least five drugs; p=0.001) and higher pre-treatment failure rates (12.2% versus 52.5% with pre-treatment multidrug-resistant TB therapy failure; p<0.001). Although the proportion of prolongation of the QT interval corrected using Fridericia's formula was higher in the combination group (>60 ms from baseline (p=0.001) or >450 ms during treatment (p=0.001)), there were no symptomatic cases or drug withdrawals in either group. Results were similar in HIV-infected patients.
A bedaquiline–delamanid combination regimen showed comparable long-term safety compared to a bedaquiline-based regimen in patients with DR-TB, irrespective of HIV status. These data inform regimen selection in patients with DR-TB from TB-endemic settings.
In the Rotterdam Study (population-based prospective cohort) we examined prevalence, trajectories and prognosis of subjects with normal spirometry (controls; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ≥0.7, FEV1 ≥80%), PRISm (FEV1/FVC ≥0.7, FEV1 <80%) and chronic obstructive pulmonary disease (COPD) (FEV1/FVC <0.7) at two study visits. Hazard ratios with 95% confidence intervals for mortality (until December 30, 2018) were adjusted for age, sex, body mass index, current smoking and pack-years.
Of 5487 subjects (age 69.1±8.9 years; 7.1% PRISm), 1603 were re-examined after 4.5 years. Of the re-examined PRISm subjects, 15.7% transitioned to normal spirometry and 49.4% to COPD. Median lung function decline was highest in subjects with incident PRISm (FEV1 –92.8 mL·year–1, interquartile range (IQR) –131.9––65.8 mL·year–1; FVC –93.3 mL·year–1, IQR –159.8––49.1 mL·year–1), but similar in persistent PRISm (FEV1 –30.2 mL·year–1, IQR –67.9––7.5 mL·year–1; FVC –20.1 mL·year–1, IQR –47.7–21.7 mL·year–1) and persistent controls (FEV1 –39.6 mL·year–1, IQR –64.3––12.7 mL·year–1; FVC –20.0 mL·year–1, IQR –55.4–18.8 mL·year–1). Of 5459 subjects with informed consent for follow-up, 692 (12.7%) died during 9.3 years (maximum) follow-up: 10.3% of controls, 18.7% of PRISm subjects and 20.8% of COPD subjects. Relative to controls, subjects with PRISm and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2–4 had increased all-cause mortality (PRISm: HR 1.6, 95% CI 1.2–2.0; COPD GOLD 2–4: HR 1.7, 95% CI 1.4–2.1) and cardiovascular mortality (PRISm: HR 2.8, 95% CI 1.5–5.1; COPD 2–4: HR 2.1, 95% CI 1.2–3.6). Mortality within <1 year was highest in PRISm, with patients often having cardiovascular comorbidities (heart failure or coronary heart disease; 70.0%).
PRISm is associated with increased mortality and this population encompasses at least three distinct subsets: one that develops COPD during follow-up, a second with high cardiovascular burden and early mortality, and a third with persistent PRISm and normal age-related lung function decline.
非结核分枝杆菌(NTM)可引起慢性、使人衰弱的肺部疾病。患者报告的结果提供了症状、功能和治疗反应的衡量标准。这里我们描述了最近开发的NTM模块的初步验证。< / p > < /秒> The study population included Northwest NTM Biobank patients in whom Mycobacterium avium complex (MAC) was isolated and who had ever met the 2007 American Thoracic Society/Infectious Diseases Society of America pulmonary disease criteria. The NTM Module was administered at enrolment and 12 months; a subset also completed the Quality of Life Questionnaire–Bronchiectasis (QOL-B). The NTM Module generates four domain scores (0–100; higher scores indicate better functioning) reflecting NTM-specific symptoms (NTM Symptoms, Body Image, Digestive Symptoms and Eating Problems). We described patient characteristics and mean scores, and evaluated psychometric properties, including response to treatment at 12 months, for each domain. Overall, 203 patients with pulmonary MAC disease were included. Average enrolment scores ranged from 76 (NTM Symptoms) to 84 (Eating Problems). Ceiling effects were observed for Body Image (26% of participants) and Eating Problems (52%). Internal consistency (Cronbach's alpha) ranged from 0.67 (Digestive Symptoms) to 0.89 (Eating Problems). The intraclass correlation for test–retest reproducibility (n=27) ranged from 0.72 (Body Image) to 0.94 (Eating Problems). Patients starting treatment (n=35) had statistically significant increases in scores for NTM Symptoms (+5, p=0.04), Digestive Symptoms (+7, p=0.002), Body Image (+7, p=0.03) and QOL-B Respiratory Symptoms (n=25, +10, p=0.006). NTM Symptoms scores increased by 15 points (p=0.002) in the 16 patients with scores ≤80 at enrolment. The NTM Module generally performs well as a valid patient-reported outcome for pulmonary MAC disease and was responsive to MAC treatment.
We prospectively contrasted the sensory and physiological responses to exercise in 42 CPFE and 16 IPF patients matched by the severity of exertional hypoxaemia. Emphysema and pulmonary fibrosis were quantified using computed tomography. Inspiratory constraints were assessed in a constant work rate test: capillary blood gases were obtained in a subset of patients.
CPFE patients had lower exercise capacity despite less extensive fibrosis compared to IPF (p=0.004 and 0.02, respectively). Exertional dyspnoea was the key limiting symptom in 24 CPFE patients who showed significantly lower transfer factor, arterial carbon dioxide tension and ventilatory efficiency (higher minute ventilation (V'E)/carbon dioxide output (V'CO2) ratio) compared to those with less dyspnoea. However, there were no between-group differences in the likelihood of pulmonary hypertension by echocardiography (p=0.44). High dead space/tidal volume ratio, low capillary carbon dioxide tension emphysema severity (including admixed emphysema) and traction bronchiectasis were related to a high V'E/V'CO2 ratio in the more dyspnoeic group. V'E/V'CO2 nadir >50 (OR 9.43, 95% CI 5.28–13.6; p=0.0001) and total emphysema extent >15% (2.25, 1.28–3.54; p=0.01) predicted a high dyspnoea burden associated with severely reduced exercise capacity in CPFE
Contrary to current understanding, hypoxaemia per se is not the main determinant of exertional dyspnoea in CPFE. Poor ventilatory efficiency due to increased "wasted" ventilation in emphysematous areas and hyperventilation holds a key mechanistic role that deserves therapeutic attention.
舌下神经刺激(HNS)通过颏舌肌激活降低阻塞性睡眠呼吸暂停(OSA)的严重程度和降低上气道折叠性。本研究评估了一种新型设备植入后6个月的安全性和有效性，该设备通过(由外部佩戴的单元激活的小型植入电极)传输双侧HNS ，用于治疗OSA: Genio™系统。< / p >
This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea–hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number NCT03048604.
22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m–2) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h–1, a mean change of 10.8 events·h–1 (p<0.001); and ODI decreased from 19.1±11.2 to 9.8±6.9 events·h–1, a mean change of 9.3 events·h–1 (p<0.001). Daytime sleepiness (Epworth Sleepiness Scale; p=0.01) and sleep-related quality of life (Functional Outcomes of Sleep Questionnaire-10; p=0.02) both improved significantly. The number of bed partners reporting loud, very intense snoring, or leaving the bedroom due to participant snoring decreased from 96% to 35%. 91% of participants reported device use >5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period.
Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm.
We analysed leukocyte transcriptomes from preschool children (6 months–3 years) at acute wheeze (n=107), and at a revisit 2–3 months later, comparing them to age-matched healthy controls (n=66). RNA-sequencing applying GlobinLock was used. The cases were followed clinically until age 7 years. Differential expression tests, weighted correlation network analysis and logistic regression were applied and correlations to 76 clinical traits evaluated.
Significant enrichment of genes involved in the innate immune responses was observed in children with wheeze. We identified a unique acute wheeze-specific gene-module, which was associated with vitamin D levels (p<0.005) in infancy, and asthma medication and FEV1%/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio several years later, at age 7 years (p<0.005). A model that predicts leukotriene receptor antagonist medication at 7 years of age with high accuracy was developed (area under the curve 0.815, 95% CI 0.668–0.962).
Gene expression profiles in blood from preschool wheezers predict asthma symptoms at school age, and therefore serve as biomarkers. The acute wheeze-specific gene module suggests that molecular phenotyping in combination with clinical information already at an early episode of wheeze may help to distinguish children who will outgrow their wheeze from those who will develop chronic asthma.
支气管扩张是一种慢性进行性疾病，通常伴有明显的症状负担，需要强化治疗。尽管存在多种潜在的潜在病因，但气道炎症、气道结构性损伤、粘液清除障碍和气道病原体获得的恶性循环是疾病进展的关键致病途径[1].
Fleischner学会白皮书和美国胸科学会(ATS)/欧洲呼吸学会(ERS)/日本呼吸学会(JRS)/拉丁美洲胸科协会(ALAT)指南最近重新定义188bet官网地址了通常间质性肺炎(UIP)的计算机断层扫描(CT)模式[1,2]。两篇论文都证实了蜂窝蜂窝是UIP类型诊断的基石，并将外周牵引性细支气管扩张(PTB)作为新的“可能UIP”类别的关键特征。因此，提高这两种特征之间的区别可能是至关重要的，特别是当特发性肺纤维化(IPF)的临床可能性不确定时;对于没有蜂窝状的PTB患者，应考虑进行肺活检，但对于蜂窝状明显且典型UIP模式[2]的患者，不建议进行肺活检
哮喘药物治疗的循序渐进方法是当前哮喘指南的一个关键特征[1–4]。通过算法，“加大”治疗强度以获得哮喘控制和降低哮喘加重风险，在一段时间的长时间控制和无加重后“降低”治疗强度。传统算法提倡所有严重程度的短效& β 2-激动剂(SABA)缓解治疗，最初作为第1步的唯一治疗，在第2步使用维持“低剂量”吸入皮质类固醇(ICS)，在第3步和第4步使用维持ICS/长效& β -激动剂(LABA)“低”、“中等”或“高”剂量，最后在第5步使用“附加”治疗
国家囊性纤维化(CF)数据登记跟踪患者随时间的特征，并提供了对新兴趋势和当前临床需求的洞察。在最近的一项研究中，B
R提出的宣言
It also prompts a key question about the balance between the effort spent on randomised clinical trials (RCTs) versus real-life research (RLR), particularly in an era where frequent monitoring of patients capturing their real life, using wearable devices, home diagnostics, smartphones, smart inhalers, collections of contextual information, cloud connectivity and the ability to analyse large complex datasets is becoming increasingly feasible [2].
我们饶有兴趣地阅读了L
欧洲呼吸杂志自愿评审。我们非常感谢以下所列人员的辛勤工作和奉献，他们在2019年为ERJ .
.The current study assessed the expression stability of nine common reference genes in sputum samples from 14 healthy volunteers, 12 asthmatics and 12 COPD patients.
Using three different algorithms (geNorm, NormFinder and BestKeeper), we identified HPRT1 and GNB2L1 as the most optimal reference genes to use for normalisation of quantitative reverse transcriptase (RT) PCR data from sputum cells. The higher expression stability of HPRT1 and GNB2L1 were confirmed in a validation set of patients including nine healthy controls, five COPD patients and five asthmatic patients. In this group, the RNA extraction and RT-PCR methods differed, which attested that these genes remained the most reliable whatever the method used to extract the RNA, generate complementary DNA or amplify it.
Finally, an example of relative quantification of gene expression linked to eosinophils or neutrophils provided more accurate results after normalisation with the reference genes identified as the most stable compared to the least stable and confirmed our findings.
Bronchoalveolar lavage fluid (BALF) was obtained from eight patients with severe asthma before and after BT. Primary bronchial epithelial cells were isolated from 23 patients before (n=66) and after (n=62) BT. Epithelial cell culture supernatant (Epi.S) was collected and applied to primary fibroblasts.
Epithelial cells obtained from asthma patients after BT proliferated significantly faster compared with epithelial cells obtained before BT. In airway fibroblasts, BALF or Epi.S obtained before BT increased CCAAT enhancer-binding protein-β (C/EBPβ) expression, thereby downregulating microRNA-19a. This upregulated extracellular signal-regulated kinase-1/2 (ERK1/2) expression, protein arginine methyltransferase-1 (PRMT1) expression, cell proliferation and mitochondrial mass. BALF or Epi.S obtained after BT reduced the expression of C/EBPβ, ERK1/2, peroxisome proliferator-activated receptor- coactivator-1α (PGC1α), PRMT1 and mitochondrial mass in airway fibroblasts. Proteome and transcriptome analyses indicated that epithelial cell-derived heat shock protein-60 (HSP60) is the main mediator of BT effects on fibroblasts. Further analysis suggested that HSP60 regulated PRMT1 expression, which was responsible for the increased mitochondrial mass and α-smooth muscle actin expression by asthmatic fibroblasts. These effects were ablated after BT. These results imply that BT reduces fibroblast remodelling through modifying the function of epithelial cells, especially by reducing HSP60 secretion and subsequent signalling pathways that regulate PRMT1 expression.
We therefore hypothesise that BT decreases airway remodelling by blocking epithelium-derived HSP60 secretion and PRMT1 in fibroblasts.
大多数已发表的研究探讨了缺氧诱导因子(HIF)在缺氧诱导肺动脉高压发展中的作用，所使用的模型可能无法概括临床环境，包括使用胚胎HIF消融或激活后继发于肺/血管缺损的动物。此外，包括HIF信号通路如何以及何时参与缺氧诱导的肺动脉高压在内的关键问题仍未得到解答。< / p >
Normal adult rodents in which global HIF1 or HIF2 was inhibited by inducible gene deletion or pharmacological inhibition (antisense oligonucleotides (ASO) and small molecule inhibitors) were exposed to short-term (4 days) or chronic (4–5 weeks) hypoxia. Haemodynamic studies were performed, the animals euthanised, and lungs and hearts obtained for pathological and transcriptomic analysis. Cell-type-specific HIF signals for pulmonary hypertension initiation were determined in normal pulmonary vascular cells in vitro and in mice (using cell-type-specific HIF deletion).
Global Hif1a deletion in mice did not prevent hypoxia-induced pulmonary hypertension at 5 weeks. Mice with global Hif2a deletion did not survive long-term hypoxia. Partial Hif2a deletion or Hif2-ASO (but not Hif1-ASO) reduced vessel muscularisation, increases in pulmonary arterial pressures and right ventricular hypertrophy in mice exposed to 4–5 weeks of hypoxia. A small molecule HIF2 inhibitor (PT2567) significantly attenuated early events (monocyte recruitment and vascular cell proliferation) in rats exposed to 4 days of hypoxia, as well as vessel muscularisation, tenascin C accumulation and pulmonary hypertension development in rats exposed to 5 weeks of hypoxia. In vitro, HIF2 induced a distinct set of genes in normal human pulmonary vascular endothelial cells, mediating inflammation and proliferation of endothelial cells and smooth muscle cells. Endothelial Hif2a knockout prevented hypoxia-induced pulmonary hypertension in mice.
Inhibition of HIF2 (but not HIF1) can provide a therapeutic approach to prevent the development of hypoxia-induced pulmonary hypertension. Future studies are needed to investigate the role of HIFs in pulmonary hypertension progression and reversal.
In the Lung Health Study (LHS)-2, 1116 COPD patients were randomised to the ICS triamcinolone acetonide (n=559) or placebo (n=557) with spirometry performed every 6 months for 3 years. We performed a pharmacogenomic genome-wide association study for the genotype-by-ICS treatment effect on 3 years of FEV1 changes (estimated as slope) in 802 genotyped LHS-2 participants. Replication was performed in 199 COPD patients randomised to the ICS, fluticasone or placebo.
A total of five loci showed genotype-by-ICS interaction at p<5x10–6; of these, single nucleotide polymorphism (SNP) rs111720447 on chromosome 7 was replicated (discovery p=4.8x10–6, replication p=5.9x10–5) with the same direction of interaction effect. ENCODE (Encyclopedia of DNA Elements) data revealed that in glucocorticoid-treated (dexamethasone) A549 alveolar cell line, glucocorticoid receptor binding sites were located near SNP rs111720447. In stratified analyses of LHS-2, genotype at SNP rs111720447 was significantly associated with rate of FEV1 decline in patients taking ICS (C allele β 56.36 mL·year–1, 95% CI 29.96–82.76 mL·year–1) and in patients who were assigned to placebo, although the relationship was weaker and in the opposite direction to that in the ICS group (C allele β –27.57 mL·year–1, 95% CI –53.27– –1.87 mL·year–1).
The study uncovered genetic factors associated with FEV1 changes related to ICS in COPD patients, which may provide new insight on the potential biology of steroid responsiveness in COPD.
毛细血管前肺动脉高压(PH)是镰状细胞病(SCD)的毁灭性并发症。SCD基因型对PH特征的影响尚不清楚。< / p > < /秒> To describe clinical phenotypes and outcomes of precapillary PH due to SCD according to disease genotype. A nationwide multicentre retrospective study including all patients with SCD-related precapillary PH from the French PH Registry was conducted. Clinical characteristics and outcomes according to SCD genotype were analysed. 58 consecutive SCD patients with precapillary PH were identified, of whom 41 had homozygous for haemoglobin S (SS) SCD, three had S-β0 thalassaemia (S-β0 thal) and 14 had haemoglobin SC disease (SC). Compared to SC patients, SS/S-β0 thal patients were characterised by lower 6-min walk distance (p=0.01) and lower pulmonary vascular resistance (p=0.04). Mismatched segmental perfusion defects on lung scintigraphy were detected in 85% of SC patients and 9% of SS/S-β0 thal patients, respectively, and 50% of SS/S-β0 thal patients had heterogeneous lung perfusion without segmental defects. After PH diagnosis, 31 patients (53%) received medical therapies approved for pulmonary arterial hypertension, and chronic red blood cell exchange was initiated in 23 patients (40%). Four patients were managed for chronic thromboembolic PH by pulmonary endarterectomy (n=1) or balloon pulmonary angioplasty (n=3). Overall survival was 91%, 80% and 60% at 1, 3 and 5 years, respectively, without influence of genotype on prognosis. Patients with precapillary PH related to SCD have a poor prognosis. Thrombotic lesions appear as a major component of PH related to SCD, more frequently in SC patients.
We employed machine learning in a cross-validation scheme based on a well-balanced selection of 4898 patients after propensity score matching to data available on admission of 6440 hospitalised patients with moderate severity (non-intensive care unit patients) from the observational, prospective, multinational CAPNETZ study. We aimed to improve the primary outcome of 180-day survival.
We found a simple decision tree of patient characteristics comprising chronic cardiovascular and chronic respiratory comorbidities as well as leukocyte counts in the respiratory secretion at enrolment. Specifically, we found that patients without cardiovascular or patients with respiratory comorbidities and high leukocyte counts in the respiratory secretion benefit from macrolide treatment. Patients identified to be treated in compliance with our treatment suggestion had a lower mortality of 27% (OR 1.83, 95% CI 1.48–2.27; p<0.001) compared to the observed standard of care.
Stratifying macrolide treatment in patients following a simple treatment rule may lead to considerably reduced mortality in CAP. A future randomised controlled trial confirming our result is necessary before implementing this rule into the clinical routine.
We determined the association of marijuana smoking with the risk of spirometrically defined chronic obstructive pulmonary disease (COPD) (post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio <0.7) in 5291 population-based individuals and the rate of decline in FEV1 in a subset of 1285 males and females, aged ≥40 years, who self-reported use (or non-use) of marijuana and tobacco cigarettes and performed spirometry before and after inhaled bronchodilator on multiple occasions. Analysis for the decline in FEV1 was performed using random mixed effects regression models adjusted for age, sex and body mass index. Heavy tobacco smoking and marijunana smoking was defined as >20 pack-years and >20 joint-years, respectively.
~20% of participants had been or were current marijuana smokers with most having smoked tobacco cigarettes in addition (83%). Among heavy marijuana users, the risk of COPD was significantly increased (adjusted OR 2.45, 95% CI 1.55–3.88). Compared to never-smokers of marijuana and tobacco, heavy marijuana smokers and heavy tobacco smokers experienced a faster decline in FEV1 by 29.5 mL·year–1 (p=0.0007) and 21.1 mL·year–1 (p<0.0001), respectively. Those who smoked both substances experienced a decline of 32.31 mL·year–1 (p<0.0001).
Heavy marijuana smoking increases the risk of COPD and accelerates FEV1 decline in concomitant tobacco smokers beyond that observed with tobacco alone.
随着越来越多的患者同时出现心肺疾病，标准诊断标准的局限性越来越多。在这里，我们应用非侵入性磁共振成像(MRI)和光谱学来识别与慢性阻塞性肺疾病(COPD)、特发性肺纤维化(IPF)、左心衰(LHF)和肺动脉高压(PAH)独特相关的区域气体转移损伤和血流动力学模式。
健康志愿者(n=23)和COPD (n=8)、IPF (n=12)、LHF (n=6)和PAH (n=10)患者行129Xe气体转移成像和动态光谱。对于每个患者，生成三维地图来描述通气、屏障吸收(129Xe溶解在间质组织中)和红细胞(RBC)转移(129Xe溶解在RBC中)。动态129Xe光谱用于量化RBC信号振幅和频移中的心源性振荡。< / p > < /秒> Compared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01). COPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar–capillary level.
Transverse airway sections were sampled in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities.
BMI ranged from 15 to 45 kg·m–2 and was greater in nonfatal asthma cases (p<0.05). Adipose tissue was identified in the outer wall of large airways (Pbm >6 mm), but was rarely seen in small airways (Pbm <6 mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm >12 mm, p<0.01), and with neutrophils in control subjects (Pbm >6 mm, p=0.04).
These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight individuals may contribute to airway pathophysiology.
A prospective cohort of persistent asthma patients in France and the UK (n=847, age 6–40 years) provided 3756 reports over up to 2 years via computer-assisted telephone interviews and text messages on ICS adherence, asthma control, reliever medication use and exacerbations. We examined adherence–outcome relationships via longitudinal models, controlling for confounders, including severity.
Considerable within-person variability was found for exacerbations (91%), asthma control (59%) and reliever use (52%); 431 (11.5%) reports signalled exacerbations and 2046 (54.5%) poor control. At between-person level, patients with higher average adherence were more likely to report asthma control (OR 1.25, 95% CI 1.06–1.47), but not asthma exacerbations (OR 0.99, 95% CI 0.87–1.12) or lower reliever use (b –0.0004, 95% CI –0.089–0.088). At within-person level, higher-than-usual adherence was associated with higher concomitant reliever use (b 0.092, 95% CI 0.053–0.131) and lower subsequent reliever use (b –0.047, 95% CI –0.005– –0.088); it was unrelated to asthma control (OR 0.93, 95% CI 0.84–1.02) or exacerbations (OR 1.04, 95% CI 0.94–1.16).
Patients maintaining high ICS adherence over time have better asthma control. Temporarily increasing ICS adherence tends to be simultaneous to higher reliever use and reduces reliever use later on. Causes of within-person variation in outcomes require more investigation.
关于不同测试诊断儿童哮喘的有效性的数据很少。< / p > < /秒> We assessed the contribution of a detailed history and a variety of diagnostic tests for diagnosing asthma in children. We studied children aged 6–16 years referred consecutively for evaluation of suspected asthma to two pulmonary outpatient clinics. Symptoms were assessed by parental questionnaire. The clinical evaluation included skin-prick tests, measurement of exhaled nitric oxide fraction (FeNO), spirometry, bronchodilator reversibility and bronchial provocation tests (BPT) by exercise, methacholine and mannitol. Asthma was diagnosed by the physicians at the end of the visit. We assessed diagnostic accuracy of symptoms and tests by calculating sensitivity, specificity, positive and negative predictive values and area under the curve (AUC). Of the 111 participants, 80 (72%) were diagnosed with asthma. The combined sensitivity and specificity was highest for reported frequent wheeze (more than three attacks per year) (sensitivity 0.44, specificity 0.90), awakening due to wheeze (0.41, 0.90) and wheeze triggered by pollen (0.46, 0.83) or by pets (0.29, 0.99). Of the diagnostic tests, the AUC was highest for FeNO measurement (0.80) and BPT by methacholine (0.81) or exercise (0.74), and lowest for forced expiratory volume in 1 s (FEV1) (0.62) and FEV1/forced vital capacity ratio (0.66), assessed by spirometry. This study suggests that specific questions about triggers and severity of wheeze, measurement of FeNO and BPT by methacholine or exercise contribute more to the diagnosis of asthma in school-aged children than spirometry, bronchodilator reversibility and skin-prick tests.
A retrospective cohort study using a nationwide surveillance database was performed in children and adolescents (aged 0–18 years) treated for TB in the Netherlands from 1993 to 2018. Logistic regression analyses were used to estimate adjusted odds ratios (aOR) for associated factors of mortality and loss to follow-up (LTFU).
Among 3253 eligible patients with known outcomes, 94.4% (95.9% children and 92.8% adolescents) were cured or completed treatment, 0.7% died during treatment and 4.9% were LTFU. There were no reported treatment failures. Risk factors of death included children aged 2–4 years (aOR 10.42), central nervous system TB (aOR 5.14), miliary TB (aOR 10.25), HIV co-infection (aOR 8.60), re-treated TB cases (aOR 10.12) and drug-induced liver injury (aOR 6.50). Active case-finding was a protective factor of death (aOR 0.13). Risk factors of LTFU were adolescents aged 15–18 years (aOR 1.91), illegal immigrants (aOR 4.28), urban domicile (aOR 1.59), unknown history of TB contact (aOR 1.99), drug-resistant TB (aOR 2.31), single adverse drug reaction (aOR 2.12), multiple adverse drug reactions (aOR 7.84) and treatment interruption >14 days (aOR 6.93). Treatment in recent years (aOR 0.94) and supervision by public health nurses (aOR 0.14) were protective factors of LTFU.
Highly successful treatment outcomes were demonstrated in children and adolescents routinely treated for TB. Special attention should be given to specific risk groups to improve treatment outcomes.
心肺运动测试(CPET)是治疗各种慢性肺部疾病的有力诊断和预后工具[1–5]。尽管在过去的几十年里，关于CPET的出版物数量显著增加[2]，但CPET在呼吸医学领域仍未得到充分利用。在临床实践和研究中使用CPET的许多挑战有待解决，包括建立与肺功能和肺弥散能力相一致的全球参考值[6,7]。在进行这种国际努力之前，必须严格标准化测试程序，以便获得有效和可靠的结果，并能够在中心和个人之间解释CPET结果。此外，国际标准化的方案是在患者登记和回顾性合作研究中使用CPET数据的先决条件
We conducted a large-scale genome-wide cross-trait association study to investigate genetic overlap between asthma from the UK Biobank and eight mental health disorders from the Psychiatric Genomics Consortium: attention deficit hyperactivity disorder (ADHD), anxiety disorder (ANX), autism spectrum disorder, bipolar disorder, eating disorder, major depressive disorder (MDD), post-traumatic stress disorder and schizophrenia (sample size 9537–394 283).
In the single-trait genome-wide association analysis, we replicated 130 previously reported loci and discovered 31 novel independent loci that are associated with asthma. We identified that ADHD, ANX and MDD have a strong genetic correlation with asthma at the genome-wide level. Cross-trait meta-analysis identified seven loci jointly associated with asthma and ADHD, one locus with asthma and ANX, and 10 loci with asthma and MDD. Functional analysis revealed that the identified variants regulated gene expression in major tissues belonging to the exocrine/endocrine, digestive, respiratory and haemic/immune systems. Mendelian randomisation analyses suggested that ADHD and MDD (including 6.7% sample overlap with asthma) might increase the risk of asthma.
This large-scale genome-wide cross-trait analysis identified shared genetics and potential causal links between asthma and three mental health disorders (ADHD, ANX and MDD). Such shared genetics implicate potential new biological functions that are in common among them.
世界卫生组织(WHO)建议各国实施药物警戒并收集有关药物安全主动监测(aDSM)和不良事件管理的信息。< / p >
The aim of this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (i.e. bedaquiline, delamanid) and repurposed (i.e. clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.
Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1–2) and 57 (11.3%) as serious (grade 3–5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.
The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
肺动脉高压(PH)是引起小肺动脉重构的多种血管疾病的集合，导致肺血管阻力和肺动脉压增加。世界卫生组织将这些疾病分为五类。III组包括与低氧性肺疾病(如COPD)相关的肺动脉高压。虽然不是每个COPD患者都会出现肺动脉高压，但那些出现肺动脉高压的患者更有可能出现急性加重、住院和预后较差的情况。由于肺泡缺氧是驱动这种反应的关键因素，研究人员研究了慢性缺氧如何促进PH.
的发展最近发表在欧洲呼吸杂志 by J
这项国际随机对照试验评估了患有合并症的COPD患者是否接受了使用患者量身定制的多疾病加重行动计划的培训，其COPD加重天数是否少于常规护理(UC)。< / p >
COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification II–IV) with ≥1 comorbidity (ischaemic heart disease, heart failure, diabetes, anxiety, depression) were randomised to a patient-tailored self-management intervention (n=102) or UC (n=99). Daily symptom diaries were completed for 12 months. The primary outcome "COPD exacerbation days per patient per year" was assessed using intention-to-treat analyses.
No significant difference was observed in the number of COPD exacerbation days per patient per year (self-management: median 9.6 (interquartile range (IQR) 0.7–31.1); UC: median 15.6 (IQR 3.0–40.3); incidence rate ratio (IRR) 0.87 (95% CI 0.54; 1.39); p=0.546). There was a significantly shorter duration per COPD exacerbation for self-management (self-management: median 8.1 (IQR 4.8–10.1) days; UC: median 9.5 (IQR 7.0–15.1) days; p=0.021), with no between-group differences in the total number of respiratory hospitalisations (IRR 0.76 (95% CI 0.42; 1.35); p=0.348), but a lower probability of ≥1 for respiratory-related hospitalisation compared to UC (relative risk 0.55 (95% CI 0.35; 0.87); p=0.008). No between-group differences were observed in all-cause hospitalisations (IRR 1.07 (95% CI 0.66; 1.72)) or mortality (self-management: n=4 (3.9%); UC: n=7 (7.1%); relative risk 0.55 (95% CI 0.17; 1.84)).
Patient-tailored exacerbation action plans for COPD patients with comorbidities did not significantly reduce exacerbation days, but reduced the duration per COPD exacerbation and the risk of having at least one respiratory-related hospitalisation during follow-up, without excess all-cause mortality.
COPD explant lungs with bronchiectasis were compared to COPD explant lungs without bronchiectasis and unused donor lungs as controls. In order to investigate all airway generations, a multimodal imaging approach using different resolutions was conducted. Per group, five lungs were frozen (n=15) and underwent computed tomography (CT) imaging for large airway evaluation, with four tissue cores per lung imaged for measurements of the terminal bronchioles. Two additional lungs per group (n=6) were air-dried for lobar microCT images that allow airway segmentation and three-dimensional quantification of the complete airway tree.
COPD lungs with bronchiectasis had significantly more airways compared to COPD lungs without bronchiectasis (p<0.001), with large airway numbers similar to control lungs. This difference was present in both upper and lower lobes. Lack of tapering was present (p=0.010) and larger diameters were demonstrated in lower lobes with bronchiectasis (p=0.010). MicroCT analysis of tissue cores showed similar reductions of tissue percentage, surface density and number of terminal bronchioles in both COPD groups compared to control lungs.
Although terminal bronchioles were equally reduced in COPD lungs with and without bronchiectasis, significantly more large and small airways were found in COPD lungs with bronchiectasis.
哮喘是低收入和中等收入国家(LMICs)急诊就诊的常见原因。虽然在高收入国家中很少有关于急诊就诊预测因素的前瞻性研究，但在中低收入国家中却没有进行过任何研究。< / p >
We followed a cohort of 5–15-year-old children treated for asthma attacks in emergency rooms of public health facilities in Esmeraldas City, Ecuador. We collected blood and nasal wash samples, and performed spirometry and exhaled nitric oxide fraction measurements. We explored potential predictors for recurrence of severe asthma attacks requiring emergency care over 6 months’ follow-up.
We recruited 283 children of whom 264 (93%) were followed-up for ≥6 months or until their next asthma attack. Almost half (46%) had a subsequent severe asthma attack requiring emergency care. Predictors of recurrence in adjusted analyses were (adjusted OR, 95% CI) younger age (0.87, 0.79–0.96 per year), previous asthma diagnosis (2.2, 1.2–3.9), number of parenteral corticosteroid courses in previous year (1.3, 1.1–1.5), food triggers (2.0, 1.1–3.6) and eczema diagnosis (4.2, 1.02–17.6). A parsimonious Cox regression model included the first three predictors plus urban residence as a protective factor (adjusted hazard ratio 0.69, 95% CI 0.50–0.95). Laboratory and lung function tests did not predict recurrence.
Factors independently associated with recurrent emergency attendance for asthma attacks were identified in a low-resource LMIC setting. This study suggests that a simple risk-assessment tool could potentially be created for emergency rooms in similar settings to identify higher-risk children on whom limited resources might be better focused.
The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm–2; range: 47.17–198.11 neutrophils·mm–2; median: 94.34 neutrophils·mm–2) were further classified as high (≥94.34 neutrophils·mm–2) or intermediate (47.17– <94.34 neutrophils·mm–2). The effect of smoking ≥10 pack-years was also assessed.
Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV1) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8+, interleukin (IL)-17-F+ and IL-22+ cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV1 and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4+ and IL-17F+ cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A+ and IL-22+ cells in highly neutrophilic patients.
We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia.
所有在法国进行的肺移植都前瞻性地登记在一个管理数据库中。我们回顾性回顾了2007年7月至2015年12月间进行的手术，并通过拟合边缘Cox模型分析了供体、受体和匹配对HELT手术后总生存期的影响。
在研究期间，2335例患者在11个法国中心接受了肺移植。排除慢性阻塞性肺疾病/肺气肿患者后，纳入1544例患者:503例HELT和1041例标准肺移植分配。HELT与死亡的危险比为1.41(95%可信区间1.22–1.64;p<0.0001)，在多元模型中纳入接受者特征后，下降到1.32 (95% CI 1.10–1.60)。用于预测长期生存的供体评分在HELT组和标准肺移植组之间有显著差异(p=0.014)。然而，在多变量模型中，供体特征与受体特征的添加并没有改变与HELT相关的风险比。< / p > < /秒> This exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics.
严重阻塞性肺病，包括哮喘、慢性阻塞性肺病(COPD)或两者兼有，仍然是一个严重的全球卫生问题和卫生保健资源的负担。然而，严重哮喘和慢性阻塞性肺病的临床定义并没有反映这些诊断的异质性或它们之间的潜在重叠，这可能导致不适当的治疗决定。此外，大多数研究排除了同时诊断为哮喘和COPD的患者。临床定义可以影响临床试验设计，同时也受到调节指征和治疗建议的影响。因此，为了确保其在靶向生物治疗时代的相关性，必须更新严重阻塞性肺病的定义，使其包括所有可能受益于新治疗方法的患者，以及相关费用合理的患者。在这里，我们回顾了严重阻塞性肺病的不断发展的临床定义，并通过总结生物疗法III期随机对照试验的合格标准和主要结果来评估这些定义如何影响试验设计。基于我们的研究结果，我们讨论了基于表型和内型的方法的优势，为可能影响监管批准和临床实践的未来试验选择合适的人群，使靶向生物疗法受益于更大比例和更广泛的患者。这就需要研究人员、药物开发人员和监管机构之间的协调努力，以确保生物疗法在严重阻塞性肺病的管理中充分发挥其潜力
In this study, 37 patients with PAH (idiopathic in 31 cases) underwent single-beat pressure–volume loop measurements of RV end-systolic elastance (Ees), arterial elastance (Ea) and diastolic elastance (Eed). Pulmonary arterial stiffness was assessed by magnetic resonance imaging. The results were correlated to CPET variables. The predictive relevance of RV function parameters for clinically relevant ventilatory inefficiency, defined as minute ventilation/carbon dioxide production (V'E/V'CO2) slope >48, was evaluated using logistic regression analysis.
The median (interquartile range) of the V'E/V'CO2 slope was 42 (32–52) and the V'E/V'CO2 nadir was 40 (31–44). The mean±
Our data suggest that impaired RV lusitropy and increased afterload are associated with ventilatory inefficiency in PAH.
过敏性疾病和自身免疫性疾病之间的联系尚不清楚。我们的目的是确定自身免疫性疾病在变应性鼻炎/结膜炎(ARC)、特应性湿疹和哮喘中的发生率，并调查其共同发生的模式。
这是一项回顾性队列研究(1990–2018)，采用从健康改善网络(英国初级保健数据库)提取的数据。暴露组包括ARC、特应性湿疹和哮喘(所有年龄)。对于每一个暴露的病人，最多随机选择两个年龄和性别匹配的对照组，没有记录过敏疾病。调整发病率比(aIRRs)采用泊松回归计算。采用关联规则挖掘(ARM)对疾病聚类进行横断面研究。< / p > < /秒> 782 320, 1 393 570 and 1 049 868 patients with ARC, atopic eczema and asthma, respectively, were included. aIRRs of systemic lupus erythematosus (SLE), Sjögren's syndrome, vitiligo, rheumatoid arthritis, psoriasis, pernicious anaemia, inflammatory bowel disease, coeliac disease and autoimmune thyroiditis were uniformly higher in the three allergic diseases compared with controls. Specifically, aIRRs of SLE (1.45) and Sjögren's syndrome (1.88) were higher in ARC; aIRRs of SLE (1.44), Sjögren's syndrome (1.61) and myasthenia (1.56) were higher in asthma; and aIRRs of SLE (1.86), Sjögren's syndrome (1.48), vitiligo (1.54) and psoriasis (2.41) were higher in atopic eczema. There was no significant effect of the three allergic diseases on multiple sclerosis or of ARC and atopic eczema on myasthenia. Using ARM, allergic diseases clustered with multiple autoimmune disorders. Three age- and sex-related clusters were identified, with a relatively complex pattern in females ≥55 years old. The long-term risks of autoimmune disorders are significantly higher in patients with allergic diseases. Allergic diseases and autoimmune disorders show age- and sex-related clustering patterns.
Between January 2008 and December 2015, we retrospectively analysed 366 children who underwent HSCT (age range 0.5–252 months; median 20.3 months). During the post-HSCT course, echocardiography scans motivated by respiratory symptoms identified 31 patients with elevated tricuspid regurgitation velocity (>2.8 m·s–1), confirmed when possible by right heart catheterisation (RHC).
22 patients had confirmed pulmonary hypertension with mean±
Pulmonary hypertension is a severe complication of HSCT with an underestimated incidence and high mortality. Aggressive and timely up-front combination therapy allowed normalisation of pulmonary pressure and improved survival.
We randomly assigned 168 patients to receive twice-daily inhalations of 80 mg AAT solution or placebo for 50 weeks. Patients used an electronic diary to capture exacerbations. The primary endpoint was time from randomisation to the first event-based exacerbation. Secondary endpoints included change in the nature of the exacerbation as defined by the Anthonisen criteria. Safety was also assessed.
Time to first moderate or severe exacerbation was a median of 112 days (interquartile range (IQR) 40–211 days) for AAT and 140 days (IQR 72–142 days) for placebo (p=0.0952). The mean yearly rate of all exacerbations was 3.12 in the AAT-treated group and 2.67 in the placebo group (p=0.31). More patients receiving AAT reported treatment-related treatment-emergent adverse events compared to placebo (57.5% versus 46.9%, respectively) and they were more likely to withdraw from the study. After the first year of the study, when modifications to the handling of the nebuliser were introduced, the rate of safety events in the AAT-treated group dropped to that of the placebo group.
We conclude that in AATD patients with severe COPD and frequent exacerbations, AAT inhalation for 50 weeks showed no effect on time to first exacerbation but may have changed the pattern of the episodes.
慢性鼻窦炎伴鼻息肉(CRSwNP)的机制尚不清楚。我们进行了全基因组基因表达分析，以确定与CRSwNP相关的通路和候选基因集。< / p > < /秒> We performed whole-transcriptome RNA sequencing on 42 polyp (CRSwNP-NP) and 33 paired nonpolyp inferior turbinate (CRSwNP-IT) tissues from patients with CRSwNP and 28 inferior turbinate samples from non-CRS controls (CS-IT). We analysed the differentially expressed genes (DEGs) and the gene sets that were enriched in functional pathways. Principal component-informed analysis revealed cilium function and immune regulation as the two main Gene Ontology (GO) categories differentiating CRSwNP patients from controls. We detected 6182 and 1592 DEGs between CRSwNP-NP versus CS-IT and between CRSwNP-NP versus CRSwNP-IT tissues, respectively. Atopy status did not have a major impact on gene expression in various tissues. GO analysis on these DEGs implicated extracellular matrix (ECM) disassembly, O-glycan processing, angiogenesis and host viral response in CRSwNP pathogenesis. Ingenuity Pathway Analysis identified significant enrichment of type 1 interferon signalling and axonal guidance canonical pathways, angiogenesis, and collagen and fibrotic changes in CRSwNP (CRSwNP-NP and CRSwNP-IT) tissues compared with CS-IT. Finally, gene set enrichment analysis implicated sets of genes co-regulated in processes associated with inflammatory response and aberrant cell differentiation in polyp formation. Gene signatures involved in defective host defences (including cilia dysfunction and immune dysregulation), inflammation and abnormal metabolism of ECM are implicated in CRSwNP. Functional validation of these gene expression patterns will open opportunities for CRSwNP therapeutic interventions such as biologics and immunomodulators.
慢性全身皮质类固醇(CS)治疗与许多慢性疾病患者死亡风险增加相关。然而，慢性全身性CS治疗是否与哮喘患者死亡率增加有关尚不清楚。本研究的目的是确定慢性全身CS治疗对成年哮喘患者长期死亡率的影响。< / p > < /秒> A population-based matched cohort study of males and females aged ≥18 years with asthma was performed using the Korean National Health Insurance Service database from 2005 to 2015. Hazard ratio (HR) with 95% confidence interval for all-cause mortality among patients in the CS-dependent cohort (CS use ≥6 months during baseline period) relative to those in the CS-independent cohort (CS use <6 months during baseline period) was evaluated. The baseline cohort included 466 941 patients with asthma, of whom 8334 were CS-dependent and 458 607 were CS-independent. After 1:1 matching, 8334 subjects with CS-independent asthma were identified. The HR of mortality associated with CS-dependent asthma relative to CS-independent asthma was 2.17 (95% CI 2.04–2.31). In patients receiving low-dose CS, the HR was 1.84 (95% CI 1.69–2.00); in patients receiving high-dose CS, the HR was 2.56 (95% CI 2.35–2.80). In this real-world, clinical practice, observational study, chronic use of systemic CS was associated with increased risk of mortality in patients with asthma, with a significant dose–response relationship between systemic CS use and long-term mortality.
Tissue cores, obtained from explant lungs of unused donors (n=10) and patients with bronchiolitis obliterans syndrome (BOS; n=18) and restrictive allograft syndrome (RAS; n=18), were scanned with micro-computed tomography before elution of antibodies. Total IgG levels were measured via ELISA. Anti-HLA class I and II IgG gDSAs were identified using Luminex single antigen beads and compared with DSAs found in serum samples.
Overall, mean fluorescence intensity was higher in RAS eluates compared with BOS and controls (p<0.0001). In BOS, two patients were sDSA+/gDSA+ and two patients were sDSA–/gDSA+. In RAS, four patients were sDSA+/gDSA+, one patient was sDSA+/gDSA– and five patients were sDSA–/gDSA+. Serum and graft results combined, DSAs were more prevalent in RAS compared with BOS (56% versus 22%; p=0.04). There was spatial variability in gDSA detection in one BOS patient and three RAS patients, who were all sDSA–. Total graft IgG levels were higher in RAS than BOS (p<0.0001) and in gDSA+ versus gDSA– (p=0.0008), but not in sDSA+ versus sDSA– (p=0.33). In RAS, total IgG levels correlated with fibrosis (r= –0.39; p=0.02).
This study underlines the potential of gDSA assessment as complementary information to sDSA findings. The relevance and applications of gDSAs need further investigation.
需要关于在寻求庇护者中实施潜伏性结核病感染(LTBI)筛查和治疗的条件的证据，以便为结核病控制政策提供信息。我们使用混合方法来评估荷兰寻求庇护者中LTBI筛查和治疗项目的实施情况。< / p > < /秒> We offered voluntary LTBI screening to asylum seekers aged ≥12 years living in asylum seeker centres from countries with a TB incidence >200 per 10 000 population. We calculated LTBI screening and treatment cascade coverage, and assessed associated factors with Poisson regression using robust variance estimators. We interviewed TB care staff (seven group interviews) and Eritrean clients (21 group and 21 individual interviews) to identify programme enhancers and barriers. We screened 719 (63% of 1136) clients for LTBI. LTBI was diagnosed among 178 (25%) clients; 149 (84%) initiated LTBI treatment, of whom 129 (87%) completed treatment. In-person TB and LTBI education, the use of professional interpreters, and collaboration with partner organisations were enhancers for LTBI screening uptake. Demand-driven LTBI treatment support by TB nurses enhanced treatment completion. Factors complicating LTBI screening and treatment were having to travel to public health services, language barriers and moving from asylum seeker centres to the community during treatment. LTBI screening and treatment of asylum seekers is feasible and effective when high quality of care is provided, including culture-sensitive TB education throughout the care cascade. Additionally, collaboration with partner organisations, such as agencies responsible for reception and support of asylum seekers, should be in place.
近年来，在动态条件下检测肺循环被提出，作为一种手段，可以进一步了解患者的症状和疾病严重程度，补充休息时的诊断评估[1–6]。由于肺血管血流动力学可以描述为流量、阻力和左房压的函数，因此有人认为，肺循环的压力流量关系可以区分正常行为和异常行为，后者符合心脏、肺或肺血管疾病[4].
美国胸科学会(ATS)、欧洲呼吸学会(ERS)、日本呼吸学会(JRS)和拉188bet官网地址丁美洲胸科学会(ALAT)最近发布了特发性肺纤维化(IPF)的新临床实践指南(ATS/ERS/JRS/ALAT2018)，同时提出了Fleischner学会的诊断标准[1,2]。两种诊断算法在大多数诊断步骤上是一致的，但对手术肺活检(SLB)的位置有不同的建议:ATS/ERS/JRS/ALAT2018[2]建议在高分辨率计算机断层扫描(HRCT)上对大多数可能为常见间质性肺炎(UIP)类型的患者进行SLB(条件推荐)，而Fleischner学会建议在确定或可能为UIP的HRCT模式的患者放弃SLB，在正确的临床背景下[3,4]。我们的目的是量化先前的方法(ATS/ERS/JRS/ALAT2011)[5]和两种新的诊断方法[1,2]对现实生活临床实践的影响，评估我们队列中多学科IPF诊断的放射分级间一致性、诊断测试特征和分流放射诊断的预后有效性。
哮喘是一种以慢性炎症和气道重塑为特征的异质性疾病。以白细胞介素(IL)-4、IL-5和IL-13为特征的t2介导的气道炎症是最近药物治疗的重点，临床医生现在可以使用许多靶向生物制剂。抗il -5受体药物benralizumab通过抗体依赖细胞介导的细胞毒性导致血液中嗜酸性粒细胞和嗜碱性粒细胞的衰竭;然而，其在组织中的作用机制尚不确定。在临床试验中，Benralizumab可减少急性发作并改善肺功能
This multicentre physician-blinded crossover trial randomised patients in two groups that started with 8 weeks of AsthmaTuner or conventional treatment using a personalised printed treatment plan, with 2 weeks of washout between the crossover treatments. Participants in a primary or paediatric care setting in Sweden with asthma diagnosis, uncontrolled symptoms and Asthma Control Test (ACT) score <20 points were included. Symptom control was analysed using t-tests for the difference between the group means of the sums of ACT scores at each treatment end-visit, with 95% confidence intervals. Medical Adherence Report Scale (MARS) scores captured differences in adherence (remembering to take asthma medication) between treatment periods.
The study population consisted of 77 patients (60% females). The ACT score significantly improved with AsthmaTuner compared with conventional treatment (mean ACT difference 0.70, 95% CI 0.06–1.34; p=0.03). Adherence did not improve significantly in all participants, but did improve among those in primary care who used AsthmaTuner an average of once a week or more compared with conventional treatment (mean MARS difference 0.45, 95% CI 0.13–0.77; p=0.01).
AsthmaTuner improved symptom control in patients with uncontrolled asthma compared with conventional treatment.
预防哮喘加重是哮喘治疗的重要目标。长期使用阿奇霉素治疗可能有助于实现这一目标。我们的目的是进行系统综述和个体参与者数据(IPD)荟萃分析，以检查阿奇霉素在减少哮喘发作以及非嗜酸性哮喘、嗜酸性哮喘和重度哮喘亚表型方面的疗效。
我们在2019年2月完成了Embase、MEDLINE、PubMed、Cochrane图书馆、< a HREF="https://clinicaltrials.gov/">ClinicalTrials.gov和以前系统综述的参考文献列表的系统检索。我们纳入了平行组、双盲、随机对照的成人试验，比较阿奇霉素治疗至少8周与安慰剂治疗，其中急性加重的结果在至少6个月内进行评估。数据从已发表的资料中提取，采用Cochrane偏倚风险工具，并向作者寻求IPD。审查一式两份。我们对急性加重的主要结局进行了IPD荟萃分析，并对次要结局进行了随机效应荟萃分析。
确定了三项研究(n=604)。在IPD荟萃分析中，阿奇霉素治疗与哮喘以及非嗜酸性粒细胞、嗜酸性粒细胞和严重哮喘亚组的恶化率(因哮喘恶化而口服皮质类固醇疗程、因下呼吸道感染使用抗生素、住院和/或急症就诊)降低相关。分别检查每种恶化类型，嗜酸性粒细胞性哮喘患者报告较少的口服皮质类固醇疗程，非嗜酸性粒细胞性和严重哮喘患者报告较少的抗生素疗程。阿奇霉素耐受性良好。< / p > < /秒> Maintenance use of azithromycin reduces exacerbations in patients with eosinophilic, noneosinophilic and severe asthma.
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慢性肺动脉高压在慢性左心衰和慢性呼吸衰竭中均有异常，已提出康复治疗[1,2]。在欧洲呼吸学会最近发表的一份声明中，G
我们想要对欧盟(EU)即将讨论的哮喘加重管理方面的潜在重大变化提出相当大的关注。全球哮喘倡议(GINA)最近改变了他们关于轻度哮喘患者管理的建议。GINA建议所有患者也应同时使用吸入性皮质类固醇(ICS)，而不是仅根据需要使用短效& 2-激动剂(SABA)。这是基于一些“根据需要”使用ICS/长效& β;2-激动剂(LABA)治疗急性哮喘的研究。一组作者称赞这一变化为“30年来哮喘管理的最根本变化”，并在最近发表在《I>欧洲呼吸杂志》上的一篇文章中详细解释了这一变化的原因
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