Respiratory Research

Bacterial pleural infection requires prompt identification to enable appropriate investigation and treatment. In contrast to commonly used biomarkers such as C-reactive protein (CRP) and white cell count (WCC), which can be raised due to non-infective inflammatory processes, procalcitonin (PCT) has been proposed as a specific biomarker of bacterial infection. The utility of PCT in this role is yet to be validated in a large prospective trial. This study aimed to identify whether serum PCT is superior to CRP and WCC in establishing the diagnosis of bacterial pleural infection. Consecutive patients presenting to a tertiary pleural service between 2008 and 2013 were recruited to a well-established pleural disease study. Consent was obtained to store pleural fluid and relevant clinical information. Serum CRP, WCC and PCT were measured. A diagnosis was agreed upon by two independent consultants after a minimum of 12 months. The study was performed and reported according to the STARD reporting guidelines. 80/425 patients enrolled in the trial had a unilateral pleural effusion secondary to infection. 10/80 (12.5%) patients had positive pleural fluid microbiology. Investigations for viral causes of effusion were not performed. ROC curve analysis of 425 adult patients with unilateral undiagnosed pleural effusions showed no statistically significant difference in the diagnostic utility of PCT (AUC 0.77), WCC (AUC 0.77) or CRP (AUC 0.85) for the identification of bacterial pleural infection. Serum procalcitonin >0.085 μg/l has a sensitivity, specificity, negative predictive value and positive predictive value of 0.69, 0.80, 0.46 and 0.91 respectively for the identification of pleural infection. The diagnostic utility of procalcitonin was not affected by prior antibiotic use (p = 0.80). The study presents evidence that serum procalcitonin is not superior to CRP and WCC for the diagnosis of bacterial pleural infection. The study suggests routine procalcitonin testing in all patients with unilateral pleural effusion is not beneficial however further investigation may identify specific patient subsets that may benefit. The trial was registered with the UK Clinical Research Network ( UKCRN ID 8960 ). The trial was approved by the South West Regional Ethics Committee (Ethical approval number 08/H0102/11).

There is currently no method that can predict whether or under what condition hypopnea, even obstructive sleep apnea (OSA), will occur during sleep for individuals based on credible parameters measured under waking condition. We propose a threshold concept based on the narrowest cross-sectional area of the upper airway (CSA-UA) and aim to prove our hypothesis on the threshold of the area for hypopnea onset (TAHO), which can be used as an indicator of hypopnea onset during sleep and measured while awake. We performed magnetic resonance imaging for 20 OSA patients to observe CSA-UA changes during fluid accumulation in the neck caused by elevating their legs, and identified TAHO by capturing the sudden enlargement in CSA-UA. Correlation analyses between TAHO and the body mass index (BMI), and between the reduction in CSA-UA and the increase in the neck circumference (NC) with fluid accumulation were performed. Logistic regression analysis was performed for identifying OSA patients based on the behaviors of their CSA-UA changes during leg raising. Shape changes of airway cross-section were also investigated. Four CSA-UA change patterns after fluid redistribution were identified. Six patients had similar CSA-UA variation behaviors observed in healthy subjects. From the other three change patterns involving 14 patients, a threshold value of CSA-UA 0.63 ± 0.21 cm2 was identified for normal breathing. Data showed a positive correlation between TAHO and BMI (r = 0.681, p = 0.0007), and a negative correlation between the reduction in CSA-UA and the increase in NC (r = − 0.513, p = 0.051) with fluid accumulation. A sigmoid function for the probability of being a OSA patient p = 1/[1 + exp. (4.836 + 3.850 t-8.4 h)] was obtained to effectively separate OSA patients from normal subjects. The upper airway narrowing occurred in anteroposterior, lateral, or both directions, suggesting different tendencies of upper airway collapse in patients. Three types of shape changes in the cross-section of the upper airway, which had different effects on airway resistance, were measured. Our findings prove TAHO hypothesis. The threshold measured while awake for normal breathing can be used clinically as the indicator of hypopnea onset during sleep, and therefore to identify OSA patients under waking condition and design effective personalized treatments for OSA patients. Both shape and size changes in the cross-section of the upper airway affect airway resistance significantly. Shape change in the cross-section of the upper airway can provide key clinical information on the collapse patterns of the upper airway for individuals.

Tobacco smoking irritates and damages the respiratory tract and contributes to a higher risk of developing lung emphysema. At present, smoking cessation is the only effective treatment for reducing the progression of lung emphysema, however, there is hardly anything known about the effects of smoking cessation on cytokine and chemokine levels in the airways. To the best of our knowledge, this is the first reported in vivo study in which cytokine profiles were determined after cessation of cigarette smoke exposure. The severity of airway remodeling and inflammation was studied by analyzing alveolar enlargement, heart hypertrophy, inflammatory cells in the bronchoalveolar lavage fluid (BALF) and lung tissue and by determining the cytokine and chemokine profiles in the BALF of A/J mice exposed to cigarette smoke for 20 weeks and 8 weeks after smoking cessation. The alveolar enlargement and right ventricle heart hypertrophy found in smoke-exposed mice remained unchanged after smoking cessation. Although the neutrophilic inflammation in the BALF of cigarette smoke-exposed animals was reduced after smoking cessation, a sustained inflammation in the lung tissue was observed. The elevated cytokine (IL-1α and TNF-α) and chemokine (CCL2 and CCL3) levels in the BALF of smoke-exposed mice returned to basal levels after smoking cessation, while the increased IL-12 levels did not return to its basal level. The cigarette smoke-enhanced VEGF levels did not significantly change after smoking cessation. Moreover, IL-10 levels were reduced in the BALF of smoke-exposed mice and these levels were still significantly decreased after smoking cessation compared to the control animals. The inflammatory changes in the airways caused by cigarette smoke exposure were only partially reversed after smoking cessation. Although smoking cessation should be the first step in reducing the progression of lung emphysema, additional medication could be provided to tackle the sustained airway inflammation.

There is an interest in the role of blood eosinophils for predicting inhaled corticosteroid (ICS) response in chronic obstructive pulmonary disease (COPD). Most data are from interventional clinical studies; data from unselected real-world populations may help better inform treatment decisions. DACCORD is a non-interventional real-world study. Cohort 3 recruited patients with COPD who had received triple therapy for ≥ 6 months; prior to entry patients either continued triple therapy, or switched to a long-acting muscarinic antagonist/long-acting beta2-agonist (LABA/LAMA), and were followed for 12 months. For these post-hoc analyses, patients were divided into four groups based on exacerbation history and baseline blood eosinophil count (< 100 vs. > 300 cells/µL). Exacerbation rates were calculated overall and for the two treatments. Among the 430 patients in the current analyses, the largest groups had low exacerbation history with high (44.2%) or low eosinophils (36.7%). Most patients did not exacerbate during follow-up (68.8% overall; 83.2% and 63.7% with LABA/LAMA and triple therapy). The highest exacerbation rates were in groups with high exacerbation history, differing significantly in the overall analyses from those with low exacerbation history (matched by eosinophil count); rates did not differ when grouped by eosinophil count (matched by exacerbation history). Although most patients in these analyses did not exacerbate during follow-up, whereas exacerbation history is a predictor of future exacerbations, blood eosinophil count is not. This suggests that although eosinophil count may help to guide ICS initiation, this is less of a consideration when ‘stepping-down’ from triple therapy to a LABA/LAMA

The COMPERA 2.0 4-stratum (4-S) risk score has been demonstrated superior over the 3-stratum (3-S) one in patients with pulmonary arterial hypertension and medically managed patients with chronic thromboembolic pulmonary hypertension (CTEPH). We aimed to determine the prognostic value of the original 4-S and 3-S COMPERA 2.0 risk score and two new derivative versions in CTEPH patients who underwent balloon pulmonary angioplasty (BPA). We retrospectively enrolled 175 BPA-treated patients with CTEPH. We assessed the risk stratification before and after each BPA session of CTEPH patients by the original 4-S and 3-S COMPERA 2.0 risk score (by rounding decimal to the nearest integer) and two new proposed derivative versions: the modified version (by rounding decimal to the next integer) and a hybrid version that fuses the original and modified versions. The primary endpoint was clinical worsening events. The secondary outcomes were achieving low-risk profile and mean pulmonary arterial pressure (mPAP) < 30 mmHg at follow-up. We used the Kaplan–Meier curve analysis to assess the survival differences between stratified patients. The comparative model’s performance was evaluated in terms of discrimination by Harrell’s C-index. All versions of COMPERA 2.0 4-S model outperformed the 3-S one in discriminating the differences in echocardiographic and hemodynamic parameters and clinical worsening-free survival rates. The original and hybrid 4-S model could independently predict the primary and secondary endpoints, and the hybrid version seemed to perform better. The first BPA session could significantly improve risk profiles, and these changes were associated with the likelihood of experiencing clinical worsening events, achieving a low-risk profile and mPAP < 30 mmHg at follow-up. The number of BPA sessions required to achieve low risk/mPAP < 30 mmHg increased as the baseline risk score escalated. The COMPERA 2.0 4-S model outperformed the 3-S one in BPA-treated patients with CTEPH. The 4-S model, especially its hybrid version, could be used to predict clinical outcome before the initiation of BPA and monitor treatment response.

The mechanisms by which viruses cause asthma exacerbations are not precisely known. Previously, we showed that, in ovalbumin (OVA)-sensitized and -challenged mice with allergic airway inflammation, rhinovirus (RV) infection increases type 2 cytokine production from alternatively-activated (M2) airway macrophages, enhancing eosinophilic inflammation and airways hyperresponsiveness. In this paper, we tested the hypothesis that IL-4 signaling determines the state of macrophage activation and pattern of RV-induced exacerbation in mice with allergic airways disease. Eight week-old wild type or IL-4 receptor knockout (IL-4R KO) mice were sensitized and challenged with OVA and inoculated with RV1B or sham HeLa cell lysate. In contrast to OVA-treated wild-type mice with both neutrophilic and eosinophilic airway inflammation, OVA-treated IL-4R KO mice showed increased neutrophilic inflammation with few eosinophils in the airways. Like wild-type mice, IL-4R KO mice showed OVA-induced airway hyperreactivity which was further exacerbated by RV. There was a shift in lung cytokines from a type 2-predominant response to a type 1 response, including production of IL-12p40 and TNF-α. IL-17A was also increased. RV infection of OVA-treated IL-4R KO mice further increased neutrophilic inflammation. Bronchoalveolar macrophages showed an M1 polarization pattern and ex vivo RV infection increased macrophage production of TNF-α, IFN-γ and IL-12p40. Finally, lung cells from OVA-treated IL-4R KO mice showed reduced CD206+ CD301+ M2 macrophages, decreased IL-13 and increased TNF-α and IL-17A production by F4/80+, CD11b+ macrophages. OVA-treated IL-4R KO mice show neutrophilic airway inflammation constituting a model of allergic, type 1 cytokine-driven neutrophilic asthma. In the absence of IL-4/IL-13 signaling, RV infection of OVA-treated mice increased type 1 cytokine and IL-17A production from conventionally-activated macrophages, augmenting neutrophilic rather than eosinophilic inflammation. In mice with allergic airways inflammation, IL-4R signaling determines macrophage activation state and the response to subsequent RV infection.

Cả tế bào T điều hòa (Tregs) và tế bào T helper sản xuất IL-17 (tế bào Th17) đã được phát hiện có liên quan đến các khối u ở người, tuy nhiên, vai trò có thể của Tregs trong việc điều chỉnh sự sinh ra và phân hóa của tế bào Th17 trong dịch màng phổi ác tính vẫn chưa được làm rõ. Số lượng cả tế bào Tregs CD39+ và tế bào Th17 trong dịch màng phổi ác tính và máu ngoại vi từ bệnh nhân ung thư phổi đã được xác định bằng phương pháp phân tích dòng tế bào (flow cytometry). Cơ chế điều hòa của Tregs đối với sự sinh ra và phân hóa của tế bào Th17 đã được khám phá. Cả tế bào Tregs CD39+ và tế bào Th17 đều tăng lên trong dịch màng phổi ác tính so với máu, và số lượng Tregs CD39+ có mối tương quan âm với số lượng tế bào Th17. Ngoài ra, cũng ghi nhận rằng mức độ cao của IL-1β, IL-6 và TGF-β1 có thể được quan sát thấy trong dịch màng phổi ác tính so với huyết thanh tương ứng, và rằng Tregs CD39+ trong màng phổi có thể biểu lộ peptide liên kết với độ trễ trên bề mặt của chúng. Khi các tế bào T CD4+ chưa được kích hoạt được nuôi cấy chung với Tregs CD39+, số lượng tế bào Th17 giảm khi số lượng Tregs CD39+ tăng, việc bổ sung kháng thể đơn dòng chống peptide liên kết với độ trễ vào nuôi cấy chung đã đảo ngược hiệu ứng ức chế mà Tregs CD39+ gây ra. Do đó, các kết quả trên cho thấy rằng Tregs CD39+ ức chế sự sinh ra và phân hóa của tế bào Th17 thông qua cơ chế phụ thuộc vào peptide liên kết với độ trễ.

Recent development in the field of COPD has focused on strategies aimed at reducing the underlying inflammation through selective inhibition of the phosphodiesterase type IV (PDE4) isoform. Although the anti-inflammatory and bronchodilator activity of selective PDE4 inhibitors has been well documented, their low therapeutic ratio and dose-dependent systemic side effects have limited their clinical utility. This study examined the effect of 2'-deoxy-2'-Fluoro-β-D-Arabinonucleic Acid (FANA)-containing antisense oligonucleotides (AON) targeting the mRNA for the PDE4B/4D and 7A subtypes on lung inflammatory markers, both in vitro and in vivo. Normal human bronchial epithelial (NHBE) cells were transfected with FANA AON against PDE4B/4D and 7A alone or in combination. mRNA levels for target PDE subtypes, as well as secretion of pro-inflammatory chemokines were then measured following cell stimulation. Mice were treated with combined PDE4B/4D and 7A AON via endo-tracheal delivery, or with roflumilast via oral delivery, and exposed to cigarette smoke for one week. Target mRNA inhibition, as well as influx of inflammatory cells and mediators were measured in lung lavages. A two-week smoke exposure protocol was also used to test the longer term potency of PDE4B/4D and 7A AONs. In NHBE cells, PDE4B/4D and 7A AONs dose-dependently and specifically inhibited expression of their respective target mRNA. When used in combination, PDE4B/4D and 7A AONs significantly abrogated the cytokine-induced secretion of IL-8 and MCP-1 to near baseline levels. In mice treated with combined PDE4B/4D and 7A AONs and exposed to cigarette smoke, significant protection against the smoke-induced recruitment of neutrophils and production of KC and pro-MMP-9 was obtained, which was correlated with inhibition of target mRNA in cells from lung lavages. In this model, PDE AONs exerted more potent and broader anti-inflammatory effects against smoke-induced lung inflammation than roflumilast. Moreover, the protective effect of PDE4B/4D and 7A AON was maintained when a once-weekly treatment schedule was used. These results indicate that inhaled AON against PDE4B/4D and 7A have unique effects on biomarkers that are believed to be important in the pathophysiology of COPD, which supports further development as a potential therapy in this disease.