Revisiting Type 2‐high and Type 2‐low airway inflammation in asthma: current knowledge and therapeutic implications

Asthma is a complex respiratory disorder characterized by marked heterogeneity in individual patient disease triggers and response to therapy. Several asthma phenotypes have now been identified, each defined by a unique interaction between genetic and environmental factors, including inflammatory, clinical and trigger‐related phenotypes. Endotypes further describe the functional or pathophysiologic mechanisms underlying the patient's disease. type 2‐driven asthma is an emerging nomenclature for a common subtype of asthma and is characterized by the release of signature cytokines IL‐4, IL‐5 and IL‐13 from cells of both the innate and adaptive immune systems. A number of well‐recognized biomarkers have been linked to mechanisms involved in type 2 airway inflammation, including fractional exhaled nitric oxide, serum IgE, periostin, and blood and sputum eosinophils. These type 2 cytokines are targets for pharmaceutical intervention, and a number of therapeutic options are under clinical investigation for the management of patients with uncontrolled severe asthma. Anticipating and understanding the heterogeneity of asthma and subsequent improved characterization of different phenotypes and endotypes must guide the selection of treatment to meet individual patients’ needs.     

Can hypertonic saline inhalation influence preformed chemokine and mediator release in induced sputum of chronic obstructive pulmonary disease patients? Comparison with isotonic saline

Background Hypertonic saline (HS) has been shown to modulate in vitro cell functions according to the state of cell activation; however, few studies have evaluated the effect of HS in vivo. Chronic airway inflammation, a major feature of chronic obstructive pulmonary disease (COPD), is associated with an activation of inflammatory and resident cells, which in turn makes them more prompt to respond to further stimuli. Objective To evaluate whether HS might modulate, also in vivo, the release of preformed mediators and intracellular chemokines from airway cells of COPD patients. Methods Sputum was induced by inhalation of either HS (4.5% w/v) or isotonic saline (IS 0.9% w/v) solution and processed by plug selection. We measured eosinophil cationic protein (ECP), neutrophil elastase (NE), IL‐8 and monocyte chemoattractant protein‐1 (MCP‐1) in sputum samples obtained by either HS or IS inhalation in 24 COPD patients. Results No significant difference in mediators measured in sputum samples obtained by the two different inductions was observed; also, there was no significant difference in sputum sample volumes, cell viability, total and differential cell counts. Repeatability between the two tests was high for ECP, NE, macrophages, neutrophils and eosinophils, and satisfactory for IL‐8 and MCP‐1. Conclusions Hyperosmolarity does not affect the levels of the inflammatory mediators and chemokines examined or the cell counts measured in induced sputum obtained from COPD patients. This study does not support the hypothesis that HS can stimulate chemokine and mediator release from airway cells of COPD patients. Therefore, HS and IS can be interchangeably used to measure inflammatory mediators in the sputum supernatant of COPD patients.     

Role of Eosinophil Granulocytes in Allergic Airway Inflammation Endotypes

Eosinophil granulocytes are intriguing members of the innate immunity system that have been considered important defenders during parasitic diseases as well as culprits during allergy‐associated inflammatory diseases. Novel studies have, however, found new homoeostasis‐maintaining roles for the cell. Recent clinical trials blocking different Th2 cytokines have uncovered that asthma is heterogeneous entity and forms different characteristic endotypes. Although eosinophils are present in allergic asthma with early onset, the cells may not be essential for the pathology. The cells are, however, likely disease causing in asthma with a late onset, which is often associated with chronic rhinosinusitis. Assessment of eosinophilia, fraction exhaled nitric oxide (FeNO) and periostin are markers that have emerged useful in assessing and monitoring asthma severity and endotype. Current scientific knowledge suggests that eosinophils are recruited by the inflammatory environment, activated by the innate interleukin (IL)‐33 and prevented from apoptosis by both lymphocytes and innate immune cells such as type two innate immune cells. Eosinophils contain four specific granule proteins that exhibit an array of toxic and immune‐modulatory activates. The granule proteins can be released by different mechanisms. Additionally, eosinophils contain a number of inflammatory cytokines and lipid mediators as well as radical oxygen species that might contribute to the disease both by the recruitment of other cells and the direct damage to supporting cells, leading to exacerbations and tissue fibrosis. This review aimed to outline current knowledge how eosinophils are recruited, activated and mediate damage to tissues and therapies used to control the cells.     

Biomarkers for Severe Asthma: Lessons From Longitudinal Cohort Studies

Severe asthma (SA) is a heterogeneous disease characterized by uncontrolled symptoms, frequent exacerbations, and lung function decline. The discovery of phenotypes and endotypes of SA significantly improves our understanding of its pathophysiology and allows the advent of biologics blocking multiple molecular targets. The advances have mainly been made in type 2-high asthma associated with elevated type 2 inflammatory biomarkers such as immunoglobulin E (IgE), interleukins (IL)-4, IL-5, and IL-13. Previous clinical trials have demonstrated that type 2 biomarkers, including blood/sputum eosinophils and the fraction of exhaled nitric oxide (FeNO), were correlated to severe airway inflammation, persistent symptoms, frequent exacerbations, and the clinical efficacy of these biomarkers in predicting treatment outcomes of type 2-targeting biologics. However, it is well known that type 2 inflammation is partially attributable to the pathogenesis of SA. Although some recent studies have suggested that type 2-low and mixed phenotypes of asthma are important contributors to the heterogeneity of SA, many questions about these non-type 2 asthma phenotypes remain to be solved. Consequently, many efforts to investigate and find novel biomarkers for SA have also made in their methods. Many cross-sectional experimental studies in large-scale cohorts and randomized clinical trials have proved their value in understanding SA. More recently, real-world cohort studies have been in the limelight for SA research, which is unbiased and expected to give us an answer to the unmet needs of the heterogeneity of SA.     

Primary lysis of eosinophils in severe desquamative asthma

Primary lysis of eosinophils liberates free eosinophil granules (FEGs) releasing toxic proteins in association with bronchial epithelial injury repair. Eosinophil lysis may be significantly pathogenic. Bronchial mucosal FEGs are associated with uncontrolled asthma, severe asthma, aspirin‐sensitive asthma, and lethal asthma. FEGs in the bronchial wall may characterize severe asthma without sputum eosinophilia. Excessive numbers of sputum FEGs occur in severe exacerbations of asthma and are reduced along with clinical improvement. Occurrence of FEGs affects interpretation of other sputum biomarkers including numbers of eosinophils, ECP, and eosinophil‐stained macrophages. Thus, eosinophil lysis produces FEGs as bronchial biomarkers of severe asthma. Blood eosinophils in severe asthma seem primed exhibiting a propensity to lyse that is greater the more severe the asthma. Proclivity of blood eosinophils to lyse also distinguished three levels of severity among children with exacerbations of asthma. Numerous FEGs releasing toxic proteins occur in association with grave derangement and shedding of epithelium in severe asthma. Subepithelial FEGs correlate negatively with intact bronchial epithelium in clinically uncontrolled asthma. Significant correlations between sputum ECP, Creola bodies, and severity of asthma exacerbations have also been demonstrated. Hence, eosinophil lysis apparently causes epithelial desquamation in severe asthma. Exaggerated epithelial repair in turn would contribute to inflammatory and remodelling features of severe asthma. Perseverance of FEGs together with maintained disease activity, despite treatment with ‘eosinophil‐depleting’ steroids and anti‐IL5 biologicals, agrees with the possibility that eosinophil lysis is worthy target for novel anti‐asthma drugs. Priming and lysis of eosinophils, and protein release from FEGs, are regulated and can be targeted. Eosinophil lysis and FEGs belong to the disease picture of severe asthma and need consideration in asthma studies concerned with phenotypes, biomarkers, roles of epithelial injury/repair, and targeting novel drugs.     

Inflammatory cell profiles and T-lymphocyte subsets in chronic obstructive pulmonary disease and severe persistent asthma

Background Severe persistent asthma (SPA) and chronic obstructive pulmonary disease (COPD) are both associated with non‐reversible airflow limitation and airway neutrophilia. Objective To compare inflammatory cell profiles and T lymphocyte subsets between SPA and COPD patients with similar severity of airflow limitation. Methods Sputum induction and lung function tests were performed in 15 COPD patients aged (mean±SD) 68±8 years, ex‐smokers, mean forced expiratory volume in 1 s (FEV₁) 45% of predicted (%pred) and 13 SPA aged 55±10 years, non‐smokers, mean FEV₁ 49%pred. All patients were on inhaled steroid treatment. Eight asthmatics exhibited irreversible airflow limitation. Differential cell count, metachromatic cell count and double immunocytochemistry for the analysis of T lymphocyte subsets were performed on sputum slides. Results COPD patients had increased sputum neutrophils in comparison with SPA (P<0.03), but similar to SPA with fixed obstruction. In COPD sputum neutrophils negatively correlated with the lung transfer factor for carbon monoxide (K_CO) (r=?0.462, P=0.04). SPA showed significantly increased eosinophils and metachromatic cells vs. COPD patients (P<0.04, P<0.007, respectively). Increased CD4/CD8 and decreased CD4‐IFN‐γ/CD4‐IL4⁺ cell ratio (P<0.001) were found in SPA vs. COPD. In SPA, CD4/CD8⁺ cell ratio correlated with sputum eosinophils (r=0.567, P=0.04). Conclusion In spite of treatment with inhaled steroids, SPA and COPD exhibit distinct sputum inflammatory cell patterns, although SPA with fixed airflow limitation and COPD patients have similar numbers of neutrophils.     

Distinct sustained structural and functional effects of interleukin‐33 and interleukin‐25 on the airways in a murine asthma surrogate

Interleukin‐25 (IL‐25) and IL‐33, which belong to distinct cytokine families, induce and promote T helper type 2 airway inflammation. Both cytokines probably play a role in asthma, but there is a lack of direct evidence to clarify distinctions between their functions and how they might contribute to distinct ‘endotypes’ of disease. To address this, we made a direct comparison of the effects of IL‐25 and IL‐33 on airway inflammation and physiology in our established murine asthma surrogate, which involves per‐nasal, direct airway challenge. Intranasal challenge with IL‐33 or IL‐25 induced inflammatory cellular infiltration, collagen deposition, airway smooth muscle hypertrophy, angiogenesis and airway hyper‐responsiveness, but neither increased systemic production of IgE or IgG1. Compared with that of IL‐25, the IL‐33‐induced response was characterized by more sustained laying down of extracellular matrix protein, neoangiogenesis, T helper type 2 cytokine expression and elevation of tissue damping. Hence, both IL‐25 and IL‐33 may contribute significantly and independently to asthma ‘endotypes’ when considering molecular targets for the treatment of human disease.     

Soluble interleukin-5 receptor alpha is increased in acute exacerbation of chronic obstructive pulmonary disease

BACKGROUND: During chronic obstructive pulmonary disease (COPD) exacerbations (AE-COPD), an influx of eosinophils into the bronchial mucosa has been described. Eosinophilic cationic protein (ECP) and soluble interleukin-5 receptor alpha (sIL5Ralpha) are secreted by eosinophils and increased in eosinophilic airway diseases. METHODS: We studied ECP and sIL5Ralpha expression in patients with COPD compared to healthy controls and smokers and investigated a possible association to viral exacerbations of COPD. Expression of sIL5Ralpha in serum was analyzed by ELISA and ECP by the Uni-Cap system. Induced sputum from patients with COPD was analyzed for six different respiratory viruses by nested PCR. RESULTS: ECP and sIL5Ralpha were significantly elevated in AE-COPD subjects (n = 54) compared to healthy controls (n = 11, p = 0.018). Furthermore, there was a significant increase in sIL5Ralpha, but not in ECP, in 30 patients with virus-associated AE-COPD compared to smokers without COPD (n = 16) and healthy controls. The increase in FEV(1) after resolution of the AE-COPD correlated with the decrease in sIL5Ralpha (r = 0.269, p = 0.034). CONCLUSIONS: sIL5Ralpha is increased in AE-COPD and not affected by smoking like ECP. sIL5Ralpha is increased in patients with virus-associated AE-COPD compared to smokers and controls. Concentrations of sIL5Ralpha mirror changes in the clinical status and lung function. These data support the involvement of eosinophils in acute exacerbations of COPD.     

EUFOREA consensus on biologics for CRSwNP with or without asthma

Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2‐targeting biologics such as anti‐IgE, anti‐IL4Rα, anti‐IL5, and anti‐IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.     

Clinical phenotypes in asthma during childhood

Asthma is a heterogeneous disease characterized by numerous phenotypes relating to age of onset, triggers, comorbidities, severity (assessed by multiple exacerbations, lung function pattern) and finally the inflammatory cells involved in the pathophysiologic pathway. These phenotypes can vary over time in relation to changes in the principal triggers involved in the aetiology of the disease. Nevertheless, in a patient with multiple allergies and early‐onset disease (defined as multiple sensitizations and allergic comorbidities), the prognosis of asthma is poor with a high risk of persistence and severity of the disease during childhood. Future research will focus on classifying phenotypes into groups based on pathophysiologic mechanisms (endotypes) and the biomarkers attached to these endotypes, which could predict prognosis and lead to targeted therapy. Currently, these biomarkers are related to inflammatory cells associated with the asthma endotype, essentially eosinophils and neutrophils (and related cytokines) attached to Th‐2 and non Th‐1 pathways, respectively. The most severe asthma (refractory asthma) is linked to neutrophil‐derived inflammation (frequently associated with female sex, obesity and possibly disorganized airway microbiota) encountered in very young children or teenagers. Severe asthma is also linked to or a marked eosinophil inflammatory process (frequently associated with multiple atopy and, more rarely, with non‐atopic hypereosinophilic asthma in children) and frequently encountered in teenagers. Severe phenotypes of asthma could also play a role in the origin of chronic obstructive pulmonary disease in adult life.     

Exacerbations of chronic obstructive pulmonary disease and chronic mucus hypersecretion

Chronic obstructive pulmonary disease (COPD) exacerbations are an important cause of the considerable morbidity and mortality found in COPD. COPD exacerbations increase with increasing severity of COPD, and some patients are prone to frequent exacerbations leading to hospital admission and readmission. These frequent exacerbations may have considerable impact on quality of life and activities of daily living. Factors that increase the risk for COPD exacerbations are associated with increased airway inflammation caused by common pollutants and bacterial and/or viral infections. These inflammatory responses cause mucus hypersecretion and, thereby, airway obstruction and associated exacerbations. While chronic mucus hypersecretion is a significant risk factor for frequent and severe exacerbations, patients with chronic mucus hypersecretion have a lower rate of relapse after initial treatment for acute exacerbation. The benefit of antibiotics for treatment of COPD exacerbations is small but significant. While the mechanisms of actions are not clear, mucolytic agents reduce the number of days of disability in subjects with exacerbations. Reducing mucous cell numbers in small airways could be a useful way to reduce chronic mucus hypersecretion. Our studies suggest that programmed cell death is crucial in the resolution of metaplastic mucous cells, and understanding these mechanisms may provide novel therapies to reduce the risk of COPD exacerbations.     

Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma

BACKGROUND: There is a large variability in clinical response to corticosteroid treatment in patients with asthma. Several markers of inflammation like eosinophils and eosinophil cationic protein (ECP), as well as exhaled nitric oxide (NO), are good candidates to predict clinical response. AIM: We wanted to determine whether we could actually predict a favourable response to inhaled corticosteroids in individual patients. METHODS: One hundred and twenty patients with unstable asthma were treated with either prednisolone 30 mg/day, fluticasone propionate 1000 microg/day b.i.d. or fluticasone propionate 250 microg/day b.i.d., both via Diskhaler. They were treated during 2 weeks, in a double-blind, parallel group, double dummy design. We measured eosinophils and ECP in blood and sputum, and exhaled nitric oxide as inflammatory parameters before and after 2 weeks in order to predict the changes in forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% fall in FEV1 (PC20 Mch), and asthma quality of life (QOL). Secondly, to test whether these results were applicable in clinical practice we determined the individual prediction of corticosteroid response. RESULTS: We found that changes in FEV1, PC20 Mch and QOL with corticosteroids were predominantly predicted by their respective baseline value and to a smaller extent by eosinophils in blood or sputum. ECP, measured in blood or sputum, was certainly not better than eosinophils in predicting clinical response to corticosteroids. Smoking status was an additional predictor for change in FEV1, but not for change in PC20 Mch or QOL. Prediction of a good clinical response was poor. For instance, high sputum eosinophils (> or = 3%) correctly predicted an improvement in PC20 Mch in only 65% of the patients. CONCLUSION: Our findings show that baseline values of the clinical parameters used as outcome parameters are the major predictors of clinical response to corticosteroids. Eosinophil percentage in blood or sputum adds to this, whereas ECP provides no additional information. Correct prediction of clinical response in an individual patient, however, remains poor with our currently used clinical and inflammatory parameters.     

Reactive Oxygen Species in Peripheral Blood and Sputum Neutrophils During Bacterial and Nonbacterial Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Chronic airway inflammation can be mediated by an enhanced neutrophil oxidative burst. However, the role of bacteria in the pathogenesis of chronic obstructive pulmonary disease (COPD) exacerbations is highly controversial. The aim of this study was to evaluate the production of reactive oxygen species (ROS) in peripheral blood and sputum neutrophils during bacterial and nonbacterial acute exacerbations of COPD (AECOPD). A total of 40 patients with AECOPD, 10 healthy nonsmokers, and 10 “healthy” smokers were enrolled into the study. Peripheral blood and sputum samples were obtained during exacerbation and after recovery. Neutrophils were isolated by high-density gradient centrifugation and magnetic separation. ROS production by neutrophils was investigated after stimulation with phorbol-myristate-acetate and Staphylococcus aureus bacteria. ROS production by neutrophils was assessed as the mean fluorescent intensity using a flow cytometer. IL-8 levels in serum and induced sputum were determinant by ELISA. Spontaneous ROS production was significantly higher in neutrophils from the patients with bacterial AECOPD as compared with nonbacterial AECOPD and stable COPD (P <0.05). ROS production stimulated with PMA and with Staphylococcus aureus was significantly higher in neutrophils isolated from the patients with bacterial AECOPD as compared with nonbacterial and stable COPD (P <0.05). The serum and induced sputum IL-8 levels were significantly increased in the patients with bacterial AECOPD than nonbacterial AECOPD, stable COPS, and “healthy” smokers and nonsmokers (P <0.05) and higher in the induced sputum as the compared with serum in all studied groups (P <0.05). Enlarge CRP level was documented during AECOPD than in all other groups (P <0.05). A markedly increased ROS production in sputum neutrophils during bacterial AECOPD shows an inflammatory response reflecting enhanced local inflammation, which can be mediated by bacterial colonization.     

Glucocorticoid sensitivity of lipopolysaccharide‐stimulated chronic obstructive pulmonary disease alveolar macrophages

It has been reported that alveolar macrophages from patients with chronic obstructive pulmonary disease (COPD) display glucocorticoid (Gc) resistance. The Gc sensitivity of inflammatory mediators released by COPD macrophages may vary. The objective of this study was to identify Gc‐insensitive inflammatory mediators produced by lipopolysaccharide (LPS)‐stimulated alveolar macrophages from COPD patients. LPS‐stimulated alveolar macrophages from 15 COPD patients, nine smokers (S) and nine healthy non‐smokers (HNS) were stimulated with LPS with or without dexamethasone (100 and 1000 nM). Luminex and enzyme‐linked immunosorbent assay were used to measure 23 inflammatory mediators. After LPS stimulation there were lower levels of inflammatory mediators in COPD patients and S compared to HNS. There was no difference between groups for the effects of dexamethasone at either concentration (P > 0·05 for all comparisons). Tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and growth‐related oncogene (GRO)‐α displayed the greatest sensitivity to dexamethasone in COPD patients, while IL‐8, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF) were the least sensitive. COPD macrophages have a reduced response to LPS. Gc sensitivity was similar in COPD macrophages compared to controls. We identify some Gc‐insensitive cytokines, including GM‐CSF, G‐CSF and IL‐8, that may be involved in the progression of airway inflammation in COPD patients.     

Characterization of innate immune signalling receptors in virus‐induced acute asthma

Background The role of toll‐like receptors (TLRs) and innate immune activation in clinical asthma exacerbations and their relationship to virus infection are unclear. Objective This study aimed to characterize TLR expression and innate immune activity during virus infection in acute asthma. Methods Subjects with acute asthma, stable asthma and healthy controls were recruited and underwent spirometry and sputum induction with isotonic saline. Selected sputum was dispersed with dithiothreitol and total and differential leucocyte counts were performed. Selected sputum was also used for quantitative real‐time PCR for TLR2, TLR3, TLR4, IL‐10 and IP‐10mRNA expression. Sputum supernatant was used for the measurement of innate immune markers, including IL‐8, matrix metalloproteinase‐9 and neutrophil elastase activity. Viruses were detected using real‐time and gel‐based PCR. Results Sputum TLR2 mRNA expression was up‐regulated in both acute and stable asthma compared with healthy controls and decreased 4–6 weeks after acute exacerbation. Sputum TLR2 mRNA expression was elevated in viral, compared with non‐viral, acute asthma. Sputum TLR3 mRNA expression was similar in controls, stable and acute asthma. However, in acute asthma, subjects with virus‐induced acute asthma had significantly higher sputum TLR3 mRNA expression. Induced sputum gene expression for IP‐10 and IL‐10 were increased in viral, compared with non‐viral, acute asthma. In virus‐induced acute asthma, levels of IP‐10 and IL‐10 mRNA expression were correlated with the mRNA expression of TLR2 and TLR3. Conclusions and Clinical Relevance Virus‐induced acute asthma leads to specific induction of TLR2, TLR3, IP‐10 and IL‐10, suggesting that signalling via TLRs may play an important role in mediating airway inflammation, via both innate and adaptive pathways, in virus‐induced exacerbations. These mediators may provide potential treatment targets for virus‐induced asthma. They may also be useful in diagnosing the nature of acute asthma exacerbations and monitoring treatment responses, which would be useful in the clinical management of asthma exacerbations. Cite this as: L. G. Wood, J. L. Simpson, P. A. B. Wark, H. Powell and P. G. Gibson, Clinical & Experimental Allergy, 2011 (41) 640–648.     

慢性阻塞性肺疾病频繁急性加重患者的临床特征分析

目的 观察慢性阻塞性肺疾病（COPD）频繁急性加重患者与非频繁急性加重患者临床特征的差异。方法 回顾性纳入2016年1月~2018年12月合肥市第一人民医院呼吸内科住院的274例COPD急性加重患者,根据患者上一年急性加重次数分为频繁组（住院次数≥2次/年）143例和非频繁组（住院次数＜2次/年）131例,比较两组性别、年龄、病程、吸烟量、mMRC评分、共患疾病（高血压、冠心病、糖尿病）、白细胞计数、中性粒细胞百分比、淋巴细胞百分比、嗜酸粒细胞百分比、降钙素原（PCT）、血气指标（pH、PaO2、PaCO2）及血氧饱和度（SpO2）,多因素Logistic回归分析COPD频繁急性加重的危险因素。结果 两组性别、年龄、白细胞计数、淋巴细胞百分比、嗜酸粒细胞百分比、PCT、pH、PaCO2、共患疾病（高血压、冠心病、糖尿病）比较,差异无统计学意义（P＞0.05）;频繁组病程、吸烟量、mMRC评分、中性粒细胞百分比、SpO2、PaO2均高于非频繁组,差异均有统计学意义（P＜0.05）;多因素Logistic回归分析显示,病程、吸烟量、mMRC评分、中性粒细胞百分比是COPD频繁急性加重的独立危险因素。结论 COPD频繁急性加重多病程较长,患者多长期吸烟,临床中应重视病程长、吸烟量大、mMRC评分高、中性粒细胞百分比高的COPD患者,加强对其的监护管理,防止发生COPD频繁急性加重。     

The role of macrophage IL‐10/innate IFN interplay during virus‐induced asthma

Activation through different signaling pathways results in two functionally different types of macrophages, the pro‐inflammatory (M1) and the anti‐inflammatory (M2). The polarization of macrophages toward the pro‐inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung. Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti‐inflammatory or pro‐inflammatory macrophages, respectively, and therefore, macrophages mediate both processes. Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL‐10, and less innate IFNs. However, the interactions between IL‐10 and innate IFNs during virus‐induced exacerbations of asthma have not been well studied. The possible role of IL‐10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL‐10–IFNs interactions and discusses the role of IL‐10 in virus‐induced asthma exacerbations. Whereas IL‐10 is important in terminating pro‐inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus‐induced asthma exacerbations. © 2014 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.     

Similar activation state of neutrophils in sputum of asthma patients irrespective of sputum eosinophilia

Inflammatory phenotypes of asthma are associated with differences in disease characteristics. It is unknown whether these inflammatory phenotypes are reflected by the activation status of neutrophils in blood and sputum. We obtained peripheral blood and induced sputum from 21 asthma patients and stratified our samples based on sputum eosinophilia resulting in two groups (>3% eosinophils: n = 13, <3%: n = 8). Eosinophils and neutrophils from blood and sputum were analysed for expression of activation and degranulation markers by flow cytometry. Data were analysed by both classical, non‐parametric statistics and a multi‐dimensional approach, using principal component analysis (PCA). Patients with sputum eosinophilia were characterized by increased asthma control questionnaire (ACQ) scores and blood eosinophil counts. Both sputum neutrophils and eosinophils displayed an activated and degranulated phenotype compared to cells obtained from blood. Specifically, degranulation of all granule types was detected in sputum cells, combined with an increased expression of the activation markers (activated) Mac‐1 (CD11b), programmed death ligand 1 (PD‐L1) (CD274) and a decreased expression of CD62L. CD69 expression was only increased on sputum eosinophils. Surface marker expression of neutrophils was similar in the presence or absence of eosinophilia, either by single or multi‐dimensional analysis. Sputum neutrophils were highly activated and degranulated irrespective of sputum eosinophilia. Therefore, we conclude that differences in granulocyte activation in sputum and/or blood are not associated with clinical differences in the two groups of asthma patients. The finding of PD‐L1 expression on sputum granulocytes suggests an immunomodulatory role of these cells in the tissue.     

Toward antiviral therapy/prophylaxis for rhinovirus‐induced exacerbations of chronic obstructive pulmonary disease: challenges,opportunities, and strategies

Chronic obstructive pulmonary disease (COPD) is a life‐threatening lung illness characterized by persistent and progressive airflow limitation. Exacerbations of COPD contribute to the severity of this pathology and accelerate disease progression. To date, pharmacological treatment of both stable COPD patients and patients experiencing exacerbations is mainly symptomatic with bronchodilators and steroids as the mainstay of therapy. Bacteria trigger such exacerbations in a number of cases; hence, antibiotics might be included in the treatment as well. Several respiratory viruses are frequently detected in sputum from patients during COPD exacerbations. These include influenza viruses, respiratory syncytial virus, and, most often, rhinoviruses. In this review, we discuss the potential use of an anti‐rhinovirus drug for the treatment and prophylaxis of rhinovirus‐induced COPD exacerbations and the path forward toward the development and use of such a drug. Copyright © 2015 John Wiley & Sons, Ltd.