Undetected chronic obstructive pulmonary disease and asthma in people over 50 years with persistent cough

Background

Chronic obstructive pulmonary disease (COPD) and asthma are underdiagnosed in primary care.

Aim

To determine how often COPD or asthma are present in middle-aged and older patients who consult their GP for persistent cough.

Design of study

A cross-sectional study in 353 patients older than 50 years, visiting their GP for persistent cough and not known to have COPD or asthma.

Setting

General practice in the Netherlands.

Method

All participants underwent extensive diagnostic work-up, including symptoms, signs, spirometry, and body plethysmography. All results were studied by an expert panel to diagnose or exclude COPD and/or asthma. The reproducibility of the panel diagnosis was assessed by calculation of Cohen''s κ statistic in a sample of 41 participants.

Results

Of the 353 participants, 102 (29%, 95% confidence interval [CI] = 24 to 34%) were diagnosed with COPD. In 14 of these 102 participants, both COPD and asthma were diagnosed (4%, 95% CI = 2 to 7%). Asthma (without COPD) was diagnosed in 23 (7%, 95% CI = 4 to 10%) participants. Mean duration of cough was 93 days (median 40 days). The reproducibility of the expert panel was good (Cohen''s κ = 0.90).

Conclusion

In patients aged over 50 years who consult their GP for persistent cough, undetected COPD or asthma is frequently present.     

强直性脊柱炎患者外周血T细胞亚群极化状态的研究

目的:分析强直性脊柱炎患者外周血中T细胞亚群的极化状态,进一步阐明强直性脊柱炎的免疫学发病机制.方法:运用流式细胞(FCM)技术,通过CD3/CD4或CD3/CD8设门,检测早、晚期AS患者和健康对照者外周血淋巴细胞的CD3 CD4 CD30 、CD3 CD4 CD30ˉ、CD3 CD8 CD30 、CD3 CD8 CD30ˉT细胞的百分率,分别表达Th1、Th2、Tc1、Tc2细胞,并进行比较分析.结果:在早期AS患者CD4 T细胞和CD4 T/CD8 T细胞的比值均明显低于健康对照组(P＜0.05),Th1细胞百分率及Th1/Th2比值明显降低(P＜0.05),CD8 T细胞的百分率明显高于健康对照组(P＜0.05),Tc2细胞明显升高(P＜0.05),且Tc1/Tc2比值明显降低(P＜0.05);在晚期AS患者Tc2细胞明显升高(P＜0.05),Tc1/Tc2比值明显降低(P＜0.05).结论:早期AS患者外周血CD4 T细胞、CD8 T细胞、CD4 T/CD8 T的变化与健康对照比较具有显著性意义,阐明了AS早期患者体内的免疫功能紊乱,呈现一种免疫功能低下的状态.重要的是Th1细胞、Th1/Th2、Tc1/Tc2的明显减少,提示在早期AS患者体内Th1/Th2、Tc1/Tc2的失调,且以Th2、Tc2占有优势,而晚期AS患者因Tc1/Tc2明显降低导致比例失衡,这些显示Th1/Th2、Tc1/Tc2的比例失衡可能是导致AS发病的重要因素,是AS发病机制之一.     

CD8 chemokine receptors in chronic obstructive pulmonary disease

Increased lung CD8 cells and their expression of chemokine receptors CXCR3 and CCR5 have been previously reported in chronic obstructive pulmonary disease (COPD). Alterations of CD8-CCR3 and -CCR4 expression and their ligands in COPD patients have not been fully investigated. The objective of this study was to assess in COPD patients: (i) broncho-alveolar lavage (BAL) CD8 CCR3 and CCR4 expression in COPD patients; and (ii) airway levels of the CCR3 ligands, CCL11 and CCL5. Multi-parameter flow cytometric analysis was used to assess BAL CD3 and CD8-chemokine receptor expression in COPD patients, smokers and healthy non-smokers (HNS). CCL5 and CCL11 levels were measured in BAL, and from the supernatants of lung resection explant cultures. CD8-CCR3 and -CCR5 expression (means) were increased in COPD patients (22% and 46% respectively) and smokers (20% and 45%) compared with HNS (3% and 22%); P < 0.05 for all comparisons. CD3CXCR3 expression was raised in smokers and COPD while CD8CXCR3 and CD3 and CD8 CCR4 expression was similar between groups. CD8CCR5 expression correlated to smoking pack years (r = 0.42, P = 0.01). COPD explants released more CCL5 compared with smokers (P = 0.02), while there was low level CCL11 production. CD8CCR3 and CCR5 expression appear to be regulated by cigarette smoke exposure. We show that COPD lung tissue released more CCL5, suggesting a role for CCL5-CCR3 signalling in pulmonary CD8 recruitment in COPD.     

Analysis of microbiota in stable patients with chronic obstructive pulmonary disease

To identify the bacterial diversity (microbiota) in expectorated sputum, a pyrosequencing method that investigates complex microbial communities of expectorated sputum was done in 19 stable chronic obstructive pulmonary disease patients (mean (SD) FEV1: 47 (18%) of predicted value). Using conventional culture, 3 phyla and 20 bacterial genera were identified, whereas the pyrosequencing approach detected 9 phyla and 43 genera (p < 0.001). In sputum the prevalent genera with pyrosequencing approach were Streptococcus, Actinomyces, Neisseria, Haemophilus, Rothia, Fusobacterium, Gemella, Granulicatella, Porphyromonas, Prevotella and Veillonella. Enterobacteriaceae, detected frequently in conventional culture, were not significantly detected with pyrosequencing methods. In addition, we found that important pathogens such as Haemophilus and Moraxella were detected more frequently with the new genetic procedures. The presence of Enterobacteriaceae is probably overestimated with conventional culture, whereas other difficult cultivable pathogens are underestimated. These studies open a new perspective for evaluating the role of bacterial colonization in chronic obstructive pulmonary disease pathogenesis and progression.     

Imbalance of circulating dendritic cell subsets in chronic obstructive pulmonary disease

Dendritic cells (DCs) play an unsettled role in chronic obstructive pulmonary disease (COPD) pathogenesis. Two main blood subsets, myeloid (m) and plasmacytoid (p) DCs, have been identified in humans. Phenotype and frequency of circulating DC subsets were assessed by multi-parametric flow cytometry in 28 COPD patients and 30 healthy controls (15 never smokers and 15 smokers). Proportion and absolute number of pDCs were significantly reduced in COPD patients in comparison with never smokers (p < 0.001 and p < 0.003) along with a marked increase of the mDC/pDC ratio (p < 0.001). Analysis of peripheral lymphocyte subsets showed that the naive/memory T cell ratio was significantly reduced in COPD patients in comparison with never smokers (p < 0.001). Similar perturbations in the distribution of DCs and T cells also occurred in control smokers. This study is the first report of an imbalance of blood DCs in COPD. Influence of smoking and clinical relevance of these findings are discussed.     

T cell senescence and contraction of T cell repertoire diversity in patients with chronic obstructive pulmonary disease

Pathogenetic mechanisms leading to chronic obstructive pulmonary disease (COPD) remain poorly understood. Because clonogenic T cells (CD4⁺CD28^null) were shown to be increased in autoimmune diseases we hypothesized that CD4⁺CD28^null T cells play a role in COPD. Here we describe that enhanced presence of CD4⁺CD28^null cells is associated with impaired lung function. Sixty‐four patients and controls were included. T cell phenotype was analysed using flow cytometry. Enzyme‐linked immunosorbent assays were utilized to determine cytokines. Statistical evaluations were performed using non‐parametric group comparisons and correlations. A logistic regression model was used to determine predictive values of CD4⁺CD28^null in the diagnosis of COPD. Populations of CD4⁺ T cells lacking surface co‐stimulatory CD28 were enlarged significantly in evaluated patients when compared with controls. Natural killer (NK)‐like T cell receptors (CD94, 158) and intracellular perforin, granzyme B were increased in CD4⁺CD28^null cells. Cytokine production after triggering of peripheral blood mononuclear cells (PBMCs) was elevated in patients at early disease stages. Receiver operating characteristic curve plotting revealed that presence of CD4⁺CD28^null T cells has a diagnostic value. These CD4⁺CD28^null T cells show increased expression of NK‐like T cell receptors (CD94, 158) and intracellular perforin and granzyme B. Furthermore, triggering of PBMCs obtained from patients with mild COPD led to increased interferon‐γ and tumour necrosis factor‐α production in vitro compared with controls. Our finding of increased CD4⁺CD28^null T cells in COPD indicates that chronic antigen exposure, e.g. through contents of smoke, leads to loss of CD28 and up‐regulation of NK cell receptors expression on T cells in susceptible patients.     

Immunohistological analysis of T cell functional subsets in chronic inflammatory periodontal disease.

IL-2, interferon-gamma (IFN-gamma), IL-4 and IL-6 producing T cells in periodontitis and gingivitis-affected human tissues were investigated by immunohistochemistry to clarify the relationship between T cell functional subsets and disease entity. Using alkaline-phosphatase anti-alkaline-phosphatase technique, the relative proportions of each cytokine-producing T cell were calculated in the crevicular 1/3, middle 1/3 and oral 1/3 areas selected in the connective tissue of sections. CD19:CD3 and CD4:CD8 ratios were determined on the serial sections. Compared with gingivitis tissues, the proportion of cytokine-producing cells in periodontitis-affected samples was higher overall in the crevicular 1/3 (P < 0.02). The middle 1/3 exhibited a higher percentage of cytokine-producing cells, except for IL-6-producing cells. Frequencies of cytokine-producing cells in the oral 1/3 did not differ. IL-4 was the prominent cytokine in periodontitis-affected tissues, with the highest proportion detected in the crevicular 1/3. The CD19:CD3 ratio was higher in periodontitis tissues irrespective of the location, indicating a B cell dominance in periodontitis lesions. Furthermore, a significant positive correlation between the proportion of IL-4-producing cells and the CD19:CD3 ratio was noted. The CD4:CD8 ratio consistently exceeded 2.0 in both periodontitis and gingivitis. These results suggest that immunoregulation of both periodontitis and gingivitis are T cell-dependent, but in periodontitis type 2 helper T cells predominate and thereby control B cell activation.     

T lymphocyte subset profile and serum alpha-1-antitrypsin in pathogenesis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by the presence of non-fully reversible airflow limitation. The study was undertaken to investigate the involvement of alpha-1-antitrypsin (alpha(1)AT) and T lymphocyte subsets in the pathogenesis of COPD. Blood samples of 50 subjects, including 25 healthy volunteers and 25 patients with COPD, were analysed. Serum trypsin inhibitory capacity (STIC) was determined by enzymatic assay. CD4(+) and CD8(+) T lymphocytes were enumerated in heparinized blood using a fluorescence activated cell sorter counter. The STIC in COPD patients was found to be decreased significantly than in controls (P < 0.01). In COPD patients with lower expression levels of alpha(1)AT, a highly significant decrease in the number of CD4(+) T lymphocytes (P < 0.0009) and CD4/CD8 ratio was observed compared with control subjects (P < 0.008). The mean +/- standard error of CD8(+) lymphocytes was found to be little different (only marginally decreased) in COPD patients compared to healthy controls; however, an alteration in the individual count of CD8(+) lymphocytes cells was observed in COPD patients. Using linear regression analysis, a negative correlation was observed between STIC and CD4(+) lymphocytes and CD8(+) lymphocytes (r = -0.40, P < 0.04; r = -0.42, P < 0.03, respectively) in COPD patients. An alteration in alpha(1)AT and T lymphocyte subsets in COPD patients suggested that interplay of these factors may be responsible for the progression of COPD.     

Characterization of a population of small macrophages in induced sputum of patients with chronic obstructive pulmonary disease and healthy volunteers

The inflammatory process in chronic obstructive pulmonary disease (COPD) is active mainly in the airways, but little is known about the properties of the inflammatory cells in this compartment. We have studied leucocytes in induced sputum of COPD patients compared to controls in order to uncover what types of macrophages might be involved in the disease. Sputum induction was performed by inhalation of nebulized sodium chloride solution. Leucocytes were isolated and stained with specific monoclonal antibodies for analysis in flow cytometry. Flow cytometry analysis revealed that a major portion of CD14+ macrophages in COPD has lower forward scatter, i.e. they are small macrophages. While in control donors these small macrophages accounted for 6.9% of all macrophages, the percentage of these cells in COPD was 45.7%. CD14 and HLA-DR expression was high on these small sputum macrophages while the large sputum macrophages expressed only low levels of these surface molecules, both in control donors and COPD patients. Small sputum macrophages of both control donors and COPD patients showed higher levels of constitutive tumour necrosis factor (TNF) compared to the large macrophages. TNF was inducible by lipopolysaccharide (LPS) preferentially in the small sputum macrophages in the control donors but there was no further induction in COPD patients. These data show that the small sputum macrophages are a major macrophage population in COPD and that these cells exhibit features of highly active inflammatory cells and may therefore be instrumental in airway inflammation in COPD.     

Leukotriene pathway inhibitors in asthma and chronic obstructive pulmonary disease

Leukotrienes can be generated from a wide variety of cells including mast cells and eosinophils. The biological properties of these products include bronchial smooth muscle contraction, stimulation of mucous production, enhancement of vascular permeability, and recruitment of eosinophils. These properties can contribute significantly to the pathobiology of asthma. Recently, zafirlukast and montelukast, and zileuton, leukotriene D₄ receptor antagonists and 5-lipoxygenase inhibitors, respectively, have been developed and are available for treating asthma. Studies have found these compounds modify bronchospasm with exercise, the pulmonary reaction to aspirin in sensitive subjects, and the airway response to inhaled antigen. Furthermore, in patients with chronic asthma, leukotriene modifiers improve airflow obstruction, decrease the need for rescue medication, and diminish symptoms. Moreover, these drugs can prevent asthma exacerbations. However, there is little evidence that these medications have potent anti-inflammatory activity. Nonetheless, leukotriene modifiers represent new, and effective, therapeutics in the treatment of asthma; at present, the positioning of these products in relationship to inhaled corticosteroids, for example, in the treatment of asthma has not been fully defined but will emerge with further study and use in the clinic setting.     

Airway inflammation and hyperresponsiveness to adenosine 5'-monophosphate in chronic obstructive pulmonary disease

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is often accompanied by bronchial hyperresponsiveness (BHR). Measurement of BHR may give information about airway inflammation. OBJECTIVE: To investigate the role of airway inflammation in hyperresponsiveness to adenosine 5'-monophosphate (AMP) in COPD. METHODS: We investigated inflammatory indices in induced sputum, bronchoalveolar lavage (BAL) fluid and bronchial biopsies in subjects with COPD with and without hyperresponsiveness to AMP. Twelve nonatopic subjects with COPD with hyperresponsiveness to AMP (mean +/- SD, age 63 +/- 8 years, FEV1% predicted 56 +/- 13%), six without BHR (age 60 +/- 6 years, FEV1% predicted 65 +/- 11%) and 11 healthy nonatopic controls without BHR (age 58 +/- 8 years, FEV1% predicted 104 +/- 11%) participated in the study. RESULTS: Subjects with COPD with BHR had significantly higher numbers of mucosal CD8 + and higher percentages of sputum eosinophils than those without BHR (median, 550 cells/mm2; range, 30-1340 vs 280 cells/mm2; range, 110-450, P = 0.045; and median, 2.7%; range, 0.5-8.5 vs 0.6%; range, 0-0.8 %, P = 0.0036, respectively). No differences were observed in BAL fluid. CONCLUSION: We conclude that hyperresponsiveness to AMP in COPD is associated with airway inflammation that is characterized by increased numbers of mucosal CD8 + cells and percentages of sputum eosinophils. Hyperresponsiveness to AMP may be used as a marker of airway inflammation in COPD, but its significance in the clinical course remains to be determined.     

Autoimmunity in chronic obstructive pulmonary disease: clinical and experimental evidence

Over the past few decades, neutrophils and macrophages had co-occupied center stage as the critical innate immune cells underlying the pathobiology of cigarette smoke-induced chronic obstructive pulmonary disease and lung parenchymal destruction (i.e., emphysema). While chronic exposure to smoke facilitates the recruitment of innate immune cells into the lung, a clear role for adaptive immunity in emphysema has emerged. Evidence from human studies specifically point to a role for recruitment and activation of pathogenic lymphocytes and lung antigen-presenting cells in emphysema; similarly, animal models have confirmed a significant role for autoimumnity in progressive smoke-induced emphysema. Increased numbers of activated antigen-presenting cells, Th1 and Th17 cells, have been associated with smoke-induced lung inflammation and production of the canonical cytokines of these cells, IFN-γ and IL-17, correlates with disease severity. These exciting new breakthroughs could open new avenues for developing effective new therapies for smoke-induced emphysema.     

聚乙二醇化干扰素α-2a对慢性乙型肝炎患者外周血T淋巴细胞亚群的影响

目的 动态观察慢性乙型肝炎患者(CHB)聚乙二醇化干扰素α-2a治疗过程中外周血T淋巴细胞亚群的变化及其临床意义.方法 给予52例CHB患者聚乙二醇化干扰素α-2a (PEG-IFNa-2a)抗病毒治疗48周.在治疗前、治疗12和48周,分别以流式细胞术检测外周血淋巴细胞亚群百分比和数量,全自动生化分析仪检测谷丙转氨酶...     

Wasp venom immunotherapy induces a shift from IL-4-producing towards interferon-gamma-producing CD4+ and CD8+ T lymphocytes

BACKGROUND: Venom immunotherapy (VIT) has proven to be very effective in hymenoptera venom anaphylaxis. However, the underlying immunoregulatory mechanisms of venom immunotherapy remain poorly understood. Recent studies measured the total amount of cytokine in culture supernatans, suggesting a shift in cytokine production from Th2 to a Th1 cytokine profile during VIT. We wanted to examine the contribution of specific T lymphocyte subpopulations, which is impossible using an extracellular method to determine cytokines in supernatants. OBJECTIVE: The present study was designed to evaluate the effect of VIT on the percentages of type 1 (IL-2, interferon-gamma (IFN-gamma)) and type 2 (IL-4) CD4+ and CD8+ T lymphocytes of patients with wasp venom anaphylaxis during immunotherapy. METHODS: Peripheral blood mononuclear cells of 20 individuals with a history of wasp sting anaphylaxis and a positive serum wasp venom specific IgE were isolated and in vitro stimulated with phorbol-12-myristate-13-acetate and ionomycin before VIT, at the end of a 5-day semirush VIT and at 6 months during VIT. Three-colour flow cytometric analysis was used for intracellular cytokine (IL-2, IFN-gamma, IL-4) detection in CD4+ (CD3+CD8-) T lymphocytes and CD8+ (CD3+CD8+) T lymphocytes. RESULTS: At the end of a 5-day semirush VIT, there was a significant decrease in percentage of IL-4-producing CD4+ and CD8+ T cells, compared with cytokine-producing cells before VIT (P = 0.0002 and 0.004). After 6 months of VIT, patients showed an increased number of IL-2-producing stimulated CD4+ and CD8+ lymphocytes compared with values before VIT (P = 0.002 and P = 0.0003). A higher amount of IFN-gamma-producing stimulated CD4+ and CD8+ cells was found after 6 months of VIT (P = 0.001 and P = 0.0006). There was no correlation between cytokine-producing cells and specific IgE for wasp. CONCLUSION: Venom immunotherapy induced a shift from IL-4-producing towards IFN-gamma-producing CD4+ as well as CD8+ T lymphocytes.     

Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles

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