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1.  Regulation of IL-17A responses in human airway smooth muscle cells by Oncostatin M 
Respiratory Research  2015;16(1):14.
Regulation of human airway smooth muscle cells (HASMC) by cytokines contributes to chemotactic factor levels and thus to inflammatory cell accumulation in lung diseases. Cytokines such as the gp130 family member Oncostatin M (OSM) can act synergistically with Th2 cytokines (IL-4 and IL-13) to modulate lung cells, however whether IL-17A responses by HASMC can be altered is not known.
To determine the effects of recombinant OSM, or other gp130 cytokines (LIF, IL-31, and IL-6) in regulating HASMC responses to IL-17A, assessing MCP-1/CCL2 and IL-6 expression and cell signaling pathways.
Cell responses of primary HASMC cultures were measured by the assessment of protein levels in supernatants (ELISA) and mRNA levels (qRT-PCR) in cell extracts. Activation of STAT, MAPK (p38) and Akt pathways were measured by immunoblot. Pharmacological agents were used to assess the effects of inhibition of these pathways.
OSM but not LIF, IL-31 or IL-6 could induce detectable responses in HASMC, elevating MCP-1/CCL2, IL-6 levels and activation of STAT-1, 3, 5, p38 and Akt cell signaling pathways. OSM induced synergistic action with IL-17A enhancing MCP-1/CCL-2 and IL-6 mRNA and protein expression, but not eotaxin-1 expression, while OSM in combination with IL-4 or IL-13 synergistically induced eotaxin-1 and MCP-1/CCL2. OSM elevated steady state mRNA levels of IL-4Rα, OSMRβ and gp130, but not IL-17RA or IL-17RC. Pharmacologic inhibition of STAT3 activation using Stattic down-regulated OSM, OSM/IL-4 or OSM/IL-13, and OSM/IL-17A synergistic responses of MCP-1/CCL-2 induction, whereas, inhibitors of Akt and p38 MAPK resulted in less reduction in MCP-1/CCL2 levels. IL-6 expression was more sensitive to inhibition of p38 (using SB203580) and was affected by Stattic in response to IL-17A/OSM stimulation.
Oncostatin M can regulate HASMC responses alone or in synergy with IL-17A. OSM/IL-17A combinations enhance MCP-1/CCL2 and IL-6 but not eotaxin-1. Thus, OSM through STAT3 activation of HASMC may participate in inflammatory cell recruitment in inflammatory airway disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0164-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4332894
Asthma; Cytokines; Chemokines; STAT signaling; Oncostatin M; Airway smooth muscle
2.  Upregulation of IL-17A/F from human lung tissue explants with cigarette smoke exposure: implications for COPD 
Respiratory Research  2014;15(1):145.
Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder marked by relative resistance to steroids. The IL-17 superfamily, which mediates cross-talk between the adaptive and innate immune systems, has been associated with diminished responses to steroids. Increasing evidence supports elevated IL-17 expression in the lung of COPD subjects. However, whether cells of the immune system (systemic) and/or local lung cells are contributing to the elevated IL-17 remains unclear. To address this issue, we utilized a human parenchymal lung tissue explant culture system with cigarette smoke exposure to investigate the expression of IL-17 and the mechanisms involved.
Parenchymal lung tissue removed from 10 non-COPD and 8 COPD patients was sectioned and cultured with different concentrations of cigarette smoke extract (CSE) for 3 or 6 hours. Tissue viability was evaluated by LDH (lactate dehydrogenase) in culture supernatants. Western blot and real-time PCR were performed to evaluate IL-17A/F expression. To investigate the mechanisms, pharmacological inhibitors for MAPK p38, ERK1/2, NF-κB and PI3K pathways were added into the culture media.
No tissue damage was observed after the cigarette smoke exposure for 3 h or 6 h compared with the control media. At the protein level, the expression of both IL-17A (2.4 ± 0.6 fold) and IL-17 F (3.7 ± 0.7 fold) in the tissue from non-COPD subjects was significantly increased by 5% of CSE at 3 h. For COPD subjects, IL-17A/F expression were significantly increased only at 6 h with 10% of CSE (IL-17A: 4.2 ± 0.8 fold; IL-17 F: 3.3 ± 0.8 fold). The increased expression of IL-17A/F is also regulated at the mRNA level. The inhibitors for NF-κB and PI3K pathways significantly inhibited CSE-induced IL-17A/F expression from lung tissue of non-COPD subjects.
We found the evidence that the expression of both IL-17A and IL-17 F is increased by the cigarette smoke exposure in explants from both non-COPD and COPD subjects, supporting that local lung cells contribute IL-17 production. The elevated IL-17A/F expression is dependent on NF-κB and PI3K pathways. These observations add to the growing evidence which suggests that Th17 cytokines play a significant role in COPD.
PMCID: PMC4268887  PMID: 25427574
COPD; IL-17; Cigarette smoke; Tissue explants
4.  Eosinophil Peroxidase in Sputum Represents a Unique Biomarker of Airway Eosinophilia 
Allergy  2013;68(9):1177-1184.
Sputum eosinophilia has been shown to be a predictor of asthma patient response to therapies. However, quantitative cell counts and differentials of sputum are labor intensive. The objective of this study was to validate a novel ELISA-based assay of eosinophil peroxidase (EPX) in sputum as a rapid and reliable marker of airway eosinophils.
The utility of EPX-based ELISA as an eosinophil-specific assay was achieved through comparisons with sputum eosinophil differential counts in freshly prepared and archived patient samples from a variety of clinical settings.
EPX levels in sputum correlated with eosinophil percentage (rs=0.84) in asthma patients with varying degrees of airway eosinophilia. Significantly, unlike assays of other eosinophil granule proteins (e.g., ECP and EDN), which often detect the presence of these proteins even in asthma patients with neutrophilic bronchitis, EPX-based ELISA levels are not increased in this subset of asthma patients or in COPD patients lacking evidence of an airway eosinophilia. Moreover, sputum EPX was a surrogate marker of airway eosinophilia in other patient studies (e.g., allergen inhalation and treatment trials the anti-(IL-5) therapeutic Mepolizumab™). Finally, EPX levels in cyto-centrifuged prepared sputum supernatants correlated with those from rapidly prepared non-centrifuged filtrates of sputum (rs 0.94).
EPX-based ELISA is a valid, reliable, repeatable, and specific surrogate marker of eosinophils and/or eosinophil degranulation in the sputum of respiratory patients.
PMCID: PMC3788081  PMID: 23931643
Sputum Eosinophils; EPX; ELISA; Asthma; COPD
5.  Lipid mediator serum profiles in asthmatics significantly shift following dietary supplementation with omega-3 fatty acids 
Molecular nutrition & food research  2013;57(8):1378-1389.
In contrast to well-characterized polyunsaturated fatty acid (PUFA) levels in serum, little is known regarding their downstream metabolic products. However, many of these compounds are lipid mediators with prominent roles during pro- and anti-inflammatory processes.
Methods and Results
In this double blind crossover study on asthmatics, shifts in serum levels of ω-3 and ω-6 PUFA-derived oxidized fatty acids (e.g., eicosanoids, oxylipins) were quantified following dietary fish oil supplementation. Serum was obtained from subjects following fasting at 3 occasions; 1) Prior to supplementation, 2) Following a 3-week supplement intake of either placebo or fish oil, and 3) Following a 3-week washout period with a subsequent 3-week period of either fish oil or placebo supplement. A total of 87 oxylipins representing cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) metabolic pathways were screened via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The primary alterations observed were in CYP- and 15-LOX-derived EPA- and CYP-derived DHA oxylipins.
The results indicate that intake of an ω-3 rich diet altars not only the PUFA ratio, but also the ratio of downstream oxylipins. These data further support that dietary manipulation with ω-3 PUFAs affects not only PUFA levels, but importantly also the downstream metabolic profile.
PMCID: PMC3943463  PMID: 23824870
asthma; eicosanoid; lipidomics; omega-3; oxylipin
6.  Sputum Hyaluronan and Versican in Severe Eosinophilic Asthma 
We examined levels of hyaluronan, a matrix glycosaminoglycan and versican, a matrix proteoglycan, in the sputum of asthmatics treated with mepolizumab (anti-IL-5 mAb) versus placebo to evaluate the utility of these measurements as possible biomarkers of asthma control and airway remodeling.
Severe, prednisone-dependent asthmatics received either mepolizumab or placebo as described in a previously published randomized, double blind, placebo controlled study. We measured hyaluronan and versican levels by enzyme-linked immunosorbent assay (ELISA) in sputum collected before and after the 16-week treatment phase. Patients underwent a predefined prednisone tapering schedule if they remained exacerbation free and sputum eosinophil percentage, asthma control questionnaire (ACQ) and spirometry were monitored.
After 6 months of mepolizumab therapy and prednisone tapering there was a significant increase in sputum hyaluronan in the placebo group compared with baseline (P=0.003). In contrast, there was a significant decrease in sputum hyaluronan in the active treatment group compared with placebo (P=0.007) which correlated with improvements in FEV1% (P=0.001) and ACQ scores (P=0.009) as well as a decrease in sputum eosinophils (P=0.02). There was a non-significant increase in sputum versican in the placebo group (P=0.16), a decrease in the mepolizumab group (P=0.13) and a significant inverse correlation between versican reduction and FEV1% improvement (P=0.03).
Sputum hyaluronan values are reduced with mepolizumab therapy and correlate with improved clinical and spirometry values suggesting this measurement may serve as a non-invasive biomarker of asthma control.
PMCID: PMC4059000  PMID: 23257685
7.  Persistence of pulmonary tertiary lymphoid tissues and anti-nuclear antibodies following cessation of cigarette smoke exposure 
Respiratory Research  2014;15(1):49.
Formation of pulmonary tertiary immune structures is a characteristic feature of advanced COPD. In the current study, we investigated the mechanisms of tertiary lymphoid tissue (TLT) formation in the lungs of cigarette smoke-exposed mice. We found that cigarette smoke exposure led to TLT formation that persisted following smoking cessation. TLTs consisted predominantly of IgM positive B cells, while plasma cells in close proximity to TLTs expressed IgM, IgG, and IgA. The presence of TLT formation was associated with anti-nuclear autoantibody (ANA) production that also persisted following smoking cessation. ANAs were observed in the lungs, but not the circulation of cigarette smoke-exposed mice. Similarly, we observed ANA in the sputum of COPD patients where levels correlated with disease severity and were refractory to steroid treatment. Both ANA production and TLT formation were dependent on interleukin-1 receptor 1 (IL-1R1) expression. Contrary to TLT and ANA, lung neutrophilia resolved following smoking cessation. These data suggest a differential regulation of innate and B cell-related immune inflammatory processes associated with cigarette smoke exposure. Moreover, our study further emphasizes the importance of interleukin-1 (IL-1) signaling pathways in cigarette smoke-related pulmonary pathogenesis.
PMCID: PMC4021094  PMID: 24754996
Tertiary lymphoid tissue; Autoantibodies; Autoimmunity; COPD; Experimental model; Inflammation
8.  Update on clinical inflammometry for the management of airway diseases 
Airway inflammation is a central feature of many airway diseases such as asthma, chronic bronchitis, bronchiectasis and chronic cough; therefore, it is only logical that it is measured to optimize its treatment. However, most treatment recommendations, including the use of anti-inflammatory therapies such as corticosteroids, are based on assessments of only airflow and symptoms. Over the past 10 years, methods have been developed to assess airway inflammation relatively noninvasively. Quantitative cell counts in sputum and the fraction of exhaled nitric oxide are the most validated tests. Judicious use of currently available drugs, such as corticosteroids, bronchodilators and antibiotics, and other anti-inflammatory therapies guided by sputum eosinophil and neutrophil counts, have been demonstrated to decrease exacerbations of asthma and chronic obstructive pulmonary disease, ameliorate cough, improve quality of life in patients with these diseases and is cost effective compared with treatment strategies based on guidelines that do not incorporate these measurements. Thus, it is unfortunate that this is not used more widely in the management of airway diseases, particularly in patients with severe asthma and chronic obstructive pulmonary disease who experience frequent exacerbations.
PMCID: PMC3630046  PMID: 23616969
Asthma; COPD; Cough; Exhaled nitric oxide; Inflammometry; Sputum
9.  Quantitative sputum cell counts to monitor bronchitis: A qualitative study of physician and patient perspectives 
Many common diseases affecting the airways are characterized by airway inflammation. The measurement of this inflammation has a significant role in the management of these diseases. Quantitative sputum cell counts provide a measurement of the type and severity of inflammation present. Sputum cell counts are used in routine clinical practice in some centres but their use is not widespread. The present study used a standardized questionnaire to determine both patients’ and physicians’ attitudes toward the use of sputum cell counts. The use of sputum cell counts was well accepted by patients and physicians. Ninety per cent of patients were satisfied with the test. Sixty per cent of family physicians were satisfied with the test and 80% were in favour of it being funded by the government. The authors recommend more widespread use of sputum cell counts to guide the management of airway diseases.
PMCID: PMC3628647  PMID: 23457675
Asthma; Bronchitis; Patient satisfaction; Sputum cell counts; Willingness to pay
10.  A Sensitive High Throughput ELISA for Human Eosinophil Peroxidase: A Specific Assay to Quantify Eosinophil Degranulation from Patient-derived Sources 
Journal of immunological methods  2012;384(1-2):10-20.
Quantitative high throughput assays of eosinophil-mediated activities in fluid samples from patients in a clinical setting have been limited to ELISA assessments for the presence of the prominent granule ribonucleases, ECP and EDN. However, the demonstration that these ribonucleases are expressed by leukocytes other than eosinophils, as well as cells of non-hematopoietic origin, limits the usefulness of these assays. Two novel monoclonal antibodies recognizing eosinophil peroxidase (EPX) were used to develop an eosinophil-specific and sensitive sandwich ELISA. The sensitivity of this EPX-based ELISA was shown to be similar to that of the commercially available ELISA kits for ECP and EDN. More importantly, evidence is also presented confirming that among these granule protein detection options, EPX-based ELISA is the only eosinophil-specific assay. The utility of this high throughput assay to detect released EPX was shown in ex vivo degranulation studies with isolated human eosinophils. In addition, EPX-based ELISA was used to detect and quantify eosinophil degranulation in several in vivo patient settings, including bronchoalveolar lavage fluid obtained following segmental allergen challenge of subjects with allergic asthma, induced sputum derived from respiratory subjects following hypotonic saline inhalation, and nasal lavage of chronic rhinosinusitis patients. This unique EPX-based ELISA thus provides an eosinophil-specific assay that is sensitive, reproducible, and quantitative. In addition, this assay is adaptable to high throughput formats (e.g., automated assays utilizing microtiter plates) using the diverse patient fluid samples typically available in research and clinical settings.
PMCID: PMC3432656  PMID: 22750539
EPX; eosinophilia; granule proteins; allergic inflammation
11.  The effects of rituximab on serum IgE and BAFF 
There are few treatment options for patients with severe atopic asthma. Antagonism of IgE is an effective strategy. We investigated, by utilizing serum samples from a clinical trial of Rituximab in patients with Idiopathic Thrombocytopenic Purpura, if B cell depletion would decrease serum IgE and therefore be a potential therapeutic option.
In a placebo-controlled randomized clinical trial of Rituximab, an anti-CD20 molecule, there were no significant differences in serum levels of IgE or BAFF levels between the two treatment groups at 3 or 6 months irrespective of the baseline serum IgE levels.
Since Rituximab did not significantly decrease serum IgE levels, this proof of concept study suggests that Rituximab may not be a useful treatment strategy for patients with severe IgE mediated disease.
PMCID: PMC3850905  PMID: 24219860
Anti-CD20; Rituximab; Immunoglobulin E; BAFF; Asthma
12.  Aryl Hydrocarbon Receptor-Dependent Retention of Nuclear HuR Suppresses Cigarette Smoke-Induced Cyclooxygenase-2 Expression Independent of DNA-Binding 
PLoS ONE  2013;8(9):e74953.
The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to man-made environmental toxicants, has emerged as an endogenous regulator of cyclooxygenase-2 (Cox-2) by a mechanism that is poorly understood. In this study, we first used AhR-deficient (AhR−/−) primary pulmonary cells, together with pharmacological tools to inhibit new RNA synthesis, to show that the AhR is a prominent factor in the destabilization of Cox-2 mRNA. The destabilization of Cox-2 mRNA and subsequent suppression of cigarette smoke-induced COX-2 protein expression by the AhR was independent of its ability to bind the dioxin response element (DRE), thereby differentiating the DRE-driven toxicological AhR pathway from its anti-inflammatory abilities. We further describe that the AhR destabilizes Cox-2 mRNA by sequestering HuR within the nucleus. The role of HuR in AhR stabilization of Cox-2 mRNA was confirmed by knockdown of HuR, which resulted in rapid Cox-2 mRNA degradation. Finally, in the lungs of AhR−/− mice exposed to cigarette smoke, there was little Cox-2 mRNA despite robust COX-2 protein expression, a finding that correlates with almost exclusive cytoplasmic HuR within the lungs of AhR−/− mice. Therefore, we propose that the AhR plays an important role in suppressing the expression of inflammatory proteins, a function that extends beyond the ability of the AhR to respond to man-made toxicants. These findings open the possibility that a DRE-independent AhR pathway may be exploited therapeutically as an anti-inflammatory target.
PMCID: PMC3785509  PMID: 24086407
13.  Proximity to major roadways is a risk factor for airway hyper-responsiveness in adults 
Proximity to major roads is reported to be associated with asthma and airway hyper-responsiveness in children. Similar studies using objective measurements in adults are not available in Canada.
To test the hypothesis that adult asthmatic patients who live close to major roads and highways in an urban environment are at a risk of moderate to severe airway hyper-responsiveness.
Airway responsiveness was determined using methacholine bronchial provocation (PC20) tests in a cohort of 2625 patients who attended an outpatient clinic in Hamilton, Ontario. Patient addresses were geocoded in a geographic information system to determine proximity to major roads and highways. Multivariate linear and multinomial regression analyses were used to assess whether proximity to roads was a risk factor for airway hyper-responsiveness as measured by PC20 methacholine.
Patients who lived within 200 m of a major road had increased odds (OR 1.38 [95% CI 1.04 to 1.85]) of having moderate airway hyper-responsiveness (0.25 mg/mL 16 mg/mL). Spatial analysis also revealed that the majority of patients with severe airway hyper-responsiveness lived within the urban core of the city while those with moderate to mild hyper-responsiveness were also dispersed in rural areas.
In an adult population of patients attending an outpatient respiratory clinic in Hamilton, living close to major roadways was associated with an increased risk of moderate airway hyper-responsiveness. This correlation suggests that exposure to traffic emissions may provoke the pathology of airway hyper-responsiveness leading to variable airflow obstruction.
PMCID: PMC3373287  PMID: 22536577
Air pollution; Airway responsiveness; Asthma; Road traffic; Spatial analysis
14.  Cystic fibrosis transmembrane conductance regulator gene abnormalities in patients with asthma and recurrent neutrophilic bronchitis 
The present case series describes four patients with asthma, airway hyper-responsiveness and neutrophilic bronchitis who harboured abnormal cystic fibrosis transmembrance conductance regulator (CFTR) gene mutations. It serves both to alert clinicians to consider CFTR-related disease in both young and elderly patients with persistent neutrophilic bronchitis, and to highlight the potential utility of future genetic testing for CFTR abnormalities in patients with asthma and recurrent bronchitis or pansinusitis, and the role of nebulized hypertonic saline as a therapeutic option in these patients.
PMCID: PMC3299051  PMID: 22332135
Asthma; CFTR gene mutations; Neutrophilic bronchitis; Sputum
15.  Local and systemic immunological parameters associated with remission of asthma symptoms in children 
The immunological and clinical parameters that are associated with asthma remission are poorly understood. The cytokine and local mediator changes associated with the resolution of asthma symptoms were examined in three groups of subjects 12–18 years of age (n = 15 in each group): (a) continuing asthma group (CA) who had persistent symptoms since early childhood, (b) an age, sex and atopic status-matched group who had persistent symptoms in early childhood but in whom these had resolved (RA), and (c) a non-atopic, non-asthmatic control group. Clinical parameters, sputum cell counts, peripheral blood mononuclear cell (PBMC) cytokine production and activation marker expression were determined. All of the CA had methacholine airway hyperresponsiveness compared with only half of the RA subjects. The CA showed elevated numbers of eosinophils and increased ECP and IL-5 in sputum, which were not observed in the RA. PBMC cytokine studies revealed increased production of the type 1 cytokines IL-12, IFN-γ and TNF-α in the CA group compared with the RA group, under a range of activation conditions, however, the production of IL-4 and IL-5 were unchanged. These findings suggest that decreased type 1 cytokine expression as well as decreased eosinophilic inflammation is associated with the resolution of asthma symptoms.
PMCID: PMC3599667  PMID: 23043798
Asthma in children; Eosinophils; IL-5; TNF-α; IL-12
16.  Effects of a short course of inhaled corticosteroids in noneosinophilic asthmatic subjects 
Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS).
To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS.
A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 μg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count ≤2%. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 μg/salmeterol 50 μg, twice daily for all subjects.
After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n=6) (decrease of 1.0±0.5) compared with the placebo group (n=6) (decrease of 0.09±0.4) (P=0.008). Forced expiratory volume in 1 s declined in the placebo group (−0.2±0.2 L) and did not change in the ICS group (0.04±0.1 L) after four weeks of treatment (P=0.02). The open-label treatment with fluticasone propionate 250 μg/salmeterol 50 μg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone.
A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.
PMCID: PMC3267606  PMID: 21969930
Asthma; Asthma Control Questionnaire; Eosinophils; Sputum cell counts
18.  Persistent sputum cellularity and neutrophils may predict bronchiectasis 
The clinical utility of using quantitative cell counts in sputum for the evaluation of obstructive airway diseases has been previously demonstrated. Although neutrophil counts and activation products have been reported to increase in the sputum of patients with bronchiectasis, it is not known whether these are predictive parameters. This study aimed to assess the accuracy and measurement properties of quantitative sputum cell counts to identify bronchiectasis detected by high-resolution computed tomography scans of the thorax. If validated in larger prospective studies, these parameters may decrease the need for high-resolution scans to detect bronchiectasis and limit radiation exposure.
Quantitative cell counts in sputum provide an accurate assessment of the type and severity of bronchitis.
To examine whether sputum cell counts could identify bronchiectasis in patients with recurrent bronchitis.
A retrospective survey of a clinical database (January 2004 to January 2005) of quantitative cell counts from sputum selected from expectorate in patients with obstructive airways diseases was used to identify predictors of bronchiectasis using ROC curves. This was prospectively evaluated (February 2005 to April 2008) using high-resolution computed tomography scans of thorax that were independently scored by a radiologist who was blinded to the clinical details.
The retrospective survey identified 41 patients with bronchiectasis among 490 patients with airway diseases. Total cell count of 60×106/g or greater of the selected sputum with predominant neutrophils on two occasions had a sensitivity of 86.7%, a specificity of 87.5%, and positive and negative predictive values of 93% and 78%, respectively, to identify bronchiectasis. In the prospective study, 10 of 14 (71%) patients who met these criteria were identified to have bronchiectasis. Both total cell count and the percentage of neutrophils correlated with radiographic bronchiectasis severity.
Persistent or recurrent intense sputum cellularity with neutrophilia is suggestive of bronchiectasis.
PMCID: PMC3205103  PMID: 22059180
Bronchiectasis; Neutrophil; Sputum cell counts
19.  Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice 
Sputum cell counts have identified inflammatory subtypes of bronchitis in relatively small numbers of subjects with asthma, chronic obstructive pulmonary disease (COPD) and chronic cough in research studies. The prevalence of different subtypes of bronchitis in routine clinical practice, however, has not been reported.
To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction.
A retrospective cross-sectional survey based on a computerized database of spontaneous or induced sputum cell counts examined in a large university tertiary respiratory outpatient clinic.
The database contained 4232 consecutive sputum records from 2443 patients with chronic cough (39%), asthma (37%), asthma with COPD (9%), COPD (13%) and bronchiectasis (3%). Total and differential cell counts were obtained from 86% of successful sputum samples. Induced sputum provided more viable samples than spontaneous expectorate. Approximately one-third of patients with asthma and one-fifth of patients with COPD experience eosinophilic bronchitis. Asthmatic patients with moderate to severe airflow obstruction had a greater number of sputum eosinophils. There was a significantly higher number of total cell counts and percentage of neutrophils in the sputum of COPD patients with moderate and severe airflow obstruction than in those with mild airflow obstruction.
There is heterogeneity in the cellularity of sputum in various airway diseases. Patients with clinically stable airway diseases may have high sputum cell counts. During exacerbations, more patients may experience neutrophilic bronchitis. Severity of airflow obstruction is associated with eosinophilic bronchitis in patients with asthma, and neutrophilic bronchitis in patients with nonasthmatic COPD.
PMCID: PMC3328881  PMID: 21766077
Asthma; Bronchitis heterogeneity; Clinical practice; COPD; Sputum cell counts
20.  Association between proximity to major roads and sputum cell counts 
Air pollution caused by motor vehicle emissions has been associated with exacerbations of obstructive airway diseases; however, the nature of the resulting bronchitis has not been quantified.
To examine whether proximity to major roads or highways is associated with an increase in sputum neutrophils or eosinophils, and to evaluate the effect of proximity to roads on spirometry and exacerbations in patients with asthma.
A retrospective study of 485 sputum cell counts from patients attending a tertiary chest clinic in Hamilton, Ontario, identified eosinophilic or neutrophilic bronchitis. Patients’ residences were geocoded to the street network of Hamilton using geographic information system software. Associations among bronchitis, lung function, and proximity to major roads and highways were examined using multinomial logistic and multivariate linear regression analyses adjusted for patient age, smoking status and corticosteroid medications.
Patients living within 1000 m of highways showed an increased risk of bronchitis (OR 3.8 [95% CI 1.0 to 13.7]; P<0.05), particularly neutrophilic bronchitis (OR 4.7 [95% CI 1.2 to 18.7]; P<0.05) as well as an increased risk of an asthma diagnosis (OR 1.9 [95% CI 1.0 to 3.4]; P<0.05). Patients living within 300 m of a major road were at increased risk for an asthma exacerbation (OR 1.9 [95% CI 1.5 to 15.5]; P<0.01) and lower lung function, particularly in women (P=0.036).
In patients with airway diseases, living close to a highway or major road was associated with neutrophilic bronchitis, an increased risk of asthma diagnosis, asthma exacerbations and lower lung function.
PMCID: PMC3071007  PMID: 21369545
Asthma; Bronchitis; Exacerbations; Geospatial analysis; Road traffic; Sputum cell counts
21.  The identification of eosinophilic gastroenteritis in prednisone-dependent eosinophilic bronchitis and asthma 
This case reports the unique association of eosinophilic gastrointestinal disease with eosinophilic bronchitis, asthma and chronic rhinosinusitis and some features of lymphocytic hypereosinophilic syndrome, describes a diagnostic protocol for patients with asthma and persistent eosinophilic bronchitis, and suggests that the use of a novel EPX-mAb provides a reliable method to identify eosinophilic inflammation.
PMCID: PMC3060837  PMID: 21362188
22.  Reproducibility, validity, and responsiveness of cell counts in blown nasal secretions 
Allergy & Rhinology  2011;2(1):3-5.
Cell counts in nasal secretions are not used in routine clinical practice to decide on anti-inflammatory or antimicrobial therapy. This study investigated the reproducibility, reliability (validity), and responsiveness of cell counts in blown nasal secretions with a view to implementing this in routine clinical practice. Nasal secretions were obtained from 19 subjects with allergic rhinitis on 3 days in random order (each separated by 1–2 days) by spontaneously blowing their noses (on 2 days) and by a nasal lavage by the modified Grunberg method on the 3rd day. Total and differential cell counts were performed after dispersing the solutions with dithiothreitol as described previously. At the end of the study, subjects had 1 week of open label treatment with nasal corticosteroids if they had nasal eosinophilia or an antibiotic if they had nasal neutrophilia. If the cell counts were normal, they were not treated. The proportion of eosinophil (%) was highly reproducible (intraclass correlation coefficient [ICC], 0.93), and the total cell count (×106/g) and the proportion of neutrophil (%) were modestly reproducible in blown nasal secretions (ICC, 0.46 and 0.55, respectively). The total cell count was consistently and significantly higher in the blown nasal secretions. The proportion of eosinophils (Rs = 0.4; p < 0.05) and neutrophils (Rs = 0.6; p < 0.05) showed modest correlation in the two types of samples. The responsiveness index for eosinophil count was 4.0 and for neutrophil count was 1.5. Total and differential cell counts can be reliably and reproducibly obtained from spontaneously blown nasal secretions. The cell counts are responsive to treatment and can help identify allergic and infective rhinosinusitis and guide therapy and are easy to implement in routine clinical practice.
PMCID: PMC3390126  PMID: 22852107
Blown nasal secretions; cell counts; nasal lavage; repeatability; validity
23.  Cost analysis of monitoring asthma treatment using sputum cell counts 
In a four-centre trial, the use of sputum cell counts (sputum strategy [SS]) to guide treatment had resulted in fewer and less severe exacerbations without the need for a higher corticosteroid dose, compared with the use of symptoms and spirometry (clinical strategy [CS]).
To compare the cost of the SS with the CS in the treatment of patients with moderate to severe asthma.
In 39 patients (19 in the SS, 20 in the CS) from one of the centres, the cost (third-party payer) of the two treatment strategies was compared. Resource use data were collected using a structured questionnaire. Corresponding unit costs in 2006 Canadian dollars were obtained.
The clinical characteristics of the patients were similar to the study population at the four centres. In the SS, the number of visits to a family physician for health disorders indirectly related to asthma (P=0.003) and the amount of inhaled long-acting beta-agonists (P=0.007) were less than that of the CS. While the total estimated median cost per patient for spirometry ($393; range $299 to $487) was less than that for sputum induction ($1,008; range $907 to $1,411), the total cost of the SS ($2,265; range $1,466 to $4,347) was less than that of the CS ($3369; range $2208 to $3927) (P=0.216). This cost difference was due to lower costs of physician and hospital visits and services (P=0.078), of inhaled short-acting bronchodilators (P=0.067), of long-acting beta-agonists (P=0.002) and of inhaled corticosteroids (P=0.064) in the SS.
In patients with moderate to severe asthma, the use of sputum cell counts to guide treatment is more effective and is likely to be less costly than management using symptoms and spirometry.
PMCID: PMC2679573  PMID: 18949107
Asthma; Cost; Spirometry; Sputum cell counts; Symptoms

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