Mepolizumab for prednisone-dependent asthma with sputum eosinophilia.

BACKGROUND: Eosinophilic inflammation, which may be a consequence of interleukin-5 action, is a characteristic feature of some forms of asthma. However, in three previous clinical trials involving patients with asthma, blockade of this cytokine did not result in a significant improvement in outcomes. We studied the prednisone-sparing effect of mepolizumab, a monoclonal antibody against interleukin-5, in a rare subgroup of patients who have sputum eosinophilia and airway symptoms despite continued treatment with prednisone. Secondary objectives were to examine its effect on the number of eosinophils in sputum and blood, symptoms, and airflow limitation. METHODS: In this randomized, double-blind, parallel-group trial involving patients with persistent sputum eosinophilia and symptoms despite prednisone treatment, we assigned 9 patients to receive mepolizumab (administered in five monthly infusions of 750 mg each) and 11 patients to receive placebo. RESULTS: There were 12 asthma exacerbations in 10 patients who received placebo, 9 of whom had sputum eosinophilia at the time of exacerbation. In comparison, only one patient who received mepolizumab had an asthma exacerbation, and this episode was not associated with sputum eosinophilia (P=0.002). Patients who received mepolizumab were able to reduce their prednisone dose by a mean (+/-SD) of 83.8+/-33.4% of their maximum possible dose, as compared with 47.7+/-40.5% in the placebo group (P=0.04). The use of mepolizumab was associated with a significant decrease in the number of sputum and blood eosinophils. Improvements in eosinophil numbers, asthma control, and forced expiratory volume in 1 second were maintained for 8 weeks after the last infusion. There were no serious adverse events. CONCLUSIONS: Mepolizumab reduced the number of blood and sputum eosinophils and allowed prednisone sparing in patients who had asthma with sputum eosinophilia despite prednisone treatment. (ClinicalTrials.gov number, NCT00292877.)

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.

Airway responsiveness to indirect challenges in COPD.

Patients with chronic obstructive pulmonary disease (COPD) demonstrate airway hyperresponsiveness to a number of indirect stimuli. Hyperresponsiveness to cold air hyperventilation, exercise, and drugs like propranalol and methoxamine seem to be able to distinguish patients with COPD from those with asthma, whereas hyperresponsiveness to stimuli like adenosine 5-monophosphate (AMP) and hypertonic saline seem unable to do so. The relationship of airway responsiveness to indirect stimuli and airway inflammation has received little study. The clinical relevance of hyperresponsiveness to an indirect challenge, including the impact on the natural history, relation to types of bronchitis, baseline airway calibre, and response to treatment need to be studied.

Quantitative sputum cell counts as a marker of airway inflammation in clinical practice.

PURPOSE OF REVIEW: Bronchitis, meaning airway inflammation, is an important component of airway disease. Yet respirologists and allergists, who have stressed the importance of measurements of airway function, have been slow to introduce airway inflammation measurements into clinical practice. Of the measurements available, quantitative sputum cell counts have the most clinical value. This article provides additional information on this topic from studies published in 2005 and 2006. RECENT FINDINGS: Airway diseases are heterogeneous within patients in terms of the disease present and the type of airway inflammation. Quantitative sputum cell counts (total cell count as well as the differential) identify noneosinophilic, mainly neutrophilic, probably infective exacerbations as common in patients with asthma and chronic obstructive pulmonary disease that may be unresponsive to corticosteroid treatment. In contrast, measurements of sputum eosinophils can be used to guide the minimum dose of corticosteroid required to control eosinophilic bronchitis and reduce eosinophilic exacerbations. SUMMARY: Measurements of quantitative sputum cell counts need to be made available, initially by tertiary care centres, to diagnose bronchitis in airway disease and to optimize treatment. Examination of how these are complemented by indirect measures of airway inflammation, specifically exhaled nitric oxide and airway hyperresponsiveness to stimuli acting indirectly through mediator release, requires further investigation.

Changing pattern of sputum cell counts during successive exacerbations of airway disease.

BACKGROUND: Exacerbations of airway disease are eosinophilic, neutrophilic, both or neither, and this determines the treatment needed. We examined changes in the cellular nature of airway inflammation between consecutive exacerbations and their predictors in individual patients. METHODS: In a retrospective survey of 1786 consecutive sputum cell counts from 1139 patients with airway disease, we identified 79 patients with two or more exacerbations at an interval of >or=6 weeks. The patients were divided into those who demonstrated a change in the type of airway inflammation and those who did not. RESULTS: There were 186 exacerbations of airway disease over 22 months. The cellular nature of inflammation was eosinophilic in 43%, neutrophilic in 40%, combined eosinophilic and neutrophilic in 5% and unclassified in 12%. A change in the type of airway inflammation was seen in 38 patients (48%). Patients, whose previous exacerbation was eosinophilic or neutrophilic were twice or nearly three times more likely, respectively, to have a subsequent exacerbation of the same type. There was no significant difference in the time to the second exacerbation or the inflammatory type of the second exacerbation in relation to the first exacerbation, irrespective of the cellular nature of the first exacerbation. CONCLUSIONS: Quantitative sputum cell counts during successive exacerbations identify that they are commonly of different type, reflecting different causes and the need for different treatment. Their use, when available, helps to optimize therapy.

Sputum neutrophilia can mask eosinophilic bronchitis during exacerbations.

BACKGROUND: Exacerbations of airway disease are eosinophilic, neutrophilic, both or neither. The primary objective of the present study was to identify whether the treatment of a neutrophilic bronchitis can unmask an associated eosinophilia. METHODS: A retrospective survey of 2160 consecutive sputum cell counts from 1343 patients with airway disease was conducted to identify patients with an isolated neutrophilic bronchitis, which was defined as a sputum total cell count of greater than or equal to 12 x 10(6) cells/g of sputum and a proportion of neutrophils of 80% or greater. The characteristics of the patients who subsequently demonstrated sputum eosinophilia (3% or greater) within eight weeks of resolving the neutrophilia were compared with the patients who subsequently did not have sputum eosinophilia. RESULTS: Two hundred thirty-seven patients had 273 neutrophilic exacerbations. The sputum was re-examined within eight weeks in 65 patients (27.4%), of whom 38 (58.5%) had resolution of the neutrophilic bronchitis after treatment with an antibiotic. Of these 38 patients, 13 (34%) showed eosinophilia. CONCLUSIONS: A neutrophilic exacerbation of airway disease was observed to mask sputum eosinophilia in one-third of patients who had sputum cell counts available before and after antibiotic therapy. Hence, the absence of sputum eosinophilia during an infective exacerbation should not be used as an indication to reduce the dose of corticosteroids. To optimize therapy, repeat sputum cell count measurements are recommended after antibiotic treatment before changing corticosteroid treatment.

The use of cellular and molecular biomarkers to manage COPD exacerbations.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) exacerbations are a common cause of respiratory morbidity and mortality, and have various etiologies. Multiple cellular and molecular biomarkers have been associated with exacerbations. Quantitative sputum cell counts are able to identify the presence and type of bronchitis, which is an important contributor to exacerbations. Their utility to monitor bronchitis and to help treat exacerbations has been evaluated, yet they are not used in routine clinical practice. Areas covered: This review will provide a brief summary of biomarkers utilized in COPD, with a focus on the application of cellular markers for the management of exacerbations. A case study will demonstrate the application of these methods. With quantitative sputum cell counts, the presence of eosinophilic bronchitis predicts corticosteroid-responsiveness, while neutrophilic bronchitis identifies infection and suggests the need for antibiotics. Gastroesophageal reflux-related aspiration and heart failure can also be identified by examining sputum. Expert commentary: Quantitative sputum cytometry is an essential tool in the management of exacerbations of COPD, particularly those prone to frequent exacerbations. Treatment based on sputum cell counts is superior to current guideline-based recommendations to prevent future exacerbations and hospitalizations in observational and single-centre controlled trials. Large multicentre clinical trials are necessary to confirm this.

Sputum cell counts to manage prednisone-dependent asthma: effects on FEV1 and eosinophilic exacerbations.

BACKGROUND: Prednisone dependence in asthma is usually described based on clinical and spirometric characteristics. It is generally believed that these patients have frequent exacerbations and lose lung function rapidly because of uncontrolled airway eosinophilia. OBJECTIVES: The objectives of this study are to report the effect on asthma exacerbations and the change in lung function over time in prednisone-dependent asthma when severe asthma is managed using a protocol that aims to maintain normal sputum cell counts. METHODS: A retrospective survey of patients prospectively assessed in a university tertiary care asthma clinic. RESULTS: 52 patients (30 males, mean age 51 years, 64% non-atopic) were followed for a median period of 5.4 years (min-max: 0.2-35.2). Monitoring with the aim of keeping sputum eosinophils below 3% resulted in higher doses of corticosteroids (median daily dose of prednisone was 10 mg and for inhaled corticosteroids was 1500 µg of fluticasone equivalent) than at baseline and this was associated with predictable adverse effects. Despite the disease severity, 10 patients (19%) did not require LABA for symptom control. Most importantly, over the period of follow-up, there were only 0.3 eosinophilic exacerbations/patient/year. Overall, there was an increase in FEV1 over the period of follow-up (mean +84.6 ml/year) rather than an expected decline. CONCLUSIONS: Monitoring of eosinophils in sputum enables to maintain symptom control and preserve FEV1 in patients with severe prednisone-dependent asthma.

Predictors of loss of asthma control induced by corticosteroid withdrawal.

BACKGROUND: Asthma guidelines recommend reducing the dose of inhaled corticosteroids after establishing control. OBJECTIVE: To identify predictors of loss of control and the kinetics of symptoms, and inflammatory and physiological measurements when inhaled corticosteroids are reduced in patients with stable asthma. PATIENTS AND METHODS: In a single-blind study, the daily dose of inhaled corticosteroid was reduced by one-half at intervals of 20+/-2 days in 17 adults with controlled asthma until loss of asthma control occurred or until the corticosteroid was replaced with placebo for 20 days. The patients recorded symptoms and peak expiratory flow each day, and forced expiratory volume in 1 s (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20), exhaled nitric oxide, and eosinophils in sputum and blood were measured every 10 days. A loss of asthma control was defined as a worsening of the symptoms score of at least 20%, and either a decrease in FEV1 of at least 15% or a decrease in PC20 of at least fourfold. RESULTS: Two patients had a respiratory infection and were withdrawn from the study. In eight patients, asthma became uncontrolled after a mean of 33 days (range 13 to 48 days). This was accurately reflected by a worsening of all parameters. The first parameter to change was the sputum eosinophil percentage (20 days before the loss of asthma control). Significant changes in exhaled nitric oxide, FEV1 and methacholine PC20 were observed only when the symptoms became uncontrolled. A high blood eosinophil count at baseline (risk ratio of 2.5, 95% CI 1.0 to 6.5) and an increase in sputum eosinophil count after the reduction of corticosteroids were predictors of loss of asthma control. CONCLUSION: In patients whose asthma is controlled on inhaled corticosteroid, it is prudent not to reduce the dose further if the blood eosinophils are increased or if the sputum eosinophils increase by as little as 1% after the reduction of corticosteroids.

Change in forced expiratory volume in 1 second after sham bronchoconstrictor in suggestible but not suggestion-resistant asthmatic subjects: a pilot study.

OBJECTIVE: Randomized controlled trials in asthma often demonstrate a benefit from placebo interventions, although no study has yet characterized this group of placebo responders. Literature points to the importance of suggestion in asthma, and we reasoned that patients' level of suggestibility might influence their likelihood of responding to placebo-like suggestion. METHODS: To determine whether suggestion differentially influenced airway tone in preselected suggestible compared with suggestion-resistant asthmatics, we performed a prospective, double-blind, crossover pilot study in which subjects were identified as being suggestible or suggestion-resistant using the Creative Imagination Scale. Responses to inhaled saline were assessed using FEV1 and a modified Borg scale after the suggestion that the saline was a bronchoconstrictor and subsequently a bronchodilator. RESULTS: Five of eight suggestible subjects compared with one of nine suggestion-resistant subjects demonstrated a fall in FEV1 greater than 150 ml in response to inhaled saline and suggestion of bronchoconstriction (p =.027). Fourteen subjects experienced dyspnea in response to sham bronchoconstrictor, but none reported increased dyspnea after sham bronchodilator. CONCLUSIONS: This is the first time that subjects with asthma have been categorized as suggestible or nonsuggestible with this distinction then used to predict response to an intervention. The results of this pilot study suggest that a subgroup of suggestible asthmatic patients is more likely to respond to a placebo-like sham bronchoconstriction challenge. The data support earlier observations that psychological factors may influence asthma, and provide insights into the placebo response.

Smoking, season, and detection of Chlamydia pneumoniae DNA in clinically stable COPD patients.

BACKGROUND: The prevalence and role of Chlamydia pneumoniae in chronic obstructive pulmonary disease (COPD) remain unclear, and molecular methods of detection may help clarify this relationship. METHODS: Consecutive clinically stable patients with smoking-related COPD attending a tertiary care outpatient clinic were enrolled in this cross-sectional study. Peripheral blood mononuclear cells were obtained from 100 patients, and induced sputum was obtained in 62 patients. C. pneumoniae DNA was detected in blood or sputum by nested polymerase chain reaction (PCR). RESULTS: Patients had mean age (standard deviation) of 65.8 (10.7) years, mean forced expiratory volume in one second (SD) of 1.34 (0.61) L, and 61 (61.0%) were male. C. pneumoniae nucleic acids were detected in 27 (27.0%) patients. Among 62 patients with both blood and sputum available, blood specimens were superior to induced sputum for detection of C. pneumoniae DNA (21 versus 7 detected, P=0.003). Current smoking (odds ratio [OR]=2.6, 95 % confidence interval [CI]: 1.1, 6.6, P=0.04), season (November to April) (OR=3.6, 95% CI: 1.4, 9.2, P=0.007), and chronic sputum production (OR=6.4, 95% CI: 1.8, 23.2, P=0.005) were associated with detection of C. pneumoniae DNA. CONCLUSIONS: C. pneumoniae DNA prevalence was higher among current smokers, and during winter/spring months. Prospective molecular studies are needed to examine the role of C. pneumoniae detection in COPD disease symptoms and progression.

Clinical models to compare the safety and efficacy of inhaled corticosteroids in patients with asthma.

There is no consensus on the methods to compare the clinical efficacy of different inhaled corticosteroids. A comparison needs to be made in terms of relative potency, and studies should include two-, or preferably, three-dose comparisons. A number of clinical models and outcomes are available; they have their relative advantages and disadvantages. While measurements of symptoms and spirometry are easy and readily available, they show a flat dose-response relationship. Measurements of bronchial hyper-responsiveness to exercise and adenosine monophosphate, allergen-induced airway responses, and measurements of inflammation in sputum and exhaled air show steep dose-response relationships, particularly to low doses of inhaled steroids. An uncontrolled asthma model followed by stabilization with a short course of additional steroid, with measurements of airway responsiveness and airway inflammation, in a crossover study seems more promising than the other models. Drug deposition studies and mathematical modelling of drug pharmacokinetics in the airway may provide complementary information to clinical drug relative potency studies. Fine particle dose and emitted doses, rather than the nominal dose, should be considered in the estimation of clinical and systemic effects, respectively. When a second entry (generic) drug is being evaluated in comparison with the innovator drug (same compound and same device), it may be appropriate to consider accepting a generic as bioequivalent if it satisfies pharmaceutical equivalence.

Reproducibility, validity, and responsiveness of cell counts in blown nasal secretions.

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 (R(s) = 0.4; p < 0.05) and neutrophils (R(s) = 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.

Association between proximity to major roads and sputum cell counts.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Heterogeneity of bronchitis in airway diseases in tertiary care clinical practice.

BACKGROUND: 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. OBJECTIVE: To examine the heterogeneity of bronchitis and its relationship to the severity of airflow obstruction. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Lipid and smoker's inclusions in sputum macrophages in patients with airway diseases.

We studied the effect of tobacco smoking on macrophage lipid index and macrophage smokers inclusions in induced sputum in 256 patients (143 non-smokers, 81 ex-smokers and 32 current smokers). Lipid index was, using the Oil red O stain, the sum of the lipid staining droplet score (range 0-4) in 100 macrophages. Smokers inclusions were assessed using Wright's stain and graded as "none", "few", "moderate" or "many". Lipid index was significantly higher in current smokers (112.5, SD 58.5 units) than ex-smokers (29.2, SD 42.8 units) or non-smokers (13.4, SD 121.7). Smokers inclusions were present in all current smokers but only in 2 non-smokers. The mean smoking history of current smokers with few macrophage inclusions was 15.0 (SD 11.2), moderate 21.6 (SD 15.7), and many 30.0 (SD 21.9) pack years. There was a significant difference between the length of time ex-smokers had quit smoking if they had no or few smokers inclusions (mean 17.6 (SD 11.2) years) compared to those with moderate or many smokers inclusions (mean 2.8 (SD 5.8) years) (p = 0.01). Lipid index was significantly correlated with smokers inclusions (r = 0.72, p < 0.01). We conclude that smoker's inclusions within sputum macrophages is a reliable indicator of cigarette smoking and that the sputum lipid index cannot be used as an assessment of oropharyngeal reflux in cigarette smokers.

Persistent sputum cellularity and neutrophils may predict bronchiectasis.

BACKGROUND: Quantitative cell counts in sputum provide an accurate assessment of the type and severity of bronchitis. OBJECTIVE: To examine whether sputum cell counts could identify bronchiectasis in patients with recurrent bronchitis. METHODS: 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. RESULTS: 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. CONCLUSIONS: Persistent or recurrent intense sputum cellularity with neutrophilia is suggestive of bronchiectasis.