Frederick E. Hargreave

Bronchial reactivity to inhaled histamine: a method and clinical survey

An easy and safe dose‐response histamine‐inhalation test is described, to measure the level of non‐specific bronchial reactivity.

Use of induced sputum cell counts to investigate airway inflammation in asthma.

BACKGROUND: Airway inflammation is considered to be important in asthma but is relatively inaccessible to study. Less invasive methods of obtaining sputum from patients unable to produce it spontaneously should provide a useful investigational tool in asthma. METHODS: A method to induce sputum with inhaled hypertonic saline was modified for use in 17 asthmatic patients and 17 normal subjects who could not produce sputum spontaneously. The success rate and safety of the method, the reproducibility of cell counts, and differences in cell counts between the asthmatic and normal groups were examined. Hypertonic saline solution 3-5% was inhaled for up to 30 minutes after inhalation of salbutamol. Subjects were asked to expectorate sputum every five minutes. The quality of the sample was scored on the volume of plugs and the extent of salivary contamination. Plugs from the lower respiratory tract were selected for a total cell count and for differential cell counts of eosinophils and metachromatic cells (mast cells and basophils) in direct smears. RESULTS: Adequate samples from the lower respiratory tract were obtained in 76% of first attempts. The mean fall in the forced expiratory volume in one second (FEV1) during inhalation of saline was 5.3% and the maximum fall 20%. Eosinophil and metachromatic cell counts were reproducible (reliability coefficient 0.8 and 0.7 respectively). When compared with sputum from normal subjects sputum from asthmatic patients contained a significantly higher proportion of eosinophils (mean 18.5% (SE 3.8%) v 1.9% (0.6%)) and metachromatic cells (0.50% (0.18%) v 0.039% (0.014%)). In the asthmatic group the differential eosinophil count correlated with the baseline FEV1. CONCLUSION: Induced sputum is capable of detecting differences in cell counts between normal and asthmatic subjects and merits further development as a potential means of assessing airway inflammation in asthma.

Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance☆

Bronchial responsiveness is the term used to describe the tendency of the airways to bronchoconstrict to specific stimuli such as allergens and isocyanates, which select a limited population of apparently sensitized subjects, and to nonspecific (nonallergic) stimuli, which affect most asthmatic persons. Specific bronchial responsiveness to allergic stimuli is difficult to quantitate because commonly available allergen extracts are not well standardized for the number and concentration of components. Nonspecific responsiveness can be quantitated by inhalation tests with histamine or methacholine, by exercise, or by isocapnic hyperventilation of cold air, and may be increased in asthma and other conditions such as chronic obstructive bronchitis and cystic fibrosis. In this article we will discuss the measurement of nonspecific bronchial responsiveness by inhalation tests with histamine or methacholine and its relationship to the occurrence and severity of asthma.

Reproducibility and comparison of responses to inhaled histamine and methacholine.

The efficiency of a standardised inhalation test procedure was studied by examining the reproducibility of responses to histamine and methacholine. In addition, the responses to the two agents were compared. Each set of duplicate tests was carried out on a separate day within one week, and all factors known or presumed to influence responses were carefully controlled. The results were expressed as the provocative concentration of the agent causing a 20% fall in forced expired volume in one second (PC20). Responses to histamine and methacholine were highly reproducible (coefficients of determination [r2] = 0.994 and 0.990 respectively). Responsiveness to histamine correlated closely with responsiveness to methacholine (r2 = 0.85). There was a small but significant cumulative dose effect with methacholine (P less than 0.01) but not with histamine. Side effects of throat irritation, flushing, and headache were more frequent with histamine than methacholine, and were dose-related. The high level of reproducibility indicates the efficiency of the test procedure. The similar severity of effects by agents with different mechanisms of action suggests that the primary cause of non-specific bronchial hyperreactivity lies at the level of bronchial smooth muscle.

Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines

Recognition of the importance of cough in clinical medicine was the impetus for the original evidence-based consensus panel report on “Managing Cough as a Defense Mechanism and as a Symptom,” published in 1998,1 and this updated revision. Compared to the original cough consensus statement, this revision (1) more narrowly focuses the guidelines on the diagnosis and treatment of cough, the symptom, in adult and pediatric populations, and minimizes the discussion of cough as a defense mechanism; (2) improves on the rigor of the evidence-based review and describes the methodology in a separate section; (3) updates and expands, when appropriate, all previous sections; and (4) adds new sections with topics that were not previously covered. These new sections include nonasthmatic eosinophilic bronchitis (NAEB); acute bronchitis; nonbronchiectatic suppurative airway diseases; cough due to aspiration secondary to oral/pharyngeal dysphagia; environmental/occupational causes of cough; tuberculosis (TB) and other infections; cough in the dialysis patient; uncommon causes of cough; unexplained cough, previously referred to as idiopathic cough; an empiric integrative approach to the management of cough; assessing cough severity and efficacy of therapy in clinical research; potential future therapies; and future directions for research.

Reslizumab for Poorly Controlled, Eosinophilic Asthma: A Randomized, Placebo-controlled Study

RATIONALE Eosinophilic asthma is a phenotype of asthma characterized by the persistence of eosinophils in the airways. IL-5 is involved in the activation and survival of eosinophils. OBJECTIVES To evaluate the effect of the antibody to IL-5, reslizumab, in patients with eosinophilic asthma that is poorly controlled with high-dose inhaled corticosteroid. METHODS Patients were randomly assigned to receive infusions of reslizumab at 3.0 mg/kg (n = 53) or placebo (n = 53) at baseline and at Weeks 4, 8, and 12, with stratification by baseline Asthma Control Questionnaire (ACQ) score less than or equal to 2 or greater than 2. The primary efficacy measure was the difference between the reslizumab and placebo groups in the change in ACQ score from baseline to end of therapy (Week 15 or early withdrawal). MEASUREMENTS AND MAIN RESULTS Mean changes from baseline to end of therapy in ACQ score were -0.7 in the reslizumab group and -0.3 in the placebo group (P = 0.054) and in FEV(1) were 0.18 and -0.08 L, respectively (P = 0.002). In those patients with nasal polyps, the changes in ACQ score were -1.0 and -0.1, respectively (P = 0.012). Median percentage reductions from baseline in sputum eosinophils were 95.4 and 38.7%, respectively (P = 0.007). Eight percent of patients in the reslizumab group and 19% of patients in the placebo group had an asthma exacerbation (P = 0.083). The most common adverse events with reslizumab were nasopharyngitis, fatigue, and pharyngolaryngeal pain. CONCLUSIONS Patients receiving reslizumab showed significantly greater reductions in sputum eosinophils, improvements in airway function, and a trend toward greater asthma control than those receiving placebo. Reslizumab was generally well tolerated.

CHRONIC COUGH: EOSINOPHILIC BRONCHITIS WITHOUT ASTHMA

Sputum cell-counts were studied in 7 non-smokers with corticosteroid-responsive chronic cough productive of sputum and 8 smokers with a clinical diagnosis of chronic bronchitis, all of whom had normal lung function tests and methacholine airway responsiveness, and in 10 non-smokers with asthma, examined during an exacerbation. Sputum from asthmatic patients and subjects with corticosteroid-responsive cough contained eosinophils and metachromatic cells. Macrophages were by far the dominant cell type in sputum from subjects with chronic bronchitis. Airway inflammation with eosinophils and metachromatic cells is not always accompanied by increased airway responsiveness, and current definitions of obstructive airways disease may need to be revised.

Airway responsiveness to histamine and methacholine: relationship to minimum treatment to control symptoms of asthma.

We have prospectively examined in 51 patients the relationship between the level of airway responsiveness to histamine and methacholine and the minimum medications required to control asthma. First we determined the least medication that was required to control symptoms so that they did not disturb sleep, were not present on waking, and did not require use of inhaled salbutamol (200 microgram) more than four times daily. When baseline FEV1 was greater than 70% of predicted and when there had been no respiratory infection or allergen exposure for six weeks, histamine and methacholine inhalation tests were carried out on separate days to determine the provocation concentration causing a fall in FEV1 of 20% (PC20). There was a close correlation between the PC20 to the two agents. The patients were grouped into 1, those who required no medication; 2, those who required salbutamol (200 microgram) occasionally but not daily; 3, those who required daily salbutamol; and 4, those who required additional beclomethasone dipropionate. The mean PC20 was highest in group 1 and lowest in group 4; there was a significant difference between each group. The results indicate that airway responsiveness to vasoactive amines is either an important determinant of the severity of asthma and the medication requirements or a consequence of the severity of asthma. They raise the possibility that measurement of responsiveness may be useful in some patients with established asthma to substantiate or question medication needs.

The use of induced sputum to investigate airway inflammation.

Clinicians have been interested in the macroscopic and protocol (fig 1), based on that described by Pin et al using a relatively low output ultrasonic nebuliser (output 0.9 ml/ microscopic appearance of sputum in asthma since the last half of the 19th century when Charcot-Leyden crystals, min, particle size 5.6 lm), results in successful sputum induction in 76% of normal and asthmatic subjects who Curschmann’s spirals, and their association with sputum eosinophilia was first recognised in patients with asthma. cannot produce sputum spontaneously. Cell counts and biochemical content of induced and spontaneous sputum Forty years ago Morrow Brown suggested that the microscopic examination of sputum might be clinically useful are similar with the exception of fibrinogen which is present in higher concentrations in spontaneous sputum. With by showing that the presence of eosinophils in a crude Leishman stained sputum smear identified patients whose salbutamol premedication and careful monitoring of forced expiratory volume in one second (FEV1) during sputum wheeze was responsive to corticosteroids. Recently, with the recognition that even mild asthma is associated with induction in mild asthma significant bronchoconstriction rarely occurs, but it is more common in patients with evidence of airway mucosal inflammation in bronchial biopsy specimens and bronchoalveolar lavage fluid, 4 there more severe or uncontrolled asthma. In a recent study a third of sputum inductions in patients with asthma has been renewed interest in the use of sputum to assess airway inflammation non-invasively. exacerbations who were overusing inhaled b2 agonists were complicated by a >10% fall in FEV1 which emphasises the This review describes the development over the last eight years of new and reliable techniques to assess airway need to perform the inductions carefully. We and other investigators have induced sputum in asthma using similar inflammation using sputum differential cell counts and measurement of molecular markers of inflammation in concentrations of hypertonic saline delivered by ultrasonic nebulisers with a higher output and, whilst there might be the sputum fluid phase. We review studies where these measurements have been made in normal and diseased a higher success rate, this is at the expense of increased adverse effects including mild bronchoconstriction. subjects and assess their validity, repeatability, and responsiveness. Finally we describe current, and speculate A recent preliminary report has suggested that the cellular and biochemical content of sputum induced by a high on future, applications of sputum measurements of airway inflammation in asthma in both research and clinical setoutput ultrasonic nebuliser changes with sequential inhalatings.

Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre

Features of asthma include increases in both bronchial responsiveness and variability of airflow rates. We examined the relationship between bronchial responsiveness to histamine and the variation of peak expiratory flow rate (PFR) during the day and in response to salbutamol (200 μg), and the initial FEV1 at the time of the histamine test and FEV1 response to salbutamol. Bronchial responsiveness to histamine was expressed as the provocation concentration causing a fall in FEV1 of 20% (PC20). PC20 ranged between 13·9 and 130 mg/ml in nonasthmatic subjects, between 10·5 and 59·9 mg/ml in five asymptomatic asthmatics, and between 0·03 and 20·8 mg/ml in 27 asthmatics with symptoms controlled by medication. The lower the PC20 (the greater the bronchial responsiveness) the lower the morning PFR (r = 0·79), the greater the increase in PFR after salbutamol (morning r = −0·75, evening r = −0·80), and the greater the difference between the highest and lowest PFR each day (r = −0·81). Measurements of PFR were abnormal, compared with those in nonasthmatic subjects, in all subjects with a PC20 less than 2 mg/ml—that is, moderate or severe increase in nonspecific bronchial responsiveness—and in none with a PC20 greater than 21 mg/ml—that is, normal responsiveness; five of nine asthmatics with controlled symptoms had abnormal PFR measurements when PC20 was between 2 and 21 mg/ml—that is, mild hyperresponsiveness. In contrast, FEV1 at the time of the histamine test was greater than 80% predicted in all subjects with a PC20 greater than 2 mg/ml and was not less than this in 10 of 18 subjects with a PC20 less than 2 mg/ml. When improvement in FEV1 was 20% or more after salbutamol, the PC20 was usually moderately or severely increased (less than 0·4 mg/ml). The results identify a close relationship between nonspecific bronchial responsiveness to histamine and the variability in flow rates which occurs spontaneously and after bronchodilator. In addition, they raise the possibility that increased airflow obstruction in asthma may be a consequence of increased responsiveness.