Background Airway inflammation is considered to be important in asthma but is relatively inaccessible to study. Less Airway inflammation is a major factor in the pathogenesis of asthma. Mast cell and eosinophil infiltration, epithelial damage, and mucus production are characteristic features.' Direct examination of the inflammatory response should help to improve understanding of the pathogenesis and treatment of asthma.In patients with stable asthma bronchial biopsy and bronchoalveolar lavage have been used to study airway inflammation2' but discomfort, inconvenience, and risks limit their use. Examination of sputum is a less invasive alternative,5 but sputum cannot always be produced spontaneously. When sputum is not otherwise available induced samples may allow secretions from the lower airways to be sampled.Sputum induction by inhalation of hypertonic saline has been successfully used to diagnose Pneumocystis carinii pulmonary infections in patients infected with HIV.'We adapted this method for use in asthmatic subjects and examined (a) the success rate and safety of the method, (b) the reproducibility of cell counts, and (c) the differences in cell counts between normal and asthmatic subjects. Methods SUBJECTSSeventeen normal subjects and 17 subjects with asthma were selected from among the staff (adults) and asthmatic patients and their siblings (adults or children) at the clinics of the Firestone Regional Chest and Allergy Unit and the Health Sciences Centre. All were nonsmokers or ex-smokers of more than five years. None had spontaneous sputum or symptoms of a respiratory tract infection, or had been exposed to a seasonal allergen within the last month. The normal subjects had no past or current symptoms of asthma, a forced expiratory volume in one second (FEVI) >80% of predicted values,9 a ratio of FEV, to vital capacity >70%, and normal airway responsiveness to methacholine (provocative concentration of methacholine causing a 20% fall in FEV, (PC20) >8 mg/ml)'0 (table 1). The asthmatic subjects had a history of episodic dyspnoea with wheeze in the previous six months and a PC20 methacholine <8 mg/ml (15 patients) or a spontaneous variability in peak expiratory flow rate (PEF of >20% (two patients). All were taking an inhaled 2 agonist when needed; 15 were treated with inhaled corticosteroid (daily dose 200-3000 Mg) and one with prednisone 5 mg daily. Although asthma was stable in all subjects, control of the condition was good" in only five subjects; the remaining 12 had more asthmatic symptoms

One important goal of asthma treatment is to reduce exacerbations. The current authors investigated if the use of sputum cell counts to guide treatment would achieve this goal.A total of 117 adults with asthma were entered into a multicentre, randomised, parallel groupeffectiveness study for two treatment strategies over a 2-yr period. In one strategy (the clinical strategy: CS) treatment was based on symptoms and spirometry. In the other (the sputum strategy: SS) sputum cell counts were used to guide corticosteroid therapy to keep eosinophils f2%; symptoms and spirometry were used to identify clinical control, exacerbations and other treatments. Patients were blind to sputum cell counts in both strategies and physicians were blind in the CS, thus removing bias. First, the minimum treatment to maintain control was identified in 107 patients (Phase 1) and then this treatment was continued (Phase 2) for the remaining of the 2 yrs. The primary outcomes were the relative risk reduction for the occurrence of the first exacerbation in Phase 2 and the length of time without exacerbation. The current authors also examined the type and severity of exacerbations and the cumulative dose of inhaled steroid needed.The duration and number of exacerbations in Phase 1 were similar in both groups. In Phase 2 there were a 126 exacerbations of which 79 occurred in the CS (62.7%) and 47 (37.3%) in the SS groups. The majority of the 126 exacerbations (101; 80.1%) were mild. The majority of the 102 exacerbations, where sputum examination was performed before any treatment (n570), were noneosinophilic. In the SS patients, the time to the first exacerbation was longer (by 213 days) especially in those considered to need treatment with a long acting b 2 -agonist (by 490 days), the relative risk ratio was lower (by 49%), and the number of exacerbations needing prednisone was reduced (5 versus 15). This benefit was seen mainly in patients needing treatment with inhaled steroid in a daily dose equivalent to fluticasone .250 mg, and was due to fewer eosinophilic exacerbations. The cumulative dose of corticosteroid during the trial was similar in both groups.Monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations.

Clinicians have been interested in the macroscopic and protocol (fig 1), based on that described by Pin et al 7 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 m), 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. 1 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. 11 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 (FEV 1 ) during sputum wheeze was responsive to corticosteroids.2 Recently, with the recognition that even mild asthma is associated with induction in mild asthma significant bronchoconstriction rarely occurs, 7 but it is more common in patients with evidence of airway mucosal inflammation in bronchial biopsy specimens and bronchoalveolar lavage fluid, 3 4 there more severe or uncontrolled asthma. 12 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 2 agonists were complicated by a >10% fall in FEV 1 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. 12 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. [13][14][15] 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. Developments in methodologyEarly attempts to provide reliable sputum differential cell counts used smears of spontaneously produced sputum stained with May-Grunwald-Giemsa. 5 Additional staining with toluidine blue was required for accurate meta...

Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract. This is in contrast to the direct challenges where agonists such as methacholine or histamine cause airflow limitation predominantly via a direct effect on airway smooth muscle.Direct airway challenges have been used widely and are well standardised. They are highly sensitive, but not specific to asthma and can be used to exclude current asthma in a clinic population. Indirect bronchial stimuli, in particular exercise, hyperventilation, hypertonic aerosols, as well as adenosine, may reflect more directly the ongoing airway inflammation and are therefore more specific to identify active asthma. They are increasingly used to evaluate the prevalence of bronchial hyperresponsiveness and to assess specific problems in patients with known asthma, e.g. exercise-induced bronchoconstriction, evaluation before scuba diving.Direct bronchial responsiveness is only slowly and to a modest extent, influenced by repeated administration of inhaled steroids. Indirect challenges may reflect more closely acute changes in airway inflammation and a change in responsiveness to an indirect stimulus may be a clinically relevant marker to assess the clinical course of asthma. Moreover, some of the indirect challenges, e.g. hypertonic saline and mannitol, can be combined with the assessment of inflammatory cells by induction of sputum.

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