Sandra D. Anderson

Indirect airway challenges

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.

Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline.

To assess non-specific bronchial reactivity the effect of inhaling ultrasonically nebulised solutions of distilled water and hypotonic (0.3%), isotonic (0.9%), and hypertonic (2.7%, 3.6%) saline was investigated in 10 asthmatic patients and nine normal subjects. Expired ventilation and the maximum percentage fall in forced expiratory volume in one second (FEV1) were recorded. The sensitivity to the inhaled solutions was determined by measuring the ventilation required to induce a fall in FEV1 of 20% from the prechallenge value. Hypotonic and hypertonic but not isotonic solutions caused a significant fall in FEV1 in the asthmatic subjects. Normal subjects showed no response to either distilled water or 3.6% saline, the only solutions with which they were challenged. The method used for this challenge is rapid, simple, and inexpensive and provides a new means of diagnosing non-immunologically mediated bronchial hyperreactivity.

Exercise-induced asthma.

A review of exercise-induced asthma is presented which describes work that has been carried out by the authors and by other investigators over recent years. The effect of exericse on lung function in asthmatic and normal subjects is compared. The influence of the type and severity of exercise on the response of the asthmatic is noted and the importance this has for interpretation of results. The effects of various drugs on exercise-induced asthma are considered in some detail. The clinical implications of the results of exercise tests in asthmatics, their relatives, and other subjects are considered in terms of the diagnosis and prognosis of asthma and its mode of inheritance. It is concluded that there is as yet no explantation for the mechanism of exercise-induced asthma, but it is a tool of potentially great value for research into the physiology and treatment of clinical asthma.

Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population.

The prevalence of bronchial hyperresponsiveness in adult populations is not known. To document its prevalence and distribution and to determine the factors associated with it, a random sample of the adult population of Busselton, Western Australia, was studied. Spirometric function, bronchial responsiveness to histamine, and atopic responses to skin prick tests were measured. Respiratory symptoms were determined by questionnaire. Data were obtained from 916 subjects. Of these, 876 underwent a histamine inhalation test and bronchial hyperresponsiveness to histamine (defined as a dose of histamine provoking a 20% fall in FEV1 equal to or less than 3.9 mumol) was found in 10.5%. Another 40 subjects with poor lung function were tested with a bronchodilator and 12 were found to have bronchial hyperresponsiveness (defined as a greater than 15% increase in FEV1), making the total prevalence of bronchial hyperresponsiveness 11.4%. The prevalence of current asthma, defined as bronchial hyperresponsiveness plus symptoms consistent with asthma in the last 12 months, was 5.9%. The distribution of bronchial hyperresponsiveness in the studied population was continuous. There was a significant association between it and respiratory symptoms, atopy, smoking, and abnormal lung function (p less than 0.001 for all associations). There was no association with age, sex, or recent respiratory tract infection.

Standardization of Exercise Tests in Asthmatic Children

Asthmatic children, known to be susceptible to exercise-induced bronchoconstriction, exercised by running or walking on a treadmill. Changes in airways obstruction were estimated by measurement of peak expiratory flow rate before, during, and after exercise. Post exercise bronchoconstriction reached a maximum when the duration of exercise was 6 to 8 minutes and when the gradient of the treadmill was 10 to 15%; exercise for longer periods or at steeper gradients produced no significant increase in bronchoconstriction. Bronchoconstriction was much greater after running than after walking at the same oxygen consumption in 4 out of the 5 subjects tested. The reproducibility of bronchoconstriction was good in individual patients when tests performed within one day or within one week were compared. Reproducibility diminished as the interval between tests increased to one month or one year. When tests were repeated at 2-hourly intervals throughout the day, no significant diminution in exercise-induced bronchoconstriction was noted. Variations in pre-exercise peak expiratory flow rate had no significant effect on exercise-induced bronchoconstriction in individual subjects. The range of response of normal children to treadmill exercise is defined and the value of the test in discriminating between asthmatic and other children is shown. If several tests are to be carried out by an individual patient, they should be performed on separate days at the same time of day and should be completed within one week. This will allow accurate comparisons to be made between tests in, for example, the assessment of the effect of different drugs in an individual patient.

Clinical exercise testing with reference to lung diseases : indications, standardization and interpretation strategies

Cardiopulmonary exercise testing (CPET) is a unique tool to assess the limits and mechanisms of exercise tolerance. It also provides indices of the functional reserves of the organ systems involved in the exercise response, with inferences for system limitation at peak exercise. Moreover, CPET is useful for establishing the profiles and adequacy of the responses of the systems at submaximal exercise. The present document is essentially focused on clinical problems commonly faced in the study of patients with pulmonary diseases. Physiological changes of the respiratory system during exercise, however, should only be considered as part of a co-ordinated sequence of oxygen and carbon dioxide transfer processes between the atmosphere and the mitochondria to meet the increased energy demand of the skeletal muscle. Consequently, even in the analysis of patients with well-identified pulmonary disease, an integrative approach to CPET [1, 2] is required. CPET is an area of growing interest in pulmonary medicine for three major reasons: 1) its large potential clinical applicability (see section on Indications); 2) the essentially noninvasive nature of the testing; and 3) provision of information that cannot be obtained through conventional lung function testing performed at rest [3– 9]. During the past few years, two factors have contributed to the current level of interest in CPET in pulmonary medicine. First, substantial progress has been made in clarifying fundamental concepts of exercise physiology (e.g., factors limiting maximal oxygen uptake, lactate threshold) which have historically been the focus of controversy. Secondly, major technological improvements have facilitated data collection, subject monitoring during the test and subsequent formatting and analysis of the results. Nowadays, CPET can be considered a primary test in the pulmonary function laboratory. The present European Respiratory Society (ERS) position document reflects the views on the topic shared by the members of the Task Force. One of the self-imposed goals of the group was to produce a relatively readerfriendly document that combined a rigorous conceptual approach with practical utility for CPET in a clinical setting. The document can be either read as a whole, or the first section (Responses to exercise in lung disease) can be used alone, as a frame of reference to clarify specific points of the document. Definitions, abbreviations,

Is there a unifying hypothesis for exercise-induced asthma?

We believe that it is the loss of water per se and not heat loss that is the most important stimulus to exercise-induced asthma (EIA). The evidence to support this concept comes from a number of observations. First, EIA may occur when expired air temperature during exercise is close to body temperature and higher than that normally observed at rest. This suggests that EIA is not always associated with cooling of the airways. Second, there is evidence to show that the temperature of the inspired air is less critical than was previously thought. Providing that the water loss is the same, the airway response is reproducible even though the heat loss may vary because of differences in the temperature of the inspired air. Because expired water concentration is relatively constant, the airway response relates well to the water concentration of the inspired air. We believe that evaporative water loss from the airway mucosa induces a transient change in osmolarity in the epithelial fluid and that this change is a more potent stimulus to bronchoconstriction than is airway cooling. We believe this hypothesis accounts for many known facts about EIA and should merit further investigation by which it may be proved or disproved.

Provocation by eucapnic voluntary hyperpnoea to identify exercise induced bronchoconstriction

The International Olympic Committee Medical Commission (IOC-MC) requires notification for use of a β2 agonist at the Winter Olympic Games in Salt Lake City. This notification will be required seven days before the event and must be accompanied by objective evidence that justifies the need to use one. The IOC-MC has expressed the viewpoint that, at present, eucapnic voluntary hyperpnoea (EVH) is the optimal laboratory challenge to confirm that an athlete has exercise induced bronchoconstriction (EIB). The EVH test recommended was specifically designed to identify EIB. EVH has been performed in thousands of subjects in both the laboratory and the field. The test requires the subject to hyperventilate dry air containing 5% carbon dioxide at room temperature for six minutes at a target ventilation of 30 times the subjects forced expiratory volume in one second (FEV1). The test conditions can be modified to simulate the conditions that give the athlete their symptoms with exercise. A reduction in FEV1 of 10% or more of the value before the test is considered positive.

The safety and efficacy of inhaled dry powder mannitol as a bronchial provocation test for airway hyperresponsiveness: a phase 3 comparison study with hypertonic (4.5%) saline

BackgroundInhaled mannitol is a new bronchial provocation test (BPT) developed to improve portability and standardisation of osmotic challenge testing. Osmotic challenge tests have an advantage over the traditional methods of measuring airway hyperresponsiveness using methacholine as they demonstrate higher specificity to identify asthma and thus the need for treatment with inhaled corticosteroids (ICS). The safety and the efficacy of mannitol (M) as a BPT to measure airway hyperresponsiveness were compared to hypertonic (4.5%) saline (HS) in people both with and without signs and symptoms of asthma.MethodsA phase III, multi-centre, open label, operator-blinded, crossover design, randomised trial, with follow-up. Asthmatics and non-asthmatics (6–83 yr) were recruited and 592 subjects completed the study. Mannitol was delivered using a low resistance dry powder inhaler and HS was delivered using an ultrasonic nebuliser. The FEV1 was measured 60 seconds after each dose of mannitol (5,10,20,40,80,160,160,160 mg) and after each exposure to HS (0.5,1.0,2.0,4.0,8.0 minutes). A 15% fall in FEV1 defined a positive test. Adverse events were monitored and diaries kept for 7 days following the tests.ResultsMean pre-test FEV1 (mean ± SD) was 95.5 ± 14% predicted. 296 were positive to mannitol (M+) and 322 positive to HS (HS+). A post study physician conducted clinical assessment identified 82.3% asthmatic (44% classified mild) and 17.7% non-asthmatic. Of those M+, 70.1% were taking ICS and of those mannitol negative (M-), 81.1 % were taking ICS. The % fall in FEV1 for mannitol in asthmatics was 21.0% ± 5.7 and for the non-asthmatics, 5.5% ± 4.8. The median PD15 M was 148 mg and PD15 HS 6.2 ml. The sensitivity of M to identify HS+ was 80.7% and the specificity 86.7%. The sensitivity of M compared with the clinical assessment was 59.8% and specificity 95.2% and increased to 88.7% and 95.0% respectively when the M- subjects taking ICS were excluded. Cough was common during testing. There were no serious adverse events. The diarised events were similar for mannitol and HS, the most common being headache (17.2%M, 19%HS), pharyngolaryngeal pain (5.1%M, 3%HS), nausea (4.3%M, 3%HS), and cough (2.2%M, 2.4%HS).ConclusionThe efficacy and safety of mannitol was demonstrated in non-asthmatic and clinically diagnosed asthmatic adults and children.

Evaluation of ultrasonically nebulised solutions for provocation testing in patients with asthma.

The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEV1) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV1 when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22 degrees C to 36 degrees C eight of 10 patients had a similar change in FEV1 with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.