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The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the 'osmotic' benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.

The need for a diagnostic test for asthma was established when it was realized that asthma symptoms could not be relied upon to predict the presence, or not, of airway hyper-responsiveness and inflammation, the hallmarks of asthma. A need to identify asthmatic patients who were overtreated or undert

Exercise is a common trigger of bronchoconstriction. In recent years, there has been increased understanding of the pathophysiology of exercise-induced bronchoconstriction. Although evaporative water loss and thermal changes have been recognized stimuli for exercise-induced bronchoconstriction, accumulating evidence points toward a pivotal role for the airway epithelium in orchestrating the inflammatory response linked to exercise-induced bronchoconstriction. Overproduction of inflammatory mediators, underproduction of protective lipid mediators, and infiltration of the airways with eosinophils and mast cells are all established contributors to exercise-induced bronchoconstriction. Sensory nerve activation and release of neuropeptides maybe important in exercise-induced bronchoconstriction, but further research is warranted.

For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930. After 1945, isoprenaline, a non-selective beta agonist, became available for oral use but it was most widely used by inhalation. Isoprenaline was short-acting with unwanted cardiac effects. More selective beta agonists, with a longer duration of action and fewer side-effects became available, including orciprenaline in 1967, salbutamol in 1969 and terbutaline in 1970. The inhaled steroid beclomethasone was available by 1972 and budesonide by 1982. Spirometry alone and in response to exercise was used to assess efficacy and duration of action of these drugs for the acute benefits of beta2 agonists and the chronic benefits of corticosteroids. Early studies comparing oral and aerosol beta2 agonists found equivalence in bronchodilator effect but the aerosol treatment was superior in preventing exercise-induced bronchoconstriction. Inhaled drugs are now widely used including the long-acting beta2 agonists, salmeterol and formoterol, and the corticosteroids, fluticasone, ciclesonide, mometasone and triamcinolone, that act locally and have low systemic bio-availability. Repurposing drugs as inhaled therapies permitted direct delivery of low doses of drug to the site of action reducing the incidence of unwanted side-effects and permitting the prophylactic treatment of asthma.

Currently bronchial provocation testing (BPT) using mannitol powder cannot be performed in children under 6 years. A primary reason is it is challenging for children at this age to generate a consistent inspiratory effort to inhale mannitol efficiently from a dry powder inhaler. A prototype system, which does not require any inhalation training from the pediatric subject, is reported here. It uses an external source of compressed air to disperse mannitol powder into a commercial holding chamber. Then the subject uses tidal breathing to inhale the aerosol.The setup consists of a commercially available powder disperser and Volumatic™ holding chamber. Taguchi experimental design was used to identify the effect of dispersion parameters (flow rate of compressed air, time compressed air is applied, mass of powder, and the time between dispersion and inhalation) on the fine particle dose (FPD). The prototype was tested in vitro using a USP throat connected to a next generation impactor. The aerosols from the holding chamber were drawn at 10 L/min. A scaling factor for estimating the provoking dose to induce a 15% reduction in forced expiratory volume in 1 second (FEV1) (PD15) was calculated using anatomical dimensions of the human respiratory tract at various ages combined with known dosing values from the adult BPT.Consistent and doubling FPDs were successfully generated based on the Taguchi experimental design. The FPD was reliable over a range of 0.8 (±0.09) mg to 14 (±0.94) mg. The calculated PD15 for children aged 1-6 years ranged from 7.1-30 mg. The FPDs generated from the proposed set up are lower than the calculated PD15 and therefore are not expected to cause sudden bronchoconstriction.A prototype aerosol delivery system has been developed that is consistently able to deliver doubling doses suitable for bronchial provocation testing in young children.

The invitation by the editor, Rafeul Alam, to guest edit this issue on exercise-induced bronchoconstriction (EIB) allowed me to bring together investigators from physiology to cellular biology of EIB. The preface contains information on how some of the contributors came together and identifies some conferences that helped broaden the scientific research in EIB in asthmatic children to include healthy elite athletes. The contributors come from Australia, Canada, Denmark, England, France, Israel, Sweden, Netherlands, and the United States and trained in pediatric, respiratory, and sports medicine and science. Most have either obtained a doctoral degree in EIB or supervised one. My first encounter with EIB was at Royal Prince Alfred Hospital, in Sydney, in 1968. In January 1970 I started research in EIB with Simon Godfrey in the Department of Paediatrics at the Brompton Hospital in London. Over the next 3 years, under Simon’s enthusiastic guidance, a group of us carried out many studies on various aspects of EIB. In 1968 Ken Fitch from Perth, Australia observed severe EIB when supervising an exercise test on an 18-year-old asthmatic Olympic swimmer, who 3 months later won an Olympic Gold Medal in Mexico. This induced Ken to do his MD in EIB. Both Simon and Ken’s laboratories were coincidentally investigating the effect of different forms of exercise to provoke EIB. In 1971, both laboratories reported running as the most provocative exercise. Being ahead of their time, Ken and Simon wrote an article in 1976 on the topic of Asthma and Athletic Performance. They now celebrate the 50 years of research since the modern description of EIB in children by R.S. Jones of Liverpool, United Kingdom, in 1962. In 1973 Simon moved to the Hammersmith Hospital and later, in 1977, to Israel, where he continued his studies, among many others, on refractoriness and EIB. The article by Larsson and coworkers discusses these early studies and presents a new hypothesis to explain refractoriness following EIB.