Charting the human lung with inhaled nanoparticles : Development of AiDA - a new diagnostic technique for respiratory disease

Abstract: Changes to the smallest structures of the distal lung are often the first sign of severe respiratory disease, but to date methods to detect and quantify these changes are limited. Chronic obstructive pulmonary disease (COPD) is currently estimated to be the third most common cause of death worldwide, but is to a large extent under-diagnosed, especially at early stages. This thesis explores a new method for examining the lung by measurements of lung deposition of airborne nanoparticles, with possible potential to be developed into a diagnostic method for detection of changes typical for early COPD. The technique is called Airspace Dimension Assessment with nanoparticles (AiDA).An instrument for lung deposition measurements was constructed and characterized on healthy subjects. The instrument produces a test aerosol containing monodisperse nanoparticles, which can be administered to subjects in inhalation experiments. The particle concentration in the inhaled test aerosol and in exhaled air from determined volumetric sample depths can be determined after controlled residence times in the lung.By comparing inhaled and exhaled concentrations, the deposition efficiency of the nanoparticles can be determined in a single breath. The instrument is, to our knowledge, currently the only instrument with this capability.Particle deposition was measured on healthy individuals and individuals with COPD. It was found that particle deposition was decreased for subjects with COPD, and this was interpreted as an effect of enlarged airspaces, pulmonary emphysema. This shows that particle deposition measured with the instrument reflects subject specific lung properties.A theory was developed for interpretation of the relation between measurements of lung deposition and properties of the lung. Nanoparticles deposit almost exclusively by diffusion in the distal lung. By measuring the half-life time of particles in the lung, effective airspace radii can be estimated which reflect lung geometry. Repeated measurements on three subjects with 15 -18 months between the measurements showed that the precision was on average ±7 μm. Particle deposition during the dynamic part of the breathing manoeuvres may also provide information about mainly the small conducting airways.The theory was evaluated by measurements on healthy subjects. It was shown that both the derived effective airspace radii and the particle deposition during the dynamic phase of the measurement were in agreement with expectations from the developed theory. It was also shown that the parameters correlated with subject characteristics and physiological measurements.An AiDA measurement protocol was developed which can be performed by most subjects in less than 15 minutes. AiDA measurements have been performed on more than 1000 subjects. This exceeds the total number of subjects included in previously published studies on lung deposition of nanoparticles. Preliminary results show that the technique fulfils several criteria for an efficient diagnostic technique. Preliminary data also indicates that the technique may give relevant medical information about the distal lung not easily obtainable by other means, and thus may be considered as a feasible future diagnostic tool for the lung.