Nasal and bronchial testing as well as treatment of patients with airway hyperresponsiveness and inflammation focusing on the united airway concept

Abstract: Allergic and non-allergic rhinitis and asthma is a global health problem on the increase that causes major illness and disability worldwide, and also results in a large financial burden on society. This thesis contains six papers, based on four different clinical studies on humans with allergic as well as non-allergic airways inflammation, such as neutrophil inflammation caused by exposure to swine dust, as well as chronic rhinosinusitis and concomitant asthma with and without NSAID intolerance. The purpose was to study different aspects of nasal and bronchial airway inflammation, with special focus on possible links between the upper and lower airways disease. In paper I and II, the nasal and bronchial airway reactivity (sensitivity to histamine) in pollen allergy sufferers was detected after pollen exposure as well as out of pollen season. We found that the histamine-induced swelling of the nasal mucosa was increased in comparison to a control group of healthy individuals, without seasonal differences and with a correlation between nasal (sneezing) and bronchial (PD20) histamine sensitivity. Counting the number of histamine-induced sneezes throughout the challenge test better than mucosal swelling correlated to the current allergic symptoms. The increase in histamine-induced nasal mucosal swelling out of pollen season was interpreted as a sign of minimal persistent inflammation , a phenomenon previously described. In paper III and IV healthy subjects were exposed to swine dust, with the purpose to study upper and lower airway inflammation. Swine dust exposure is a model previously developed for inducing airways inflammation in healthy subjects, and until now used to mainly study the effects on the lower airways. We found the model useful for studying both nasal and bronchial inflammatory parameters, as swine dust exposure caused an increase in upper as well as lower airway sensitivity in healthy subjects, however without any mutual correlation. In this group of healthy volunteers, under inflammatory conditions after exposure to swine dust, we found an increase in histamine-induced nasal swelling and a decrease in bronchial function as measured by histamine-PC20. That is in contrast to the pollen allergy sufferers, where exposure to pollen did not induce such changes. Consequently, the airways reactivity was similar under inflammatory conditions in the allergy sufferers and in the group of healthy volunteers, and the main difference was under non-inflammatory conditions. Moreover, nasal lavage before a histamine challenge affected the outcome of the nasal mucosal swelling, microcirculation as well as nasal patency, which implies that this has to be kept in mind when studies are designed, but it also sheds light on nasal irrigation as a treatment method of rhinitis. As we focused on measurements of the vascular response of the nasal mucosa, rhinostereometry was used in paper I -IV, and in paper IV the method was developed to also contain a laser Doppler flowmeter, in order to perform simultaneous measurements of nasal mucosal swelling and microcirculation at the same area. In paper V, this equipment was also evaluated as a method of detecting aspirin sensitivity throughout the nasal airways challenge test, but also to measure possible concomitant reactions of the nasal mucosa throughout the bronchial challenge. We found that the microcirculatory measurements differed between AIA and ATA patient groups, and that the main reaction, including vascular parameters as well as PNIF and symptom scores, occurred two hours or later after challenge. We therefore conclude that a three hour observation time after a nasal lysineaspirin challenge may be recommended in order to improve the sensitivity of the method. We also found signs of a bronchio-nasal reflex in the AIA patients throughout the bronchial challenge test; with changes in the nasal microcirculation at the time they developed asthma. In paper VI, we evaluated the benefits of local steroid treatment and functional sinus surgery (FESS) on the upper and lower airways, in asthmatic subjects with nasal polyposis. Statistically significant improvements in mean asthma symptom scores and daily PEFR were noted despite the fact that the asthma in general was well controlled with inhaled corticosteroids. Moreover, in addition to a clear-cut improvement in the other nasal parameters, both subjective aspects of the olfactory function and the butanol test improved significantly. Together, these results further highlight FESS as a potent anti-inflammatory treatment method of the upper and lower airways, which could be considered early in the natural course of the disease with concomitant asthma, and a second-line treatment in nasal polyposis patients with a reduced sense of smell. Finally, the findings that FESS has benefits on subjective and clinical asthma parameters, the detection of simultaneous changes in the nasal mucosal microcirculation at the time the AIA patients developed asthma throughout a bronchial lysine-ASA challenge, and the positive correlation between the number of sneezes following a nasal histamine challenge and histamine-PC20-PEF are findings that support the idea that the nose and bronchi are linked in a common functional airway system, also defined as the united airways .