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

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 airways 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 without correlation to the bronchial 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 the second study 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 lysine-aspirin 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 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”. LIST OF PUBLICATIONS The present thesis is based on the following papers, which will be referred to by their Roman numerals. I. Karl-Gustav Kölbeck, Anders Ehnhage, Jan-Erik Juto Nasal and Bronchial Histamine Reactivity in Patients with Allergic Rhinitis Out of Season. Ann Allergy Asthma Immunol 1999; 82:55–60. II. Anders Ehnhage, Karl-Gustav Kölbeck, Björn Mossberg, Jan-Erik Juto Nasal and Bronchial Histamine Responsiveness in Pollen-Exposed Patients with Seasonal Rhinitis. ORL 2002; 64:191–199. III. Karl-Gustav Kölbeck, Anders Ehnhage, Jan-Erik Juto, Sune Forsberg, Hans Gyllenhammar, Lena Palmberg, Kjell Larsson. Airway reactivity and exhaled NO following swine dust exposure in healthy volunteers. Respiratory Medicine 2000; 94: 1065–1072. IV. Anders Ehnhage, Karl-Gustav Kölbeck, Pär Stjärne, Hans Grudemo, Jan-Erik Juto. Swine dust exposure is a model for rapid induction of non-allergic neutrophil inflammation in the nasal mucosa of healthy volunteers, and the symptoms as well as the microcirculation are modified by nasal lavage. Rhinology 2007; 45(4): 292-298. V. Anders Ehnhage A, Karl-Gustav Kölbeck, Jan-Erik Juto, Barbro Dahlén, Pär Stjärne. Evaluation of nasal mucosal swelling and microcirculation throughout nasal and bronchial provocation tests with lysine-aspirin in asthmatics with nasal polyposis. Clinical & Experimental Allergy, Submitted. VI. Anders Ehnhage, Petter Olsson, Karl-Gustav Kölbeck, Maria Skedinger, Barbro Dahlén, Martin Ålenius, Pär Stjärne. Functional Endoscopic Sinus Surgery (FESS) improved asthma symptoms as well as PEFR and olfaction in patients with Nasal Polyposis. Allergy, in press. LIST OF ABBREVIATIONS ACE-inhibitors: Angiotensine-converting enzyme-inhibitors, a group of drugs with potent vasoconstrictor effects. AE: Adverse event AIA: Aspirin-intolerant asthmatics ASA: Acetylsalicylic acid ATA: Aspirin-tolerant asthmatics BAL: Bronchial lavage BH: Bronchial histamine provocation test BHR Bronchial hyperresponsiveness CMBC: The concentration of moving blood cells (in the microvascular blood flow) COX: Cyclooxygenase enzyme CRS: Chronic rhinosinusitis CSF: Cerebrospinal fluid CT: Computer tomography ELISA: Enzyme-linked immunosorbent assay EP 3 OS: European position paper on rhinosinusitis and nasal polyps FEV1: Forced expiratory volume for 1 second FESS: Functional endoscopic sinus surgery FPND: Fluticasone proprionate nasal drops FVC: Forced vital capacity GINA: The Global Initiative for Asthma Histamine-PC20: The concentration of histamine producing a 20% decline in FEV1 Histamine-PD-20: The dose of histamine producing a 20% decline in FEV1 IAR: Intermittent allergic rhinitis IgE: Immunoglobin E ITT: Intent to treat LPS: Lipopolysacharides LT: Leukotriene Lysine-ASA: Water soluble Acetylsalicylic acid NAL: Nasal lavage NAR: Nasal airway resistance NARES: Persistent non-allergic rhinitis with eosinophilia syndrome NO: Nitric Oxide NSAID: Non-steroid anti-inflammatory drugs OCS: Oral corticosteroids PEF: Peak expiratory flow, measured by a spirometer PEFR: Peak expiratory flow rate, measured by a portable apparatus. PER: Persistent allergic rhinitis PG: Prostaglandine PNIF: Peak nasal inspiratory flow PNEF: Peak nasal expiratory flow PP: Per protocol PU: Perfusion units QoL: Quality of life RAST: Radioallergosorbent test, a blood test for assessing the presence of specific IgE antibodies, used to determine what a person is allergic to. RSM-LDF: A rhinostereometer with a connected laser Doppler flowmeter apparatus SF-36: Study Short Form 36, a standardised questionnaire of the patient ́s overall health status SIT: Specific immunotherapy VAS: Visual analogue scales VC: Vital capacity