Original article Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure The diisocyanates, toluene diisocyanate (TDI), diph- enylmethane diisocyanate (MDI), and hexamethylene diisocyanate (HDI) are commonly used in the manufac- ture of plastics, paints and foam products. They are also the most common chemicals causing occupational asthma. Earlier study has shown that a considerable proportion of patients do not recover from occupational asthma (1). In diisocyanate-induced asthma (DIA), bronchial inflammation, including lymphocytic infiltration and eosinophilia (2, 3), resembling that present in allergic asthma has been demonstrated. After cessation of expo- sure, a slight decrease in the count of mononuclear cells, eosinophils, and mast cells or a reduced thickness of subepithelial fibrosis has been found (4), suggesting a reversal of remodelling of the airway wall. However, respiratory symptoms and nonspecific bronchial hyper- responsiveness (1, 5, 6) have been reported to persist for years in the majority of patients with DIA despite cessation of exposure. In the follow-up of lung function of DIA patients treated with inhaled steroids, a decrease in nonspecific bronchial hyperreactivity (NSBH) has typically been reported (6, 7). In our previous study (7), the degree of lung function impairment and NSBH increased compared with the baseline results in patients with DIA 35% of whom used asthma medication and 7% were still exposed to diiso- cyanates at work. There was a need to increase or start asthma medication after a mean follow-up of 12 years. Our aim was to follow up patients with DIA after cessation of exposure and to treat them with regular inhaled steroid medication to investigate the prognosis of DIA by spirometry and measurement of NSBH. In addition, the relation between lung function and markers Background: The clinical outcome of diisocyanate-induced asthma has been found to be poor despite cessation of exposure. Our aim was to study the outcome of diisocyanate-induced asthma after initiation of inhaled steroid treatment at a mean period of 7 months (range 2–60 months) after cessation of exposure by following up lung function and bronchial inflammation. Methods: Bronchoscopy was performed on 17 patients 2 days after a positive inhalation challenge test, after which budesonide 1600 lg a day was started. Bronchoscopy, spirometry, and histamine challenge tests were repeated at 6 months and on average 3 years. The results were also compared with those obtained from 15 healthy control subjects. Results: Nonspecific bronchial hyperreactivity diminished significantly (P = 0.006); however, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values decreased, with a median yearly reduction of FEV1 of 79 ml. The count of mast cells in bronchial mucosa decreased (P = 0.012) and that of macrophages increased (P = 0.001). Interleukin-4 level in mucosa was during the first year significantly higher than in controls but its level decreased in the follow-up. Interleukin-6, interleukin-15, and tumour necrosis factor alpha messenger-RNA levels were significantly higher in hyperreactive patients than in nonhyperreactive patients at the end of the follow-up. Conclusion: Our results indicate that inflammation may persist in diisocyanate- induced asthma despite inhaled steroid medication. However, TH2-type inflammation diminished. Persistent nonspecific bronchial hyperreactivity was associated with proinflammatory acting cytokines produced mainly by macro- phages. Considering the poor prognosis of the disease the findings could be utilized to develop the follow-up and treatment of diisocyanate-induced asthma. P. L. Piirilä 1 , A. Meuronen 2 , M.-L. Majuri 3 , R. Luukkonen 4 , T. Mäntylä 5 , H. J. Wolff 6 , H. Nordman 7 , H. Alenius 3 , A. Laitinen 2 1 Department of Clinical Physiology, Helsinki University Hospital, HUSLAB, Helsinki, Finland; 2 Department of Anatomy, University of Helsinki, Helsinki, Finland; 3 Unit of Excellence in Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland; 4 Statistical Services Team, Finnish Institute of Occupational Health, Helsinki, Finland; 5 Department of Pulmonary Diseases, Helsinki University Hospital, Helsinki, Finland; 6 Department of Pathology, Finnish Institute of Occupational Health, Helsinki, Finland; 7 Department of Occupational Diseases, Finnish Institute of Occupational Health, Helsinki, Finland Key words: asthma; diisocyanates; inflammation; interleukin-4; macrophages; nonspecific bronchial hyperreactivity; TNF-alpha. P. Piirilä Laboratory of Clinical Physiology HUSLAB PO Box 340 00029 HUS Finland Accepted for publication 26 October 2007 Allergy 2008: 63: 583–591 Ó 2008 The Authors Journal compilation Ó 2008 Blackwell Munksgaard DOI: 10.1111/j.1398-9995.2007.01606.x 583