Bronchiolitis Obliterans Syndrome in Chemical Workers Producing Diacetyl for Food Flavorings. F. G. van Rooy, J. M. Rooyackers, M. Prokop, R., L. A. Smit, D. J. Heederik. Am J Respir Crit Care Med. 2007 Sep 1;176(5):498–504. Epub 2007 May 31.
Rationale: Workers in microwave popcorn plants are at risk of developing bronchiolitis obliterans associated with exposure to butter flavoring volatiles, including diacetyl. Objectives: To investigate the risk of bronchiolitis obliterans for chemical workers producing diacetyl, with exposure to less complex mixtures of chemicals. Methods: We interviewed and conducted spirometry on 175 of 196 workers from a chemical production plant that produced diacetyl between 1960 and 2003. We used all available historical exposure data to classify all workers into three exposure groups with varying exposure profiles to diacetyl, based on frequency and level of exposure. Measurements and Main Results: Workers with fixed airway obstruction underwent further pulmonary function testing (including diffusing capacity and lung volumes) and paired inspiratory and expiratory high-resolution computed tomography studies. We identified three cases consistent with bronchiolitis obliterans syndrome with air trapping on high-resolution computed tomography of the lungs, in the highest exposure group of 102 process operators. Two of these cases were lifelong nonsmokers. Potential exposures included acetoin, diacetyl, acetaldehyde, and acetic acid, with diacetyl exposures in the range previously reported to be associated with fixed airway obstruction in the microwave popcorn industry. Conclusions: Exposure to an agent during diacetyl production appears to be responsible for causing bronchiolitis obliterans syndrome in chemical process operators, consistent with the suspected role of diacetyl in downstream food production.
Comments: There has been interest in the association between exposure to diacetyl a flavoring agent used in such foods as microwave popcorn and there is much in the literature with regard to the incidence of cases of bronchiolitis obliterans in popcorn workers. Several studies including case reports, cross sectional epidemiological studies and a few animal exposure studies have indicated that diacetyl is the primary agent causing the injury. In this case series only one of the subjects had a smoking history but they had been diagnosed with COPD prior to their identification as having CT and physiologic findings most consistent with bronchiolitis obliterans. Only one subject had a tissue biopsy confirmation (VATS). This report is significant because it identifies cases where exposures were limited to diacetyl, acetoin and acetaldehyde and the latter 2 agents have not been shown to cause this type of airway injury previously. This is in contrast to the complex exposures of the popcorn workers. These reports further emphasize that occupational related airway diseases are often overlooked and not appreciated. Occupational exposures should clearly be considered in non-smokers or young smokers who demonstrated evidence of chronic airflow limitation with limited reversibility. Dr K Kreiss from NIOSH provides an insightful an eloquent editorial in the same issue entitled “Occupational Bronchiolitis Obliterans Masquerading as COPD” (Pages 428-429)
Effect of an MMP-9/MMP-12 Inhibitor on Smoke-Induced Emphysema and Airway Remodeling in Guinea Pigs. A. Chug, R. Wang, X. Wang, P. O. Unnerve, K. Them, J. L. Wright, Thorax. 2007 Aug;62(8):706-13. Epub 2007 Feb 20.
Background: Matrix metalloproteases (MMPs) are believed to be important in the pathogenesis of cigarette smoke-induced emphysema, but this hypothesis has only been proved in the mouse and its applicability to other species, particularly humans, is uncertain. The role of MMPs in smoke-induced small airway remodelling is unknown. Methods: The effects of a dual MMP-9/MMP-12 inhibitor, AZ11557272, on the development of anatomical and functional changes of chronic obstructive pulmonary disease (COPD) in guinea pigs exposed daily to cigarette smoke for up to 6 months were examined. Results: At all times, smoke-induced increases in lavage inflammatory cells, lavage desmosine (a marker of elastin breakdown) and serum tumour necrosis factor alpha (TNFalpha) were completely abolished by AZ11557272. At 6 months there was an increase in lung volumes and airspace size. AZ11557272 returned the pressure-volume curve to control levels, decreased smoke-induced increases in total lung capacity, residual volume and vital capacity by about 70%, and also reversed smoke-induced airspace enlargement by about 70%. There was a very strong correlation between surface to volume ratio and both lavage desmosine and serum TNFalpha levels. AZ11557272 protected against smoke-mediated increases in small airway wall thickness but did not prevent smoke-induced increases in mean pulmonary artery pressure. Conclusions: An MMP-9/MMP-12 inhibitor can substantially ameliorate morphological emphysema, small airway remodelling and the functional consequences of these lesions in a non-murine species. These findings strengthen the idea that MMPs are important mediators of the anatomical changes behind COPD in humans, and suggest that MMP-9 and MMP-12 may be potential intervention targets.
Comments: Churg and colleagues have shown that another animal model besides the mouse model indicates an association between MMP-9 and/or MMP-12 activity and development of morphologic emphysema. Neutrophils are a major source of MMP-9 and MMP-12 and this may help explain their central role not only in COPD but also in a subset of severe asthma. MMP-12 is proposed to cause the release of active tumor necrosis factor α (TNF-α) which in turn promotes an influx of neutrophils that release protease enzymes leading to parenchymal destruction. In this study 6 to 10 animals were in each group (control, smoke exposed or treated with AZ11557272) and were sacrificed and examined at 1, 3 or 6 months. They showed that a highly selective inhibitor for MMP-9 and MMP-12 and not other MMPs was capable of reducing neutrophils, macrophages, TNF and desmosine (marker of elastin breakdown). These findings are exciting, and hopefully studies in humans will be forthcoming. An important question will be whether these matrix metalloproteases will have their greatest impact only in those who are continuing to smoke and do not have significant parenchymal destruction already, or whether they will also be important in subjects who may have stopped smoking but have persistent inflammation due to particulates that remain resident in the lung long after cigarette smoking has ceased.
Morbidity Associated with Systemic Corticosteroid Preparation for Coronary Artery Bypass Grafting in Patients with Chronic Obstructive Pulmonary Disease: A Case Control Study. D. Starobin, M. R. Kramer, M. Garty, D. Shitirt. J Cardiothorac Surg. 2007 Jun 4;2:25.
Background: Coronary artery bypass grafting (CABG) is associated with high morbidity in patients with chronic obstructive pulmonary disease (COPD).We examine the effect of preoperative systemic corticosteroids on morbidity in this setting. Methods: Ninety candidates for elective CABG participated in a prospective, open randomized trial, including 30 patients with COPD who received a single injection of a long-acting corticosteroid, 30 with COPD who received placebo, and 30 without COPD who served as controls. Primary end-points were postoperative pulmonary and nonpulmonary complications. Secondary end-points were length of hospital stay (LOS), ICU stay of less than 24 hours and more than 48 hours, duration of mechanical ventilation, and time to walking and sitting. Results: The rate of pulmonary complications was similar in the two COPD groups and in the COPD patients and controls. The placebo group had more major nonpulmonary complications than the treatment group, but the difference was not statistically significant (26% vs. 17%, P = NS). The non-COPD control group had significantly fewer nonpulmonary complications than the COPD patients (treatment+placebo) (33% vs 70%, P = 0.014) and a similar rate of pulmonary complications. There was a statistically significant difference between the treated and placebo COPD groups in ICU stay less than 24 hours (P < or = 0.001) and more than 48 hours (P = 0.03) and hospital stay (P = 0.013). On stepwise analysis, only age and number of coronary grafts were predictors of pulmonary complications. Conclusion: The use of preoperative systemic corticosteroids in patients with COPD undergoing CABG may shorten ICU and hospital stay.
Comments: While this is a relatively small study it should give pause for pre-op consultants for COPD patients to ponder whether preoperative treatment with systemic steroids should be recommended for all COPD patients undergoing major surgery given the accumulating evidence supporting the significant systemic inflammatory and other effects of COPD. Further studies are clearly warranted to not only look at patients undergoing coronary bypass but any other major surgical procedure.