Irritants and asthma variants Susan M Tarlo Toronto Western Hospital and Gage Occupational and Environmental Health Unit, University of Toronto

Respiratory irritant effects l Sx which mimic asthma: e.g. transient eye / upper airway irritation, ? RUDS, sx of vocal cord dysfunction, IEI, ? GERD l Acute aggravation of underlying asthma l Irritant-induced asthma (IIA: includes RADS) l ? Increased risk of respiratory sensitization with concurrent allergen exposures l Other acute or chronic lung effects (ARDS, pneumonitis, bronchiolitis, bronchitis, COPD) Relate to exposure factors (levels, chemical, particle size etc, and host factors)

Criteria for RADS ( Brooks et al 1985) l No preceding respiratory complaints l Sx onset after a single specific exposure incident or accident l Exposure was to a gas, smoke, fume, or vapor in very high concentration and being an irritant l Sx onset 3mo. l Sx simulate asthma l PFTs may show airflow obstruction l Methacholine challenge positive l Other lung disease excluded Many subsequent reports expanded the criteria, with the term IIA

Agents reported to cause IIA or RADS l Acids l Calcium oxide l Chlorine gas l Glacial acetic acid l Ammonia l Metam sodium l Isocyanates l Ethylene oxide l Tear gas l Phosgene l Welding fumes l Spray paint l Smoke inhalation l Locomotive exhaust l Silo gas l WTC dusts

Definitions will affect Prevalence Irritant-induced asthma (IIA) l IIA: as for RADS but exposure extended to one or more exposures to a high concentration of inhaled respiratory irritant, and onset of sx within 24h of this (others have extended the onset time up to 7 days post-exposure or even longer). l Prevalence of IIA in an occupational lung disease clinic (using criteria of 1 or more acute exposures), was 6% of 154 consecutive referrals (3% if restricted to RADS criteria, similar to Brooks’ prevalence) l 16% of all OA patients in the clinic had IIA, (8% RADS) ( Chest 1989)

Practical difficulties in diagnosis of IIA/RADS l Exposure levels often hard to assess l Emerg / physician visit may have been delayed l Usually no previous PFTs l Often a smoking or atopic history l PFTs / methacholine challenge may not have been done when sx were present l Often hard to exclude unrelated sx or disease l Pathology not clearly distinctive from other asthma

Prevalence of Irritant asthma effects in a Ontario compensation population l 9% of all accepted OA claims were for new-onset irritant-induced OA (IIA) [3% very probable, RADS] l 50% accepted work-related asthma claims were for aggravation of unrelated asthma (AA) »usually from moderate, allowable levels of respiratory irritants with previous asthma l Workplace inhalation accidents (19% of all accepted asthma claims) : »attributed symptoms shorter for AA v IIA ( 32d vs. 112d ), p<0.001 and less lost work (p<0.001). Chatkin et al, Chest 1999

Surveillance studies Prevalence, risks l Prevalence: »Ross and McDonald ‘96, 8% among all inhalation accidents reported to SWORD, (5% with PFT support) l Risk factors for an asthmatic response: »Blanc et al ‘93, poison centre, post- inhalation: self-reported wheeze increased with smoking (RR1.6) and prior asthma (RR1.3). Combined RR2.8 (CI )

Is the risk of sensitizer-induced OA greater with spills? l Some sensitizers can be irritant in high levels l A few documented cases of IIA and concurrent sensitization to the same agent (e.g. diisocyanates) [Leroyer et al Thorax ‘98] l SWORD report, risk of new asthma with reported spills was highest with spills of sensitizers [Ross, Ann Occ Hyg 1996]

Asthma RR with presumed non-massive irritant occupations ( * significant risk)

Radiographers in Ontario, l Cross-sectional questionnaire mail survey, MRTs, physiotherapists »Analyses involve 1110 MRTs and 1523 physiotherapists who never smoked Gary M. Liss, Susan Tarlo, J Purdham, J Doherty, M Kerr, L McCaskell OEM 2003

*adjusted for age and gender†adjusted for age **significant interaction with gender p=0.016‡adjusted for gender, age and childhood asthma WR = work-related RESULTS Asthma and Respiratory Symptoms

Examples of Work Tasks/ Exposures Past 12 months Associated with Respiratory Symptoms - Workplace Factors

Examples of Work Tasks/ Exposures Past 12 Months Associated with Respiratory Symptoms - Tasks (1) *  1/wk and daily vs never and < 1/wk

Examples of Work Tasks/ Exposures Past 12 months Associated with Respiratory Symptoms - Tasks (2)

Frequency of Exposures by Gender Past 12 months Percent Reporting

? Irritant effects l Increased new onset asthma among MRTs vs physios l Excess of resp symptoms among MRTs, l Only a subset of MRTs with asthma had IgE antibodies to GA l MRTs vs physios had induced sputum neutrophilia +/- respiratory symptoms but not eosinophilia l Associations with tasks and scenarios involving irritant exposures, but not with routine tasks, especially in men: l Workplaces of those with symptoms had higher levels of acetic acid and SO2 (although all levels were relatively low) »suggests work-related contribution due to possible irritants/ aerosol generation, especially among the men

WTC cough in firefighters with at least 4 weeks off work P<0.01 Prezant DJ, et al N Engl J Med 2002;347:

New York Fire Fighters Oct Self reported symptoms among those with cough (similar % in those with cough among all 3 exposure levels) l new or worsened GERD (82-88%), l post-nasal drip (33-42%) l exertional dyspnoea (94-96%) l wheeze (57-77%) l chest discomfort (82-86%)

Course of WTC cough l Medical attention for cough: incidence peaked 6-8 weeks after exposure l At that time cough was non-productive in 58% l 65% with cough but normal responsiveness returned to work vs 20% of those with hyperresponsiveness (RR 4.8 [CI ]) mostly by 4-6 months after exposure: normal PFTs / methacholine responses by time of return

Without WTC cough (103 firefighters) methacholine response RR exposure level 21.0 [CI ] P=0.01

6 month follow-up of 179 workers (none with WTC cough at entry) (Banauch et al AJRCCM ’03) l Methacholine responses at 1,3,6 months l Significant differences with exposure groups only seen by 3 months l High exposure – 6.8 x increased risk of hyper- responsiveness at 6 mo (CI ) (and dose- response slope rose 46% over time) l Hyper-responsiveness persisted to 6 months in 55% of those +ve at 1 or 3 months. l At 6 mo, 16% of all exposed had resp sx + hyper- responsiveness (20% with high exposure, 8% with moderate exposure).

WTC airway effects l Cough may have had several contributing causes (GERD/ PN Drip/ airway hyper- responsiveness l Findings support development of irritant- induced asthma/hyperresponsiveness, but time-course differs from previous criteria l This is the largest group of exposed workers with preceding medical surveillance l Should criteria for IIA be revised?

Endotoxin: irritant/? adjuvant? l Animal workers: 38-67% have rhinitis/asthma without animal sensitization l Pacheco et al (AJRCCM ‘03) in lab mouse workers found 22% had mouse-attributed sx but only 43% of these were sensitized to mice l Among those not sensitized, »rhinitis was associated with endotoxin (current and cumulative) but not mouse allergen. »Asthma was associated with both endotoxin and allergen even in non-sensitized workers

Controversy with IIA l How commonly do irritants cause asthma? l Should our criteria change for diagnosis? l How can coincidental asthma-onset be excluded, especially if atopy/smoking are risk factors also for IIA? l Endotoxin / fungal glucans effects? l What criteria should be used for Aggravation of asthma (currently mostly history-based)? l Compensation implications