Irritants and asthma variants

Susan M TarloToronto Western Hospital and

Gage Occupational and Environmental Health Unit,

University of Toronto

Respiratory irritant effects Sx which mimic asthma: e.g. transient eye / upper airway

irritation, ? RUDS, sx of vocal cord dysfunction, IEI, ? GERD Acute aggravation of underlying asthma Irritant-induced asthma (IIA: includes RADS) ? Increased risk of respiratory sensitization with concurrent

allergen exposures 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)

No preceding respiratory complaints Sx onset after a single specific exposure incident or accident Exposure was to a gas, smoke , fume, or vapor in very high

concentration and being an irritant Sx onset <24h of exposure, lasting >3mo. Sx simulate asthma PFTs may show airflow obstruction Methacholine challenge positive Other lung disease excludedMany subsequent reports expanded the criteria, with the term IIA

Agents reported to cause IIA or RADS

Acids Calcium oxide Chlorine gas Glacial acetic acid Ammonia Metam sodium Isocyanates Ethylene oxide

Tear gas Phosgene Welding fumes Spray paint Smoke inhalation Locomotive exhaust Silo gas WTC dusts

Definitions will affect PrevalenceIrritant-induced asthma (IIA)

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) .

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)

16% of all OA patients in the clinic had IIA, (8% RADS) (Chest 1989)

Practical difficulties in diagnosis of IIA/RADS

Exposure levels often hard to assess Emerg / physician visit may have been delayed Usually no previous PFTs Often a smoking or atopic history PFTs / methacholine challenge may not have been

done when sx were present Often hard to exclude unrelated sx or disease Pathology not clearly distinctive from other asthma

Prevalence of Irritant asthma effects in a Ontario compensation

population

9% of all accepted OA claims were for new-onset irritant-induced OA (IIA) [3% very probable, RADS]

50% accepted work-related asthma claims were for aggravation of unrelated asthma (AA)» usually from moderate, allowable levels of respiratory

irritants with previous asthma 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 studiesPrevalence, risks

Prevalence:» Ross and McDonald ‘96, 8% among all inhalation

accidents reported to SWORD, (5% with PFT support)

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 1.9-4.3)

Is the risk of sensitizer-induced OA greater with

spills?

Some sensitizers can be irritant in high levels

A few documented cases of IIA and concurrent sensitization to the same agent (e.g. diisocyanates) [Leroyer et al Thorax ‘98]

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)

Toren ‘99

Kogevinas ‘99

Karjalainen ‘01

Textiles 1.9* 1.59 1.49/1.34*

Cleaners 1.1 1.97* 1.61/1.51*

Welding 2.0* 1.26

Vapor/gas/ Fumes: s.r

1.19*

Vapor/gas Fumes: matrix

1.37*

Radiographers in Ontario,

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

Outcome MRTs (%)

Physios (%)

OR Adj (95% Cl)

P value

Asthma

Physician-diagnosed asthma

13.3 13.8 1.0* (0.8-1.3) 0.96

New onset-asthma 6.44 3.95 F: 1.3 (0.9-1.9) †

M: 5.3 (1.4-20.1) †

0.13 **

0.015**

Respiratory symptoms past 12 months

3 or more of 9 20.9 12.4 1.9 (1.5-2.3) ‡ <0.0001

2 or more WR 11.1 3.1 3.8 (2.7-5.4) ‡ <0.0001

3 or more WR 6.1 1.9 3.2 (2.0-5.1) ‡ <0.0001

* 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

0

0.1

0.2

0.3

0.4

0.5

0.6Odds Ratio

All machines have LEV Ventilation in area where films processedperceived as adequate

3 or more Respiratory Symptoms 2 or more WR Respiratory Symptoms

0.3-0.80.4-0.95 0.4-0.7

0.2-0.6

Examples of Work Tasks/ Exposures Past 12 Months Associated with Respiratory Symptoms - Tasks (1)

0

0.5

1

1.5

2

2.5

3Odds Ratio

Processor leak Delay of leak clean-up > 1 day

Floor drain clogged Free a film jam *

3 or more Respiratory Symptoms 2 or more WR Respiratory Symptoms

* 1/wk and daily vs never and < 1/wk

1.0-2.20.97-2.6

1.6-3.5 1.3-3.3

1.2-2.41.2-3.2

1.5-3.4

1.8-4.7

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

0

0.5

1

1.5

2

2.5

3Odds Ratio

Unblock processordrain †

Mix fixer/developer

chemicals †

Clean up aprocessor

chemical spill †

Detect odour ofprocessing

chemicals in work area ‡

3 or more Respiratory Symptoms 2 or more WR Respiratory Symptoms

1.6-3.8

1.0-3.1

0.9-1.7

1.1-2.51.5-2.7

1.9-4.2 1.7-4.3

1.2-2.4

0 10 20 30 40 50 60 70 80 90 100

Clogged drain

Removed used chemicals

Wet film developing

Unblock processor drain

Clean processor chemical spill

Clean processor (periodic)

Free film jam

Female (%) Male (%)

Frequency of Exposures by Gender Past 12 months

Percent Reporting

? Irritant effects

Increased new onset asthma among MRTs vs physios Excess of resp symptoms among MRTs, Only a subset of MRTs with asthma had IgE antibodies to GA MRTs vs physios had induced sputum neutrophilia +/-

respiratory symptoms but not eosinophilia Associations with tasks and scenarios involving irritant

exposures, but not with routine tasks, especially in men: 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

0

2

4

6

8

%

% with cough 8 3 1 0

high exposure

moderate exposure

low exposure

no exposure

P<0.01

Prezant DJ, et al N Engl J Med 2002;347:806-15.

New York Fire Fighters Oct 1-14 2001

Self reported symptoms among those with cough (similar % in those with cough among all 3 exposure levels)

new or worsened GERD (82-88%), post-nasal drip (33-42%) exertional dyspnoea (94-96%) wheeze (57-77%) chest discomfort (82-86%)

Course of WTC cough

Medical attention for cough: incidence peaked 6-8 weeks after exposure

At that time cough was non-productive in 58% 65% with cough but normal responsiveness

returned to work vs 20% of those with hyperresponsiveness (RR 4.8 [CI 2.5-9.2]) mostly by 4-6 months after exposure: normal PFTs / methacholine responses by time of return

Without WTC cough (103 firefighters) methacholine

response

0

5

10

15

20

25

%

methacholinehyperresponsiveness

23 8

High exposure Moderate exposure

RR exposure level 21.0 [CI 1.8-164] P=0.01

6 month follow-up of 179 workers (none with WTC cough at entry) (Banauch et al

AJRCCM ’03)

Methacholine responses at 1,3,6 months Significant differences with exposure groups only seen

by 3 months High exposure – 6.8 x increased risk of hyper-

responsiveness at 6 mo (CI 1.8-25.2) (and dose-response slope rose 46% over time)

Hyper-responsiveness persisted to 6 months in 55% of those +ve at 1 or 3 months.

At 6 mo, 16% of all exposed had resp sx + hyper-responsiveness (20% with high exposure, 8% with moderate exposure).

WTC airway effects

Cough may have had several contributing causes (GERD/ PN Drip/ airway hyper-responsiveness

Findings support development of irritant-induced asthma/hyperresponsiveness, but time-course differs from previous criteria

This is the largest group of exposed workers with preceding medical surveillance

Should criteria for IIA be revised?

Endotoxin: irritant/? adjuvant?

Animal workers: 38-67% have rhinitis/asthma without animal sensitization

Pacheco et al (AJRCCM ‘03) in lab mouse workers found 22% had mouse-attributed sx but only 43% of these were sensitized to mice

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

How commonly do irritants cause asthma? Should our criteria change for diagnosis? How can coincidental asthma-onset be excluded,

especially if atopy/smoking are risk factors also for IIA?

Endotoxin / fungal glucans effects? What criteria should be used for Aggravation of

asthma (currently mostly history-based)? Compensation implications