Long-Term Outcomes of Acute Irritant-induced Asthma

Jean-Luc Malo
1
, Jocelyne LArcheveque
1
, Lucero Castellanos
1
, Kim Lavoie
1
, Heberto Ghezzo
1
, and Karim Maghni
1
1
Axe de Recherche en Sante Respiratoire, Hopital du Sacre-Coeur de Montreal, Montreal, Quebec
Rationale: The long-termoutcomes of acute irritant-induced asthma
(IIA) are mostly unknown.
Objectives: To study the long-term outcomes of IIA.
Methods: We reassessed 35 subjects who experienced IIA at a mean
interval of 13.6 65.2 years.
Measurements and Main Results: The causal agent was chlorine in 20
cases (57%). At diagnosis, the mean 6 SD FEV
1
was 74.5 6 19.5%
predicted, and all subjects showed bronchial hyperresponsiveness.
At reassessment, all subjects reportedrespiratory symptoms, and24
(68%) were on inhaled steroids. There were no signicant improve-
ments in FEV
1
and FEV
1
/FVC values. Twenty-three subjects had
a methacholine test, and only six subjects had normal levels of
responsiveness. Of the remaining 12 subjects, six had improvement
in FEV
1
after bronchodilator >10%. In samples of induced sputum
obtained from 27 subjects, six had eosinophils >2%. Levels of
inammatory and remodeling mediators were higher than in con-
trol subjects but were no different from subjects with occupational
asthma due to sensitization. Quality of life score was 4.4 6 1.5 on
a 0 (worst) to 7 (best) scale. Twelve subjects had an abnormal
depression score.
Conclusions: This study provides therst evidenceof signicant long-
term impact of acute IIA on various outcomes.
Keywords: occupational asthma; reactive airways dysfunction syn-
drome; inammation, remodeling
Acute irritant-induced asthma (IIA), also named reactive air-
ways dysfunction syndrome, is a condition that is caused by an
inhalational accident that can happen at work (in which case it
is considered a type of occupational asthma [OA]) (1) or in the
general environment (2, 3). The most well-known outbreak of
this syndrome is the World Trade Center catastrophe, in which re
ghters were exposed to various contaminants (4). Most of the
cases of OA are caused by a specic sensitization to a workplace
agent, but 10 to 15% of the cases compensated in Ontario (5)
and Quebec (6) are caused by an inhalational accident.
Although acute IIA is considered a type of OA, there are
features that distinguish IIA from allergic OA. At the time of
the acute event, coughing is generally a predominant symptom.
Thereafter, bronchial obstruction, if present, does not respond
as well to bronchodilators (7), which might be explained by
marked airway remodeling and collagen deposition in the
bronchial wall, as shown in human (8) and animal models (9,
10). In addition, obliterative bronchiolitis has been described in
victims of the Bhopal accident (11) and, more recently, in
soldiers exposed to mustard gas (12).
The long-term outcome of allergic OA has been examined in
many studies that show clinical and functional recovery in about
one-third to one-fourth of cases (6), with persisting airway
inammation and remodeling even in subjects who become
asymptomatic and have normal airway function (13, 14). Few
studies have examined the outcome of subjects with IIA. In
a previous follow-up study performed 2.5 years after inhala-
tional accidents, we showed that 75% of subjects were left with
increased bronchial responsiveness (15).To the best of our
knowledge, no study has examined the long-term outcomes of
IIA, including quality of life and psychological status, these
indices being relevant to assess disability (16). We therefore
collected information on the long-term clinical, functional, airway
inammatory, and remodeling as well as of the psychological
disability of IIA.
METHODS
Subjects
We obtained from the Commission de la sante et se curite du travail du
Que bec (CSST) (the medicolegal agency that offers diagnosis and
compensation for claims due to work-related accidents and occupa-
tional diseases) the list of claimants who received compensation for
acute IIA from 1988 onward, as assessed by four committees of chest
physicians who offer expertise for the CSST (6). There were 0 to 10
claims accepted each year (6). The diagnosis of acute IIA was accepted
by the CSST provided the claimant had a suggestive history of a well-
identied inhalational accident followed by symptoms that appeared in
the rst 24 hours, had no previous history of asthma or chronic
obstructive lung diseases, and showed signicant airway obstruction
or hyperresponsiveness (see levels below) when they were assessed
3 months or more after the accident. Subjects then received full
compensation for lost salary (6) for a maximum period of 2 years if
they are unable to go back to work at their usual workplace. Workers
may return to work provided the risk of inhalational accident is no
longer present and if their respiratory condition is satisfactory for their
work. Generally, these subjects are reconvened by the CSST 2 years after
the inhalational accident to assess permanent impairment/disability that
is afforded as a lump sum. Therefore, at the time of assessment,
participants no longer received nancial assistance from the CSST
except for respiratory medication, which is refunded for good after the
diagnosis is accepted.
The protocol was examined by the ethics committee of Sacre -Coeur
Hospital, and each participant signed a consent form.
Design and Assessments
An open questionnaire was rst used to ensure that the subjects
respiratory symptomatology reected a stable status. Information
AT A GLANCE COMMENTARY
Scientic Knowledge on the Subject
The long-term clinical, psychological, and pathological out-
comes of acute irritant-induced asthma are mostly unknown.
What This Study Adds to the Field
Acute irritant-induced asthma has signicant long-term
impact on pulmonary function, quality of life and psycho-
logical parameters.
(Received in original form October 6, 2008; accepted in nal form February 19, 2009)
Supported by the Center for Asthma in the Workplace, Canadian Institutes for
Health Research, the Canadian and Quebec Lung Associations and the Institut de
recherche Robert-Sauve en sante et securite du travail du Quebec.
Correspondenceandrequests for reprints shouldbeaddressedtoJean-LucMalo, M.D.,
Department of Chest Medicine, Hopital du Sacre-Coeur de Montreal, 5400 West
Gouin Blvd, Montreal, PQ, H4J 1C5 Canada. E-mail: malojl@meddir.umontreal.ca
This article has an online supplement, which is available from the issues table of
contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 179. pp 923928, 2009
Originally Published in Press as DOI: 10.1164/rccm.200810-1550OC on February 20, 2009
Internet address: www.atsjournals.org
about medication was obtained from a questionnaire administered to
every subject by a trained research assistant.
Routine tests included spirometry (17) and assessment of bronchial
responsiveness to methacholine using a standardized procedure with
a Wrights nebulizer (output 5 0.14 ml/min) (18) if the FEV
1
was 1.5 L
or more. If the FEV
1
was less than 1.5 L, inhaled albuterol (200 mg) was
administered, and FEV
1
was assessed 20 minutes later. The additional
tests proposed to the participants were induced sputum; completion of
an asthma-specic quality-of-life questionnaire (Asthma Quality of
Life Questionnaire) (19); completion of the St. Georges Asthma
Severity Questionnaire (20); and completion of three psychological
questionnaires, the Psychiatric Symptom Index (PSI) (21), and the
Beck Depression (22) and Anxiety (23) Inventories (see online
supplement for details).
Sputum Analysis
Sputum samples were collected as previously described (24). Different
levels of sputum eosinophils were considered, and signicant eosino-
philic airway inammation was dened when sputum eosinophils were
>2%. The percentage of neutrophils was also assessed, and values
above 60% were judged to be elevated. The supernatant of induced
sputum was examined for inammatory and remodeling mediators.
Structural markers of the ongoing airway remodeling were determined
after concentration of sputum samples on Amicon columns as pre-
viously described (13). Procollagen type I C Peptide (Takara Mirus
Bio, Otsu, Japan) was quantied as a marker of collagen synthesis, and
C-terminal telopeptide of the collagen type I (Nordic Bioscience
Diagnostic, Herlev, Denmark) as a marker of collagen synthesis (25)
(see online supplement for details). Results were compared with two
groups of subjects: (1) 10 normal subjects (9 men, 1 women, 26 6 8
years of age, all nonsmokers, with no respiratory symptom and normal
responsiveness to methacholine) entering an apprenticeship program in
spray-painting and (2) 10 subjects with conrmed allergic OA and still
symptomatic of asthma and with a positive methacholine challenge
2 years after cessation of exposure who took part in a previous
study (16).
Analysis of Results
Reference values used for spirometry were taken from Knudson and
colleagues (26). Signicant airway obstruction was dened as a FEV
1
,80% predicted and/or a FEV
1
/FVC ,70%. Signicant bronchial
hyperresponsiveness was set at a provocative concentration of meth-
acholine causing a 20% fall in FEV
1
(PC
20
) <16 mg/ml (27).
Logarithmic transformation of PC
20
was used for the statistical anal-
ysis. Changes in PC
20
were considered signicant when there was a
twofold or greater difference from the value obtained at the time of
diagnosis (28).
Continuous variables that were normally distributed were
expressed as mean 6 SD. The other variables were expressed as
median and interquartile ranges. Statistical analysis included unpaired
t test, Kruskal-Wallis test, and regression coefcients. They were
performed by means of a statistical software package (SPSS for
Windows, version 16). The level of statistical signicance was set at
a P , 0.05 unless there were multiple comparisons, for which
Bonferronis correction was applied.
RESULTS
Of 68 eligible subjects, 35 (52%) participated. Of the 33 non-
participants, 14 could not be traced, 14 refused to participate, and
5 lived in remote areas. Participants (Table 1) and nonpartici-
pants were not different in terms of age, gender, and type of
causal agent. However, the interval since the accident was longer
in nonparticipants, although this difference did not reach signif-
icance. Some information was not available (the need for an
emergency visit and treatment with inhaled steroids) or were
partially available (smoking) at the time of diagnosis in non-
participants. At the time of follow-up, 21 workers were retired, 12
were still at work, and 2 were unemployed. Although the mean
interval since the inhalational accident was 13.6 6 5.2 years
(range, 424 yr) (Table 1), the interval since the diagnosis was
accepted by the CSST was 12 6 4.6 years (range, 322 yr). Table
1 shows that respiratory symptoms were common at the time of
follow-up, wheezing being present in 80% of subjects. One third
of the subjects were on inhaled steroids. The current symptom
scores obtained from the St. Georges questionnaire were rela-
tively high. About one third of the participants had a psycholog-
ical distress score considered to be abnormal. Nine subjects were
judged to experience mild, moderate, or severe depression
according to the Beck Inventory score, and ve subjects had
moderate to severe anxiety.
Table 2 lists results of pulmonary function tests and of
inammatory cells in induced sputum. Airway caliber assessed
at an interval close to the accident was more satisfactory,
although not signicantly, in nonparticipants. There were no
signicant changes in FEV
1
and in FEV
1
/FVC(%) from the
time of the inhalational accident. Approximately half of the
subjects had a FEV
1
,80% predicted at baseline and at follow-
up visits, whereas nearly one third had an abnormal FEV
1
/FVC
ratio. Mean baseline FEV
1
and FEV
1
/FVC values as well as
proportions of subjects with normal values for these indices
were higher in nonparticipants, but these differences were not
statistically different. Methacholine inhalation tests were possi-
ble in 23 subjects at follow-up because these subjects had
a FEV
1
>1.5 L. Although overall there were no signicant
changes in PC
20
at follow-up, six subjects (6/23, 26% or 6/35,
17%) had a normal PC
20
value at follow-up, and three others
had improved their PC
20
by twofold or more. Of the 12 subjects
who were administered a bronchodilator because their FEV
1
was ,1.5 L, four had an improvement in FEV
1
of 20% or more,
one had improvement between 16 and 19%, and three had
improvement from 11 to 15%.
Induced sputum was obtained and interpretable in 27 subjects.
Six subjects (22%) had eosinophils >2%, and 8 subjects (30%)
had neutrophils >60%. Table 3 shows signicantly higher levels
in IIA subjects by comparison with normal control subjects for
the majority of inammatory and remodeling mediators, includ-
ing all MMPs tested, except for MMP-1, MMP-3, and MMP12.
Levels were not signicantly different from those for subjects
with allergic OA, however. The control subjects with allergic OA
were not signicantly different from the IIA subjects who pro-
duced interpretable sputum in terms of sex (90% vs. 85% men),
age (48 6 12 vs. 56 6 13 yr), current smoking habits (40% vs.
33%), current use of inhaled steroids (60 vs. 56%), FEV
1
(80 6
16% vs. 71 621% predicted), and FEV/FVC (72 610% vs. 69 6
12%). There were no signicant correlations between levels of
sputum mediators on the one hand and anthropometric (such as
age), clinical (such as interval since diagnosis), functional, and
psychological outcomes on the other hand.
There were no signicant differences in the functional,
inammatory, and psychological outcomes based on the need
for a visit to an emergency room or hospitalization at the time
of the acute event or to the type of causal agent (chlorine vs.
others). Smokers at the time of diagnosis had signicantly lower
FEV
1
(55 6 23% predicted) and FEV
1
/FVC (61 6 14%) values
at follow-up compared with with nonsmokers (80 6 20%
predicted for FEV
1
and 75 6 11% for FEV
1
/FVC%; P 5 0.002
for both comparisons). However, smokers at follow-up did not
have signicantly lower FEV
1
(63 6 23% vs. 74 6 24%
predicted) and FEV
1
/FVC (64 6 12% vs. 72 6 14%) compared
with nonsmokers at the same visit. The nine subjects who showed
a normal level of PC
20
(n 5 6) or improved their PC
20
by twofold
or more (n 53) compared with the 26 other subjects who showed
no signicant improvement: (1) Their results were not signi-
cantly different regarding interval since the inhalational accident
(12.1 6 5.7 vs. 14.1 6 5.0 yr), gender (7/9 men vs. 21/26 men), or
924 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
smoking habit at the time of diagnosis (2/9 vs. 12/26 smokers) and
follow-up (3/9 vs. 9/26 smokers); (2) they were signicantly
younger at the time of the inhalational accident (37.8 6 11.4
vs. 47.3 6 10 yr; P 5 0.02) and at follow-up (49 6 12 vs. 59 6
12 yr; P , 0.01); (3) they tended (P 5 0.1) to have a higher FEV
1
at the time of the rst assessment after the accident (82.2 621 vs.
71 6 19% predicted); (4) they had a signicantly (P 5 0.05)
higher PC
20
at the time of the rst assessment after the accident
(5.87 vs. 1.12 mg/ml); and (5) they showed signicantly higher
FEV
1
(89.5 6 12.9 vs. 63.5 6 23.8% predicted; P 5 0.005) and
FEV
1
/FVC (79 6 8% vs. 66 6 14%, P 5 0.02) at the time of
follow-up.
DISCUSSION
Our study shows that the long-term outcome of subjects with
IIA is at least as poor as that found in subjects with allergic OA.
From the functional point of view, only six subjects (17%) included
in the current study had normal airway caliber and responsive-
ness at follow-up. This is to be compared with 28 cured subjects/
103 subjects (27%) with allergic OA who were examined at
a mean interval of 9 years after stopping exposure (13).
Subjects included in our study are workers who applied to
the Workers Compensation Board, suggesting that the inhala-
tional accident was severe. This is also shown by the fact that
half of the subjects consulted in an emergency room or were
hospitalized, the other half paying a visit to their physician for
this specic purpose. The nonparticipants had less signicant
airway obstruction at an interval close to the accident (although
not signicantly so), which also suggests that our sample is
representative of a more severe subset of IIA. There are
probably many instances of IIA in workers who do not see
a physician because they experience short-lived coughing (29).
It is possible that these subjects may experience a more
satisfactory recovery.
A previous follow-up study of 25 subjects with IIA was
performed 2.5 years after the inhalational accident that was due
to chlorine (15). Only 25% had a normal level of bronchial
responsiveness, a slightly higher proportion than in the current
study (17%). This suggests that the time-course of improvement
in allergic OA and in IIA can differ. In allergic OA, the
maximum improvement occurs in the rst 2 years and slows
down thereafter (30). It is possible that in IIA there is no
improvement after the 2.5-year time point.
TABLE 1. ANTHROPOMETRIC AND CLINICAL CHARACTERISTICS OF SUBJECTS
Participants (n 5 35) Nonparticipants (n 5 33)
Sex, male/female 29(83%)/6(17%) 30(90%)/3(10%)
Age at diagnosis, years 45 6 11 42 6 10
Interval since inhalational accident, years 13.6 6 5.2 19.1 6 23.3
Visits to an emergency room 18 (51%)
Treatment with inhaled steroids at diagnosis 12 (34%)
Agents, chlorine/others 20(57%)/15(43%) 14(42%)/19(58%)
Smoking at diagnosis 14 (40%) 7/15 (47%)
Smoking at follow-up 12 (34%)
Current symptoms
Daytime wheezing 28 (80%) NA
Dyspnea 32 (91%) NA
Cough 20 (57%) NA
Current treatment with inhaled steroids 12 (34%) NA
Current symptom score* 356 (276455) NA
Current psychological status
Psychological distress PSI
Anxiety score 18 (1233) NA
Number with score .25 11 (31%) NA
Depression score 20 (740) NA
Number with score .25 14 (40%) NA
Anger score 17 (042) NA
Number with score .25 14 (40%) NA
Cognitive disturbance score 17 (033) NA
Number with score .25 10 (29%) NA
Total score 17 (932) NA
Number with score .25 12 (34%) NA
Beck Depression Inventory score 8.1 (3.215.3) NA
Mild depression (score 1419), n 2 NA
Moderate depression (score 2028), n 2 NA
Severe depression (score 2963), n 5 NA
Beck Anxiety Inventory score 10 (419) NA
Mild anxiety (score 21 to ,35), n 5 NA
Moderate to severe anxiety (score >35), n 3 NA
Current quality of life

Symptom 4.2 (3.35.6) NA

Limitation in daily activities 4.1 (2.35.4) NA
Emotional aspects 5.6 (3.46.6) NA
Reactions to environmental stimuli 4.3 (2.55.5) NA
Total score 4.3 (3.35.9) NA
Mean 6 SD values are given except for symptom score and all psychological and quality of life indices for which median and rst
and third quartile values (in parentheses) are shown.
Denition of abbreviations: NA 5 not assessed; PSI 5 Psychiatric Symptom Index.
* St Georges Asthma Severity Questionnaire (scale from 0 to 662 [severe]).

Scale from 1 (bad) to 7 (excellent).

Malo, LArcheveque, Castellanos, et al.: Outcomes of Acute Irritant-Induced Asthma 925
In the current study, we assessed levels of psychological
distress using a general symptom index (the PSI), a depression
inventory, and an anxiety inventory. Levels of psychological
distress observed in the present study were moderately elevated
according to scores on the PSI: average levels of anxiety,
depression, and cognitive disturbance were in the clinical range
(.25), suggesting that the psychological consequences of IIA
are not only signicant but also affect a range of psychological
functions. Subjects who experienced IIA are highly anxious, and
some experience depression, a nding that is consistent with
previous studies of OA (16) and subjects with nonoccupational
asthma (31). However, the frequency of depressive and anxious
symptomatology in this study were much higher than those
observed in Lavoie and colleagues study on tertiary care
patients with asthma, which reported rates of anxiety disorders
at 23% and rates of depressive disorders at 20% (31). The study
by Lavoie and colleagues reported frequencies of actual psy-
chiatric disorders assessed using a psychiatric interview rather
than levels of anxious and depressive symptomatology assessed
via self-report questionnaires. The former method may provide
a more conservative estimate of rates of anxiety and depression
than self-report questionnaires (32).
Six subjects had increased levels of eosinophils (22%), and
eight subjects (30%) had neutrophils >60%. This is close to the
18% and 26% of subjects with increased eosinophils and
neutrophils, respectively, found in a follow-up study of allergic
TABLE 2. FUNCTIONAL AND INFLAMMATORY STATUS NONPARTICIPANTS
Participants Nonparticipants
Baseline (n 5 35) Follow-up (n 5 35) Baseline* (n 5 23)
FEV
1
% predicted 74.5 6 19.5 70.2 6 24.3 81.1 6 19.5
n with values ,80% predicted 19 (54%) 20 (54%) 9 (39%)
FEV
1
/FVC
% 72.6 6 11.2 69.5 6 14.0 77.3 6 8.8
n with values ,70% 13 (37%) 12 (34%) 4 (17%)
PC
20
(mg/ml)
n with values <16 mg/ml 30/30 (100%)

17/23 (74%)

23 (100%)
Induced sputum (n 5 27) (median
with Q1Q3
x
values)
Total cells 3 10
6
3.5 (2.65.4)
Eosinophils (%) 0.8 (01.7)
n with values >2% 6 (22%)
Neutrophils (%) 49 (2667)
n with values >60% 8 (29%)
* Values at baseline were available in 23/33 (70%) nonparticipants.

Five subjects with FEV

1
values , 1.5 liters in whom methacholine testing was not done.

Reversibility of FEV
1
after inhaled bronchodilator in 12 subjects who had baseline FEV
1
values , 1.5 liters; , 5%: two subjects;
510%: two subjects; 1115%: three subjects; 1619%: one subject; > 20%: four subjects.
x
Q1Q3 5 values for the rst and third quartiles of distribution.
TABLE 3. INFLAMMATORY AND REMODELING MEDIATORS
Mediators
Normal Control
Subjects (n 5 10)
Allergic Occupational
Asthma (n 5 10)
Acute Irritant-induced
Asthma (n 5 20)
ECP, ng/ml 9.8 (815)
,
95 (53268)
x,{
72 (31194)
MPO, ng/ml 60 (2696) 166 (71272)
,{
314 (219446)
IL-8, ng/ml 0.009 (0.0060.02)
,x
0.05 (0.030.18)
,{
0.2 (0.10.26)
TIMP-1, ng/ml 8.4 (6.326)
,
139 (104170)
,{
115 (64157)
PIP, ng/ml 0.03 (0.030.2) 1.1 (0.52.3)
,{
4.2 (2.415)
ICTP, ng/ml 0.29 (0.190.4) 0.1 (0.060.13) 0.08 (0.050.2)
TGF-b pg/ml 0.004 (0.0020.01) 0.08 (0.10.2)
x,{
0.1 (0.20.2)
MMP-1, pg/ml 9.1 (9.19.1) 30 (9.180) 9.1 (9.139)
MMP-2, pg/ml 81 (8181) 81 (81291)
x,{
194 (105548)
MMP-3, pg/ml 16 (1616) 21 (16117) 44 (16108)
MMP-7, ng/ml 0.05 (0.010.2)
,
1.9 (0.90.29)
,{
1.3 (0.627)
MMP-8, ng/ml 0.2 (0.090.5)
,x
1.8 (0.82.3)
,{
2.9 (1.55.7)
MMP-9, ng/ml 2.4 (1.63.8) 4.5 (3.88.7)
,{
7.7 (5.813.1)
MMP-12, pg/ml 93 (15194) 48 (15140) 68 (15139)
VEGF, ng/ml 0.03 (0.020.05)
,
0.18 (0.10.2)
,{
0.2 (0.10.3)
bFGF, pg/ml 6 (1.519)
,
70 (43100)
,{
73 (30100)
PDGF, pg/m) 0.5
,
1.7 (0.511)
,{
9.5 (3.920)
See online supplement for mediators.
* Median with rst (Q1) and third (Q3) quartiles values of distribution (in parentheses) except for PDGF values in control subjects,
where all values equaled the lowest detectable concentrations (i.e., 0.5).

P < 0.001.

Comparison between normal controls and subjects with allergic occupational asthma.
x
Statistically signicant at P < 0.01.
{
Comparison between normal controls and acute irritant-induced asthma subjects. There were no signicant differences
between subjects with allergic occupational asthma and acute irritant-induced asthma. See text for description of normal control
subjects and subjects with allergic occupational asthma. MMP-13 was also assessed; levels were undetectable in all samples tested
except for two subjects with acute irritant-induced asthma.
926 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 179 2009
OA (13) of similar duration. As shown in the current study,
similarities are also found in the proles of inammatory and
remodeling mediators that were not signicantly different in
IIA and subjects with allergic OA, although they were signif-
icantly higher than in control subjects. Therefore, from an
inammatory and remodeling point of view, the outcome
of IIA does not seem to differ from what is seen in allergic OA,
at least as regards information obtained from induced sputum.
The physiopathology of IIA that has been examined in rat and
mouse models involves an acute shedding of the airway mucosa
(9) and an oxidative process (10). The epithelial injury causes
cell release of inammatory mediators that lead to lymphocyte
recruitment as evidenced by increased lymphocytosis in bron-
choalveolar lavage 2 and 6 months after an inhalational accident
(33). In a model of IIA in rats, increased numbers of neutrophils
and lymphocytes have also been described in bronchoalveolar
lavage uid (9). Subsequent release of inammatory and
remodeling mediators is therefore likely (3). Analysis of sputum
in subjects with IIA revealed the same type of alterations in
mediators involved in airway inammation and remodeling as in
other forms of chronic asthma (34), including allergic OA, as
found in our work.
We cannot not exclude the possibility that some subjects
included in our study were affected with obliterative bronchio-
litis, which has been described after inhalational accidents, such
as the Bhopal event due to methylisocyanate (35) and in
soldiers exposed to mustard gas (12). CT scans and open lung
biopsies were not performed in our subjects and biopsies
provided information on central and not peripheral airways.
The type of the causal agent (chlorine vs. others), the
interval since the accident, and a visit to an emergency room
or a hospitalization did not inuence the prognosis. However,
being a smoker at the time of the inhalational accident resulted
in lower airway caliber at follow-up, which might suggest that
smoking plays an additive role. In a prospective study of 3 years
duration in workers exposed to puffs of chlorine, Gautrin and
coworkers showed that smoking and the number of puffs of
chlorine (dened by the occurrence of symptoms that did not
result in visits to the rst-aid unit) exerted a signicant additive
effect on the diminution in airway caliber and on the increase in
responsiveness with time (29). Being older and having greater
hyperresponsiveness at the time of the accident were associated
with the absence of recovery or improvement in PC
20
at the
follow-up. Having a lower PC
20
at the time of diagnosis and
a longer duration of exposure with symptoms are also generally
associated with a worse prognosis in the case of allergic OA (6).
It is possible that it is not the duration of exposure with symp-
toms per se but rather the age (i.e., the fact that these subjects
are older when they stop being exposed) that exerts a deleteri-
ous effect on recovery.
The participation in our study was 52%. However, we do not
think that our results were biased because nonparticipants were
not signicantly different from participants in terms of the
variables that may have affected outcomes, such as age and
baseline spirometry.
In conclusion, by comparison with a long-term follow-up
of subjects with allergic OA of similar duration, subjects with
IIA show a comparable lung function prognosis (13). The
inammatory cell (eosinophils, neutrophils) proles in induced
sputum are also similar (13). This study, which is the rst to
assess inammatory and remodeling mediators in induced
sputum, shows a prole similar to the one shown in allergic
OA after removal from exposure. The psychological outcome in
terms of proportion of depression and anxiety is also similar
(16). It would be relevant to examine pathological airway
changes to see how these compare with nonoccupational and
occupational asthma because previous studies have shown
distinctive features (7, 8).
Conict of Interest Statement: None of the authors has a nancial relationship
with a commercial entity that has an interest in the subject of this manuscript.
Acknowledgment: The authors thank Kate Lieber for reviewing this manuscript.
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