Review

10.1586/1744666X.1.1.123 2005 FutureDrugsLtd ISSN 1744-666X 123 www.future - d rug s.c om

Occupational asthma: risk factors,
diagnosis and preventive measures
Paul Cullinan
Department of Occupational and
Environmental Medicine,
Royal Brompton Hospital/
Imperial College(NHLI),
London, UK
Tel.: +44 207 351 8328
Fax: +44 207 351 8336
p.cullinan@imperial.ac.uk
KEYWORDS:
asthma, diagnosis, epidemiology,
irritant, occupation, occupational
asthma, prevention
In a dulthood, ne w or re c urre nt a sthma is c a use d by work in a pproxima te ly 10% of c a se s.
The te rm oc c upa tiona l a sthma is re se rve d for those c a se s a rising from re spira tory
hype rse nsitivity to a spe c ific workpla c e a ge nt; in othe rs ( work- e xa c e rba te d a sthma ) the
me c ha nism is of nonspe c ific a irwa y irrita tion on a ba c kground of bronc hia l hype r- re a c tivity.
Some 300 workpla c e a ge nts a re c a pa ble of induc ing a sthma de novo; fortuna te ly, most
c a se s a re a ttribute d to a muc h sma lle r numbe r to whic h e xposure oc c urs in a fe w high- risk
oc c upa tions. Exposure le ve l is the most importa nt re me dia ble risk fa c tor; the fa c tors
gove rning individua l susc e ptibility a re poorly unde rstood. Dia gnosis is ge ne ra lly
stra ightforwa rd. Ma na ge me nt is ra re ly pha rma c olog ic a nd ofte n diffic ult sinc e the
dia gnosis inc urs importa nt e mployme nt a nd othe r soc ia l c onse que nc e s.
Expert Rev. Clin. Immunol. 1(1), 123132 (2005)
Asthma is termed occupational when it is initi-
ated by an inhaled workplace agent. Classi-
cally, occupational asthma results from an
immediate-type hypersensitivity response to an
airborne allergen or haptenprotein conjugate.
Patients with pre-existing asthma or bronchial
hyper-responsiveness whose condition is exac-
erbated by any one or more of a limitless
number of workplace irritants are said to have
work-exacerbated asthma. Often the distinc-
tion between occupational and work-exacer-
bated asthma is difficult; indeed some claim it
is unhelpful [1]. In either instance, an employee
has developed asthma as a result of a workplace
exposure. It is not clear whether the progno-
sis of such asthma is related to its mecha-
nism and, arguably, the broad implications
for management and prevention are similar.
However, most jurisdictions view occupa-
tional asthma as especially undesirable and
the distinction from work-exacerbated
asthma has important legal consequences for
the industry responsible.
Asthma may also arise at work from the
inhalation of toxic quantities of irritant fumes
that do not, as far as it is known, give rise to
allergic responses. First described in 1985 as
reactive airways dysfunction syndrome
(RADS), this is now more commonly termed
irritant-induced asthma [2]. The original
description was of a disease functionally
indistinct from asthma, including heightened
bronchial responsiveness, consequent on a
single, high-dose exposure in the context of
normal lung function. More recently, it has
been proposed that lower repeated exposures
to irritant compounds might induce the
same disease, but the evidence remains
inconclusive. The incidence of high-dose
irritant-induced asthma is unknown but it is
certainly less common than hypersensitive
occupational asthma.
C a usa tive a g e nts & p a thop hysiology
Some 300 agents have been recognized as
being capable of inducing occupational
asthma; a useful list is provided by Bernstein
and colleagues [3]. Happily for the clinician
and the policy maker, far fewer are responsible
for the bulk of disease in most industrialized
countries. In clinical practice it is probably
most useful to be familiar with the occupations
that incur high risk of asthma rather than with
the responsible agents. Lists of important such
occupations are given in TABLE 1. At the same
time, a high index of suspicion should be
retained for any patient presenting with adult-
onset (or recurrent) asthma, especially when
this has occurred shortly after commencing
new employment. Any airborne protein
CONTENTS
Ca usa tive a ge nts &
pa thophysiology
Dise a se fre que nc y
Risk fa c tors
Dia gnosis
Outc ome s
Pre ve ntion
Expe rt opinion &
five - ye a r vie w
Informa tion re sourc e s
Ke y issue s
Re fe re nc e s
Affilia tion
For re p rint ord e rs, p le a se c onta c t re p rints@future - d rug s.c om
C ullina n
124 Expert Rev. Clin. Immunol. 1(1), (2005)
should be considered as a potential sensitizing agent; every year
a dozen or so occupational agents capable of inducing asthma
are newly identified. The wise physician must always take a
careful occupational history.
For convenience, occupational respiratory sensitizing agents
are generally categorized as being of either high or low mole-
cular mass. The former are of biologic origin, often proteins,
and are understood to act as complete allergens capable of cross-
linking immunoglobulin (Ig)E antibodies on cell surfaces and
of producing an immune response characterized by the produc-
tion of T-helper (Th)2 cytokines and the induction of specific
IgE antibodies. In these ways they mimic the action of, for
example, house dust mites or cat allergens in the initiation of
asthma in childhood. Important high-molecular-weight occu-
pational allergens include proteins excreted by laboratory ani-
mals, flour allergens, enzymes used in the food and detergent
industries and proteins arising from natural rubber latex.
Low-molecular-mass or chemical agents probably act as
haptens, becoming allergenic only after conjugation with one
or more autologous or heterologous proteins. Some of these
notably the various acid anhydrides and complex platinum
salts appear to induce asthma through a typical allergic
Th2-type mechanism with attendant specific IgE production.
In some cases of asthma induced by diisocyanates an impor-
tant group of causative agents a similar mechanism may be
responsible; serum-specific IgE antibodies to conjugates of
diisocyanate and human serum albumen are detected in
approximately a third of cases. In the remainder, and for most
other low-molecular-weight allergens, mechanisms appear to
be non-IgE associated, are probably more complex and may
be comparable with nonatopic asthma encountered outside
the workplace [4]. As in patients with nonoccupational intrin-
sic asthma, T-cell clones from patients with asthma induced
by toluene diisocyanate are largely CD8
+
and capable of
inducing the production of interleukin (IL)-5 and interferon
(IFN)- [5]. A similar process has been demonstrated in T-cells
stimulated with plicatic acid, the chemical agent implicated in
asthma induced by workplace exposure to red cedar [6].
Repeated invitro antigenic stimulation of peripheral mono-
nuclear cells from patients with diisocyanate asthma induces
the production of C-C cytokine, mononuclear chemoattract-
ant protein-1 and tumor necrosis factor- in the absence of
IL-4 or -5 [7]. Sputum neutrophilia induced by controlled
exposure to diisocyanates may be related to leukotriene B
4
,
perhaps enhanced by IL-8 release and/or an increase in leuko-
triene B
4
receptor expression [8]. Neurogenic inflammation
may also play an important role; in animal models, toluene
diisocyanate stimulates the release of both calcitonin gene-
related peptide and substance P and inhibits neural
endopeptidase [9]. It is not known whether this is important
in human disease.
Dise a se fre q ue nc y
Estimates of the frequency of occupational asthma are
derived in three ways. While two are generic, the third is
workplace specific.
Table1. Workplace agents and occupations associated with a high risk of occupational asthma.
High-molecular-mass allergens Low-molecular-mass allergens
Agent(s) Occupation(s) Agent(s) Occupation(s)
Rat, mouse, guinea-pig, hamster
and other animal proteins
Laboratoryanimal researchers
and technicians
Diisocyanates Spraypainters, French polishers,
plasticsand foam manufacturers
Flour(s), -amylase and
other enzymes
Baking, milling, pastryand
pizza making
Acid anhydridesand epoxyresins Plasticsand foam manufacturers
and assemblers
Egg proteins Laboratoryanimal researchers
(embryology), bakersand food
processors
Colophonyfume Electronic solderers
Prawn, crab and other (shell)fish
proteins
Seafood processors Glutaraldehyde, methyl/butyl
methacrylate
Healthcare workers
Latex Healthcare workers Penicillins, morphine, cimetidine Pharmaceutical manufacturers,
healthcare workers
Detergent protease, amylase,
lipase and cellulase
Detergent enzyme manufacturers Red cedar, iroko and other
tropical sawdusts
Woodworkers, lumberjacks
Herbal teasand green coffee bean Tea packersand coffee processors Reactive dyes Textile workers
Garlic and enzymes Other food processors Persulfates Hairdressersand manufacturers
of circuit boards
Pollens Flower and vegetable farmers Complex platinum salts
and chrome
Metal refinersand electroplaters
O c c up a tiona l a sthma
www.future-drugs.com 125
Is a sthma a ttributa ble to oc c upa tiona l exposure ?
A number of epidemiologic studies have attempted to esti-
mate the proportion of adult asthma that is attributable to
occupational exposures. Each uses a stochastic approach to
causation, based in probabilities, and is thus very different
from the individual approach used in clinical practice and in
the surveillance schemes described below. Their method
begins by measuring the frequency of disease in a representa-
tive sample of the community under study and then relates
the excess risk of asthma in separate occupational groups to
the risk in a referent (unexposed) group, generally office
workers. The sum of increased occupation-specific risks is
used to generate an estimate of the total proportion of disease
attributable to occupational exposures.
The body of such studies is usefully summarized by Blanc
and Toren, whose systematic review includes a meta-analysis
indicating that approximately one in ten of all incident or
recurrent cases of adult asthma is caused by workplace expo-
sures [10]. Population-based methods such as these are useful in
a public health context and perhaps also in the identification of
the increased risks of asthma among occupational groups not
traditionally recognized in clinical practice. Two such examples
include cleaners [11] and bar staff [12].
Population-based methods do not easily distinguish occupa-
tional from work-exacerbated asthma. Furthermore, it is not
always clear whether the apparently high rates of asthma in
some occupations arise from a risk inherent to a job or
whether people with asthma migrate to that job, an issue of
directionality. Remarkably little is known about the extent and
nature of the processes that determine job selection by people
with asthma.
Surve illa nc e sc he me s
In several countries notably Finland, the UK, France and
parts of the USA and Australia established surveillance
schemes exist for occupational lung diseases including
asthma. In some instances these are embedded in programs
that cover all occupational diseases. In each case the schemes
measure disease recognized and reported by specialized phy-
sicians, generally in occupational or respiratory medical
practice. Where denominators are available, occupation-spe-
cific incidence rates may be estimated, although these are
often crude.
Surveillance of this nature sacrifices sensitivity complete-
ness of disease capture for practicality, rapidity and uni-
formity. As a result, the true incidence of occupational
asthma is underestimated perhaps by as much as two- or
threefold and especially so when the workforce denominators
are nonspecific [13].
Nonetheless, surveillance schemes provide valuable informa-
tion on the approximate size and distribution of the problem at
a national level. Using such methods, the annual incidence of
occupational asthma in industrially developed societies is esti-
mated to reside between 12 and 170 casesper million employees,
with a median value of 47 cases per million [10,1416].
Alternative surveillance methods rely on the enumeration of
compensation claims or mandatory industrial notifications for
occupational asthma. The completeness of these methods is
dependent on a variety of external factors and is poorly under-
stood. In general they provide substantially different estimates
from the clinical schemes above.
Workpla c e / oc c upa tiona l me thods
The third measurement technique is specific to an occupation
or workplace. Estimates of the prevalence and more occa-
sionally incidence of occupational asthma within a work-
place or industrial group are made using standard cross-sec-
tional or cohort epidemiologic techniques, or by analysis of
records from routine health surveillance. The latter technique
may underestimate the true frequency of disease if the methods
of surveillance (generally questionnaires and spirometry) are
insensitive. Workplace methods provide valuable information
on the frequency of disease in high-risk settings but may be
difficult to generalize.
These methods provide little evidence that the overall inci-
dence of occupational asthma in the industrially developed
world isfalling; the trend generally appearsto be flat. It isnot
known to what extent thisreflectsgreater ascertainment of dis-
ease, the wider use of potential respiratory-sensitizing agents in
industry, a more susceptible population or the continuing failure
of disease control in high-risk industries.
There are notable exceptions to this pattern. For example,
latex asthma among healthcare workers appears to have been
largely prevented by the use of powder-free, low-protein latex
gloves [17], and asthma among manufacturers of biologic deter-
gent powders is much less common than previously [18].
Asthma among farmers in Finland has decreased dramatically,
probably following changes in agricultural practice. Issues of
disease prevention are discussed in greater detail below.
Risk fa c tors
As in many, if not most diseases, the factors recognized to
increase the risk of occupational asthma are both external and
host related. Several have been identified and reasonably well
characterized.
High exposure to a causative allergen increases the risk of
both specific IgE production and occupational asthma. Expo-
sureresponse relationships have been clearly demonstrated for
several workplace sensitizing agents including laboratory ani-
mal allergens, detergent enzymes, diisocyanates, latex, acid
anhydrides and flour dust in bakeries and mills [1826]. In some
cases, the evidence is stronger than for others; and the relation-
ships are generally more clear cut for the development of spe-
cific IgE sensitization than they are for occupational asthma, a
less frequent outcome. In every case the detailed shape of the
relationship is incompletely understood; it is suspected to be
of a sigmoid nature with an attenuation of the risk gradient at
higher doses of exposure [20]. For some agents and perhaps
most the thresholds for sensitization and asthma appear to
be extremely low. This implies that exposure control in the
C ullina n
126 Expert Rev. Clin. Immunol. 1(1), (2005)
primary prevention of all cases may be difficult to achieve in
practice. There may be important analogies with the role of
domestic allergen exposures in childhood disease [27].
The hypersensitive nature of most types of occupational
asthma and the obvious fact that not all exposed workers
develop the disease implies that there are important factors
governing individual susceptibility. Atopic employees who
readily produce an IgE response to inhaled aeroallergens are,
unsurprisingly, at a clearly increased risk of occupational sensi-
tization and asthma following exposure to high-molecular-
weight allergens [20,2830]. There is probably no increase in risk
incurred with most low-molecular-weight exposures, at least
where these are not associated with specific IgE antibody pro-
duction. Where relevant, atopy appears to increase risks
between two- and fourfold. The increasingly high prevalence of
the trait in young European populations means that it is poorly
discriminatory in both clinical and employment practice and is
likely to become more so. This pattern also implies that an
increasingly susceptible population of young adults is now
entering the labor market.
In the past 10 years, interest has emerged in the potential role
of genetic markers and, to a lesser extent, in the interaction
between these and environmental exposures in the risk profile
for occupational asthma. While occupational asthma offers sev-
eral advantages in this respect over other forms of asthma in
particular the relative ease of specific phenotyping and the access
to enumerated populations with high-quality exposure informa-
tion the comparative rarity of occupational asthma within any
one workplace has limited its potential. Most studies have been
of small, clinic-based populations and of case-control design
examining candidate genes, particularly those governing classII
human leukocyte antigen (HLA) phenotypes (TABLE2). Similar
study designs have been used in the exploration of the role of
genes coding for respiratory antioxidant defense mechanisms
[3133]. In general and as in the larger field of asthma genetics,
these studies have been difficult to replicate and are thus rarely
attempted. Genetic studies of workplace populations are fewer
still. If large enough, these studies offer the potential of compar-
ing the relative roles of both host-specific and environmental
risk factors and of examining any interaction between them.
Two such studies have examined workforces exposed to labora-
tory animal allergens [34] and complex platinum salts[35], respec-
tively. The former suggested that certain HLA phenotypes were
related to an increase or decrease in the risk of sensitization to
rat urinary proteins; but that these risks were of lower magni-
tude than those associated with high allergen exposure. In the
latter, an interaction between HLA status and exposure was
observed such that the effect of the former was more pro-
nounced at lower levels of allergen exposure. At high levels of
exposure, HLA phenotype had little discernible effect on risk.
This ismost likely explained by competing risk factors.
Cigarette smoking appears to be an independent risk factor
for the development of asthma after exposure to some agents
[25,3638]. The effect is probably not generalizable and may be
confined to agents of low molecular mass.
Dia g nosis
As a result of its essentially immunologic nature, the onset
of symptomatic occupational asthma is not immediate and
generally takes several months after first exposure to a causa-
tive allergen due to the latent period required for sensitiza-
tion. Often, but not always, first exposure equates to a new
occupation. Alternatively, there may have been important
changes in the exposures associated with a job in which case
the apparent latent period may be longer. With the possible
exception of asthma among bakers, it is otherwise unusual
for the symptoms of occupational asthma to arise many
years after the onset of a new occupation. Detailed enquiry
into the time relationship between entry into a new job or
changes within an existing job and the onset of asthma
symptoms is helpful in distinguishing occupational asthma
from work-exacerbated or irritant-induced disease. Once
occupational asthma has developed, symptoms may be pro-
voked (due to its hypersensitive nature) by very low-inten-
sity exposures to the initiating agent; this too may be helpful
in a careful clinical history. Thus, in most cases the patient
with occupational asthma will recount a remarkably invari-
ant history of wheeze that began within 2 years of new
employment. These symptoms are relieved by absence from
work and are increasingly easily provoked by being at work.
This symptom pattern is highly sensitive, except that as the
disease progresses the relief afforded by being away from the
workplace tends to take longer.
These patterns, while frequently obvious, may sometimes be
complicated by:
Variable shift patterns
Differences in day-to-day exposures within a job
Clinical responses that are confined to a late phase asthmatic
reaction in which symptoms, confusingly, may be felt only
after, rather than at work; waking from sleep with wheeze or
cough after periods at work is a useful clue
Table2. HLA association studies in occupational asthma.
Agent n Positive
associations
Negative
associations
Ref.
TDI 28 DQB1*0503 DQB1*0501 [67]
TDI 30 DQB1*0503
DQA1 negative
DQB1*0501
DQA1 negative
[68]
Isocyanates 32 None None [69]
TDI 67 DQA1*0104
DQB1*0503
DQA1*0101
DQB1*0501
[70]
Western red
cedar
56 DQB1*0603
DQB1*0302
DQB1*0501 [71]
Acid
anhydrides
30 DR3 - [72]
HLA: Human leukocyteantigen; TDI: Toluenediisocyanate.
O c c up a tiona l a sthma
www.future-drugs.com 127
Pre-existing (nonoccupational) asthma in these cases con-
siderable skill may be required to distinguish an occupational
component from continuing or recurrent disease that arose
outside the workplace
The bronchial hyper-responsiveness that accompanies active
occupational asthma patients with established disease expe-
rience wheeze on exposure to a variety of nonspecific respira-
tory irritants both at and away from work. This can be a
source of diagnostic confusion
Those whose disease is the result of exposure to a high-mole-
cular-mass agent generally (but not exclusively) report asso-
ciated symptoms typical of an immune response to an airborne
protein. These symptoms are of rhinitis, itching and watering of
the eyes and sometimes an urticarial rash. Often, upper respira-
tory symptoms have a shorter latency (an earlier onset) than do
those of asthma. Upper respiratory and ocular symptoms are
less common responses to low-molecular-mass agents.
The importance of a high index of suspicion in any adult
with new or recurrent asthma especially those working in
high-risk occupations is emphasized.
Inve stiga tions
A stepwise approach to further investigation of possible
occupational asthma is useful:
Does this patient have asthma?
If so, is this related to his or her work?
If so, is the relationship causal?
Asthma variable airflow limitation can be verified using
standard techniques. Crucially, it must be remembered that
measurements of lung function, reversibility and bronchial reac-
tivity may be normal if the patient hasnot recently been exposed
to the causative agent (i.e., has not recently been at work). Thus,
a normal forced expiratory volume in the first second (FEV1)
with no response to a bronchodilator or a normal test for non-
specific bronchial hyper-reactivity does not necessarily rule out a
diagnosis of occupational asthma.
A very useful investigative tool is serial measurement of peak
flow at both home and work, at least four-times a day (prefera-
bly more) over a period of 4 or moreweeks. With experienced
readers, and in the context of a specialist clinic with a relatively
high prior probability of disease, this technique has a sensitivity
of approximately 80%, a specificity of approximately 90% and
a positive predictive value of approximately 90% [24,3944]. In
clinical or workplace settings where occupational asthma is less
common, the predictive value will be lower. Statistical or com-
puted methods of peak flow analysis are reported to have diag-
nostic properties similar to those achieved by expert readers
[41,42,4446], but this may not always be the case [47]. Such meth-
ods, however, may be useful when there is no access to expert
readers. If carefully explained, adequate peak flow series can be
obtained from approximately 80% of patients or employees. In
some quarters there is concern over the potential fabrication of
readings; certainly comparisons of manually filled records with
those from data-logging meters indicate differences but it is
not clear whether these are important or whether they truly
constitute fabrication.
Some centers advocate the use of cross-shift measurements of
FEV1 or bronchial responsiveness that are made at each end of
a work shift. These techniques require ready access to the work-
place, are often difficult to organize and are likely to have lower
diagnostic value than serial peak flow measurement.
Where feasible, the detection of specific IgE antibodies in
serum or a positive response to an appropriate skin prick test
provides valuable supportive evidence. For occupational asthma
arising from high-molecular-mass agents, evidence of specific
IgE sensitization is considered a highly (possibly entirely) sensi-
tive test. It follows that the absence of such evidence effectively
rules out diagnosis. This is true only if high-quality tests to all
relevant allergens have been carried out; an experienced labora-
tory is essential. The high sensitivity of the method needs to be
appreciated alongside its lower specificity; the detection of spe-
cific antibodies or the presence of a positive skin prick test does
not necessarily mean that the patient has occupational asthma
since a state of isolated sensitization exists.
Immunologic testing isgenerally lesshelpful with low-molecu-
lar-mass agents, although there are important exceptions. At
present, there are reliable techniquesfor measuring IgE antibodies
to several acid anhydridesand to reactive dyes, teststhat again are
considered to be highly sensitive. Occupational asthma induced
by complex platinum saltsisalmost alwaysaccompanied by a pos-
itive skin prick test. As above, specific IgE antibodies to diiso-
cyanatehuman serum albumen conjugates are detected in
approximately a third of patients with diisocyanate-induced
asthma, a finding that isdependent to some extent on the interval
between last exposure and venesection [48]. When present, they
may be highly specific for a diagnosisof occupational asthma. At
present, there are no diagnostically helpful immunologic testsof
sensitization to many important low-molecular-mass agents
including colophony fume, glutaraldehyde and persulfate salts.
The difficulty of detecting specific IgE antibodies in asthma
caused by exposure to diisocyanates a high proportion of all
cases of occupational asthma has led to the consideration of
alternative techniques. The most promising of these is the
invitro assay of monocyte chemoattractant protein-1 after
stimulation of peripheral blood mononuclear cells by diisocy-
anatehuman serum albumen antigens [49]. In direct compari-
son with specific inhalation challenge, the sensitivity of this
method has been reported to be almost 80% with a specificity
of approximately 90%. Similar cellular immunoassays may be
equally helpful in the future.
There hasbeen recent interest in extrapolating newer methods
used for the diagnosisand study of asthma outside the workplace
to the investigation of patientssuspected to have occupational dis-
ease. For example, the detection of eosinophilsin induced sputum
may enhance the specificity and, to a lesser extent the sensitivity,
of serial peak flow measurement [47,50,51]. Measurements of late
phase exhaled nitric oxide may be useful in patientswith certain
typesof low-molecular-massoccupational asthma [52].
C ullina n
128 Expert Rev. Clin. Immunol. 1(1), (2005)
Specific inhalation testing is considered to be the gold stand-
ard test of diagnosis for occupational asthma. Some centers
routinely apply the test, a practice reflecting local requirements
for compensation claims rather than clinical need. In most set-
tings, it is reserved for patients in whom there remains diagnos-
tic doubt after completion of the simpler tests described previ-
ously. Thus, patients who are unable to return to work and thus
cannot complete appropriate measurements of peak flow, those
who have completed serial measurements but in whom these
remain nondiagnostic, and those whose asthma may be related
to a previously unidentified agent, are all suitable candidates for
specific inhalation testing. Testing is hazardous and should be
undertaken only by experienced or supervised staff with access
to medical cover in which case the risk is low.
There are no universally agreed standards for the conduct of
occupational inhalation testing but most experts would agree
that the following are minimal criteria for an adequate test:
Tests should take place in a sealed exposure chamber
Patients should be tested when off their normal asthma med-
ication; or if necessary such medication should be taken at
the lowest dose required to achieve functional stability
Active exposures should be controlled by comparison with
inhalation of an inert agent
Tests should be at least single blind with the patient unaware
of whether he or she is undergoing active or inert exposure
Active exposuresshould be graded and started at very low doses
Functional responses should be measured for at least 8 h
after exposure
Other desirable features include sufficient separation of dif-
ferent exposure periods, careful measurement of dose and
assessment of any exposure-related changes in nonspecific
bronchial hyper-reactivity.
Equipment for the delivery of carefully controlled doses of
occupational dusts and fumes has been developed and is used in
some centers where large numbers of patients are tested. The
machinery is expensive and most centers employ a variation of
the realistic exposure method developed by Pepys in his original
descriptions of the disease in the 1970s. Nebulized administra-
tion of allergens should generally be avoided since it may give
rise to false-positive early phase responses in sensitized patients.
Through regular measurements of FEV1, and if feasible
bronchial reactivity, following active inhalations, a variety of
asthmatic responses may be elicited. These are typically of
dual (early and late phase), isolated late phase or prolonged
pattern. An isolated early response in the presence of an
increase in nonspecific bronchial reactivity also suggests an
immunologic response; otherwise early responses alone are
difficult to distinguish from nonspecific irritant reactions.
Care must be taken to avoid false-negative inhalation chal-
lenges. These may arise when the wrong agent or an insufficient
dose of the right agent is used, or when responses are masked by
continued treatment with anti-inflammatory drugs, particu-
larly inhaled corticosteroids. Testing of patients who have had a
long period away from exposure requires especial skill.
O utc ome s
In general, allergen exposuresin the workplace are far higher than
those encountered in other indoor or outdoor environments.
Patientswith occupational asthma who continue to beexposed to
the causative allergen at work will continue to experience symp-
tomsand, in most cases, these will continue to deteriorate. In time,
symptomswill be provoked by extremely small exposures. In these
situations, medical treatment, which should be prescribed exactly
asfor patientswith other formsof asthma, isineffective. The fate
of patientswho, in one way or another, avoid further exposure is
lesswell understood. While many or even most will experience an
improvement in their asthma thisisnot universal; prognosismay
in part bedependent on the agent. A smaller proportion (perhaps
a minority) will experience complete remission. It is widely
believed that the eventual prognosisisdependent on the duration
of exposure following theonset of disease [5356]. In fact, the evi-
dence base for thisseemingly reasonable claim isboth small and
contradictory especially in the case of asthma induced by high-
molecular-mass allergens. There is some evidence that improve-
ment continuesafter the cessation of exposure[57,58]. A single rand-
omized controlled trial hasdemonstrated a beneficial albeit small
effect of treatment with inhaled corticosteroidsin thissituation [59].
Since exposures to allergen in occupational asthma gener-
ally occur only in the workplace, the patient who changes his
or her job provides a potentially valuable model for the study
of immunologic recovery. Thus, exponential declines in spe-
cific IgE antibody levels have been reported with half-lives
dependent on the time away from exposure [60,61].
Broadly speaking, a patient with occupational asthma will only
improve and can only be managed effectively if exposure to
the causative allergen can be avoided. Regrettably, this isusually
achieved only by a change in job and in effect a loss of employ-
ment. There are instances where it ispossible for a patient to con-
tinue in hisor her original job if suitable modificationsare made.
Thus, healthcare workers with latex allergy induced by surgical
gloves may be advised that they can continue at work if they
themselvesdo not wear latex glovesand those around them use
only powder-free, low-protein (or nonlatex) brands [62]. There
are a few other examplesof situationsin which increased respira-
tory protection is both feasible and effective [6365], but this
approach isunusual and generally only of temporary value.
Patients who have been diagnosed with occupational asthma
face economic and social difficulties that are probably greater
than those experienced by patients with other forms of
asthma. These disadvantages appear to diminish with time
after diagnosis and are modified by:
Skills levels, qualifications and other factors that affect an
employees market value
Employer attitudes
The adequacy of any local system of compensation and/or
retraining
Nonetheless, false-positive diagnoses of occupational asthma
are generally disastrous and may even lead to a patient losing
their job without regaining their health.
O c c up a tiona l a sthma
www.future-drugs.com 129
Pre ve ntion
Sufficient information is known about the causes of most
cases of occupational asthma and about how these can be rec-
tified for primary disease prevention to be realistic. Occupa-
tionally induced disease is thus a rare example of asthma that
can, theoretically at any rate, be prevented and, frequently,
cured. With few exceptions, however, prevention appears to
be difficult to attain and has generally been unsuccessful. As a
result there appears to be no less occupational asthma in
Europe or North America than there was 30 years ago. The
reasons for this application gap are poorly understood. It may
be that the disease is too sporadic for it to be considered a
major problem for most industries or workplaces. Similarly, it
may not be perceived as being either serious enough it is
very rarely life threatening or peculiar enough. Asthma in all
its forms is, after all, familiar to almost everybody in the
industrialized world. Occupational diseases in general have a
low public profile, certainly lower than other more fashiona-
ble environmental diseases. As a result of one or more of these
factors, the impulses that encourage an industry to prevent
the disease or conversely those that discourage it from doing
so are not known in detail.
There are several approaches to the primary prevention of
occupational asthma. Elimination of the causative agent or its
substitution by an effective but safe(r) alternative has occasion-
ally been successful. The premarket analysis and testing of new
agents for their sensitizing potential is widely practiced but it is
unclear how valuable it has been in avoiding the use of new
workplace asthmagens. The issue of screening of individuals
before their employment is often discussed in this context.
With knowledge of specific individual risk factors and through
the consequent selection of low-risk employees it is argued that
the incidence of occupational asthma could be reduced; indeed
several industries have implemented such pre-employment pol-
icies. Leaving aside their dubious morality and, increasingly,
legality, it is probable that such methods are highly inefficient
[66], and certain that they result in a substantial reduction in the
pool of potential employees to an industry, and of employment
opportunities for an individual.
Most preventive programs have employed a mix of
employee education, exposure reduction and, as a method of
secondary prevention, routine health surveillance of the work-
force. The successful results of several such programs have
been published and are summarized in TABLE3; together they
strongly suggest that primary disease prevention is possible
given sufficient motivation.
Exp e rt op inion & five - ye a r vie w
There is no evidence that occupational asthma in its entirety is
becoming any less frequent. Indeed the incorporation of newly
industrialized states, such as those of Eastern Europe, into
highly regulated communities, the ever-increasing use of
potential allergens in the workplace and the apparently inexo-
rable rise in the prevalence of childhood atopic conditions, all
mitigate against the disappearance of this important disease.
Significant improvements in the clinical management of
occupational asthma will be in the development of simpler,
in-clinic diagnostic techniques of high sensitivity and specifi-
city. There are likely to be considerable advances in this area
as an offshoot of similar movements in the wider field of
asthma diagnosis and monitoring. The focus will be on
invitro cellular immunoassays. The wider applicability of
such methods may assist in moving the disease from its cur-
rent position as the preserve of a small number of specialist
centers. This will only be valuable if the profile of occupa-
tional asthma is also raised, a process that will be achieved in
part by improvements in the epidemiologic technique used to
study its distributions.
The present state of knowledge regarding the prognosis of
occupational asthma is weak. As a reult, clinicians con-
fronted by a patient with occupational asthma are in a poor
position to offer useful advice. This shameful situation is
only likely to be rectified by standardized, multicenter studies
of prospective design.
Many will continue to push for an improved understanding
of how the disease may be prevented and how this knowledge
may be applied. This will require a broader understanding of
the industrial and societal determinants of disease than have tra-
ditionally been studied. Current regulatory approaches, which
have largely failed, will be replaced by techniques that have a
stronger evidence base developed, in all probability, and by
collaboration between academic centers and industrial part-
ners. Traditional risk factor epidemiology will be supple-
mented by clinical epidemiology with the careful evaluation of
new preventive approaches that can be generalized.
Table3. Summary of studies of the primary prevention
of occupational asthma.
Agent Methods of prevention Ref.
Employee
education
Health
surveillance
Exposure
control
Acid anhydrides No No Yes [73]
Acid anhydrides NS NS Yes [74]
Latex Yes No Yes [75]
Latex Ns NS Yes [76]
Latex Yes No Yes [17]
Latex Yes Yes Yes [77]
Laboratoryanimal
allergens
Yes Yes Yes [78]
Laboratoryanimal
allergens
Yes Yes Yes [79]
Diisocyanates No Yes Yes [80]
Detergent enzymes Yes Yes Yes [18]
NS: Not stated.
C ullina n
130 Expert Rev. Clin. Immunol. 1(1), (2005)
Informa tion re sourc e s
Bernstein IL, Chan Yeung M, Malo J-L, Bernstein DI.
Asthma in theWorkplace. Second edition. Marcel Dekker, NY,
USA (1999).
Very useful and comprehensive handbook with a great deal of
concentrated information. Includesan invaluable (referenced)
list of agents reported to cause occupational asthma
Nicholson PJ, Cullinan P, Newman Taylor AJ, Burge PS,
Boyle C. Evidence-based guidelines for the prevention, iden-
tification and management of occupational asthma. Occup.
Environ. Med. 62(5), 290299 (2005).
First evidence-based guidelinesin thisfield that provide readily
accessible and applicable information on epidemiology, risk
factors, diagnosis, management and prevention of the disease.
Re fe re nc e s
Papersof special note have been highlighted as:
of interest
of considerable interest
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Occupational asthma isinduced by an agent inhaled at work.
Work-related asthma ismore common than isgenerally realized and isbelieved to account for 10% of all new or recurrent cases
of the adult disease.
While over 300 workplace agentshave been reported to cause occupational asthma, most casesof the disease are attributable to a
much smaller number. Several high-risk industriesare recognized.
Atopic patientsare at increased risk of developing occupational asthma from many but not all workplace agents. Other
constitutional risk factorsare lesswell understood.
The root of successful diagnosisliesin a high index of suspicion.
The clinical history of occupational asthma isstereotypic. Diagnosisismost valuably confirmed by the careful use of serial
measurementsof peak flow at home and at work; specific provocation testing issometimesrequired.
There have been several recent advancesin the use of immunologic and physiologic diagnostic techniques.
Patientswho have occupational asthma do not improve if allergen exposure persists, even with the use of otherwise appropriate
pharmacologic treatmentsfor asthma.
Enough isknown about the etiology of the disease for it to be prevented successfully in most instances. Lessisknown about
why thisknowledge hasnot been widely effective.
O c c up a tiona l a sthma
www.future-drugs.com 131
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Affilia tion
Paul Cullinan, MD
Reader and Consultant Physician, Department
of Occupational and Environmental Medicine,
Royal Brompton Hospital/Imperial College
(NHLI), London, UK
Tel.: +44 207 351 8328
Fax: +44 207 351 8336
p.cullinan@imperial.ac.uk