Asma Ocupacional Factors Riesgo

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Review

10.1586/1744666X.1.1.123 2005 Future Drugs Ltd ISSN 1744-666X 123www.future-drugs.com

Occupational asthma: risk factors,diagnosis and preventive measuresPaul Cullinan

Department of Occupati onal and

Environmental Medicine,

Royal Brompton Hospit al/

Imperi al College (NHLI ),

London, UK

Tel.: +44 207 351 8328

Fax: +44 207 351 8336

[email protected]

KEYWORDS:asthma, diagnosis, epidemiology,irritant, occupation, occupationalasthma, prevention

In adulthood, new or recurrent asthma is caused by work in approximately 10% of cases.

The term oc cup a tiona l asthm a is rese rved for those c a ses a rising from re spira tory

hypersensit iv ity to a spe cific workpla ce a ge nt; in others (work-e xac erba ted asthma ) the

m ec ha nism is of nonspe c ific a irwa y irritation on a ba ckg round o f bronc hial hype r-rea ctivity.

Som e 300 workp lace ag ents a re c a pa b le o f induc ing a sthma de novo ; fortuna tely, m ost

ca se s a re a ttributed to a m uch sma lle r num be r to which exp osure oc curs in a few high- riskoc cup a tions. Expo sure level is the m ost imp orta nt rem ed iable risk fac tor; the fa ctors

gove rning individual susce ptibility a re po orly unde rstood. Diag nosis is ge ne ra lly

straightforward. Management is rarely pharmacologic and often difficult since the

diagnosis incurs important employment and other social consequences.

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 animmediate-type hypersensitivity response to anairborne allergen or haptenprotein conjugate.

Patients with pre-existing asthma or bronchialhyper-responsiveness whose condition is exac-erbated by any one or more of a limitlessnumber of workplace irritants are said to havework-exacerbated asthma. Often the distinc-tion between occupational and work-exacer-bated asthma is difficult; indeed some claim itis unhelpful [1]. In either instance, an employeehas developed asthma as a result of a workplaceexposure. 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 andthe distinction from work-exacerbatedasthma has important legal consequences forthe industry responsible.

Asthma may also arise at work from theinhalation of toxic quantities of irritant fumesthat do not, as far as it is known, give rise toallergic responses. First described in 1985 asreactive airways dysfunction syndrome(RADS), this is now more commonly termedirritant-induced asthma [2]. The original

description was of a disease functionallyindistinct from asthma, including heightenedbronchial responsiveness, consequent on asingle, high-dose exposure in the context ofnormal lung function. More recently, it has

been proposed that lower repeated exposuresto irritant compounds might induce thesame disease, but the evidence remainsinconclusive. The incidence of high-doseirritant-induced asthma is unknown but it iscertainly less common than hypersensitiveoccupational asthma.

Causat ive agents & pathophysiology

Some 300 agents have been recognized asbeing capable of inducing occupationalasthma; a useful list is provided by Bernstein

and colleagues[3]

. Happily for the clinicianand the policy maker, far fewer are responsiblefor the bulk of disease in most industrializedcountries. In clinical practice it is probablymost useful to be familiar with the occupationsthat incur high risk of asthma rather than withthe responsible agents. Lists of important suchoccupations are given in TABLE 1. At the sametime, a high index of suspicion should beretained for any patient presenting with adult-onset (or recurrent) asthma, especially whenthis has occurred shortly after commencingnew employment. Any airborne protein

CONTENTS

Ca usat ive ag ents &

pathophysiology

Disease frequency

Risk fa c tors

Diagnosis

O u t c o m e s

Prevention

Expert opinion &

five-year view

Informa tion resources

Key issue s

References

Affilia tion

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C ullina n

124 Expert Rev. Cli n. Immunol.1(1), (2005)

should be considered as a potential sensitizing agent; every yeara dozen or so occupational agents capable of inducing asthmaare newly identified. The wise physician must always take acareful occupational history.

For convenience, occupational respiratory sensitizing agentsare 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 andof producing an immune response characterized by the produc-tion of T-helper (Th)2 cytokines and the induction of specificIgE antibodies. In these ways they mimic the action of, forexample, house dust mites or cat allergens in the initiation ofasthma in childhood. Important high-molecular-weight occu-pational allergens include proteins excreted by laboratory ani-mals, flour allergens, enzymes used in the food and detergentindustries and proteins arising from natural rubber latex.

Low-molecular-mass or chemical agents probably act as

haptens, becoming allergenic only after conjugation with oneor more autologous or heterologous proteins. Some of these notably the various acid anhydrides and complex platinumsalts appear to induce asthma through a typical allergicTh2-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 beresponsible; serum-specific IgE antibodies to conjugates ofdiisocyanate and human serum albumen are detected inapproximately a third of cases. In the remainder, and for most

other low-molecular-weight allergens, mechanisms appear tobe non-IgE associated, are probably more complex and maybe comparable with nonatopic asthma encountered outsidethe workplace [4]. As in patients with nonoccupational intrin-sic asthma, T-cell clones from patients with asthma inducedby toluene diisocyanate are largely CD8+ and capable of

inducing the production of interleukin (IL)-5 and interferon(IFN)-[5]. A simi lar process has been demonstrated in T-cellsstimulated with plicatic acid, the chemical agent implicated inasthma induced by workplace exposure to red cedar [6].Repeated in vi t roantigenic stimulation of peripheral mono-nuclear cells from patients with diisocyanate asthma inducesthe production of C-C cytokine, mononuclear chemoattract-ant protein-1 and tumor necrosis factor- in the absence ofIL-4 or -5 [7]. Sputum neutrophilia induced by controlledexposure to diisocyanates may be related to leukotriene B4,perhaps enhanced by IL-8 release and/or an increase in leuko-triene B4 receptor expression [8]. Neurogenic inflammation

may also play an important role; in animal models, toluenediisocyanate stimulates the release of both calcitonin gene-related peptide and substance P and inhibits neuralendopeptidase [9]. It is not known whether this is importantin human disease.

Disease f requency

Estimates of the frequency of occupational asthma arederived in three ways. While two are generic, the third isworkplace 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

Laboratory animal researchers

and technicians

Diisocyanates Spray painters, French polishers,

plasticsand foam manufacturers

Flour(s),-amylase and

other enzymes

Baking, milling, pastry and

pizza making

Acid anhydridesand epoxy resins Plasticsand foam manufacturers

and assemblers

Egg proteins Laboratory animal researchers

(embryology), bakersand food

processors

Colophony fume 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, i roko 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

M etal refinersand electroplaters


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Is a sthma a ttributab le to oc cup a tiona l exposure?

A number of epidemiologic studies have attempted to esti-mate the proportion of adult asthma that is attributable tooccupational exposures. Each uses a stochastic approach tocausation, based in probabilities, and is thus very differentfrom the individual approach used in clinical practice and in

the surveillance schemes described below. Their methodbegins by measuring the frequency of disease in a representa-tive sample of the community under study and then relatesthe excess risk of asthma in separate occupational groups tothe risk in a referent (unexposed) group, generally officeworkers. The sum of increased occupation-specific risks isused to generate an estimate of the total proportion of diseaseattributable to occupational exposures.

The body of such studies is usefully summarized by Blancand Toren, whose systematic review includes a meta-analysisindicating that approximately one in ten of all incident orrecurrent cases of adult asthma is caused by workplace expo-

sures [10]. Population-based methods such as these are useful ina public health context and perhaps also in the identification ofthe increased risks of asthma among occupational groups nottraditionally recognized in clinical practice. Two such examplesinclude cleaners [11]and bar staff [12].

Population-based methods do not easily distinguish occupa-tional from work-exacerbated asthma. Furthermore, it is notalways clear whether the apparently high rates of asthma insome occupations arise from a risk inherent to a job orwhether people with asthma migrate to that job, an issue ofdirectionality. Remarkably little is known about the extent andnature of the processes that determine job selection by peoplewith asthma.

Surveilla nce sche me s

In several countries notably Finland, the UK, France andparts of the USA and Australia established surveillanceschemes exist for occupational lung diseases includingasthma. In some instances these are embedded in programsthat cover all occupational diseases. In each case the schemesmeasure disease recognized and reported by specialized phy-sicians, generally in occupational or respiratory medicalpractice. Where denominators are available, occupation-spe-cific incidence rates may be estimated, although these areoften 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 occupationalasthma is underestimated perhaps by as much as two- orthreefold and especially so when the workforce denominatorsare nonspecif ic [13].

Nonetheless, surveillance schemes provide valuable informa-tion on the approximate size and distribution of the problem ata national level. Using such methods, the annual incidence ofoccupational asthma in industrially developed societies is esti-mated to reside between 12 and 170 cases per million employees,with a median value of 47 cases per million [10,1416].

Alternative surveillance methods rely on the enumeration ofcompensation claims or mandatory industrial notifications foroccupational asthma. The completeness of these methods isdependent on a variety of external factors and is poorly under-stood. In general they provide substantially different estimatesfrom the clinical schemes above.

Workplace / occ upational methods

The third measurement technique is specific to an occupationor 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 ofrecords from routine health surveillance. The latter techniquemay underestimate the true frequency of disease if the methodsof surveillance (generally questionnaires and spirometry) areinsensitive. Workplace methods provide valuable informationon 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 developedworld is falling; the trend generally appears to be flat. It is notknown to what extent this reflects greater ascertainment of dis-ease, the wider use of potential respiratory-sensitizing agents inindustry, a more susceptible population or the continuing failureof disease control in high-risk industries.

There are notable exceptions to this pattern. For example,latex asthma among healthcare workers appears to have beenlargely prevented by the use of powder-free, low-protein latexgloves [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 ofdisease prevention are discussed in greater detail below.

Risk fa c tors

As in many, if not most diseases, the factors recognized toincrease the risk of occupational asthma are both external andhost related. Several have been identified and reasonably wellcharacterized.

High exposure to a causative allergen increases the risk ofboth 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, acidanhydrides and flour dust in bakeries and mills [1826]. In somecases, 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, aless frequent outcome. In every case the detailed shape of therelationship is incompletely understood; it is suspected to beof a sigmoid nature with an attenuation of the risk gradient athigher doses of exposure [20]. For some agents and perhapsmost the thresholds for sensitization and asthma appear tobe extremely low. This implies that exposure control in the


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primary prevention of all cases may be difficult to achieve inpractice. There may be important analogies with the role ofdomestic allergen exposures in childhood disease [27].

The hypersensitive nature of most types of occupationalasthma and the obvious fact that not all exposed workersdevelop the disease implies that there are important factors

governing individual susceptibility. Atopic employees whoreadily 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 riskincurred with most low-molecular-weight exposures, at leastwhere these are not associated with specific IgE antibody pro-duction. Where relevant, atopy appears to increase risksbetween two- and fourfold. The increasingly high prevalence ofthe trait in young European populations means that it is poorlydiscriminatory in both clinical and employment practice and islikely to become more so. This pattern also implies that an

increasingly susceptible population of young adults is nowentering 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 interactionbetween these and environmental exposures in the risk profilefor occupational asthma. While occupational asthma offers sev-eral advantages in this respect over other forms of asthma inparticular the relative ease of specific phenotyping and the accessto enumerated populations with high-quality exposure informa-tion the comparative rarity of occupational asthma within anyone workplace has limited its potential. Most studies have beenof small, clinic-based populations and of case-control designexamining candidate genes, particularly those governing class IIhuman leukocyte antigen (H LA) phenotypes (TABLE 2). Similarstudy designs have been used in the exploration of the role ofgenes 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 rarelyattempted. Genetic studies of workplace populations are fewerstill. If large enough, these studies offer the potential of compar-ing the relative roles of both host-specific and environmentalrisk 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 torat urinary proteins; but that these risks were of lower magni-tude than those associated with high allergen exposure. In thelatter, an interaction between HLA status and exposure wasobserved such that the effect of the former was more pro-nounced at lower levels of allergen exposure. At high levels ofexposure, HLA phenotype had little discernible effect on risk.This is most likely explained by competing risk factors.

Cigarette smoking appears to be an independent risk factorfor the development of asthma after exposure to some agents[25,3638]. The effect is probably not generalizable and may beconfined to agents of low molecular mass.

Diagnosis

As a result of its essentially immunologic nature, the onsetof symptomatic occupational asthma is not immediate andgenerally 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 importantchanges in the exposures associated with a job in which casethe apparent latent period may be longer. With the possibleexception of asthma among bakers, it is otherwise unusualfor the symptoms of occupational asthma to arise manyyears after the onset of a new occupation. Detailed enquiryinto the time relationship between entry into a new job orchanges within an existing job and the onset of asthmasymptoms is helpful in distinguishing occupational asthmafrom work-exacerbated or irritant-induced disease. Onceoccupational 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 helpfulin a careful clinical history. Thus, in most cases the patientwith occupational asthma will recount a remarkably invari-ant history of wheeze that began within 2 years of newemployment. These symptoms are relieved by absence fromwork and are increasingly easily provoked by being at work.This symptom pattern is highly sensitive, except that as thedisease progresses the relief afforded by being away from theworkplace tends to take longer.

These patterns, while frequently obvious, may sometimes becomplicated 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 onlyafter, rather than at work; waking from sleep with wheeze orcough after periods at work is a useful clue

Table2. HLA association studies in occupational asthma.

Agent n Positiveassociations

Negativeassociations

Ref.

TDI 28 DQB1*0503 DQB1*0501 [67]

TDI 30 DQB1*0503DQA1 negative DQB1*0501DQA1 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 leukocyte antigen; TDI: Toluene diisocyanate.


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Pre-existing (nonoccupational) asthma in these cases con-siderable skill may be required to distinguish an occupationalcomponent from continuing or recurrent disease that aroseoutside the workplace

The bronchial hyper-responsiveness that accompanies activeoccupational 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 asource 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 airborneprotein. These symptoms are of rhinitis, itching and watering ofthe eyes and sometimes an urticarial rash. Often, upper respira-tory symptoms have a shorter latency (an earlier onset) than dothose of asthma. Upper respiratory and ocular symptoms areless common responses to low-molecular-mass agents.

The importance of a high index of suspicion in any adultwith new or recurrent asthma especially those working inhigh-risk occupations is emphasized.

Investigations

A stepwise approach to further investigation of possibleoccupational 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 usingstandard techniques. Crucially, it must be remembered thatmeasurements of lung function, reversibility and bronchial reac-tivity may be normal if the patient has not recently been exposedto 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 adiagnosis of occupational asthma.

A very useful investigative tool is serial measurement of peakflow at both home and work, at least four-times a day (prefera-bly more) over a period of 4 or more weeks. With experiencedreaders, and in the context of a specialist clinic with a relativelyhigh prior probabil ity of disease, this technique has a sensitivity

of approximately 80%, a specificity of approximately 90% anda positive predictive value of approximately 90% [24,3944]. Inclinical or workplace settings where occupational asthma is lesscommon, 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 expertreaders. I f carefully explained, adequate peak flow series can beobtained from approximately 80% of patients or employees. Insome quarters there is concern over the potential fabrication ofreadings; certainly comparisons of manually filled records with

those from data-logging meters indicate differences but it isnot clear whether these are important or whether they trulyconstitute fabrication.

Some centers advocate the use of cross-shift measurements ofFEV1 or bronchial responsiveness that are made at each end ofa work shift. These techniques require ready access to the work-

place, are often difficult to organize and are likely to have lowerdiagnostic value than serial peak flow measurement.

Where feasible, the detection of specific IgE antibodies inserum or a positive response to an appropriate skin prick testprovides valuable supportive evidence. For occupational asthmaarising from high-molecular-mass agents, evidence of specificIgE sensitization is considered a highly (possibly entirely) sensi-tive test. It follows that the absence of such evidence effectivelyrules out diagnosis. This is true only if high-quality tests to allrelevant allergens have been carried out; an experienced labora-tory is essential. The high sensitivity of the method needs to beappreciated alongside its lower specificity; the detection of spe-

cific antibodies or the presence of a positive skin prick test doesnot necessarily mean that the patient has occupational asthmasince a state of isolated sensitization exists.

Immunologic testing is generally less helpful with low-molecu-lar-mass agents, although there are important exceptions. Atpresent, there are reliable techniques for measuring IgE antibodiesto several acid anhydrides and to reactive dyes, tests that again areconsidered to be highly sensitive. Occupational asthma inducedby complex platinum salts is almost always accompanied by a pos-itive skin prick test. As above, specific IgE antibodies to diiso-cyanatehuman serum albumen conjugates are detected inapproximately a third of patients with diisocyanate-inducedasthma, a finding that is dependent to some extent on the intervalbetween last exposure and venesection [48]. When present, theymay be highly specific for a diagnosis of occupational asthma. Atpresent, there are no diagnostically helpful immunologic tests ofsensitization to many important low-molecular-mass agentsincluding colophony fume, glutaraldehyde and persulfate salts.

The difficulty of detecting specific IgE antibodies in asthmacaused by exposure to diisocyanates a high proportion of allcases of occupational asthma has led to the consideration ofalternative techniques. The most promising of these is thein vitro assay of monocyte chemoattractant protein-1 afterstimulation of peripheral blood mononuclear cells by diisocy-anatehuman serum albumen antigens [49]. In direct compari-

son with specific inhalation challenge, the sensitivity of thismethod has been reported to be almost 80% with a specificityof approximately 90%. Similar cellular immunoassays may beequally helpful in the future.

There has been recent interest in extrapolating newer methodsused for the diagnosis and study of asthma outside the workplaceto the investigation of patients suspected to have occupational dis-ease. For example, the detection of eosinophils in induced sputummay enhance the specificity and, to a lesser extent the sensitivity,of serial peak flow measurement [47,50,51]. Measurements of latephase exhaled nitric oxide may be useful in patients with certaintypes of low-molecular-mass occupational asthma [52].


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Specific inhalation testing is considered to be the gold stand-ard test of diagnosis for occupational asthma. Some centersroutinely apply the test, a practice reflecting local requirementsfor 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 thuscannot complete appropriate measurements of peak flow, thosewho have completed serial measurements but in whom theseremain nondiagnostic, and those whose asthma may be relatedto a previously unidentified agent, are all suitable candidates forspecific inhalation testing. Testing is hazardous and should beundertaken only by experienced or supervised staff with accessto medical cover in which case the risk is low.

There are no universally agreed standards for the conduct ofoccupational inhalation testing but most experts would agreethat 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 atthe lowest dose required to achieve functional stability

Active exposures should be controlled by comparison withinhalation of an inert agent

Tests should be at least single blind with the patient unawareof whether he or she is undergoing active or inert exposure

Active exposures should be graded and started at very low doses

Functional responses should be measured for at least 8 hafter exposure

Other desirable features include sufficient separation of dif-ferent exposure periods, careful measurement of dose andassessment of any exposure-related changes in nonspecificbronchial hyper-reactivity.

Equipment for the delivery of carefully controlled doses ofoccupational dusts and fumes has been developed and is used insome centers where large numbers of patients are tested. Themachinery is expensive and most centers employ a variation ofthe realistic exposure method developed by Pepys in his originaldescriptions of the disease in the 1970s. Nebulized administra-tion of allergens should generally be avoided since it may giverise to false-positive early phase responses in sensitized patients.

Through regular measurements of FEV1, and if feasiblebronchial reactivity, following active inhalations, a variety of

asthmatic responses may be elicited. These are typically ofdual (early and late phase), isolated late phase or prolongedpattern. An isolated early response in the presence of anincrease in nonspecific bronchial reactivity also suggests animmunologic response; otherwise early responses alone aredifficult 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 insuff icientdose of the right agent is used, or when responses are masked bycontinued treatment with anti-inflammatory drugs, particu-larly inhaled corticosteroids. Testing of patients who have had along period away from exposure requires especial skill.

O u t c o m e s

In general, allergen exposures in the workplace are far higher thanthose encountered in other indoor or outdoor environments.Patients with occupational asthma who continue to be exposed tothe causative allergen at work will continue to experience symp-toms and, in most cases, these will continue to deteriorate. In time,

symptoms will be provoked by extremely small exposures. In thesesituations, medical treatment, which should be prescribed exactlyas for patients with other forms of asthma, is ineffective. The fateof patients who, in one way or another, avoid further exposure isless well understood. While many or even most will experience animprovement in their asthma this is not universal; prognosis mayin part be dependent on the agent. A smaller proportion (perhapsa minority) will experience complete remission. It is widelybelieved that the eventual prognosis is dependent on the durationof exposure following the onset of disease [5356]. In fact, the evi-dence base for this seemingly reasonable claim is both small andcontradictory especially in the case of asthma induced by high-

molecular-mass allergens. There is some evidence that improve-ment continues after the cessation of exposure [57,58]. A single rand-omized controlled trial has demonstrated a beneficial albeit smalleffect of treatment with inhaled corticosteroids in this situation [59].

Since exposures to allergen in occupational asthma gener-ally occur only in the workplace, the patient who changes hisor her job provides a potentially valuable model for the studyof immunologic recovery. Thus, exponential declines in spe-cific IgE antibody levels have been reported with half-livesdependent on the time away from exposure [60,61].

Broadly speaking, a patient with occupational asthma will onlyimprove and can only be managed effectively if exposure tothe causative allergen can be avoided. Regrettably, this is usuallyachieved only by a change in job and in effect a loss of employ-ment. There are instances where it is possible for a patient to con-tinue in his or her original job if suitable modifications are made.Thus, healthcare workers with latex allergy induced by surgicalgloves may be advised that they can continue at work if theythemselves do not wear latex gloves and those around them useonly powder-free, low-protein (or nonlatex) brands [62]. Thereare a few other examples of situations in which increased respira-tory protection is both feasible and effective [6365], but thisapproach is unusual and generally only of temporary value.

Patients who have been diagnosed with occupational asthmaface economic and social difficulties that are probably greater

than those experienced by patients with other forms ofasthma. These disadvantages appear to diminish with timeafter diagnosis and are modified by:

Skills levels, qualifications and other factors that affect anemployees market value

Employer attitudes

The adequacy of any local system of compensation and/orretraining

Nonetheless, false-positive diagnoses of occupational asthmaare generally disastrous and may even lead to a patient losingtheir job without regaining their health.


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Prevention

Sufficient information is known about the causes of mostcases 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 thatcan, theoretically at any rate, be prevented and, frequently,

cured. With few exceptions, however, prevention appears tobe difficult to attain and has generally been unsuccessful. As aresult there appears to be no less occupational asthma inEurope or North America than there was 30 years ago. Thereasons for this application gap are poorly understood. It maybe that the disease is too sporadic for it to be considered amajor problem for most industries or workplaces. Similarly, itmay not be perceived as being either serious enough it isvery rarely life threatening or peculiar enough. Asthma in allits forms is, after all, familiar to almost everybody in theindustrialized world. Occupational diseases in general have alow public profile, certainly lower than other more fashiona-

ble environmental diseases. As a result of one or more of thesefactors, the impulses that encourage an industry to preventthe disease or conversely those that discourage it from doingso are not known in detail.

There are several approaches to the primary prevention ofoccupational asthma. Elimination of the causative agent or itssubstitution by an effective but safe(r) alternative has occasion-ally been successful. The premarket analysis and testing of newagents for their sensitizing potential is widely practiced but it isunclear how valuable it has been in avoiding the use of newworkplace asthmagens. The issue of screening of individualsbefore their employment is often discussed in this context.With knowledge of specific individual risk factors and throughthe consequent selection of low-risk employees it is argued thatthe incidence of occupational asthma could be reduced; indeedseveral 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 thepool of potential employees to an industry, and of employmentopportunities for an individual.

Most preventive programs have employed a mix ofemployee education, exposure reduction and, as a method ofsecondary prevention, routine health surveillance of the work-force. The successful results of several such programs have

been published and are summarized in TABLE 3; together theystrongly suggest that primary disease prevention is possiblegiven sufficient motivation.

Expe rt op inion & f ive- ye a r view

There is no evidence that occupational asthma in its entirety isbecoming any less frequent. Indeed the incorporation of newlyindustrialized states, such as those of Eastern Europe, intohighly regulated communities, the ever-increasing use ofpotential allergens in the workplace and the apparently inexo-rable rise in the prevalence of childhood atopic conditions, allmitigate against the disappearance of this important disease.

Significant improvements in the clinical management ofoccupational 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 areaas an offshoot of similar movements in the wider field ofasthma diagnosis and monitoring. The focus will be onin vi t ro cellular immunoassays. The wider applicability ofsuch methods may assist in moving the disease from its cur-rent position as the preserve of a small number of specialistcenters. This will only be valuable if the profile of occupa-tional asthma is also raised, a process that will be achieved inpart by improvements in the epidemiologic technique used tostudy i ts distributions.

The present state of knowledge regarding the prognosis ofoccupational asthma is weak. As a reult, clinicians con-fronted by a patient with occupational asthma are in a poorposition to offer useful advice. This shameful situation isonly 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 knowledgemay be applied. This will require a broader understanding ofthe industrial and societal determinants of disease than have tra-ditionally been studied. Current regulatory approaches, whichhave largely failed, will be replaced by techniques that have astronger evidence base developed, in all probability, and bycollaboration between academic centers and industrial part-ners. Traditional risk factor epidemiology will be supple-mented by clinical epidemiology with the careful evaluation ofnew preventive approaches that can be generalized.

Table3. Summary of studies of the primary preventionof 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]

Laboratory animal

allergens

Yes Yes Yes [78]

Laboratory animal

allergens

Yes Yes Yes [79]

Diisocyanates No Yes Yes [80]

Detergent enzymes Yes Yes Yes [18]

NS: Not stated.


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Informa t ion resourc es

Bernstein IL, Chan Yeung M, Malo J-L, Bernstein DI.Asthma in the Workplace. Second edi tion. Marcel Dekker, NY,USA (1999).Very useful and comprehensive handbook with a great deal ofconcentrated information. Includes an 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 guidelines in this field that provide readilyaccessible and applicable information on epidemiology, risk

factors, diagnosis, management and prevention of the disease.

R efer ences

Papers of special note have been highlighted as:

of interest

of considerable interest1 Wagner GR, Wegman D H. Occupational

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Bernstein DI. Asthma in the Workplace.

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Occupational asthma. European RespiratoryMonograph11,255285 (1999).

5 Maestrelli P, Del Prete GF, De Carli M et al.

CD8 T-cell clones producing interleukin-5

and interferon-in bronchial mucosa of

patients with asthma induced by toluene

diisocyanate.Scand. J. Work Envi ron.

Health20, 376381 (1994).

6 Frew A, Chang JH, Chan H et al.

T-lymphocyte responses to plicatic

acidhuman serum albumin conjugate in

occupational asthma caused by western red

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7 Lummus ZL, Alam R, Bernstein JA,

Bernstein DI. Diisocyanate antigen-

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8 Lemiere C, Pelissier S, Tremblay C et al.

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diisocyanate decrease tachykinin and

calcitonin gene-related peptide

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263269 (1998).10 Blanc PD, Toren K. How much adult

asthma can be attributed to occupational

factors?Am. J. Med.107, 580587 (1999).

Systematic review of studies examining the

attribution of workplace exposures to

adult asthma.

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Kromhout H, Burney P. Occupational

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12 Jaakkola JJ, Piipari R, Jaakkola MS.

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13 Draper A, Newman Taylor A, Cull inan P.

Estimating the incidence of occupational

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14 Ameille J, Pauli G, Calastreng-Crinquand

A et al.Reported incidence of occupational

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17 Allmers H, Schmengler J, Skudlik C.

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Key issues

Occupational asthma is induced by an agent inhaled at work.

Work-related asthma is more common than is generally realized and is believed to account for 10% of all new or recurrent cases

of the adult disease.

While over 300 workplace agents have been reported to cause occupational asthma, most cases of the disease are attributable to a

much smaller number. Several high-risk industries are recognized.

Atopic patients are at increased risk of developing occupational asthma from many but not all workplace agents. Other

consti tutional risk factors are less well understood.

The root of successful diagnosis lies in a high index of suspicion. The clinical history of occupational asthma is stereotypic. Diagnosis is most valuably confirmed by the careful use of serial

measurements of peak flow at home and at work; specific provocation testing is sometimes required.

There have been several recent advances in the use of immunologic and physiologic diagnostic techniques.

Patients who have occupational asthma do not improve if allergen exposure persists, even with the use of otherwise appropriate

pharmacologic treatments for asthma.

Enough is known about the etiology of the disease for it to be prevented successfully in most instances. Less is known about

why this knowledge has not been widely effective.


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province-wide program of secondary and

primary prevention.

Affilia tion

Paul Cull inan, MD

Reader and Consultant Physician, Department

of Occupational and Envi ronmental Medicine,

Royal Brompton Hospital/Imperi al Coll ege

(NH LI ), London, UK

Tel.: +44 207 351 8328

Fax: +44 207 351 8336

[email protected]

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