Gassert, Thomas H. MD, MSc; Hu, Howard MD, ScD, MPH; Kelsey, Karl T. MD, MOH; Christiani, David C. MD, MPH
Asthma has become the most prevalent occupational lung disorder in industrialized nations.1-3 This is unfortunate because occupational asthma is a preventable disease that often becomes chronic and may disable millions of people worldwide at considerable personal and social cost.4 Occupational asthma affects workers of all ages and in rare cases may lead to death.5,6
Estimates suggest that occupational asthma accounts for 15%-20% of all adult onset asthma in the United States and Japan,7-9 and it is the most frequently reported occupational lung disorder in the United Kingdom, Finland, and some Canadian provinces.10-13 However, true prevalence may be underestimated, in part because of symptomatic worker attrition (healthy worker effect) and failure of primary care providers to suspect asthma or to use objective diagnostic tests. True prevalence in other parts of the world is presumed even higher wherever primary prevention, in the form of workplace hazard regulations and controls, is relatively lacking. If it does not resolve, occupational asthma tends to plateau with treatment 1-2 years after removal from the causative exposure and remains chronic.2 Long-term health and socioeconomic outcomes for some people with occupational asthma are probably worse wherever secondary and tertiary prevention in the form of access to affordable primary health care is not universal, such as in the United States, and where doctors and nurses are not trained to consider a diagnosis of work-related asthma or aware of workplace conditions that can cause asthma.
Approximately 250 substances have been reported to cause occupational asthma.1,2,14 Many have the potential to incite an irreversible asthma condition, even if the worker is removed from exposure.
Follow-up studies of occupational asthma cases years after removal from causative exposures showed that the major determinants of long-term asthma outcomes are duration of exposure to the inciting agent, duration of symptoms, and severity of asthma when first diagnosed and treated.15-20 In all follow-up studies of occupational asthma in countries where universal health insurance afforded easier access to care, 45%-90% of subjects studied remained asthmatic several years after diagnosis.15-17,19-24
The costs of occupational asthma can be devastating for chronically disabled workers and significant for employers, insurers, and governments. Unemployment and financial costs can be high, and in follow-up studies from Canada and the United Kingdom such outcomes were worse for industrial, female, and older workers.15,20,23,25-29 Costs of compensation for occupational asthma in Canada correlated with illness severity and employment status at follow-up.23
Little is known about the fate of workers with occupational asthma in the United States. We describe the fate of 55 patients seen in a clinic specializing in occupational, environmental, and pulmonary medicine.
The subject population was identified retrospectively by searching a computerized patient database at a hospital-affiliated ambulatory occupational and environmental medicine (OEM) clinic and by screening for those with "definite/probable" occupational asthma as determined by case review.
The primary subject pool consisted of all new clinic patients 16 years of age or older who had been seen during the two-year period from January 1, 1993, through December 31, 1994, and who had been assigned a provisional diagnosis of "asthma" by one of three attending physicians board-certified in occupational medicine.
Eligibility was established by a two-phase screening process that began with clarification of the baseline diagnosis. One investigator (T.H.G.), blinded to all patients by having never met or spoken with them, conducted a comprehensive medical chart review and compiled a baseline data set for each that included third-party physician work-ups if present. Information was extracted on chronology of illness onset and occupational exposures, physical symptoms and signs, causative agents, job descriptors, asthma predictors, and laboratory tests.
In order to standardize diagnosis, diagnostic certainty, diagnostic reasoning, work-relatedness, identification of causative agent, disability status, and original follow-up plan for each patient, a separate survey was conducted of the three attending physicians. Each physicians completed a diagnostic questionnaire for each of their respective patients using the baseline data set and, when needed for further clarification, the medical chart. Each patient was thereby assigned a diagnostic category and diagnostic certainty, described below. The blinded physician addressed and sought agreement on inter- and intra-physician inconsistencies.
A diagnostic certainty assignment of "definite/probable" asthma required either a known baseline history of asthma prior to work exposure, or a clinical history consistent with asthma and documented American Thoracic Society (ATS) criteria30 for asthma (methacholine challenge PC20 ≤8 mg/mL [ie, ≥20% change in forced expiratory volume in one second (FEV1) with a dose of methacholine ≤8 mg/mL], or postbronchodilator FEV1 improvement of at least 12.0%). Wheeze on examination was considered supportive. Any other potential causative or confounding cardiopulmonary, otorhinolaryngologic (ear, nose, throat [ENT]), or other condition was taken into account. A clinical history suggestive of asthma but with lack of adequate documented ATS criteria constituted"possible" asthma. Remaining cases were assigned "not asthma" or "cannot determine."
Based upon established definitions for asthma induced by sensitizer and irritant agents1,14 and the high-dose irritant mechanism described as reactive airways dysfunction syndrome(RADS),31 patients with "definite/probable" and"possible" asthma were then assigned to one of six asthma categories: occupationally aggravated asthma (OAA), sensitizer-induced occupational asthma (OA sensitizer), non-RADS irritant-induced occupational asthma (OA irritant), RADS-variant of irritant-induced occupational asthma (OA RADS), occupational asthma unspecified (OA unspecified), and ANO (asthma, not occupational). A symptom history consistent with work exposure to an identifiable causative agent was required for assignment to one of the five occupational asthma categories.
Most patients who had a history of asthma prior to the workplace exposure and who had work-related exacerbations were assigned a diagnosis of "OAA." The exception for some with prior asthma was if there was a current clinical history clearly related to exposure to a sensitizer at work, in which case a diagnosis of "OA sensitizer" was given. If a patient reported exposure to more than one potential causative agent that included both a probable irritant and a probable sensitizer without evidence of which was the likely cause, the patient was assigned a diagnosis of "OA unspecified."
In the second phase, the ANO and "possible" occupational cases were eliminated, and the "definite/probable" occupational asthma cases(n = 72) were chosen for follow-up. A letter describing the study and inviting participation was sent to this group. One investigator (T.H.G.) then attempted to telephone all 72 cases and conducted all questionnaire interviews.
Each interviewed subject (n = 55) was then assigned to one of five asthma severity categories (mild, mild-moderate, moderate, moderate-severe, or severe) based on responses to specific clinical history questions about symptoms, daily activity, and medication use. Because only 31 of 47 subjects who had peak expiratory flow rate (PEFR) meters completed serial 24-hour PEFR readings, peak flow variability was not included among the rating criteria. The five severity categories were derived from criteria recommended by the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health and by the World Health Organization (WHO) for rating severity as mild (intermittent or persistent), moderate, or severe,32-34 wherein the NHLBI/WHO moderate category was further divided into the three moderate subgroups for this study. To facilitate analysis, subjects rated as moderate-severe and severe were reassigned the status of "severe," and all others were designated"not severe." To be considered "moderate-severe," a subject had to have a moderate rating for nearly all criteria for moderate asthma thus bordering on severe.
Computer software (Stata 4.0, 1995; Stata Corp., College Station, TX) was used for statistical analysis. Univariate statistics and distributions were examined for four continuous variables, which are listed at the top ofTable 1. Mean values were compared between subjects with"not severe" asthma outcomes and subjects with "severe" outcomes, usingt tests. Chi-square tests were used to compare these two groups of subjects with respect to the discrete variables listed inTable 1, as well as work sector (service or industrial), type of pay (hourly wage or salary), years since removed from work/exposure(more or less than 3 years), and union membership.
Subjects were then re-grouped into those who were employed and unemployed, and the comparisons made above were repeated. In addition, employed subjects were compared with unemployed subjects with respect to asthma severity.
Finally, backward stepwise logistic regression models were used to look for predictors of severe asthma and then for predictors of unemployment. Variables that were significantly different at P < 0.15 in the bivariate comparisons of "severe" vs "not severe" asthma were included along with other selected variables in the initial model. The model terminated when all remaining variables retained significance at P < 0.05. The procedure was repeated in the identification of predictors of unemployment.
Results of subject selection appear in Figure 1. The initial pool of provisional "asthma" cases (n = 129) represented 22.4% of all 575 new patients during the 1993-1994 period. Of the 129, 7 (5%) were determined to be "not asthma" and a diagnosis could not be determined for 4 (3%), leaving 118 (92%) "possible" or "definite/probable" asthma cases. Of the 118, shown in Table 2, 102 (86%) had evidence suggesting occupational etiology, 82 (70%) had definite/probable asthma, and 72 (61%) were definite/probable occupational asthma cases. These 72 were selected, 57 were found, and 55 (76%) completed the follow-up interview. Of the 55 interviewed, there were 4 with no prior asthma or lung disease history about whom the attending physicians felt very strongly on clinical grounds that they had definite/probable asthma despite borderline or inadequate ATS criteria.
Occupations and asthma causing agents appear inTable 3. Twenty subjects (19 women) were employed in several departments in a newly built large general hospital.
Personal characteristics are summarized in Table 1. Mean age at baseline was 41 (±9.8) years. At follow-up, all subjects had been removed from the causative environment at an average of 30.8(± 14.9) months, 4 of them for more than 4 years. Those with severe asthma were more likely to be out of work for longer periods (P< 0.03 for months out of work at follow-up).
The mean number of years on the job that led to occupational asthma was 10.7 (±6.9). Industrial sector workers were employed an average of 15.3 (±8.5) years, significantly longer than 9.5 (±5.9) years for service sector workers (t = 2.49, P < 0.02), even after excluding 20 service workers from one large hospital (t= 2.51, P < 0.02).
Other possible confounding characteristics are also summarized inTable 1. Fourteen subjects (25%) had an asthma history pre-dating the work exposure that had been either mildly active or quiescent(including remote resolved childhood asthma). Nine were given a diagnosis of OAA, and 5 OA sensitizer. None of the 3 African Americans had a prior history of asthma. Three other cases (5%) were found to have chronic obstructive pulmonary disease (COPD), of which one had alpha-1-antitrypsin deficiency emphysema with no smoking history. Three of 5 smokers at baseline reported they had stopped smoking at least 6 months prior to the follow-up interview. Two of 5 smokers at baseline (both of whom had quit) and 2 of 3 subjects with COPD had "severe" asthma at follow-up. Data on family history of atopy or asthma were incomplete, with 14 of 39 subjects reporting positively for atopy or asthma in first or second degree relatives and 7 of those 14 reporting an asthma history pre-dating the work exposure.
No one reported new heart, lung, blood, or ENT disorders at follow-up, but 19 (35%) reported occasional symptoms consistent with dyspepsia, gastritis, or gastroesophageal reflux disorder requiring periodic or ongoing medication. Data were incomplete to determine if gastrointestinal symptoms were present in the study group at baseline. Of the 55 subjects, 16 (29%) reported a sustained weight gain of more than 20 pounds since removal from the causative work exposure, 6 (11%) reported more than 20 pounds weight loss, and the remaining 33 (60%) reported no weight change exceeding 20 pounds.
Only one subject reported being symptom-free for more than six months off medication, and his asthma was considered quiescent and possibly resolved. No subject had required hospitalization for asthma in the year prior to follow-up interview, but a few had required treatment in an emergency department or urgent care center, and one developed anaphylaxis perioperatively. Of 53 (96%) who said they currently used bronchodilator and/or anti-inflammatory asthma medication, 40 (73%) used inhalable medication daily and 13 (24%) only as needed.
While 54 (98%) had health insurance at the time of diagnosis, at follow-up 6 (11%) were not insured and paid full price for their asthma care and medications, and of these 5 were unemployed. All 6 said they could not afford health insurance and were paying full price for medications. One subject with insurance said the insurer would not cover costs related to the asthma condition. Five (9%) said they did not have a doctor who knew them and who was managing their asthma condition. Six (11%) had not seen a doctor for asthma management in the 12 months prior to the follow-up interview.
Outcome results for asthma severity, generalization of asthma to new environmental stimuli, self-report of new diagnosis of "multiple chemical sensitivity" (MCS) syndrome by a physician, and employment status are also summarized in Tables 1 and 4. In order to analyze dichotomous outcome variables, 26 (47%) who had moderate-severe and severe asthma were combined and assigned a rating of "severe" asthma and the remaining 29 (53%) were designated "not severe." A majority of 46 (84%), including 100% of those with RADS, reported new environmental asthma precipitants outside of work. Seventeen (31%) subjects said they had received a physician diagnosis of MCS, of whom 13 had been employed at one hospital experiencing indoor air quality and other chemical-exposure problems.
After controlling for the large subset of female employees at one hospital, backward stepwise logistic regression analysis shown inTable 5 revealed that women and industrial sector workers were at increased risk of severe asthma at follow-up. For women workers, the odds ratio (OR) was 13.8 (95% confidence interval [95% CI] = 1.3, 151.7). For industrial sector workers the OR was 11.9 (95% CI = 1.3, 109.8). Having a diagnosis of OA sensitizer, OAA, or an asthma history that pre-dated the work exposure was not associated with having severe asthma at follow-up. Tobacco use at baseline or at follow-up was also not a risk factor.
Overall, 38 (69%) reported being unemployed at follow-up(Table 1). Of the 17 employed, some were under-employed(<40 hours/week), including one working less than half-time, and 10 had new employers. Only 4 (7%) had the same job with the same employer, all reporting a change of workplace or adequate exposure control. Total time unemployed, after removal from exposure to the asthma causing work environment, averaged 21.6 (±17.9) months, ranging from 0 to 89 months. Ten of 33 union members at diagnosis were no longer union members at follow-up.
Analysis by backward logistic regression as shown inTable 6 showed that independent risk factors for unemployment at follow-up included the following: having "severe" asthma (OR= 20.9, 95% CI = 1.9, 229.8); lack of a college degree (OR = 7.3, 95% CI= 1.2, 43.4); or a self-reported physician diagnosis of MCS (OR = 7.8, 95% CI = 1.1, 53.2). Gender, ethnicity, age, work sector, union membership, tobacco use, and type of occupational asthma diagnosis (including OAA) were not predictors of employment status at follow-up, although, all 5 (100%) with irritant occupational asthma (not RADS) were unemployed.
Occupational asthma is preventable yet often leads to long-term illness, disability, and economic loss for young workers, and-in rare cases-death.5,6 The high prevalences of chronic active asthma (98%) and unemployment (69%) in this study group at an average age of 42 years and at an average of 31 months after removal from exposure to the inciting agents are important, despite the fact that these prevalences are not generalizable to the general population. Prevalence of chronic occupational asthma would more reliably be determined prospectively at the primary care level.
Study Population Features
These subjects were seen and most were diagnosed initially at a specialty referral clinic. They represented a broad spectrum of occupations with exposure to a wide range of causative agents. Inclusion of a large number of employees from a large general hospital (n = 20) did not appear to influence results, with the exception of the high rate of reported physician diagnosis of MCS for this sub-group. Long-term follow-up was achieved for 76% of the 72 occupational asthma cases, and asthma severity assessment was based on NHBLI/WHO criteria that relies on subject reporting, an unavoidable potential for recall bias.
It was not possible to determine how many of the 575 new entries to the clinic presented with symptoms that might suggest asthma but who were given a different diagnosis on the tracking system. Only 72 of 102 potential asthma cases had their work-ups completed, leaving 30 possible cases who were lost to follow-up or who were referred elsewhere. A more systematic approach to the baseline evaluation of asthma-like complaints in new patients should improve the proportion of cases receiving a definitive diagnosis.
The Diagnostic Process
An attempt was made to standardize the retrospective diagnostic process in order to minimize the effect of baseline variability in the initial patient work-ups. Documentation criteria were not excessively strict. For example, it was not necessary to have present in the medical record work-related expiratory flow measurements, industrial hygiene measurements, and material safety data sheets (MSDSs) for causative agents in order for a subject to receive a diagnosis of definite/probable occupational asthma. MSDSs were available for many subjects but lacking for most indoor air cases. Clinical history or work-related symptoms was a very important criterion, and in 51 cases was supported by documented ATS criteria for asthma or known pre-existing asthma history. Indeed, the follow-up findings help confirm the baseline asthma certainty ratings.
For those subjects reporting a baseline history of asthma prior to work exposure, work-related expiratory flow measures were considered valuable, if not imperative, but were not documented for all cases of OAA. Five subjects with a baseline history of asthma prior to work exposure received a sensitizer-induced occupational asthma diagnosis. More often, these subjects had asthma that had resolved or been quiescent until exposure at work to a specific sensitizing agent led to new symptoms. Except in some cases of latex sensitization in which serum radioallergosorbent test (RAST) or skin-prick test was confirmatory, it was impossible to tell without conducting specific inhalation challenge testing whether a sensitizer was a new cause or whether there was another unidentified aggravator of an asthma condition that had been subclinical for years. Specific inhalation challenge testing is not practical and can be fraught with hazard, and thus is not necessary for diagnosing occupational asthma.
The 98% rate of chronic active asthma at follow-up in this study group is consistent with findings from other nations, where 45%-94% in follow-up clinical case series or cohort studies remained symptomatic or had abnormal methacholine challenge.15-17,19,20,23,24 Asthma severity was worse for women and blue-collar (industrial sector) workers, as reported elsewhere15,20,23,25-29 and was associated with higher risk for unemployment and greater income loss at follow-up.
What explains the fact that such a high proportion remained symptomatic, with 47% having "severe" asthma? Is chronicity and severity largely due to failure of secondary prevention? Does generalization to environmental precipitants play an important role, as suggested in 84% of those we studied?
Other studies have provided concurring evidence that risk for sustained occupational asthma is directly related to the duration a worker is exposed to the causative agent while having symptoms of asthma rather than of individual susceptibility or of exposure dose,16-21,35 although dose is also important for RADS, and any of these may be risk factors in cases due to certain immunoglobulin E (IgE)-mediated sensitizers.35-37 Baseline data on either duration of symptoms or duration of exposure to the causative agent was lacking for 30 subjects in this study group, so these variables could not be analyzed. Severity of asthma at the time of diagnosis, as measured by objective tests such as methacholine challenge, has also been shown to be associated with poorer long-term health outcomes.35 However, data were insufficient to allow retrospective determination of baseline asthma severity for comparison with outcomes in this study group.
It could be argued for this group that early tertiary referral may have increased their chance of being diagnosed correctly with occupational asthma and may have expedited their removal from work exposure, thus perhaps reducing the overall duration of symptomatic work exposure and in turn reducing the risk of long-term illness severity. On the other hand, referral to a tertiary specialty center may have represented a failure of secondary lines of prevention to diagnose appropriately and promptly intervene and thus meant a delay in removal from symptomatic work exposure and delayed treatment, leading to greater long-term illness severity. The fact that many subjects were seen at this clinic for diagnosis and then referred back to a primary physician for routine management may have had some bearing on asthma severity outcome, as might other factors of access to health care, health insurance availability and restrictions, and compliance with medication use.
There may be a difference, as yet unproved, in outcome between those with certain types of sensitizer-induced occupational asthma, as suggested by studies of red cedar and isocyanate-exposed workers.16-18 In other words, IgE-mediated asthma specific for certain substances may be more amenable to resolution once exposure is stopped. Although the numbers are small, our findings (Table 4) appear to suggest that irritant-induced occupational asthma, including RADS, may have a greater tendency to generalize and be sustained by new environmental stimuli, as compared with OAA and sensitizer-induced occupational asthma.
Personal factors of atopy and tobacco smoking appear to have only limited significance for cause and probably no significance for outcome. Other studies have suggested that a personal history of atopy or smoking may predispose some individuals to develop occupational asthma if they work with certain IgE-mediated sensitizers,35-36 but this has not been shown to be the case for most sensitizers. Some evidence suggests that non-atopic persons and non-smokers may be at increased risk of asthma due to most low-molecular weight substances that induce asthma without an IgE-mediated mechanism. There are no known personal risk factors for irritant-induced asthma, making control of exposure conditions for airway irritants critical.37,38
Indoor air quality, often involving exposure to complex mixtures of chemicals, particulates, and sometimes fungal spores, was an important contributor to asthma outcomes in service sector workers in this study. These subjects were employed predominantly in hospitals, schools, libraries, and offices where demolition, renovation, cleaning chemicals, new materials or latex, or a move to a new building was frequently associated with symptom onset.
A majority (84%) of subjects reported new environmental inciters of their asthma. When asked an open-ended question to identify the most common substances, nearly all subjects listed one or more of the following: perfumes; exhaust fumes or smoke; chemical cleaning agents; fresh paint vapors; and indoor air environments, such as shops or malls, containing new fabrics or upholstery. Very few listed animals, exertion, or change in atmospheric humidity or temperature. Although tobacco smoke was reported to be an environmental inciter for asthma symptoms, tobacco use was not a risk factor for sustained severe asthma.
The high (31%) prevalence of physician-diagnosed MCS reported by this group may be explained as either a phenomenon specific to a worksite or a physician-specific phenomenon. While it was a feature predominantly, but not entirely, of the large subset of nursing employees at one hospital experiencing indoor air problems, it is noteworthy that the substances provoking continued symptoms identified by the MCS group were virtually the same as those identified by the vast majority of the others who reported new environmental triggers.
The wide 95% confidence intervals are explained by the small number of subjects. Therefore, point estimates may be imprecise but are unlikely to change our conclusions. Larger prospective studies are needed for more accurate estimates of risk.
The 69% unemployment rate in those reached for follow-up was similar for most occupational asthma types, with the exception of those with irritant occupational asthma, all of whom remained unemployed. Having "severe" asthma at follow-up appeared to increase the risk of unemployment(Table 6), as did having a diagnosis of MCS. Having a college degree appeared to provide an advantage for employment, but union membership did not. Union membership at diagnosis appeared to have no significant effect for this group by any of the two main health or socioeconomic outcome measures studied.
Preliminary data from this survey indicate that financial loss was personally devastating for most subjects and was worse if the asthma remained more active and if one was earning more at the time of diagnosis. The financial impact of occupational asthma for this group is the subject of a separate report.
Occupational asthma is a common preventable disease that is often diagnosed late and leads to prolonged disabling asthma and a high rate of unemployment. Industrial sector and women workers appear to be at greater risk for irreversible severe asthma despite removal from exposure. Those subjects without a college degree and those with severe asthma at long-term follow-up appear to be at greater risk for unemployment.
In workplaces where primary prevention of asthma has failed or not been introduced, employers, building owners, and their insurers may be at risk of incurring significant costs as employees with occupational asthma, including OAA, must be removed from exposure and are entitled to disability compensation. At the level of secondary prevention, long-term health and employment outcomes appear to depend on the astuteness of primary care providers to recognize asthma symptoms early, diagnose it rapidly using standardized testing, remove the patient promptly from exposure or eliminate the inciting agent, treat aggressively, and look for other affected workers. Failure to do so, or to refer promptly to a specialist in occupational medicine, allergy, or pulmonology, will undoubtedly compound the disability and drive up costs for all parties. It is perhaps the failure of secondary prevention that, in part, explains the high frequency of seemingly irreversible asthma despite removal from exposure, as reported in all studies, including this one.
Although early intervention at the primary care level may make an important difference in overall health and socioeconomic outcomes for those subjects with occupational asthma, a large number of workers are still likely to have poor outcomes unless employers implement primary asthma prevention strategies for all employees.
We are grateful to the subjects of this study, to the institutions providing financial support for this study, and to Sandra Catto, Rokho Kim, MD, DrPH, and P. Mark Glencross, MD, MPH, for technical assistance.
This study was supported by the Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, Educational Resource Center, grant no. T42/CCT110421; and the National Institutes of Health, National Institute of Environmental Health Sciences, grant no. ES00002. Dr Gassert was supported during part of this research by a scholarship from the American College of Occupational and Environmental Medicine, Occupational Physicians Scholarship Fund.
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