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Search Result 2 From: Kathi ( snipped-for-privacy@earthlink.net) Subject: Diisocyanate-induced OA: This is the only article in this thread View: Original Format Newsgroups: alt.support.breast-implant Date: 2003-06-17 13:19:54 PST
Diisocyanate-induced OA: How to be sure, what to do.
Author/s: Susan M. Tarlo Issue: Jan, 2000
It may take weeks--or even years--before symptoms occur
ABSTRACT: Diisocyanates are among the most common causes of occupational asthma (OA). Significant exposure to these agents has been associated with spray painting and a number of manufacturing processes. Consider the possibility of OA if a patient presents with new-onset asthma, dry cough and/or shortness of breath, wheeze, and chest tightness. Peak flow readings that are lower during and/or after work and improved when the patient is off from work support the diagnosis; pulmonary function tests pre- and post-bronchodilator and a histamine or methacholine challenge provide objective assessment. An early, accurate diagnosis and removal from exposure provide the best outcomes. Other environmental control measures and pharmacologic therapies for patients with OA are the same as for those with nonoccupational asthma. (J Respir Dis. 2000;21 (1):58-67)
Occupational asthma (OA) is defined as asthma caused by conditions in a particular occupational environment. [1] It may be provoked by an immunologic mechanism (IgE-mediated) or, less commonly, by exposure to high levels of a respiratory irritant (as in reactive airways dysfunction syndrome [2] or irritant-induced asthma [3]). OA is the most common nonacute occupational lung disease in many industrialized countries, and among the most commonly reported causative agents are the diisocyanates. [4,5] For example, spray painting, which may result in significant exposure to diisocyanates, accounts for the highest proportion of OA cases in Britain. [6]
In this article, I use the example of diisocyanate-induced asthma to present the approach to diagnosis and management of OA suggested in recent clinical guidelines. [7]
BACKGROUND
Diisocyanates are very reactive, low molecular weight chemicals characterized by two - N=C=O groups per aromatic or aliphatic monomer. They are commonly used in the manufacture of polyurethane foam (used for car seats, bumpers, upholstered furnishings, and mattresses), in spray paints (used in auto-body shops), and in urethane coatings and sealants. Diisocyanates are also used in manufacturing refrigerators and bathtubs and in foundries to make molds.
There are many different diisocyanate compounds; the most commonly used are toluene diisocyanate (TDI), diphenylmethane diisocyanate (MDI), and hexamethylene diisocyanate. Besides the monomeric form of these diisocyanates, dimers and larger polymers (common in spray paints) have been produced.
At high airborne exposure levels (such as following a spill or when workers without respiratory protective equipment are exposed to spray paint), diisocyanates are respiratory irritants and may cause OA. [2,3] Diisocyanate-exposure may also lead to conditions other than a new onset of asthma (see "Other effects of diisocyanates").
Levels of diisocyanates below 20 parts per billion have not been demonstrated to cause respiratory irritation but may cause OA by sensitization. This immunologic airway response is similar to OA resulting from workplace allergens (such as animal dander, wheat, and latex) in the following ways: * There is a latent period of exposure that may range from weeks to years before the onset of asthma.
- OA develops in only a minority of workers exposed to diisocyanates (up to 11% of spray painters).
- Once a worker is sensitized to diisocyanates and OA develops, even minute levels of exposure can trigger exacerbations.
However, unlike sensitization to high molecular weight allergens (such as animal or plant proteins) and to some low molecular weight chemicals (such as complex platinum salts and epoxy compounds), IgE antibodies to diisocyanates have been demonstrated in only about 20% of patients with diisocyanate-induced asthma, [8] and the immunologic mechanism of this sensitization remains unclear. [9,11] At present, there is no sensitive specific immunologic test for diisocyanate-induced asthma.
This may in part relate to the low molecular weight of diisocyanates
--they require binding to a hapten to be antigenic. In addition, they are very reactive and may form neoantigens or other immune stimulants by binding with proteins in the airway [12] Other proposed mechanisms include direct T-cell activation and activation of histamine-releasing factors.
DIAGNOSIS
Whether OA results from diisocyanate exposure or contact with other occupational sensitizers, an early, accurate diagnosis is key to providing the best outcome.
The primary care physician or the occupational physician affiliated with a plant producing or using diisocyanates has the best opportunity to first suspect the diagnosis. A comprehensive occupational history is essential in the evaluation of all patients in whom asthma symptoms develop during their working life.
When to suspect OA
If a patient who works presents with a history of new-onset asthma, dry cough and/or shortness of breath, wheeze, and chest tightness, inquire about any temporal relationship of symptoms to the workplace.
About 60% of patients with diisocyanate-induced asthma note a worsening of symptoms 4 to 8 hours after the onset of each exposure (an isolated late response). [13] About 10% of patients have only an isolated immediate response, occurring within minutes of the exposure and clearing within an hour of leaving the exposure. The remaining 30% of patients have a dual response--an immediate response followed by a late response. [13] Thus, patients frequently notice the onset or worsening of asthma at the end of a workshift, or in the evening after leaving work, with symptoms disturbing sleep.
Improvement is frequently noted on weekends after 1 to 2 days' absence from work (about 70% of patients) and, more frequently, on holiday after 7 to 10 days' absence from work (about 90% of patients), with worsening after 1 to 2 days back at work. [13] Such a history should raise suspicion of OA and lead to more investigation (Figure 1).
History of exposure
Work performed in an environment where there is spray painting or the manufacture or use of polyurethane foam should raise suspicions of diisocyanate exposure; this type of exposure may also occur in foundries and in plants that manufacture bathtubs or refrigerators. The following suggestions will help you evaluate an occupational exposure:
- Request copies of material safety data sheets (MSDS) or workplace hazardous materials information system (WHMIS) sheets listing the hazardous chemicals in your patient's work setting. Employees are entitled to MSDS relating to products to which they are exposed as well as to chemicals used by co-workers. Your patient may directly obtain the MSDS from an employer (especially with a physician's note) or may need the assistance of a health and safety representative, or union, to get copies.
- Obtain details about the frequency and intensity of the patient's exposure, including information about the ventilation/containment measures and the use and type of respiratory protective equipment provided and worn. However, appropriate face masks and ventilation may not completely prevent exposure to diisocyanates. Also, respiratory exposure is increased if masks do not fit well or are not worn consistently at times of exposure.
- Find out how many other employees were exposed and whether they are having respiratory symptoms similar to those of your patient.
Consider other causes
The patient's clinical history may lead you to suspect an alternative cause for symptoms. Rhinitis with postnasal drip may cause cough; hyperventilation, vocal cord dysfunction, anemia, or other respiratory or cardiac disease may cause dyspnea. Include the following information in the clinical history:
- Are there symptoms of allergic rhinoconjunctivitis or nonallergic rhinitis?
- Could there be other triggers or environmental exposures, such as seasonal patterns or a cat?
- Does the patient have a history of smoking?
- What are indications of symptom severity? Has the patient had to limit exercise? Have there been sleep disturbances or visits to the emergency department? What are the patient's medication needs?
The proportion of patients with a family history of asthma is similar among those with occupational and those with nonoccupational asthma. Physical examination findings may be helpful in the differential diagnosis but may be normal in nonoccupational asthma and OA, especially if the patient is asymptomatic at the time of the visit.
Peak expiratory flow rate
When OA is a consideration, instruct the patient to use a peak expiratory flow (PEF) meter and to record serial PEF readings (three times on each occasion) at least four times a day on both working days and days off (Figure 2). Patients should also record their symptoms and use of medications. [7] Medications (other than bronchodilators as needed) should, if possible, be kept at a stable, regular dosage during this time, sufficient to control but not completely suppress symptoms.
Compliance has been poor with such PEF recording, especially when patients were asked to record values six times per day. [14] Nevertheless, the sensitivity and specificity of PEF recordings have been shown to be high compared with other tests if the patient keeps an adequate record (encompassing several weeks at work as well as a holiday period) and if the recordings show a clear pattern to support or refute the relationship of asthma to work. [15,16] If recordings at work show no significant changes, such changes may have been masked by asthma medications; in this case, have the patient use less medication and repeat the recordings. Electronic PEF meters or portable spirometers provide more objective information about patient compliance, but their cost makes it impractical to lend them to patients for several weeks.
Interpreting test results
Both pre- and post-bronchodilator pulmonary function tests, as well as a histamine or methacholine challenge test, are necessary to objectively diagnose asthma and to assess the relationship of asthma symptoms to work. Normal results do not exclude OA if tests are performed when the patient is absent from work and free of symptoms. In that case, the results can serve as a baseline for comparison with spirometry and methacholine or histamine challenge responses obtained toward the end of a typical work week, within 24 hours of symptom occurrence, when the patient returns to work. If results at that time do not show asthma, OA is virtually ruled out. [7]
It is rare for patients with diisocyanate-induced asthma to have normal airway responsiveness to histamine or methacholine challenge within 24 hours of an exposure that has induced asthma symptoms, although a few cases have been reported. [17] If the patient is working when first assessed and a methacholine or histamine challenge confirms airway hyperresponsiveness, repeat the testing after a holiday of 10 to 14 days (before the patient returns to work) to objectively assess whether there is improvement, which would support a diagnosis of OA.
Depending on the individual pulmonary function Laboratory, a minimum of a twofold to fourfold improvement in provocative concentration of an inhaled agonist producing a 20% decrease in forced expiratory volume in 1 second ([PC.sub.20]) when a patient is absent from work is significant. [18] However, lack of significant improvement in [PC.sub.20] when a patient is on holiday does not exclude OA, since a minority of sensitized persons with asthma may require a longer period away from exposure before significant improvement occurs. Therefore, in the face of a convincing history, PEF responses that suggest an occupational component, and a trend toward improvement in histamine or methacholine [PC.sub.20], a longer period away from work with repeated tests may help establish the diagnosis.
To interpret changes in PEF rates and methacholine or histamine responses during weeks at work compared with weeks absent from work, consider confounding factors, [18] such as intercurrent respiratory viral infections within the preceding 6 weeks or nonoccupational allergen exposures. (Information may be obtained from the patient's history and environmental allergy assessment, including skinprick testing for sensitivity to common aeroallergens). For example, there may be improvement during a holiday if a patient who is allergic to a cat or to ragweed travels away from these triggers.
Work-related changes in asthma severity as assessed by serial PEF monitoring and methacholine or histamine challenges generally provide a clear, objective method to confirm or refute the diagnosis of OA. If PEF monitoring can be adequately performed and interpreted but methacholine or histamine challenges cannot (or vice versa), and if the resulting changes are clearly positive or negative, this may be sufficient to confirm or refute the diagnosis (although not ideal). However, if the patient is removed from exposure to diisocyanates and cannot or will not return to the site for testing, the diagnosis will remain unproved.
Demonstration of asthma by a significant bronchodilator response, spirometry, or a positive methacholine or histamine challenge in a patient whose symptoms began while working in a setting with diisocyanate exposure does not prove the diagnosis of OA (although it raises suspicion). Nonoccupational asthma is common and frequently has its onset in adult life.
Laboratory challenge
In patients who have a history that suggests diisocyanate-induced asthma but who have left work before being assessed, the absence of objective findings does not exclude previous OA. In these circumstances (and when a patient clearly has OA but if confirmation of the causative agent is needed), specific laboratory challenge testing with diisocyanates may be helpful. [19] Such testing requires specialized facilities that are available in only a few centers, [19] and it is time-consuming and costly.
Although laboratory challenge has been considered a gold standard of diagnosis, false-negative responses can occur if the wrong diisocyanate is used. For example, some patients can be sensitized to TDI but not MDI; some to a pre-polymer but not a polymer [20]; and some to a specific isomer, such as TDI 2,4 but not TDI 2,6. [21] After a long period away from exposure, sensitivity may be lost, or there may be a need for multiple days of reexposure before measurable changes occur in PEF, spirometry, or methacholine/histamine responsiveness. [22] During challenges, levels of diisocyanates need to be continuously monitored, since excessive levels may be irritating or may sensitize the patient. Therefore, when feasible, workplace studies provide the most practical means of diagnosis. Workers' compensation claims are greatly facilitated if a clear, objective diagnosis has been made before the patient is advised to stop working with diisocyanate exposure.
MANAGEMENT
The best prognosis for OA caused by sensitization to diisocyanates is associated with an early, accurate diagnosis and removal from further exposure (Figure 3). [13,23] Other indicators of a favorable prognosis are an early onset and milder asthma at the time of diagnosis. [13] Asthma occurring within the first 2 years of work exposure is considered to be early-onset; this is when diisocyanate-induced asthma most commonly becomes apparent.
Changes in ventilation at work and use of protective respirators have been associated with a less beneficial outcome. Other environmental control measures and medications for the treatment of OA are the same as for nonoccupational asthma.
The patient's co-workers should also be considered when a diagnosis of diisocyanate-induced asthma is made. A diagnosis of OA should be considered a "sentinel event" and lead to assessment of the workplace practices by the employer or by a public health agency, the goals of which are to ensure that diisocyanates are being appropriately and safely handled, to ensure that workers have appropriate health and safety education concerning risks, and to allow early detection of OA in co-workers. Evidence suggests that there may be some benefit from surveillance programs that monitor and control diisocyanate exposure levels and provide medical surveillance for workers with the use of respiratory questionnaires and workplace spirometry, as has been done in Ontario. [24]
Other effects of diisocyanates
In addition to anew onset of asthma, diisocyanate exposure may lead to the following conditions:
- Irritant-induced asthma: A spill or other very high exposure to diisocyanates can induce, an inflammatory airway response resulting in an asthma syndrome that can persist for weeks to years. [2,3] To make this diagnosis, document the occurrence of the exposure (when possible) and the new onset of asthma symptoms within 24 hours of such exposure, persisting for at least 12 weeks, and obtain objective evidence of asthma based on a spirometric bronchodilator response or a methacholine or histamine challenge. [2,3]
The patient may also have been sensitized to diisocyanates at the time of the exposure [25] and may have a worsening of asthma even on exposure to very low levels. In this case, total removal from further exposures is required. However, if irritant-induced asthma has occurred without concurrent sensitization, the patient may return to the workplace provided that there is appropriate asthma management and that measures to reduce the risk of similar high-level exposures are in place. [7]
- Aggravation of underlying asthma: Patients with nonoccupational asthma may experience an exacerbation of their symptoms while working with diisocyanates if levels are high or if there is exposure to other concurrent nonspecific respiratory irritants, such as dusts, smoke, or fumes. In that case, peak flow readings may show an immediate worsening with work exposure and improvement on weekends and holidays, but the degree of nonspecific airway responsiveness (20% decrease in forced expiratory volume in 1 second) to histamine or methacholine would not be expected to differ significantly during holidays, compared with work weeks. To treat such a patient, optimize asthma therapy, and instruct the patient how to control environmental respiratory irritant exposure when possible--by a move to a cleaner area of the plant; by ventilation improvements; and by short-term, appropriate respirator use when levels of workplace irritants are temporarily increased. [7]
- Diisocyanate-induced rhinitis: Rhinitis is commonly reported by patients with diisocyanate-induced asthma [13] and has been confirmed by challenge testing, [26] but the prevalence-of diisocyanate-induced rhinitis alone is not known, and its prognostic significance concerning the development of occupational asthma has not been reported.
- Hypersensitivity pneumonitis: This is uncommon and has been reported mainly in case series in relation to diphenylmethane diisocyanates. [27] Clinical features are similar to those of hypersensitivity pneumonitis from other causes, and specific IgG antibodies to diisocyanate human serum albumin conjugates have been demonstrated. Treatment is removal from further exposure to diisocyanates and, when necessary administration of oral corticosteroids.
Dr Tarlo is associate professor of medicine at the University of Toronto and is affiliated with the respiratory division of the Toronto Western Hospital in Ontario.
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