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Increases in Airway Responsiveness Following Acute Exposure to Respiratory Irritants
Increases in Airway Responsiveness Following Acute Exposure to Respiratory Irritants· Reactive Airway Dysfunction Syndrome or Occupational Asthma? Louis-Philippe Boulet, M.D.
We describe a persistent increase in nonspecific bronchial responsiveness following acute exposure to strong respiratory irritants in four subjects with no past history of asthma or' atopy and in a subject with mild asthma. They were exposed either to a bleaching agent, sulfuric acid, hydrochloric acid, ,perchloroethylene, or toluene diisocyanate fumes. In all cases the inhalation of high concentrations of irritant fumes was brief (less than one hour) and induced acute symptoms of cough and dyspnea. The asthmatic subject developed a severe bronchospasm which required mechanical ventilation, In' all subjects the exposure led to prolonged (more than one year) symptoms of variable airflow obstruction induced on contact with common respiratory irritants. In the previously normal subjects, a mild hyperresponsiveness to methacholine could be observed. The asthmatic subject became dependent' on steroids. No change in the forced expiratory volume in one second was
observed when the subject exposed to sulfuric acid was rechallenged in the laboratory, but her nonspecific bronchial responsiveness was then back to normal. at this time. When those exposed to perchloroethylene or toluene diisocyanate fumes were reexposed to these agents, a late asthmatic response occurred, suggesting that" the subjects developed occupational asthma after an intense short-term exposure to perchloroethylene or toluene diisocyanate. We conclude that airway hyperresponsiveness can develop or increase after the inhalation of high concentrations of irritants and that these changes may be prolonged. Occupational asthma following intense short-term 'exposure to sensitizing agents should be differentiated from airway hyperresponsiveness which results from a nonsensitizing mechanism, as in' the reactive airway dysfunction syndrome. (Chest 1988; 94:47li-81)
~rbome particles such as common aeroallergens,
Clinical and physiologic findings associated with this syndrome are different from bronchiolitis and from the typical presentation of occupational asthma due to sensitization; however, its distinct entity remains to be further documented. We report five cases of persistent increase in nonspecific bronchial responsiveness after acute highlevel exposure to sulfuric acid, a bleaching agent, hydrochloric acid, perchloroethylene, or toluene diisocyanate. The two last cases are suggestive of occupational asthma following intense short-term exposure to sensitizing agents, while in the first three, airway hyperresponsiveness seems to result from a nonsensitizing mechanism such as the reactive airway dysfunction syndrome.
sensitizing agents, pollutants, or viruses can increase nonspecific (nonallergic) bronchial responsiveness to' various degrees in asthmatic and normal subjects.':" Although transient increases in bronchial smooth muscle responsiveness have been reported with nonspecific irritants, these agents are not usually expected to induce marked and prolonged changes nor cause worsening of asthma.v'' It is generally believed that an exposure to nontoxic levels of irritant dust or fumes does not lead to impaired' pulmonary function, although little is known on the long-term consequences of an acute high-level or a chronic exposure to these substances.I'v'! Their potential role as inducers of bronchial asthma is still unknown. Brooks et al ll , 12 have described a condition called the "reactive airway dysfunction syndrome." This is characterized by the appearance of asthma-like symptoms and an increase in nonspecific bronchial responsiveness after acute massive exposure to irritants. *From the Unite de Recherche en Pneumologie, Hopital Laval, Sainte-Fey Quebec, Canada. Manuscript received October 15; revision accepted February 12. Reprint requests: Dr. Boulet, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5
476
CASE REPORTS CASE
1
A 45-year-old woman, a nonsmoker with no personal or familial history of asthma or atopy presented symptoms of marked nonproductive cough, chest tightness, and dyspnea immediately after a 45minute exposure to a cleaning compound containing. sulfuric acid (66 percent) in an unventilated washroom. Symptoms of mild rhinoconjunctivitis were also present. Such symptoms had never occurred previously and there was no clinical evidence of intercurrent respiratory infection or contact with known sensitizing agents. There was no fever or colored phlegm. The subject had not been Increases in Airway Responsiveness after Exposure to Irritants (Louis-Philippe Boulet)
significantly exposed to sulfuric acid before that episode. The patient consulted her physician three weeks after the exposure because of persisting symptoms of daily cough and intermittent dyspnea which worsened on exposure to strong odors or fumes and on exercise. Albuterol (salbutamol), theophylline, and oral steroids were administered in order to control her symptoms. Two months later, bronchodilators were still required to control these symptoms, and the patient was referred to us. Initial evaluation disclosed normal spirometric data, pulmonary volumes, and carbon monoxide diffusing capacity. Nonspecific bronchial responsiveness to histamine, measured by the method described by Cockcroft et aI,13 was slightly increased with a PC 20 F~V1 of 5.5 mg/ml (Table 1). On bronchoscopy; there was evidence of moderate inflammation of the mucosa of the large airways. The chest roentgenogram was normal. Skin prick tests to 16 common airborne antigens showed a positive reaction to house dust and Dermatophagoides farinae. The patient had no further exposure to the involved cleaning agent. Her bronchial response to histamine was still increased one year after the initial exposure to sulfuric acid (PC20 of3.2 mg/ml). At that time, chest symptoms still occurred daily and were controlled by albuterol aerosol as needed. Two years after the exposure, PC 20 was normal (31.7 mg/ml), and the patient was asymptomatic. At that time, she was reexposed in a provocation chamber to the same agent containing sulfuric acid. She poured this liquid in a 2-L bath of warm water and then stirred the mixture for progressive periods of time (total, 20 minutes). The chamber was ventilated only at the end of each exposure. Although she experienced a burning sensation of the eyes and a mild cough, no other symptom or fall in the forced expiratory volume in one second (FEV 1) was observed up to seven hours after the test. No change in PC 20 was observed (32.4 mg/ml) after the challenge, and no symptom was reported in the following days. A control exposure with hydrochloric acid had led to the same symptoms of cough and ocular irritation without change in flows or PC 20 • CASE
2
A 69-year-old man was referred for an evaluation of his asthma. He reported the acute onset of dyspnea and cough following accidental exposure, six years ago, to the fumes which resulted when a bleaching agent was poured into a large volume of boiling water. This agent contained low-density phosphates and sodium metasilicate and had a chloride concentration of 18 percent. The patient had no history of asthma or allergy before this episode. He had stopped smoking ten years previously; at a time when he had
no chest symptoms. He was never reexposed to the causal agent afterwards. The patient consulted his family physician 24 hours after this acute exposure, because of persisting shortness of breath and wheezing. Bronchodilators relieved his symptoms. Since then, he had episodic dyspnea, chest tightness, wheezing, and a mildly productive cough on exposure to common respiratory irritants. He required regular therapy with theophylline and inhaled albuterol to control his symptoms. When the patient was first seen in our clinic, six years after the acute event, the pulmonary function tests showed moderate airway obstruction (Table 1). A methacholine inhalation test showed a mild bronchial hyperresponsiveness with a PC 20 of 6.9 mg/ml. Skin prick tests to common allergens were negative. CASE
3
A 41-year-old nonsmoking nonatopic subject had a six-year history of mild asthma. His respiratory symptoms were stable and controlled with albuterol aerosol as needed and a long-acting (12-hour) preparation of theophylline. After cleaning a pool for almost one hour with a product containing hydrochloric acid, the patient had developed a rapidly progressive and severe bronchospasm. On arrival at the hospital, he was in respiratory distress and had to be intubated and mechanically ventilated. The chest roentgenogram was normal. The patient was treated with bronchodilators (albuterol and aminophylline) and intravenous steroids and could be weaned off the ventilator in three days. He was discharged on therapy with prednisone and his usual bronchodilators. One year after this accident, although still receiving bronchodilators and oral steroids (dose of prednisone between 20 and 40 mg/ day), the patient continued to have marked symptoms of asthma. These symptoms were triggered by the inhalation of trivial concentrations of irritants or minimal exercise. The patient had frequent episodes of nocturnal asthma. Higher doses of oral or intravenous steroids only led to modest and transient reductions of his asthmatic symptoms. Since the patient was unable to stop his medication, we were unable to measure nonspecific bronchial responsiveness. He showed severe spontaneous fluctuations of his expiratory flows, with mornirig dipping. Although airflow obstruction could be completely reversed with albuterol, a progressive fall in FEV 1 was observed up to more than 20 percent at four hours after inhalation, suggesting a severe bronchial hyperresponsiveness. Carbon monoxide diffusion was normal. Since this accident, the patient has been frequently admitted to the hospital for exacerbations of his asthma.
Table I-Characteristics of Subjects* Subjects, Sex, Age (yr) Data Agent FEV b Lis (percent predicted) FVC, L (percent predicted) PC 20 M (mg/ml)§ Specific challenge Diagnosis'[
2,M,69
3,M,41
Sulfuric acid 2.71 (118)
Bleaching agent 2.09 (76)
Hydrochloric acid 2.10 (4.04)*
Perchloroethylene 2.29 (52)
Polyurethane foam (TDI)t 2.25 (3.10)
3.28 (101)
3.14 (74)
4.18 (5.38)*
3.85 (76)
3.05 (4.12)
5.5 No response] RADS
6.9
2.211 Dual response Occupational asthma
4.3 Dual response Occupational asthma
1,F,45
RADS
RADS
4,M,18
5,M,47
*Carbon monoxide diffusion was normal in all cases. tTDI, Toluene diisocyanate. *Four hours after 200f-Lg of albuterol. §Methacholine. IIThis challenge was, however, performed when bronchial responsiveness was back to normal. ~RADS, Reactive airway dysfunction syndrome. CHEST / 94 / 3 / SEPTEMBER, 1988
477
CASE 4 An 18-year-bld student, without personal or family history of bronchial asthma, was seen with a six-week history of intermittent dyspnea, with chest tightness, cough, and wheezing, after exercise or exposure to. nonspecific respiratory irritants. He had begun to work in. a cleaning factory two months previously The patient was regularly exposed for short periods of time to dry-cleaned linen residues containing perchloroethylene (PCE: C 2CI4), while working on maintenance ofdry-cleaningmachines, He left his job because of Increasing severity of respiratory symptoms, occurring at work and persisting in the evening and at night after work shifts. These symptoms first appeared following an unusually prolonged exposure to perchloroethylene while cleaning a dry-cleaning washer, which provoked an acute episode of severe dyspnea, cough, chest tightness, and epistaxis. Six months after the onset of symptoms, the patient was referred to us for persisting cough and dyspnea on exertion. The findings from physical examination and the chest roentgenogram were normal. Skin prick tests to common airborne allergens showed mild wheal-and-flare reactions to D farinaeand mixed tree pollens, which on questionnaire were not clinically relevant. Spirometry revealed moderate airflow obstruction, with FEV! and forced vital capacity (FVC) of 2.29 Lis and 3.85 L, increasing to 4.46 Lis and 4.74 L, respectively after 200~g of inhaled albuterol (predicted FEV/FVC, 4.33/5.04). One month later, the patients spirometric data were normal (FE V/FVC, 4.08/5.13), and he had normal nonspecific bronchial responsiveness with a fall in FEV1 of 9 percent with methacholine (8 mg/ml). The patient was exposed in a provocation chamber, fora total of five minutes, to the spontaneous emanations of dry-cleaning residues containing perchloroethylene, freshly obtained from a drycleaning machine. These vapors were very volatile and irritating, inducing a cough even in normal subjects. Our subject developed a marked cough and progressive dyspnea with a fall in FEV1 reaching a maximum of 40 percent from baseline at 60 minutes. This was followed by a slow recovery to within 10 percent of the initial value at six hours after exposure (Fig 1). On a controlday no symptom or significant fall in FEV! occurred when the subject was exposed to lactose according to the method described by Pepys and Hutchcroft.'! After the perchloroethylene
5.0
• PERCHlOROETHYlENE o CONTROL
challenge, the PC 20 was 8.0 mg/ml seven hours and 2 mg/ml two weeks later. Mild intermittent symptoms of cough and dyspnea abated progressively CASE 5
A 47-year-old factory worker reported the acute onset of asthmalike symptoms immediately following the accidental inhalation 15 years ago of vapors of toluene diisocyanate used in the production of polyurethane foam. He had been working In this factory for two months, and although exposed regularly to this kind of material, he had never before been exposed to high concentrations of isocyanates. Since that acute episode.. the patient had had symptoms of intermittent dyspnea and wheezing following exposure to nonspecific irritants. He uses inhaled albuterol as needed and inhaled beclomethasone during exacerbations of his asthma. When seen at the clinic (15 years after the initial exposure to toluene diisocyanate), skin tests to common allergens were negative. Findings from physical examination and the chest roentgenogram were normal. Pulmonary function tests showed normal spirometric data and a mild bronchial hyperresponsiveness to methacholine with a PC 20 of 4.3 mg/ml. A bronchial provocation test was performed with isocyanates (toluene diisocyanate) The patient was exposed in a provocation chamber to the vapors of toluene diisocyanate produced by a compound used in the making of polyurethane foam. Less than one minute after this exposure, a marked cough and dyspnea occurred. A 26 percent fall in FEV1 was documented immediately following this inhalation, followed by a more severe fall where FEV1 could not be measured. A complete recovery was observed at two hours but was followed by a 15 percent fall in FEVl six hours later, despite the fact that the patient had received albuterol (2.5 mgby nebulization) and 400~g of beclomethasone (with a metered-dose inhaler) following the immediate response (Fig 2). There was no change in nonspecific bronchial responsiveness 24 hours following .this provocation with toluene diisocyanate (PC 2o,3.8 mg/ml). On a control. day when the patient was exposed to a varnish without toluene diisocyanate, no fall in FEVl was observed. DISCUSSION
We report five cases of an increase in nonspecific airway responsiveness with development of asthmatic Symptoms after acute exposure to irritants in poorly ventilated workplaces. The first three cases are sug-
4.5
2
->
UJ
u.
4.20
4.0
2
s
3.5
w u,
3.0 2.5
ISOCYANATE EXPOSURE (TDI)
3.80 3.60 3.40 3.20 3.0
EXPOSURE EXPOSURE
1---I
1 5
,
~
SALBUTAMOL
, ,
\
-1-/ I-r-r--I/i
1 5
-"r--.,.,-_,-.,..-..,.....-
ll-r-:15 30 45 60 90 2 i.
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i
minutes TIME
post
3
4
i
5
I
6
1
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i
7
INHALATION
\
1
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" I
10
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MINUTES
hours
FIGURE 1.. Bronchial provocation test with perchloroethylene (solid dots) and control (open dots). Progressive fall in FEVl is observed after inhalation of perehloroethylene, with maximum fall of 40 percent from baseline at 60 minutes and complete recovery at six hours. No significant change in FEVl occurred on control day
478
,
4.00
HOURS
FIGURE 2. Bronchial challenge with toluene diisocyanate (TDI) (solid line) and control day (broken line). A few seconds of exposure to toluene diisocyanate was sufficient to induce a severe fall in FEV b requiring administration of bronchodilators and steroids. Fifteen percent fall from baseline was noted six hours after initial exposure. No significant change in FEV l was observed on control da~
Increases in Airway Responsiveness after Exposure to Irritants (LOUis-Philippe Boulet)
gestive of the reactive airway dysfunction syndrome, developing after the inhalation of sulfuric acid, hydrochloric acid, and a bleaching agent, and the last two cases are suggestive of occupational asthma to perchloroethylene and isocyanates (toluene diisocyanate). Four subjects were previously normal, and one had mild stable asthma. In all cases the increase of nonspecific bronchial responsiveness and chest symptoms persisted from one to more than 15 years after the initial exposure. The previously normal subjects were not exposed to other relevant sensitizing agents and had no evidence of intercurrent respiratory infection which could have led to increased airway responsiveness, and although they were not tested before the acute exposure described, they had no clinical evidence of previously increased bronchial responsiveness. The subject with mild stable asthma was well controlled with daily bronchodilators. He developed a severe steroid-dependent asthma after an acute exposure to hydrochloric acid with clinical evidence of marked nonspecific bronchial responsiveness which seemed mostly due to smooth muscle hyperexcitability his expiratory Hows returning to normal with inhaled albuterol. The first three cases fulfill most of the criteria for the "reactive airway dysfunction syndrome," as reported by Brooks et al,11,12 although previous asthma was excluded from this definition. The criteria used to define the entity are as follows." (1) the absence of previous respiratory symptoms or disease; (2) the possibility for the patient to date the onset of the reactive airway dysfunction syndrome with a specific event; (3) a high-level exposure to gas, smoke, fume, or vapor; (4) the onset of symptoms occurring within a few hours after exposure; (5) asthma-like symptoms such as cough, wheezing, and dyspnea; (6) pulmonary function tests that usually show airflow obstruction and increased response to methacholine; and (7) no evidenceof other pulmonary disease. Persistent airway hyperresponsiveness following exposure to high concentrations of irritants was described after inhalation of paint fumes, uranium hexafluoride, floor sealant, hydrazine, heated acid, fumigating fog, metal coat remover, propylene glycol, welding, alpha-chlorophane, and fire or smoke. 12,14 In two of these subjects, airway inflammation was observed on bronchial biopsies. The features of the reactive airway dysfunction syndrome contrast with the classic definition of occupational asthma. Occupational asthma is usually defined as variable airway narrowing causally related to the exposure to environmental inhalants at work. Most authors restrict this definition to asthma caused by sensitization, excluding asthma caused by an irritant mechanism.P In occupational asthma, an increase in nonspecific bronchial responsiveness is observed after
exposure. As we know nonspecific bronchial responsiveness is a continuum where the asthmatic subjects represent one end of the curve (those who respond to lower concentrations of histamine or other nonspecific agents). Acute irritant-induced inflammatory changes may increase the level of nonspecific bronchial responsiyeness in previously normal subjects, but we think that this may occur as well in subjects with increased baseline nonspecific bronchial responsiveness. Although it is well known that respiratory symptoms may occur at work in subjects with a heightened airway responsiveness, the consequences of exposure to high concentrations of irritants are not well known. Candevia'" has previously described a type of acute inflammatory bronchoconstriction caused by accidental exposure to high concentrations of irritants. Furthermore, the development of airway obstruction has also been described after inhalation of different irritant gases and fumes, such as drain-cleaning agents, chlorine, sulfur dioxide, or ammonia. 17-21 In many of these cases, the defects persisted for years; however, nonspecific bronchial responsiveness had not been measured after such exposure until recently In the case of irritants, the typical pattern of response following inhalation of a nonspecific agent is usually short-lasting, occurs in subjects with a heightened nonspecific airway responsiveness, and does not increase nonspecific bronchial responsiveness. A highlevel exposure and a severe inflammatory reaction in the airways is probably required to induce massive release of mediators and to change smooth muscle responsiveness for a prolonged period of time. The overwhelming aggression to the airway may consequently impede the defense mechanisms that switch off the inflammatory process potentially induced by inhalation of irritants at lower concentrations. The mechanisms of increase in smooth muscle responsiveness following acute inflammation are still to be documented. The reactive airway dysfunction syndrome probably occurs with a large variety of substances which share the characteristic of being strong irritants which can induce airway inflammation, however, the effects of high-level exposures to sensitizing agents are not well known. Occupational asthma developing after such exposures, usually following accidental spills, has been reported in some cases. 14,22 With toluene diisocyanate, a dose-related response has been described, with increased concentrations causing greater effects.23 In the subject exposed to perchloroethylene, chest symptoms appeared for the first time after an episode of intense exposure to this substance, and the development of a prolonged bronchospasm after rechallenge suggests the development of occupational asthma from sensitization; however, we cannot rule out the possiCHEST / 94 I 3 I SEPTEMBER, 1988
479
bility that the type of early-late response observed could be induced by a nonsensitizing process, although unusual. To our knowledge, we describe the first case of occupational asthma from exposure to perchloroethylene. This agent, an organic solvent, .is widely used for dry-cleaning purposes; .however, little is known about its potential detrimental effects on the airways. Perchloroethylene may cause neurologic disorders when inhaled in toxic quantities. It can also induce an irritation of the upper respiratory tract and acute pulmonary edema after severe intoxication by inhalation. 24,25 In our subject with isocyanate-induced asthma, the exposure to toluene diisocyanate was acute and intense, and the previous period of exposure was quite short (two months). These findings suggest that highlevel exposure to sensitizing agents may be an important determinant of clinical sensitization. Isocyanates are commonly used, in the production of polyurethane foam, plastics.fibers, and adhesives. Toluene diisocyanate may induce airway irritation,. occupational asthma by sensitizationand alveolitis. 26-29 Exposure to low levels of toluene diisocyanatc may induce asthma in sensitized subjects. Mechanisms of respiratory effects of toluene diisocyanate remain to be 'clarified. An allergic-type. reaction involving IgE has been suggested, although confirmation of this hypothesis is lacking, and in many of those who react to toluene diisocyanate, there is no evidence of immunologic mechanisms. 30,31 The observation that subjects developing asthma due to toluenediisocyanate have often been previously exposed to.high concentrations of this substance from accidental spills suggests that high-level exposures to these compounds may be involved in the development of occupational asthma." The mechanisms by which Table 2-Characteristics,ojOccupati()nal Asthma and
High-Level Irritant-Induced Asthma
Data Agent Level of-exposure Symptoms History of asthma or atopy Pulmonary function
Occupational Asthma
Irritant Sensitizing Low (high in some High cases) Progressive Acute Possible Possible but unusual Normal or airflow Normal or obstruction airflow obstruction Normal Normal
Carbon monoxide diffusion Nonspecific bronchial Increased after responsiveness exposure Mechanism Sensitization Prognosis
480
High-Level IrritantInduced Asthma
Recovery if early withdrawal
Increased after exposure Acute inflammatory reaction? Prolonged bronchial hyperresponsiveness?
high-level exposures to sensitizing agents may precipitate sensitization remain to be elucidated. High-level exposure to materials such as toluene diisocyanate may damage the bronchial epithelium. This could contribute to increased airway permeability or expose irritant receptors. The development of occupational asthma after rather acute exposure to toluene diisocyanate and perchloroethylene in our cases stresses the difficulty of classifying this type of problem as a sensitizing or irritative effect. Asthma induced by nonsensitizing high-level exposure to irritants such as in the reactive airway dysfunction syndrome should be considered as a separate entity from asthma following sensitization, based on clinical features (Table 2). In our highly industrialized society; we are regularly exposed to a wide range of chemical products, Little is known of their effects on respiratory function, We believe that these effects should be characterized by their mechanism of action, differentiating .the acute inflammatory reaction from massive irritant effect and that following the inhalation of high concentrations of sensitizing agents with irritant properties. The so-called reactive airway dysfunction syndrome or its equivalent should be clearly identified as an occupational disease, although it should be differentiated from the classic occupational asthma induced or exacerbated at work by a specific sensitizing agent. The incidence, natural history; and prognosis of the reactive airway dysfunction syndrome and asthma from sensitization after high-level exposure have to be further documented. In summary; we describe the clinical features of three cases of the reactive airway dysfunction syndrome following acute exposure to acids and bleaching agents and report the development of this syndrome in an asthmatic subject. Moreover, the reported cases suggest that asthma may develop following high-level exposure to nonsensitizing irritative agents, that this may occur in subjects with previous asthma, and that occupational asthma may occur after short-term ex- , posure to high concentrations of sensitizing agents. ACKNOWLEDGMENTS: We thank Dr. Andre Cartier for reviewing the manuscript.
REFERENCES 1 Davies RJ, Blainey AD. Occupational asthma: classification and clinical aspects. Semin Respir Med 1984; 5:229-40 2 Orehek J, Massari JI?, Gayrard I?, Grimaud C, Charpin J. Effect of short-term, low level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients. J Clin Invest 1976; 57:301-07 3 Hargreave FE, Ryan G, Thomson NC, O'Byrne PM, Latimer K, Juniper EF, et al. Bronchial responsiveness to histamine' or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol1981; 68:347-55 4 Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. Am Rev Respir Dis 1980; 121:389-413 5 Hargreave FE, Ramsdale EH, Pugsley SO. Occupational asthma Increases in Airway Responsiveness after Exposure to Irritants (Louis-Philippe Boulet)
6
7
8
9
10 11 12
13
14
15 16 17
18
19
without bronchial hyperresponsiveness, Am Rev Respir Dis 1984; 130:513-15 Enipey D~ Laitinen LA, Jacobs L, GoldenWM, Nadel JA. Mechanism of a bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131-39 Holtzman MJ, Cunningham JH, Sheller JR, Irsigler GB, Nadel JA, Boushey HA. Effect of ozone on bronchial reactivity in atopic and nonatopic subjects. Am Rev Respir Dis 1979; 120:1059-67 Mattoli S, Foresi A, Corbo G, Valente S, Petalano F, Ciappi G. Increase in bronchial responsiveness to methacholine and late asthmatic response to the inhalation of ultrasonically nebulized distilled water. Chest 1986; 90:726-32 Wilson NM, Dixon C, Silverman M. Increased bronchial responsiveness caused by ingestion of ice. Eur J Respir Dis 1985; 66:25-30 Becklake MR. Chronic airflow limitation: its relationship to work in dusty occupations. Chest 1985; 88:608-17 Brooks 8M, Weiss MA, Bernstein IL. Reactive airway dysfunctionsyndrome, J Occup Med 1985; 27:473-76 Brooks SM, Weiss MA, Bernstein IL. Reactive airway dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985; 88:376-84 CockcroftD~ Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey Clin Allergy 1977; 7:235-43 Brooks SM. Occupational asthma. In:· Weiss EB, Segal MS, Stein M, eds. Bronchial asthma, 2nd ed. Boston: Little, Brown and Co, 1985:461-93 , Chan-Yeung M, Lam S. Occupational asthma. Am Rev Respir Dis 1986; 133:686-703 Gandevia B. Occupational asthma, Med J Aust 1970; 2:332-35 Murphy DMF, Fairman R:p, Lapp NL, Morgan WKC. Severe airway disease due to inhalation of fumes from cleaning agents. Chest 1976; 69:372-76 Hasan FM, GehshanA, Fulehan FJD. Resolution of pulmonary dysfunction following acute chlorine exposures. Arch Environ Health 1983; 38:760-80 Harkonen H, Nordman H, Korhonen 0, Wimblad 1. Long-term
effects of exposure to sulfur dioxide: lung function four years after a pyrite dust explosion. Am Rev Respir Dis 1983; 128:84993 20 Charan NB, Myers CG, Lakshiminarayan S, Spencer TM. Pulmonary injuries associated with acute sulfur dioxide inhalation. Rev Respir Dis 1979; 119:555-60 21 Flury KE, Ames DE, R~darte JR, Rodgers it Airwayobstruction due to inhalation of ammonia. Mayo Clin Proc1983; 58:389-93 22 Brooks SM. Epidemiologic study of workersexposed to isocyanate: NIOSH Health Hazard Evaluation report HHE 78-39. 1980 23 Butcher 131: Jones,RN, O'Neil CE; Glindmeyer H'W: Diem JE, Dharmarojon \; et al. Longitudinal study of workers employed in the manufacture of toluene-diisocyanate. Am Rev Respir Dis 1977; 116:411-21 24 Tuttle TC, Wood CD, Grether CB. A behavioral and neurological , evaluation of dry cleaners exposed to perchloroethylene, NIOSH No. 77-214. Department of Health, Education, and Welfare, 1977 25 Baker EL Jr. Neurological disorders. In: Rom WN, ed. Environmental and occupational medicine, 1st ed. Boston: Little, Brown and Co, 1983:323-24 26 Maxon FC Jr. Respiratory irritation from toluene diisocyanate. Arch Environ Health 1964; 8:755 27 Butcher B1: Salvaggio JE, Weili H, Ziskind MM. Toluene diisocyanate (TDI) pulmonary disease: immunologic and inhalation challenge st~dies. J Allergy Clin Immunol 1976; 58:89100 28 O'Brien 1M, Newman-TaylorAJ, Burge PS, Harries MG, Fawcett I~ Pepys J. Toluene diisocyanate-induced asthma: 2. Inhalation challenge tests and bronchial reactivity studies. Clin Allergy 1979; 9:7-15 29 Charles J, Bernstein A, Jones B, et aL Hypersensitivity pneumonitis after exposure to isocyanates, Thorax 1976; 31:127-36 30 BrucknerHC, Avery SB, Stetson DM, DodsonVN, Arlor A, Ronayne JJ. Clinical and immunological appraisal of workers exposed to diisocyanates. Arch Environ Health 1968; 16:619-25 31 Bernstein IL. Isocyanate-induced pulmonary diseases: a current perspective. J Allergy Clin Immunol1982; 70:24-31
Am
CHEST I 94 I 3 / SEPTEMBER, 1988
481
We describe a persistent increase in nonspecific bronchial responsiveness following acute exposure to strong respiratory irritants in four subjects with no past history of asthma or' atopy and in a subject with mild asthma. They were exposed either to a bleaching agent, sulfuric acid, hydrochloric acid, ,perchloroethylene, or toluene diisocyanate fumes. In all cases the inhalation of high concentrations of irritant fumes was brief (less than one hour) and induced acute symptoms of cough and dyspnea. The asthmatic subject developed a severe bronchospasm which required mechanical ventilation, In' all subjects the exposure led to prolonged (more than one year) symptoms of variable airflow obstruction induced on contact with common respiratory irritants. In the previously normal subjects, a mild hyperresponsiveness to methacholine could be observed. The asthmatic subject became dependent' on steroids. No change in the forced expiratory volume in one second was
observed when the subject exposed to sulfuric acid was rechallenged in the laboratory, but her nonspecific bronchial responsiveness was then back to normal. at this time. When those exposed to perchloroethylene or toluene diisocyanate fumes were reexposed to these agents, a late asthmatic response occurred, suggesting that" the subjects developed occupational asthma after an intense short-term exposure to perchloroethylene or toluene diisocyanate. We conclude that airway hyperresponsiveness can develop or increase after the inhalation of high concentrations of irritants and that these changes may be prolonged. Occupational asthma following intense short-term 'exposure to sensitizing agents should be differentiated from airway hyperresponsiveness which results from a nonsensitizing mechanism, as in' the reactive airway dysfunction syndrome. (Chest 1988; 94:47li-81)
~rbome particles such as common aeroallergens,
Clinical and physiologic findings associated with this syndrome are different from bronchiolitis and from the typical presentation of occupational asthma due to sensitization; however, its distinct entity remains to be further documented. We report five cases of persistent increase in nonspecific bronchial responsiveness after acute highlevel exposure to sulfuric acid, a bleaching agent, hydrochloric acid, perchloroethylene, or toluene diisocyanate. The two last cases are suggestive of occupational asthma following intense short-term exposure to sensitizing agents, while in the first three, airway hyperresponsiveness seems to result from a nonsensitizing mechanism such as the reactive airway dysfunction syndrome.
sensitizing agents, pollutants, or viruses can increase nonspecific (nonallergic) bronchial responsiveness to' various degrees in asthmatic and normal subjects.':" Although transient increases in bronchial smooth muscle responsiveness have been reported with nonspecific irritants, these agents are not usually expected to induce marked and prolonged changes nor cause worsening of asthma.v'' It is generally believed that an exposure to nontoxic levels of irritant dust or fumes does not lead to impaired' pulmonary function, although little is known on the long-term consequences of an acute high-level or a chronic exposure to these substances.I'v'! Their potential role as inducers of bronchial asthma is still unknown. Brooks et al ll , 12 have described a condition called the "reactive airway dysfunction syndrome." This is characterized by the appearance of asthma-like symptoms and an increase in nonspecific bronchial responsiveness after acute massive exposure to irritants. *From the Unite de Recherche en Pneumologie, Hopital Laval, Sainte-Fey Quebec, Canada. Manuscript received October 15; revision accepted February 12. Reprint requests: Dr. Boulet, 2725 Chemin Ste-Foy, Ste-Foy, Quebec, Canada G1V 4G5
476
CASE REPORTS CASE
1
A 45-year-old woman, a nonsmoker with no personal or familial history of asthma or atopy presented symptoms of marked nonproductive cough, chest tightness, and dyspnea immediately after a 45minute exposure to a cleaning compound containing. sulfuric acid (66 percent) in an unventilated washroom. Symptoms of mild rhinoconjunctivitis were also present. Such symptoms had never occurred previously and there was no clinical evidence of intercurrent respiratory infection or contact with known sensitizing agents. There was no fever or colored phlegm. The subject had not been Increases in Airway Responsiveness after Exposure to Irritants (Louis-Philippe Boulet)
significantly exposed to sulfuric acid before that episode. The patient consulted her physician three weeks after the exposure because of persisting symptoms of daily cough and intermittent dyspnea which worsened on exposure to strong odors or fumes and on exercise. Albuterol (salbutamol), theophylline, and oral steroids were administered in order to control her symptoms. Two months later, bronchodilators were still required to control these symptoms, and the patient was referred to us. Initial evaluation disclosed normal spirometric data, pulmonary volumes, and carbon monoxide diffusing capacity. Nonspecific bronchial responsiveness to histamine, measured by the method described by Cockcroft et aI,13 was slightly increased with a PC 20 F~V1 of 5.5 mg/ml (Table 1). On bronchoscopy; there was evidence of moderate inflammation of the mucosa of the large airways. The chest roentgenogram was normal. Skin prick tests to 16 common airborne antigens showed a positive reaction to house dust and Dermatophagoides farinae. The patient had no further exposure to the involved cleaning agent. Her bronchial response to histamine was still increased one year after the initial exposure to sulfuric acid (PC20 of3.2 mg/ml). At that time, chest symptoms still occurred daily and were controlled by albuterol aerosol as needed. Two years after the exposure, PC 20 was normal (31.7 mg/ml), and the patient was asymptomatic. At that time, she was reexposed in a provocation chamber to the same agent containing sulfuric acid. She poured this liquid in a 2-L bath of warm water and then stirred the mixture for progressive periods of time (total, 20 minutes). The chamber was ventilated only at the end of each exposure. Although she experienced a burning sensation of the eyes and a mild cough, no other symptom or fall in the forced expiratory volume in one second (FEV 1) was observed up to seven hours after the test. No change in PC 20 was observed (32.4 mg/ml) after the challenge, and no symptom was reported in the following days. A control exposure with hydrochloric acid had led to the same symptoms of cough and ocular irritation without change in flows or PC 20 • CASE
2
A 69-year-old man was referred for an evaluation of his asthma. He reported the acute onset of dyspnea and cough following accidental exposure, six years ago, to the fumes which resulted when a bleaching agent was poured into a large volume of boiling water. This agent contained low-density phosphates and sodium metasilicate and had a chloride concentration of 18 percent. The patient had no history of asthma or allergy before this episode. He had stopped smoking ten years previously; at a time when he had
no chest symptoms. He was never reexposed to the causal agent afterwards. The patient consulted his family physician 24 hours after this acute exposure, because of persisting shortness of breath and wheezing. Bronchodilators relieved his symptoms. Since then, he had episodic dyspnea, chest tightness, wheezing, and a mildly productive cough on exposure to common respiratory irritants. He required regular therapy with theophylline and inhaled albuterol to control his symptoms. When the patient was first seen in our clinic, six years after the acute event, the pulmonary function tests showed moderate airway obstruction (Table 1). A methacholine inhalation test showed a mild bronchial hyperresponsiveness with a PC 20 of 6.9 mg/ml. Skin prick tests to common allergens were negative. CASE
3
A 41-year-old nonsmoking nonatopic subject had a six-year history of mild asthma. His respiratory symptoms were stable and controlled with albuterol aerosol as needed and a long-acting (12-hour) preparation of theophylline. After cleaning a pool for almost one hour with a product containing hydrochloric acid, the patient had developed a rapidly progressive and severe bronchospasm. On arrival at the hospital, he was in respiratory distress and had to be intubated and mechanically ventilated. The chest roentgenogram was normal. The patient was treated with bronchodilators (albuterol and aminophylline) and intravenous steroids and could be weaned off the ventilator in three days. He was discharged on therapy with prednisone and his usual bronchodilators. One year after this accident, although still receiving bronchodilators and oral steroids (dose of prednisone between 20 and 40 mg/ day), the patient continued to have marked symptoms of asthma. These symptoms were triggered by the inhalation of trivial concentrations of irritants or minimal exercise. The patient had frequent episodes of nocturnal asthma. Higher doses of oral or intravenous steroids only led to modest and transient reductions of his asthmatic symptoms. Since the patient was unable to stop his medication, we were unable to measure nonspecific bronchial responsiveness. He showed severe spontaneous fluctuations of his expiratory flows, with mornirig dipping. Although airflow obstruction could be completely reversed with albuterol, a progressive fall in FEV 1 was observed up to more than 20 percent at four hours after inhalation, suggesting a severe bronchial hyperresponsiveness. Carbon monoxide diffusion was normal. Since this accident, the patient has been frequently admitted to the hospital for exacerbations of his asthma.
Table I-Characteristics of Subjects* Subjects, Sex, Age (yr) Data Agent FEV b Lis (percent predicted) FVC, L (percent predicted) PC 20 M (mg/ml)§ Specific challenge Diagnosis'[
2,M,69
3,M,41
Sulfuric acid 2.71 (118)
Bleaching agent 2.09 (76)
Hydrochloric acid 2.10 (4.04)*
Perchloroethylene 2.29 (52)
Polyurethane foam (TDI)t 2.25 (3.10)
3.28 (101)
3.14 (74)
4.18 (5.38)*
3.85 (76)
3.05 (4.12)
5.5 No response] RADS
6.9
2.211 Dual response Occupational asthma
4.3 Dual response Occupational asthma
1,F,45
RADS
RADS
4,M,18
5,M,47
*Carbon monoxide diffusion was normal in all cases. tTDI, Toluene diisocyanate. *Four hours after 200f-Lg of albuterol. §Methacholine. IIThis challenge was, however, performed when bronchial responsiveness was back to normal. ~RADS, Reactive airway dysfunction syndrome. CHEST / 94 / 3 / SEPTEMBER, 1988
477
CASE 4 An 18-year-bld student, without personal or family history of bronchial asthma, was seen with a six-week history of intermittent dyspnea, with chest tightness, cough, and wheezing, after exercise or exposure to. nonspecific respiratory irritants. He had begun to work in. a cleaning factory two months previously The patient was regularly exposed for short periods of time to dry-cleaned linen residues containing perchloroethylene (PCE: C 2CI4), while working on maintenance ofdry-cleaningmachines, He left his job because of Increasing severity of respiratory symptoms, occurring at work and persisting in the evening and at night after work shifts. These symptoms first appeared following an unusually prolonged exposure to perchloroethylene while cleaning a dry-cleaning washer, which provoked an acute episode of severe dyspnea, cough, chest tightness, and epistaxis. Six months after the onset of symptoms, the patient was referred to us for persisting cough and dyspnea on exertion. The findings from physical examination and the chest roentgenogram were normal. Skin prick tests to common airborne allergens showed mild wheal-and-flare reactions to D farinaeand mixed tree pollens, which on questionnaire were not clinically relevant. Spirometry revealed moderate airflow obstruction, with FEV! and forced vital capacity (FVC) of 2.29 Lis and 3.85 L, increasing to 4.46 Lis and 4.74 L, respectively after 200~g of inhaled albuterol (predicted FEV/FVC, 4.33/5.04). One month later, the patients spirometric data were normal (FE V/FVC, 4.08/5.13), and he had normal nonspecific bronchial responsiveness with a fall in FEV1 of 9 percent with methacholine (8 mg/ml). The patient was exposed in a provocation chamber, fora total of five minutes, to the spontaneous emanations of dry-cleaning residues containing perchloroethylene, freshly obtained from a drycleaning machine. These vapors were very volatile and irritating, inducing a cough even in normal subjects. Our subject developed a marked cough and progressive dyspnea with a fall in FEV1 reaching a maximum of 40 percent from baseline at 60 minutes. This was followed by a slow recovery to within 10 percent of the initial value at six hours after exposure (Fig 1). On a controlday no symptom or significant fall in FEV! occurred when the subject was exposed to lactose according to the method described by Pepys and Hutchcroft.'! After the perchloroethylene
5.0
• PERCHlOROETHYlENE o CONTROL
challenge, the PC 20 was 8.0 mg/ml seven hours and 2 mg/ml two weeks later. Mild intermittent symptoms of cough and dyspnea abated progressively CASE 5
A 47-year-old factory worker reported the acute onset of asthmalike symptoms immediately following the accidental inhalation 15 years ago of vapors of toluene diisocyanate used in the production of polyurethane foam. He had been working In this factory for two months, and although exposed regularly to this kind of material, he had never before been exposed to high concentrations of isocyanates. Since that acute episode.. the patient had had symptoms of intermittent dyspnea and wheezing following exposure to nonspecific irritants. He uses inhaled albuterol as needed and inhaled beclomethasone during exacerbations of his asthma. When seen at the clinic (15 years after the initial exposure to toluene diisocyanate), skin tests to common allergens were negative. Findings from physical examination and the chest roentgenogram were normal. Pulmonary function tests showed normal spirometric data and a mild bronchial hyperresponsiveness to methacholine with a PC 20 of 4.3 mg/ml. A bronchial provocation test was performed with isocyanates (toluene diisocyanate) The patient was exposed in a provocation chamber to the vapors of toluene diisocyanate produced by a compound used in the making of polyurethane foam. Less than one minute after this exposure, a marked cough and dyspnea occurred. A 26 percent fall in FEV1 was documented immediately following this inhalation, followed by a more severe fall where FEV1 could not be measured. A complete recovery was observed at two hours but was followed by a 15 percent fall in FEVl six hours later, despite the fact that the patient had received albuterol (2.5 mgby nebulization) and 400~g of beclomethasone (with a metered-dose inhaler) following the immediate response (Fig 2). There was no change in nonspecific bronchial responsiveness 24 hours following .this provocation with toluene diisocyanate (PC 2o,3.8 mg/ml). On a control. day when the patient was exposed to a varnish without toluene diisocyanate, no fall in FEVl was observed. DISCUSSION
We report five cases of an increase in nonspecific airway responsiveness with development of asthmatic Symptoms after acute exposure to irritants in poorly ventilated workplaces. The first three cases are sug-
4.5
2
->
UJ
u.
4.20
4.0
2
s
3.5
w u,
3.0 2.5
ISOCYANATE EXPOSURE (TDI)
3.80 3.60 3.40 3.20 3.0
EXPOSURE EXPOSURE
1---I
1 5
,
~
SALBUTAMOL
, ,
\
-1-/ I-r-r--I/i
1 5
-"r--.,.,-_,-.,..-..,.....-
ll-r-:15 30 45 60 90 2 i.
i
i
minutes TIME
post
3
4
i
5
I
6
1
o
i
7
INHALATION
\
1
I
I
" I
10
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MINUTES
hours
FIGURE 1.. Bronchial provocation test with perchloroethylene (solid dots) and control (open dots). Progressive fall in FEVl is observed after inhalation of perehloroethylene, with maximum fall of 40 percent from baseline at 60 minutes and complete recovery at six hours. No significant change in FEVl occurred on control day
478
,
4.00
HOURS
FIGURE 2. Bronchial challenge with toluene diisocyanate (TDI) (solid line) and control day (broken line). A few seconds of exposure to toluene diisocyanate was sufficient to induce a severe fall in FEV b requiring administration of bronchodilators and steroids. Fifteen percent fall from baseline was noted six hours after initial exposure. No significant change in FEV l was observed on control da~
Increases in Airway Responsiveness after Exposure to Irritants (LOUis-Philippe Boulet)
gestive of the reactive airway dysfunction syndrome, developing after the inhalation of sulfuric acid, hydrochloric acid, and a bleaching agent, and the last two cases are suggestive of occupational asthma to perchloroethylene and isocyanates (toluene diisocyanate). Four subjects were previously normal, and one had mild stable asthma. In all cases the increase of nonspecific bronchial responsiveness and chest symptoms persisted from one to more than 15 years after the initial exposure. The previously normal subjects were not exposed to other relevant sensitizing agents and had no evidence of intercurrent respiratory infection which could have led to increased airway responsiveness, and although they were not tested before the acute exposure described, they had no clinical evidence of previously increased bronchial responsiveness. The subject with mild stable asthma was well controlled with daily bronchodilators. He developed a severe steroid-dependent asthma after an acute exposure to hydrochloric acid with clinical evidence of marked nonspecific bronchial responsiveness which seemed mostly due to smooth muscle hyperexcitability his expiratory Hows returning to normal with inhaled albuterol. The first three cases fulfill most of the criteria for the "reactive airway dysfunction syndrome," as reported by Brooks et al,11,12 although previous asthma was excluded from this definition. The criteria used to define the entity are as follows." (1) the absence of previous respiratory symptoms or disease; (2) the possibility for the patient to date the onset of the reactive airway dysfunction syndrome with a specific event; (3) a high-level exposure to gas, smoke, fume, or vapor; (4) the onset of symptoms occurring within a few hours after exposure; (5) asthma-like symptoms such as cough, wheezing, and dyspnea; (6) pulmonary function tests that usually show airflow obstruction and increased response to methacholine; and (7) no evidenceof other pulmonary disease. Persistent airway hyperresponsiveness following exposure to high concentrations of irritants was described after inhalation of paint fumes, uranium hexafluoride, floor sealant, hydrazine, heated acid, fumigating fog, metal coat remover, propylene glycol, welding, alpha-chlorophane, and fire or smoke. 12,14 In two of these subjects, airway inflammation was observed on bronchial biopsies. The features of the reactive airway dysfunction syndrome contrast with the classic definition of occupational asthma. Occupational asthma is usually defined as variable airway narrowing causally related to the exposure to environmental inhalants at work. Most authors restrict this definition to asthma caused by sensitization, excluding asthma caused by an irritant mechanism.P In occupational asthma, an increase in nonspecific bronchial responsiveness is observed after
exposure. As we know nonspecific bronchial responsiveness is a continuum where the asthmatic subjects represent one end of the curve (those who respond to lower concentrations of histamine or other nonspecific agents). Acute irritant-induced inflammatory changes may increase the level of nonspecific bronchial responsiyeness in previously normal subjects, but we think that this may occur as well in subjects with increased baseline nonspecific bronchial responsiveness. Although it is well known that respiratory symptoms may occur at work in subjects with a heightened airway responsiveness, the consequences of exposure to high concentrations of irritants are not well known. Candevia'" has previously described a type of acute inflammatory bronchoconstriction caused by accidental exposure to high concentrations of irritants. Furthermore, the development of airway obstruction has also been described after inhalation of different irritant gases and fumes, such as drain-cleaning agents, chlorine, sulfur dioxide, or ammonia. 17-21 In many of these cases, the defects persisted for years; however, nonspecific bronchial responsiveness had not been measured after such exposure until recently In the case of irritants, the typical pattern of response following inhalation of a nonspecific agent is usually short-lasting, occurs in subjects with a heightened nonspecific airway responsiveness, and does not increase nonspecific bronchial responsiveness. A highlevel exposure and a severe inflammatory reaction in the airways is probably required to induce massive release of mediators and to change smooth muscle responsiveness for a prolonged period of time. The overwhelming aggression to the airway may consequently impede the defense mechanisms that switch off the inflammatory process potentially induced by inhalation of irritants at lower concentrations. The mechanisms of increase in smooth muscle responsiveness following acute inflammation are still to be documented. The reactive airway dysfunction syndrome probably occurs with a large variety of substances which share the characteristic of being strong irritants which can induce airway inflammation, however, the effects of high-level exposures to sensitizing agents are not well known. Occupational asthma developing after such exposures, usually following accidental spills, has been reported in some cases. 14,22 With toluene diisocyanate, a dose-related response has been described, with increased concentrations causing greater effects.23 In the subject exposed to perchloroethylene, chest symptoms appeared for the first time after an episode of intense exposure to this substance, and the development of a prolonged bronchospasm after rechallenge suggests the development of occupational asthma from sensitization; however, we cannot rule out the possiCHEST / 94 I 3 I SEPTEMBER, 1988
479
bility that the type of early-late response observed could be induced by a nonsensitizing process, although unusual. To our knowledge, we describe the first case of occupational asthma from exposure to perchloroethylene. This agent, an organic solvent, .is widely used for dry-cleaning purposes; .however, little is known about its potential detrimental effects on the airways. Perchloroethylene may cause neurologic disorders when inhaled in toxic quantities. It can also induce an irritation of the upper respiratory tract and acute pulmonary edema after severe intoxication by inhalation. 24,25 In our subject with isocyanate-induced asthma, the exposure to toluene diisocyanate was acute and intense, and the previous period of exposure was quite short (two months). These findings suggest that highlevel exposure to sensitizing agents may be an important determinant of clinical sensitization. Isocyanates are commonly used, in the production of polyurethane foam, plastics.fibers, and adhesives. Toluene diisocyanate may induce airway irritation,. occupational asthma by sensitizationand alveolitis. 26-29 Exposure to low levels of toluene diisocyanatc may induce asthma in sensitized subjects. Mechanisms of respiratory effects of toluene diisocyanate remain to be 'clarified. An allergic-type. reaction involving IgE has been suggested, although confirmation of this hypothesis is lacking, and in many of those who react to toluene diisocyanate, there is no evidence of immunologic mechanisms. 30,31 The observation that subjects developing asthma due to toluenediisocyanate have often been previously exposed to.high concentrations of this substance from accidental spills suggests that high-level exposures to these compounds may be involved in the development of occupational asthma." The mechanisms by which Table 2-Characteristics,ojOccupati()nal Asthma and
High-Level Irritant-Induced Asthma
Data Agent Level of-exposure Symptoms History of asthma or atopy Pulmonary function
Occupational Asthma
Irritant Sensitizing Low (high in some High cases) Progressive Acute Possible Possible but unusual Normal or airflow Normal or obstruction airflow obstruction Normal Normal
Carbon monoxide diffusion Nonspecific bronchial Increased after responsiveness exposure Mechanism Sensitization Prognosis
480
High-Level IrritantInduced Asthma
Recovery if early withdrawal
Increased after exposure Acute inflammatory reaction? Prolonged bronchial hyperresponsiveness?
high-level exposures to sensitizing agents may precipitate sensitization remain to be elucidated. High-level exposure to materials such as toluene diisocyanate may damage the bronchial epithelium. This could contribute to increased airway permeability or expose irritant receptors. The development of occupational asthma after rather acute exposure to toluene diisocyanate and perchloroethylene in our cases stresses the difficulty of classifying this type of problem as a sensitizing or irritative effect. Asthma induced by nonsensitizing high-level exposure to irritants such as in the reactive airway dysfunction syndrome should be considered as a separate entity from asthma following sensitization, based on clinical features (Table 2). In our highly industrialized society; we are regularly exposed to a wide range of chemical products, Little is known of their effects on respiratory function, We believe that these effects should be characterized by their mechanism of action, differentiating .the acute inflammatory reaction from massive irritant effect and that following the inhalation of high concentrations of sensitizing agents with irritant properties. The so-called reactive airway dysfunction syndrome or its equivalent should be clearly identified as an occupational disease, although it should be differentiated from the classic occupational asthma induced or exacerbated at work by a specific sensitizing agent. The incidence, natural history; and prognosis of the reactive airway dysfunction syndrome and asthma from sensitization after high-level exposure have to be further documented. In summary; we describe the clinical features of three cases of the reactive airway dysfunction syndrome following acute exposure to acids and bleaching agents and report the development of this syndrome in an asthmatic subject. Moreover, the reported cases suggest that asthma may develop following high-level exposure to nonsensitizing irritative agents, that this may occur in subjects with previous asthma, and that occupational asthma may occur after short-term ex- , posure to high concentrations of sensitizing agents. ACKNOWLEDGMENTS: We thank Dr. Andre Cartier for reviewing the manuscript.
REFERENCES 1 Davies RJ, Blainey AD. Occupational asthma: classification and clinical aspects. Semin Respir Med 1984; 5:229-40 2 Orehek J, Massari JI?, Gayrard I?, Grimaud C, Charpin J. Effect of short-term, low level nitrogen dioxide exposure on bronchial sensitivity of asthmatic patients. J Clin Invest 1976; 57:301-07 3 Hargreave FE, Ryan G, Thomson NC, O'Byrne PM, Latimer K, Juniper EF, et al. Bronchial responsiveness to histamine' or methacholine in asthma: measurement and clinical significance. J Allergy Clin Immunol1981; 68:347-55 4 Boushey HA, Holtzman MJ, Sheller JR, Nadel JA. Bronchial hyperreactivity. Am Rev Respir Dis 1980; 121:389-413 5 Hargreave FE, Ramsdale EH, Pugsley SO. Occupational asthma Increases in Airway Responsiveness after Exposure to Irritants (Louis-Philippe Boulet)
6
7
8
9
10 11 12
13
14
15 16 17
18
19
without bronchial hyperresponsiveness, Am Rev Respir Dis 1984; 130:513-15 Enipey D~ Laitinen LA, Jacobs L, GoldenWM, Nadel JA. Mechanism of a bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 1976; 113:131-39 Holtzman MJ, Cunningham JH, Sheller JR, Irsigler GB, Nadel JA, Boushey HA. Effect of ozone on bronchial reactivity in atopic and nonatopic subjects. Am Rev Respir Dis 1979; 120:1059-67 Mattoli S, Foresi A, Corbo G, Valente S, Petalano F, Ciappi G. Increase in bronchial responsiveness to methacholine and late asthmatic response to the inhalation of ultrasonically nebulized distilled water. Chest 1986; 90:726-32 Wilson NM, Dixon C, Silverman M. Increased bronchial responsiveness caused by ingestion of ice. Eur J Respir Dis 1985; 66:25-30 Becklake MR. Chronic airflow limitation: its relationship to work in dusty occupations. Chest 1985; 88:608-17 Brooks 8M, Weiss MA, Bernstein IL. Reactive airway dysfunctionsyndrome, J Occup Med 1985; 27:473-76 Brooks SM, Weiss MA, Bernstein IL. Reactive airway dysfunction syndrome (RADS): persistent asthma syndrome after high level irritant exposures. Chest 1985; 88:376-84 CockcroftD~ Killian DN, Mellon JJA, Hargreave FE. Bronchial reactivity to inhaled histamine: a method and clinical survey Clin Allergy 1977; 7:235-43 Brooks SM. Occupational asthma. In:· Weiss EB, Segal MS, Stein M, eds. Bronchial asthma, 2nd ed. Boston: Little, Brown and Co, 1985:461-93 , Chan-Yeung M, Lam S. Occupational asthma. Am Rev Respir Dis 1986; 133:686-703 Gandevia B. Occupational asthma, Med J Aust 1970; 2:332-35 Murphy DMF, Fairman R:p, Lapp NL, Morgan WKC. Severe airway disease due to inhalation of fumes from cleaning agents. Chest 1976; 69:372-76 Hasan FM, GehshanA, Fulehan FJD. Resolution of pulmonary dysfunction following acute chlorine exposures. Arch Environ Health 1983; 38:760-80 Harkonen H, Nordman H, Korhonen 0, Wimblad 1. Long-term
effects of exposure to sulfur dioxide: lung function four years after a pyrite dust explosion. Am Rev Respir Dis 1983; 128:84993 20 Charan NB, Myers CG, Lakshiminarayan S, Spencer TM. Pulmonary injuries associated with acute sulfur dioxide inhalation. Rev Respir Dis 1979; 119:555-60 21 Flury KE, Ames DE, R~darte JR, Rodgers it Airwayobstruction due to inhalation of ammonia. Mayo Clin Proc1983; 58:389-93 22 Brooks SM. Epidemiologic study of workersexposed to isocyanate: NIOSH Health Hazard Evaluation report HHE 78-39. 1980 23 Butcher 131: Jones,RN, O'Neil CE; Glindmeyer H'W: Diem JE, Dharmarojon \; et al. Longitudinal study of workers employed in the manufacture of toluene-diisocyanate. Am Rev Respir Dis 1977; 116:411-21 24 Tuttle TC, Wood CD, Grether CB. A behavioral and neurological , evaluation of dry cleaners exposed to perchloroethylene, NIOSH No. 77-214. Department of Health, Education, and Welfare, 1977 25 Baker EL Jr. Neurological disorders. In: Rom WN, ed. Environmental and occupational medicine, 1st ed. Boston: Little, Brown and Co, 1983:323-24 26 Maxon FC Jr. Respiratory irritation from toluene diisocyanate. Arch Environ Health 1964; 8:755 27 Butcher B1: Salvaggio JE, Weili H, Ziskind MM. Toluene diisocyanate (TDI) pulmonary disease: immunologic and inhalation challenge st~dies. J Allergy Clin Immunol 1976; 58:89100 28 O'Brien 1M, Newman-TaylorAJ, Burge PS, Harries MG, Fawcett I~ Pepys J. Toluene diisocyanate-induced asthma: 2. Inhalation challenge tests and bronchial reactivity studies. Clin Allergy 1979; 9:7-15 29 Charles J, Bernstein A, Jones B, et aL Hypersensitivity pneumonitis after exposure to isocyanates, Thorax 1976; 31:127-36 30 BrucknerHC, Avery SB, Stetson DM, DodsonVN, Arlor A, Ronayne JJ. Clinical and immunological appraisal of workers exposed to diisocyanates. Arch Environ Health 1968; 16:619-25 31 Bernstein IL. Isocyanate-induced pulmonary diseases: a current perspective. J Allergy Clin Immunol1982; 70:24-31
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