Irritant-induced asthma

INTRODUCTION — Irritant-induced asthma (IIA) is a type of asthma that results from a single exposure to a high concentration of irritant agents or repeated exposure to moderate to low doses of irritant agents [1-9]. The acute form is also referred to as "reactive airways dysfunction syndrome" (RADS).

The diagnosis and management of IIA will be reviewed here. The diagnosis of asthma and the causes, evaluation, and management of occupational asthma are discussed separately.

●(See "Asthma in adolescents and adults: Evaluation and diagnosis".)

●(See "Occupational asthma: Definitions, epidemiology, causes, and risk factors".)

●(See "Occupational asthma: Clinical features, evaluation, and diagnosis".)

●(See "Occupational asthma: Management, prognosis, and prevention".)

DEFINITIONS — Irritant-induced asthma (IIA) is a general (umbrella) term to describe an asthma-like syndrome that results from a single or multiple high dose exposures to irritant products [3,10]. The rapid onset of asthma within a few hours after a single exposure to very high levels of irritant substances (ie, acute-onset IIA or reactive airways dysfunction syndrome [RADS]) is the phenotype of IIA that has been the best characterized. Other clinical phenotypes such as "low-dose reactive airways dysfunction syndrome," "not-so-sudden IIA," or "IIA with latency" are mainly described in epidemiologic studies because the causal relationship with irritant exposures at the workplace and occurrence of respiratory symptoms is difficult to establish at the individual level [11-15]. When IIA is caused by workplace exposures, it is considered a type of occupational asthma (the nonimmunologic type).

●Acute onset IIA – Acute onset IIA is described as the development of respiratory symptoms in the minutes or hours after a single accidental inhalation of a high concentration of irritant gas, aerosol, vapor, or smoke; these initial symptoms are followed by asthma-like symptoms and airway hyperresponsiveness that persist for a prolonged period (table 1) [1,3]. Acute IIA can occur after exposure to a variety of chemicals generated as gas or aerosol, or exposure to high levels of particulates (table 2). Clinical and functional criteria for the diagnosis of acute IIA are listed in the table (table 1) [1,3]. IIA can be caused by multiple exposures to high doses of irritants which induce acute symptoms requiring acute medical care [16].

●Subacute IIA – The term "sub-acute IIA" has been proposed to describe instances of multiple high exposures to irritants where the onset of symptoms may be more insidious, as seen following the World Trade Center catastrophe [8,9], or less well-documented exposures in which the affected individuals are able to identify the timing, nature, and frequency of events [10,17].

●Low-dose IIA – IIA may also include a condition resulting from multiple exposures to low concentrations of an irritant that have led to bronchial mucosal injury and persistent asthma-like symptoms, although this is less well-established [11]. The term "low-dose IIA" (also called low-dose RADS) has been used to describe individuals in the latter group, but the pattern of repeated low-dose (as opposed to a single high-dose) exposure means that they do not formally fulfill the original criteria for acute IIA. In addition, when the intensity of the exposure is less, but is of greater duration (eg, >24 hours), symptoms may start after several hours or days, rather than within minutes of inhalation, thus further "widening the spectrum of IIA" [12]. However, "low-dose IIA" cannot currently be reliably diagnosed in an individual worker. The term Low Intensity Chronic Exposure Dysfunction Syndrome (LICEDS) has also been suggested to describe this form of IIA [17].

A position paper from the European Association of Allergy and Clinical Immunology has proposed definitions for different IIA phenotypes [3]:

●Definite IIA relates to acute-onset IIA manifested by rapid onset of asthma within 24 hours of a single very high-intensity exposure to an irritant compound (similar to the classic RADS phenotype).

●Probable IIA is characterized by the development of asthma following multiple symptomatic moderate-high level exposures to irritants.

●Possible IIA describes a delayed development of asthma following chronic and/or repeated exposure to low-moderate levels of irritant substances.

EPIDEMIOLOGY — Acute IIA may occur after inhalational accidents at home, in the workplace, or in the general environment. IIA due to multiple exposures is most commonly associated with inhaled irritants in the workplace. It is estimated that 60,000 inhalational accidents occur in the home and lead to medical consultation yearly in the United States [18]. Industrial accidents also have the potential to expose nonemployees to noxious inhalants; the release of isocyanates at Bhopal, for example, led to more than 2000 deaths due to pulmonary edema, and caused acute IIA in many others [19,20].

Estimating the incidence of acute IIA is difficult for several reasons. Precise, subject-specific information regarding the duration and magnitude of exposure at the time of an accident is rarely available. This is further complicated in IIA, where multiple exposures to irritant products are involved; the level of exposure to the inhaled irritant can vary between exposures and between exposed subjects; and several irritant agents can also be involved simultaneously [21,22]. The size of populations at risk after an incident can only be determined approximately in many cases.

The following observations, in which large numbers of patients were exposed to a chemical irritant, illustrate the variation in reported rates of development of IIA:

●After an accidental exposure to high concentrations of glacial acetic acid, the incidence of acute IIA among 51 hospital employees who were present during the 2.5 hours immediately following the accident was 16 percent [23].

●Among 289 workers exposed to chlorine gas in a pulp and paper mill, 71 (25 percent) developed respiratory symptoms shortly after the event [24]. Among 239 workers with repeated exposures to chlorine and other gases over a three-year period, significant respiratory symptoms were reported by 38 (16 percent) [22]. No association between exposure level and persistence of symptoms was documented. Subsequently, a longitudinal follow-up of the same workers over a three-year period showed: (1) an effect on airway function related to the estimated number of symptomatic exposures and incidents, mostly among smokers; (2) a detectable increase in airway responsiveness associated with gassing incidents [25].

●Professional cleaning is considered a high risk occupation for work-related asthma based on studies conducted in Europe and in the United States [26-28]. Among 123 cases of work-related IIA reported in a sentinel notification program in four states in the United States, cleaning agents were the most common reported implicated agent (15 percent) [29]. Some epidemiologic studies have supported the role of repeated and/or chronic exposure to lower levels of cleaning agents in the development of asthma in workers exposed to those agents [30].

Cleaning agents may also cause occupational asthma by a mechanism of sensitization. More frequent atopy and higher levels of total IgE are found in these workers [31]. In a group of 44 workers with symptoms on exposure to cleaning agents, 17 (39 percent) were found to have immunological occupational asthma [32]. Asthmatic symptoms are also associated to the domestic use of cleaning agents [33,34].

●Approximately 15 percent of all cases of occupational asthma accepted for compensation in Ontario, Canada, were of the acute IIA type [35]; a similar proportion (14 percent) was found in a sentinel notification program in four states in the United States [29].

●A number of studies have assessed the effects of exposure to the plume of particulate dust and smoke due to the fires and structural collapse of the World Trade Center towers on September 11, 2001 [8,9,36,37]. The rate of newly diagnosed asthma among workers and volunteers was almost 4 percent and correlated with an earlier time of arrival and greater duration of time at the site [36,38].

●Exposure to a low/moderate level of irritants has been shown to be associated with the diagnosis of asthma (OR 1.88, 95% CI 1.48-2.37) [39].

CAUSES AND RISK FACTORS — A number of agents have been implicated in the development of IIA, most commonly chlorine, isocyanates, oxides of nitrogen, acetic acid, and sulphur dioxide (table 2) [40,41]. As an example, one study identified 46 different agents as having caused occupational irritant-induced asthma, associated with apparently high concentration exposures without a latency period [42]. A separate study reported that paper, metal and chemical industries were responsible for the majority of their cases of IIA. Cases of acute IIA were related to accidents whereas subacute IIA occurred mainly among industrial operators performing usual work tasks with poor hygiene conditions [43].

Definitive risk factors for the development of IIA have not been confirmed, but probable risk factors likely include the chemical and physical nature and concentration of the irritant agent in addition to certain host factors such as atopy and cigarette smoking.

●High concentration exposure – Increased concentrations of offending agents are associated with higher risk, and vapors and wet aerosols generally appear to be more provocative of acute IIA than dry particulates [23,44]. Workers exposed to bleaching agents in paper mills (including chlorine) [45] and cleaning products [27,44] are particularly at risk. Excess rates of asthma have been documented in workers exposed to cleaning agents, and IIA may explain this phenomenon (table 2) [46]. The main risk factor for developing respiratory diseases identified among the World Trade Center (WTC) rescue workers was the presence on the site of the WTC during the first 48 hours and the duration of exposure during rescue [47].

●Atopy – While atopy has been described as a risk factor for the occurrence of the not-so-sudden-onset variant of IIA that develops days after an irritant exposure [12], there is no evidence that atopy is a risk factor for the development of IIA [23,24,48].

●Airway hyperresponsiveness – Previously documented airway hyperresponsiveness did not predispose to the development of acute IIA in firefighters at the World Trade Center [49]. It is likely that the pre-existing airway hyperresponsiveness was infrequent among these firefighters given that asthma is an exclusion criterion for recruitment. However, lifetime prevalence of asthma was increased in WTC responders by comparison with a large control population [50].

●Smoking – Smoking is more common among workers with acute IIA than in those with other types of occupational asthma and seems to increase the risk of functional decline in workers repeatedly exposed to puffs of chlorine [25,35]. However, some studies have suggested that the development of acute and sub-acute IIA was not associated with smoking [23,24].

●Genetic factors – Although some observations suggest a possible genetic predisposition to be more susceptible to the effects of irritants, as for sensitizing agents, this remains to be further examined [51].

PATHOLOGY AND MECHANISMS — Serial observations from two cases of acute IIA illustrate the histopathologic features of the disease (table 3) [52,53]. The initial change was rapid denudation of the mucosa with a fibrinohemorrhagic exudate in the submucosa. This was followed by subepithelial edema and signs of regeneration of the epithelial layer with proliferation of basal and parabasal cells. Desquamation, subepithelial fibrosis, thickening of the reticular basement membrane, and regeneration of basal cells are all more striking in acute IIA than in occupational asthma with a latency period (table 4). In addition, bronchoalveolar lavage (BAL) reveals neutrophilia in acute IIA, whereas lymphocytes and eosinophils are more numerous in occupational asthma with a latency period. (See "Occupational asthma: Pathogenesis", section on 'Pathology'.)

The histopathologic changes seen in acute IIA have been reproduced by exposing rats to high concentrations of gaseous chlorine [54]. Histologic evaluation revealed epithelial flattening, necrosis, and evidence of epithelial regeneration. Bronchoalveolar lavage showed an increased number of neutrophils. Abnormalities in epithelial pathology and bronchial hyperresponsiveness were most prominent one to three days following injury. Epithelial abnormalities persisted in some animals for up to three months [54]. Similar findings have been described in a mouse model of acute IIA [55]. Chlorine can induce direct oxidative epithelium injury, but further damage may also occur with migration and activation of inflammatory cells such as neutrophils within the airway epithelium, with subsequent release of reactive oxygen species and proteolytic enzymes. In a mouse model, airway barrier impairment led to the development of airway hypersensitivity after low-dose chlorine exposure [56], suggesting that airway epithelial damage may be a risk factor for developing IIA after exposure to irritant agents.

The release of reactive oxygen species can contribute to airflow limitation and airway hyperreactivity [57]. In a separate study, an antioxidant preparation diminished many features of tissue damage following exposure to chlorine gas, including the increase in BAL neutrophils and macrophages [58].

The long term (approximately 10 years) pathological abnormalities of acute IIA have been described [59]. Bronchial biopsies obtained from 10 subjects with IIA at a mean of 10 years following an industrial accident showed neutrophilic and eosinophilic inflammation [59]. In addition, reticular basement membranes were thicker among patients with acute IIA than those with mild immunologic occupational asthma or healthy controls.

In one patient with subacute IIA secondary to multiple exposures, an inflammatory infiltrate consisting of lymphocytes and polymorphonuclear cells was found on bronchial biopsy [16]. In the chronic stage of irritant-induced asthma, the infiltrate consisted of lymphocytes and eosinophils, with thickening of connective tissue and deposition of collagen fibers [16,60].

In a cross-sectional study of 999 adults, occupational exposure to irritants was associated with a specific respiratory endotype, suggesting that oxidative stress and neutrophilic inflammation were potentially associated biological mechanisms [61].

CLINICAL MANIFESTATIONS

●History – The clinical manifestations (eg, cough, dyspnea, wheeze, chest tightness) of acute and not-so-sudden onset variants of IIA differ mainly in the rapidity of onset of symptoms.

•The onset of symptoms in acute IIA is usually so abrupt that subjects are able to date their occurrence precisely, although a few patients report respiratory symptoms developing up to seven days after the exposure [17,62]. Patients with multiple exposures to high concentrations of products such as chlorine may be able to identify the timing, nature, and frequency of most events [10,17].

•Patients with the not-so-sudden onset variant of IIA may not be aware of multiple low level irritant exposures and may report episodic symptoms that are not precisely linked to known exposures.

After an acute exposure to gas, smoke, fumes, or vapors with irritant properties, some subjects with no history of respiratory complaints report a burning sensation in the throat and nose referred to as respiratory upper airways distress syndrome (RUDS) [63], in addition to cough, dyspnea, wheeze, and chest pain [1,23,64]. These symptoms typically develop within 24 hours of the exposure and are severe enough that approximately 78 percent seek emergency room treatment [29]. In most series, cough is the predominant symptom in IIA [1,65,66]. (See 'Definitions' above.)

Patients with subacute IIA due to multiple low-level exposures to irritant agents describe essentially the same symptoms as patients with acute IIA (eg, cough, dyspnea, chest tightness, and wheezing), although the time course of onset differs. Symptoms of nasal mucosal irritation, such as nasal congestion, sneezing, nasal pruritus and/or increased nasal secretions, may accompany the asthma-like symptoms and are often exacerbated by recurrent exposure in the workplace [67]. Occupational rhinitis is discussed in greater detail separately. (See "Occupational rhinitis".)

●Physical examination – Physical examination findings are not well described, but have included conjunctivitis, pharyngeal erythema, tearing, tachypnea, and wheezing [24,68]. After an accidental chlorine exposure, 67 percent (42 of 63) had wheezing on initial presentation, and 84 percent had wheezing at some point in their hospitalization [64]. Exposure to ammonia may be associated with burns and blisters on exposed skin and damage to the surface structures of the eye. (See "Topical chemical burns: Initial evaluation and management".)

EVALUATION — IIA should be suspected in patients with asthma-like symptoms following a well-defined exposure. An important component of the evaluation is to review the details of the history, particularly when the patient is seen weeks or months after the initial exposure. Some relevant questions to be asked to all subjects when first assessed for possible asthma, and particularly for IIA, are listed in the table (table 5).

The evaluation of a patient with the acute onset of respiratory symptoms following an irritant exposure typically includes assessment of oxygenation by pulse oximetry or arterial blood gases and a chest radiograph to look for noncardiogenic pulmonary edema, pneumonia, or other causes of dyspnea. As soon as possible, spirometry should be performed to determine whether airflow limitation is present and reversible. (See "Approach to the adult with dyspnea in the emergency department".)

For patients with persistent symptoms due to IIA, the evaluation is the same for the two processes. In addition to spirometry, testing includes more complete pulmonary function testing with assessment of nonspecific hyperresponsiveness. An approach to the patient with dyspnea is provided separately. (See "Approach to the patient with dyspnea".)

Laboratory testing — Routine laboratory testing is usually not helpful in the diagnosis of irritant exposures. However, a complete blood count and differential are appropriate to help exclude other processes in the differential diagnosis of dyspnea such as anemia, eosinophilic pneumonia, and infection.

Skin and immunologic testing — For patients with chronic symptoms due to IIA, either allergy skin testing or immunoassay to a panel of common aeroallergens is appropriate to exclude allergic asthma due to common aeroallergens or a sensitizing process evocating immunologic occupational asthma. (See "Overview of skin testing for IgE-mediated allergic disease" and "Overview of in vitro allergy tests".)

In vitro immunoassay for IgE antibodies to occupational sensitizers is available for a limited number of low molecular weight chemical-protein conjugates (eg, diisocyanates), but these are not standardized or commercially available. An acute increase in specific IgE antibodies to formaldehyde has been described in a case of acute IIA associated with high level exposure to formaldehyde, although the significance of this observation is not known [69].

Pulmonary function testing — One of the first steps in the evaluation of a patient with respiratory symptoms after an irritant inhalational exposure is pulmonary function testing to assess the presence, severity, and reversibility of airflow limitation. For patients without significant airflow obstruction, bronchoprovocation challenge can be used to document non-specific airways hyperresponsiveness. The roles of spirometry and bronchoprovocation challenge in the diagnosis of asthma are discussed separately. (See "Pulmonary function testing in asthma", section on 'Tests for the diagnosis of asthma' and "Bronchoprovocation testing".)

Spirometry — Baseline spirometry is obtained in all patients suspected of having IIA; bronchodilator reversibility is assessed if airflow limitation is present. In a series of 19 patients seen after chlorine exposure, 10 had airflow limitation when assessed soon after the exposure; many showed reversal of obstruction with time [70]. In a separate study of 10 subjects with acute IIA due to high level exposures to a variety of agents, four had airflow obstruction with a forced expiratory volume in one second/forced vital capacity (FEV₁/FVC) ratio <70 percent [1]. (See "Office spirometry" and "Pulmonary function testing in asthma", section on 'Tests for the diagnosis of asthma'.)

Following baseline spirometry, bronchodilator reversibility is assessed by inhalation of a short-acting beta-agonist. In general, reversibility is defined as a postbronchodilator increase in FEV₁ by more than 10 percent of its predicted value [71]. Airway obstruction is generally less responsive to a bronchodilator in acute IIA than in asthma, although some degree of reversibility may be present. A comparison of 30 subjects with immunologic occupational asthma and 15 subjects with acute IIA found a mean improvement in FEV₁ after bronchodilator of close to 20 percent in the subjects with immunologic occupational asthma, nearly double the response seen among those with acute IIA. However, significant heterogeneity was seen among the acute IIA group: 6 of the 15 subjects had a postbronchodilator improvement in FEV₁ of more than 15 percent [22]. (See "Pulmonary function testing in asthma", section on 'Bronchodilator responses'.)

In a minority of patients, a restrictive defect is noted on pulmonary function testing, although an obstructive pattern is much more common [72]. (See "Overview of pulmonary function testing in adults", section on 'Lung volumes'.)

Nonspecific bronchoprovocation challenge — If baseline spirometry shows absent or minimal airflow limitation and no significant bronchodilator reversibility, nonspecific (or nonallergic) bronchial challenge (eg, methacholine) is performed to assess for non-specific bronchial hyperresponsiveness. The performance of bronchoprovocation challenge, contraindications to testing, and adjustments of medication prior to testing, are described separately. (See "Bronchoprovocation testing" and "Bronchoprovocation testing", section on 'Pharmacologic challenge'.)

Among various case reports, a positive bronchoprovocation challenge was present at initial evaluation in virtually all patients who were able to perform the testing. (See "Pulmonary function testing in asthma", section on 'Bronchodilator responses'.)

Specific bronchoprovocation challenge — Specific inhalation challenges are not performed to diagnose IIA with agents that are known to cause IIA [2]. The majority of these agents are not sensitizers and would not induce an acute asthmatic reaction when inhaled at low levels for a short period of time. (See "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Specific inhalation challenge'.)

However, rare individuals can experience acute IIA after exposure to agents that have both irritant and sensitizing properties (eg, isocyanates) and subsequently develop occupational asthma. For example, a subject developed occupational asthma while exposed to lower levels of diisocyanates after an initial high exposure to this agent that induced acute IIA [73]. In this instance, performing specific inhalation was useful to confirm the diagnosis of occupational asthma. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Low-molecular-weight' and "Occupational asthma: Clinical features, evaluation, and diagnosis", section on 'Specific inhalation challenge'.)

Imaging — A chest radiograph is typically obtained to exclude noncardiogenic pulmonary edema, alveolitis, or pneumonia in patients presenting after an acute irritant exposure or other causes of dyspnea in those presenting later in the course of acute IIA or after multiple lower dose irritant exposures. The chest radiograph in patients with IIA is typically normal or may show hyperinflation. (See "Approach to the adult with dyspnea in the emergency department", section on 'Plain chest radiograph' and "Approach to the patient with dyspnea", section on 'Chest computed tomography'.)

High-resolution computed tomography (HRCT) is not required in the evaluation of IIA but may be performed in atypical cases to exclude alternative diagnoses. HRCT scans, obtained in 29 symptomatic rescue and recovery workers at the World Trade Center site, showed evidence of air-trapping based on a mosaic pattern on the end-expiratory images in 25 of these workers [74].

DIAGNOSIS — The diagnosis of IIA is based upon a combination of exposure history (table 5), time course of symptom onset, and evidence of reversible airflow limitation and/or non-specific bronchial hyperresponsiveness.

The diagnosis of acute IIA is likely in individuals with:

●A history of acute exposure to an irritant agent or material preceding the onset of respiratory symptoms (see 'Clinical manifestations' above)

●Acute onset of respiratory symptoms within 24 hours of the exposure, or within seven days at the latest (see 'Clinical manifestations' above)

●Persistence of airway obstruction and/or hyperresponsiveness, generally for three months or more (see 'Pulmonary function testing' above)

The diagnosis of subacute IIA is often not as straightforward as the diagnosis of acute IIA due to the lack of a single episode of high-level exposure. However, a history of single or multiple exposures to an irritating inhalational agent (table 5), the presence of asthma-like symptoms, and the presence of reversible airway obstruction and/or hyperresponsiveness are necessary to the diagnosis. (See 'Pulmonary function testing' above.)

The absence of specific testing that can establish a causal role of an irritant agent makes it difficult to establish the diagnosis of IIA with certainty. However, data from epidemiologic studies that have identified occupations with an increased risk of asthma, such as cleaners [46,75] and pulp mill workers [45], can be used to support a diagnosis of IIA in a patient with similar exposures [21] (see 'Epidemiology' above). However, distinguishing IIA caused by repeated, moderate or low level exposures from coincidental non-work related asthma is very difficult and often impossible on a clinical basis.

DIFFERENTIAL DIAGNOSIS

Acute presentation — At the time of an acute presentation with IIA, the differential diagnosis includes the following:

●Underlying asthma that may have been exacerbated by an irritant exposure

●Acute respiratory infection

●Cardiogenic or noncardiogenic pulmonary edema

●Other causes of an acute onset of dyspnea

A careful history provides guidance regarding the severity of the exposure and thus the likelihood of acute IIA versus an exacerbation of underlying asthma. A conventional chest radiograph can help exclude pneumonia, pulmonary edema, and acute eosinophilic pneumonia. A complete blood count and differential provides supportive information for or against infectious or eosinophilic pneumonia. (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Diagnosis' and "Acute bronchitis in adults" and "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults" and "Approach to the adult with dyspnea in the emergency department".)

Persistent symptoms — For patients presenting with persistent symptoms, the differential diagnosis of IIA typically includes underlying asthma that may have been exacerbated by an irritant exposure, occupational asthma due to an immunologic reaction to an agent in the workplace, paradoxical motion of the vocal cord (also known as vocal cord dysfunction or irritable larynx syndrome), and nonasthmatic eosinophilic bronchitis as well as other causes mimicking asthma.

●Pre-existing asthma – A history of prior symptoms of cough or dyspnea, possibly exacerbated by respiratory infection or exposure to irritants, favors a diagnosis of pre-existing asthma.

●Occupational asthma – A number of features are common to IIA and immunologic occupational asthma. Wheezing and airflow obstruction are common to both conditions. A differentiating feature is that immunologic occupational asthma is reproduced by inhalation challenge with low levels of the offending workplace agent, while IIA is not (table 4). Differentiation may also be based on the type of exposure. As an example, exposure to chlorine and cleaning agents is associated with IIA [28,76], while exposure to flour and latex is associated with occupational asthma. A few of these agents, however, have been associated with both syndromes (eg, diisocyanates, cleaning agents). (See 'Clinical manifestations' above and 'Pulmonary function testing' above and "Occupational asthma: Clinical features, evaluation, and diagnosis" and "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Causative agents'.)

●Paradoxical vocal fold motion – Paradoxical vocal fold motion (PVFM) refers to abnormal closure of the vocal cords, usually on inspiration; it may mimic asthma or accompany asthma. A temporal association of onset of PVFM and irritant exposure has been described, adding to the importance of differentiating these entities [77]. The diagnosis of PVFM is usually suggested by the presence of dysphonia and abnormal slowing of the inspiratory flow volume loop obtained during routine spirometry or nonspecific bronchoprovocation challenge. The diagnosis is confirmed by direct visualization of the vocal cords by laryngoscopy. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Evaluation' and "Bronchoprovocation testing", section on 'Pharmacologic challenge'.)

●Nonasthmatic eosinophilic bronchitis – Nonasthmatic eosinophilic bronchitis (NAEB) is characterized by a cough that is usually nonproductive, eosinophilia in induced sputum, and the absence of airflow limitation or bronchial hyperresponsiveness. NAEB has been described in workers exposed to a variety of occupational agents that are associated with IgE-mediated sensitization [2,78-80]. The key differentiating feature is the negative non-specific bronchoprovocation challenge among patients with NAEB. While induced sputum shows eosinophilia in NAEB, induced sputum analysis has not been fully evaluated in IIA and is not widely available. (See 'Nonspecific bronchoprovocation challenge' above and "Causes and epidemiology of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

TREATMENT

Management of acute irritant-induced asthma — The management of acute IIA is essentially the same as the treatment of an acute asthma exacerbation [60]. However, the optimal treatment of this condition has never been assessed prospectively in a clinical trial. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management" and "Acute exacerbations of asthma in adults: Home and office management".)

●Bronchodilators – Bronchodilator therapy is administered based on the severity of symptoms and response to treatment, even though the response to inhaled bronchodilator may be blunted in acute IIA compared with asthma. If a short-acting beta-agonist (SABA) does not provide adequate symptomatic relief, we typically add ipratropium, although data in support of this are limited.

●Systemic glucocorticoids – Treatment of acute IIA includes prompt administration of systemic glucocorticoids (eg, prednisone 40 to 60 mg daily) for patients with moderate to severe symptoms and a forced expiratory volume in one second (FEV₁) less than 70 percent predicted. No formal trials have been performed on glucocorticoid therapy in acute IIA, so the use of systemic glucocorticoids for acute IIA is based upon clinical experience and their well-documented role in asthma [52,53]. Support for systemic glucocorticoid therapy comes from their use in an animal model of IIA. Parenteral glucocorticoids, given for one week immediately after exposure, significantly attenuated expected increases in lung resistance and bronchial hyperresponsiveness; bronchoalveolar lavage (BAL) and histologic parameters were likewise improved [54].

We typically continue oral prednisone for 10 to 15 days, which is longer than that used for typical exacerbations of asthma, as it is our clinical observation that patients improve slowly and do not tolerate tapering sooner. High-dose inhaled glucocorticoids (eg, fluticasone propionate 1000 mcg/day or the equivalent), with or without concomitant inhaled long-acting beta-2 agonist, are also started to help control asthma symptoms developing upon tapering of prednisone. Relatively high doses of inhaled glucocorticoids may be required for long-term treatment as pathological evidence shows the persistence of eosinophils [59].

●Inhaled glucocorticoids – For patients who have a documented irritant exposure but whose initial symptoms and airflow obstruction are less severe (eg, FEV₁ ≥70 percent predicted), we suggest initiation of inhaled glucocorticoids rather than systemic glucocorticoids or inhaled beta agonist therapy alone. Data in support of inhaled glucocorticoids are limited, but a case report of a subject with acute IIA reflects our experience. In the report, treatment with inhaled glucocorticoids normalized bronchial hyperresponsiveness, but hyperresponsiveness worsened when therapy was stopped [53].

The initial dose of inhaled glucocorticoids is based on the step-wise approach to asthma outlined in the Global Initiative for Asthma (GINA) [81]; in our experience the majority of patients require a high dose to control symptoms (table 6). (See "An overview of asthma management", section on 'Initiating therapy in previously untreated patients'.)

Once patients have demonstrated symptomatic improvement, inhaled glucocorticoids can be tapered as tolerated. Airflow limitation is assessed serially with spirometry as the inhaled glucocorticoids are tapered. If asthma has remained well-controlled for several weeks and the FEV₁ is stable, then the inhaled glucocorticoids are decreased by 25 to 50 percent increments. When the FEV₁ is greater than 70 percent of predicted, bronchial responsiveness to methacholine may be used to guide tapering inhaled glucocorticoids, although this approach is not well-validated. The weaning of inhaled glucocorticoids may take six weeks to six months, and many patients require more long-term therapy. (See 'Prognosis' below.)

Chronic management of irritant-induced asthma — For patients with IIA who require long-term pharmacologic treatment for asthma symptoms, the step-wise approach described in the Global Initiative for Asthma (GINA) guidelines is followed even though it has not been formally assessed in this setting [81]. Over time, if the patient's asthma remains well-controlled, therapy is tapered according to the same guidelines. The long-term treatment of acute or less acute forms of IIA is the same, even though the specific timing and pattern of onset differ. (See "An overview of asthma management", section on 'Adjusting controller medication'.)

Nonpharmacologic treatment of IIA has not been studied directly; however, based on clinical experience patients are advised to avoid exposure to other respiratory irritants, including cigarette smoke [82]. For those patients who have underlying atopy, avoidance of known allergens to which they are sensitive is also appropriate. (See "Trigger control to enhance asthma management" and "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Overview of smoking cessation management in adults".)

EXPOSURE AVOIDANCE AND RETURNING TO WORK — Unlike workers with immunologic occupational asthma, most workers with IIA can return to their working environment with proper asthma treatment as long as their asthma is well-controlled and safety measures are taken to avoid unintentional high-level exposures [2,3]. Ongoing monitoring of symptoms and respiratory physiology is, however, key to early identification of any deterioration.

PROGNOSIS — The long-term outcome of IIA is unclear as longitudinal, prospective data are limited. The available evidence suggests a range of responses from complete clearance of symptoms and signs to persistent respiratory disability [59,65,67,83-87]. As examples:

●Among 20 patients who had repeated exposures to chlorine gas during a three-month period, two-thirds still had an abnormal response to methacholine three years later, and 85 percent reported wheezing, shortness of breath, or cough [83]. In a separate series of 71 workers suspected to have acute IIA following exposures to chlorine, 90 percent had persistent respiratory symptoms 18 to 24 months after exposure and 57 percent had bronchial hyperresponsiveness [24].

●A population-based study of 145 subjects exposed to chlorine gas found no changes in pulmonary function testing over the six-year follow-up period; however, airway responsiveness was not assessed [85].

●In a 10-year follow-up of 197 veterans of the Iran-Iraq war with acute poisoning with sulfur mustard gas, asthma symptoms, reversible airflow obstruction, and excessive diurnal peak expiratory flow variability were present in 11 percent [86]. In addition, chronic bronchitis or bronchiectasis occurred in 68 percent of patients, presumably due to extensive bronchial necrosis following acute exposure.

●Among 35 workers with IIA, almost all continued to have symptoms consistent with asthma and one-third were still using inhaled glucocorticoids at follow-up eight or more years later [65]. Spirometry was persistently abnormal in 74 percent. Among 23 who had repeat measurements of methacholine responsiveness, nine (25 percent) were no longer hyperresponsive. Bronchial biopsies were performed in 10 subjects at a mean of 10.9 years following the initial exposure and eosinophilic inflammation similar to that found in subjects with mild to moderate asthma was noted, but with more pronounced basement membrane thickening [59].

●Among 13,954 Fire Department of New York City rescue workers present on the site of the World Trade Center in September 2001, 91.6 percent participated in a routine surveillance program. After a median of 6.1 years of follow-up, the significant decline in FEV₁ seen during the first year persisted without recovery [72,88]. Greater than normal lung functions declines were associated with initial bronchodilator response and weight gain in a five year follow-up by the World Trade Center Worker and Volunteer Monitoring Program [89].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occupational asthma".)

SUMMARY AND RECOMMENDATIONS

●Definitions – IIA is a general term to describe an asthmatic syndrome that results from single or multiple exposures to irritant products (table 2) that induce bronchial hyperresponsiveness. When symptoms promptly follow a single high-dose exposure, the syndrome is called acute IIA (aka, reactive airways dysfunction syndrome [RADS]). (See 'Definitions' above and 'Epidemiology' above.)

●Clinical manifestations – Symptoms associated with acute IIA include a rapid onset of a burning sensation in the throat and nose, chest pain, dyspnea, cough and wheeze. In subacute IIA, the symptoms are similar, but the onset is slower. Questions that are helpful in the evaluation of IIA are listed in the table (table 5). (See 'Clinical manifestations' above.)

●Diagnosis of acute IIA – The diagnosis of acute IIA requires the combination of exposure to a high-dose of an inhalational irritant, onset of symptoms within hours (rarely days), and evidence of reversible airflow limitation (eg, spirometry with bronchodilator reversibility or positive non-specific bronchoprovocation challenge), although a restrictive defect can also be present. A chest radiograph is often obtained to exclude other causes of dyspnea. Criteria for the diagnosis of acute IIA are summarized in the table (table 1). (See 'Evaluation' above and 'Diagnosis' above.)

●Diagnosis of subacute IIA – The diagnosis of subacute IIA is based upon a history of single or multiple exposures to an irritating inhalational agent, the presence of asthma-like symptoms, and the presence of reversible airway obstruction and/or hyperresponsiveness. (See 'Diagnosis' above and 'Pulmonary function testing' above.)

●Initial treatment of acute IIA – For patients who present with acute IIA, we use the same treatment approach that is used for acute asthma exacerbations in other settings, including oral glucocorticoids and inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) with or without concomitant long-acting inhaled beta-2 agonists (LABAs). In our experience, medium- or high-dose ICS-LABA combination therapy is often needed to control symptoms. Inhaled rather than oral glucocorticoids are appropriate initial therapy for patients who present with less severe symptoms. (See 'Treatment' above and "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)

●Controller therapies for IIA – For patients with persistent symptoms due to IIA, we follow the standard stepwise approach used in asthma management. In addition, patients are advised to avoid respiratory irritants, including cigarette smoke, and allergens to which they are sensitive. (See 'Chronic management of irritant-induced asthma' above and "An overview of asthma management", section on 'Initiating pharmacologic treatment' and "Trigger control to enhance asthma management".)

●Return to work – In general, workers with IIA are able to return to their working environment with appropriate asthma treatment and safety measures to prevent further high-dose exposures. The worker should have ongoing monitoring to detect any deterioration in respiratory status. (See 'Exposure avoidance and returning to work' above.)

●Prognosis – The majority of patients with IIA improve over time, although many continue to have some respiratory symptoms for at least a year and have physiologic abnormalities such as nonspecific bronchial hyperresponsiveness for several years. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Denyse Gautrin, MD, Moira Chan-Yeung, MD, Jean-Luc Malo, MD, André Cartier, MD, and Louis-Philippe Boulet, MD who contributed to earlier versions of this topic review.