THE MONTHLY ADJUSTMENT

Reactive Airways Dysfunction Syndrome (RADS) and Irritant-Induced Asthma (IIA) are both new-onset, irritant-induced, non-allergic asthma. These two pulmonary disorders are clinically very similar; both are caused by the inhalation of irritating substances such as smoke, dust, fumes, gases, and vapors. A major difference between the two is that in the case of RADS, symptoms of asthma such as cough, wheezing, chest tightness, and breathlessness, appear within 24 hours after the causal irritant exposure - often by the end of the day. Symptoms of IIA (identical to those of RADS) also appear within 24 hours after exposure is terminated, but typically not until after exposure has continued for several days, weeks, or months, usually on a more-or-less daily basis. It is critical to emphasize here that respiratory symptoms beginning more than 24 hours after irritant exposure has terminated cannot properly be termed either RADS or IIA. For example, a person who is exposed to irritating substances in the air on and off for several days (or weeks, months, years) who remains symptom free for more than 24 hours after terminating the exposure process cannot be properly diagnosed as either RADS or IIA. Once symptoms do become clinically apparent, both RADS and IIA behave clinically like non-allergic asthma, which, of course is what they are.

Because of the close similarity of their clinical pictures, in the past there has been some confusion in the medical literature about which name to use, RADS or IIA. In order to keep things as clear as possible in this review, I will use the term IIA rather than RADS when referring to irritant induced asthma wherein the clinical onset of symptoms occurred after more than one day of exposure. The term RADS will be reserved for irritant induced asthma wherein the symptoms initially appear within 24 hours of first exposure.

Undoubtedly, RADS has been with us for a very long time. The first description of this condition that I can find in the medical literature was published in The Medical Journal of Australia in 1970 by an Australian physician, Brian Gandevia. Dr. Gandevia referred to the condition as "Acute Inflammatory Bronchoconstriction." Dr. Stuart Brooks and his associates are generally credited with defining the criteria for irritant-induced asthma and designating the illness as RADS (Brooks, et al., 1985). These investigators initially listed the following eight clinical criteria for the diagnosis of RADS:

1. A documented absence of preceding respiratory complaints.
2. The onset of symptoms occurred after a single specific exposure incident or accident.
3. The exposure was to a gas, smoke, fume, or vapor, which was present in very high concentrations and had irritant qualities to its nature.
4. The onset of symptoms occurred within 24 hours after the exposure and persisted for at least three months.
5. Symptoms simulated asthma with cough, wheezing, and dyspnea predominating.
6. Pulmonary function tests may show airflow obstruction.
7. Positive Methacholine Challenge Test [An indication of non-specific bronchial hyperresponsiveness.]
8. Other types of pulmonary diseases ruled out.

Over the ensuing years, as additional observations have been reported, the 1985 Brooks, at al. criteria have been clarified and modified by the following authors: Tarlo and Broder, 1989; Cone, et al., 1994; Kipen, et al., 1994; Alberts and do Pico, 1996; Brooks, et al., 1998; Tarlo, 2000 ; and others.

Tarlo and Broder (1989) described IIA patients whose exposure to workplace irritants was not limited to a single incident or accident. These included three subjects with IIA who had been exposed at work for over six months before the onset of their symptoms. They were still working when diagnosed, but were unable to link the initial onset of their respiratory symptoms to any given accident or unusual workplace event.

Cone, et al. (1994) reported the occurrence of persistent irritant-induced asthma (RADS) in 20 individuals exposed to an environmental spill of the pesticide metam sodium. These investigators broadened the original criteria for the diagnosis of RADS allowing the diagnosis to include persons who developed lower respiratory irritative symptoms (cough, wheeze, shortness of breath, or sputum production) within one week of exposure if they had experienced eye or upper respiratory irritation (throat or nasal irritation) within 24 hours of initial exposure.

Kipen, et al. (1994) reported 10 cases of what they termed "low-dose RADS" wherein symptoms developed following repetitive, daily exposures to low doses of irritants over periods of months or years. These investigators described the irritant exposure levels as noticeable but distinctly "tolerable.".

Brooks, et al. (1998) reported a series of cases they described as "not-so-sudden-onset" irritant induced asthma. Characteristically, the irritant exposures of the not-so-sudden asthma cases were neither massive nor single and ensuing asthma took longer to develop, sometimes days or weeks after repeated exposures. In order to qualify for a diagnosis of IIA, symptoms of asthma began during exposure or within 24 hours thereafter. The authors differentiated between RADS and IIA as follows: if clinical symptoms appear within 24 hours of the causal irritant exposure, the consequent asthma is referred to as RADS. Put slightly differently, RADS is new-onset, irritant-induced asthma without latency. If more than 24 hours of exposure to the causal irritant is required before asthma symptoms appear, the resulting asthma is called IIA. Brooks, et al. (1998) emphasized that for either condition, initiation of asthma symptoms must be temporally related to the irritant exposure, that is, asthma symptoms must develop during the period when the irritant exposure is taking place, although this exposure can be intermittant or continuous in nature. Of course, IIA must be differentiated from sensitizer-induced asthma. To complicate thing further, allergy/atopy status and preexisting asthma are risk factors for IIA, but not for RADS (Brooks, et al., 1998).

Below, I have summarized the criteria for the diagnosis of RADS defined in The American College of Chest Physicians Consensus Statement. (cited in Alberts and do Pico, 1996). I have also added several recently suggested modifications to these criteria and some comments and clarifications drawn from the literature, which I hope will be useful to the reader. A discussion of the mechanisms proposed to explain the persistent airway hyperresponsiveness in patients with RADS/IIA is beyond the scope of this communication. The interested reader is referred to Alberts and do Pico (1996), Bardana (1999), and Tarlo (2000) for a discussion of this point.

1. A documented absence of preceding respiratory complaints.
   
   Recent authors (Henneberger, et al., 2003) have modified this criterion to include people who had asthma, and then did not have asthma symptoms or treatment for asthma during the two years before entering a new work setting where they then developed work-related, irritant induced asthma. These people are eligible for a diagnosis of RADS or IIA. For example, irritant induced asthma appearing in an adult with a history of childhood or adolescent asthma that had been quiescent for years could qualify for a diagnosis of RADS or IIA if other factors were consistent with the diagnosis.
   
   The phrase "A documented absence of preceding respiratory complaints" is probably too vague to be of much use to the diagnostician. I will not attempt to clarify the word "documented" as used here. However, Alberts and do Pico (1996) have interpreted the remainder of the phrase -- "absence of preceding respiratory complaints" as follows: a "negative history of obstructive [pulmonary] symptoms prior to exposure".
   
    
2. Onset of asthma symptoms after a single exposure incident or accident.
   
   Of course, we now have a recognized condition called IIA which does not fit this criterion; this is discussed above.
   
    
3. Exposures to a gas, smoke, fume, or vapor with irritant properties present in very high concentrations.
   
   Asthma induced by repeated exposure to lower concentrations of irritants is now referred to as IIA.
   
    
4. Onset of symptoms within 24-hours after exposure with persistence of symptoms for at least three months.
   
   As discussed above, onset of symptoms after more than 24 hours of exposure to the causative irritant is now referred to as IIA.
   
    
5. Symptoms of asthma with cough, wheeze, and dyspnea.
   
   These are the characteristic manifestations of asthma.
   
    
6. Presence of airflow obstruction on pulmonary function tests and/or the presence of nonspecific bronchial hyperresponsiveness.
   
   Airflow obstruction may not be readily identifiable on pulmonary function tests if RADS/IIA is not clinically active at the time of testing, that is, a pulmonary function test may be normal between periods of active disease. This is a critical point because clinical manifestations of asthma wax and wane. In addition, it should be noted that a restrictive rather than obstructive pulmonary function test pattern has been reported (Gilbert and Auchincloss, 1989; Brooks, et al., 1998). Nonspecific bronchial hyperresponsiveness may be demonstrated by a significant spirometric response to an inhaled bronchodilator or a positive nonspecific bronchoprovocation challenge test (the Methacholine Challenge is such a test). A positive Methacholine Challenge test is required by some to validate a diagnosis of RADS/IIA. However, a Methacholine Challenge test should not be performed in individuals with significant impairment of lung function (Brooks, et al., 1998). I have seen several patients with RADS/IIA-related airway hyperresponsiveness far too reactive to safely undergo this test.
   
    
7. Other pulmonary diseases ruled out.
   
   Diseases included in the differential diagnosis of RADS/IIA include acute tracheobronchitis, vocal cord dysfunction syndrome, gastroesophageal reflux disease (GERD), hypersensitivity pneumonitis, adult onset allergic asthma, and organic toxic dust syndrome (Bardana, 1995).

Special Issues

Diagnostic criteria. There is no "gold standard" for the diagnosis of RADS (Alberts and do Pico, 1996). An unambiguous exposure history and demonstration of persistent nonspecific bronchial hyperresponsiveness are required elements of the diagnosis. Above, I have presented the diagnostic criteria for RADS/IIA in some detail.

Agents demonstrated to be capable of causing RADS/IIA. These are numbered in the hundreds and undoubtedly others will be added as additional observations are reported. Here are two citations that list 165 cases: Rosenman, et al., 2003 (42 RADS cases); Henneberger, et al., 2003 (123 RADS cases). The largest agglomeration of Occupational Asthmagens of which I am aware can be found at: http://www.aoec.org/aoeccode.htm. On this site, asthmagens are not classified as to whether they induce RADS, IIA, or sensitizer-induced work related asthma.

Exposure/Dose. In my experience, it is rarely possible to ascertain through standard industrial hygiene procedures the airborne concentration of the causative chemical agent In the case of RADS, air-analysis instrumentation is rarely if ever available at the time of exposure; for IIA, the prolonged or intermittant nature of exposure does not lend itself to meaningful quantitative measurement. The medical literature reflects this problem; few, if any, reports on RADS/IIA include quantitative exposure data.

Chronicity: The medical literature is not clear on the issue of RADS/IIA chronicity, that is, how long symptoms will persist. Some investigators have reported RADS lasting for months, some for years (Rosenman, et al., 2003). I personally have seen one case of RADS clinically active after more than six years; others have described even longer periods of chronicity (Demeter, et al., 2001).

Bronchial biopsy: It has been proposed that the diagnostic criteria for RADS include a requirement for a bronchial biopsy demonstrating minimal lymphocyte inflammation without eosinophilia (Bardana, 1999.) However, to date, most studies of RADS/IIA patients do not include a bronchial biopsy. Tarlo (2000) noted that RADS airway histology has not shown features sufficiently distinctive to be helpful in diagnosis of the individual case. In my opinion, there is little justification for requiring a biopsy in order to validate a diagnosis of RADS/IIA. The biopsy procedure is invasive, uncomfortable, not without risk, and most importantly, the histopathology has been shown to be of little or no diagnostic help.

A real clinical entity? Current scientific evidence appears to support the conclusion that RADS is a distinct clinical entity. This view is held by the American Thoracic Society, the Canadian Thoracic Society, the American College of Chest Physicians (Alberts and do Pico, 1996), and the legal community (personal experience).

RADS/IIA and the World Trade Center Disaster. Perhaps the most noteworthy outbreak of RADS/IIA yet described was reported in 2002 among firefighters exposed to irritants before and after the World Trade Center (WTC) disaster. The "World Trade Center Cough" has been defined as a persistent cough that developed after exposure to the site (Prezant, et al., 2002). This cough is often accompanied by airway obstruction, nonspecific bronchial hyperresponsiveness, and clinical signs and symptoms of asthma. By the time the authors of the WTC article presented their data, they had examined nearly 100 firefighters who exhibited symptoms thought to be consistent with RADS/IIA.

Conclusions

Reactive Airways Dysfunction Syndrome (RADS) and Irritant Induced Asthma (IIA) are similar clinical pathological entities caused by exposure to a toxic, irritating agent and characterized by a negative history of asthma symptoms for at least two years prior to exposure, persistence of asthma symptoms for at least three months, objective evidence of nonspecific bronchial hyperresponsiveness, and arguably, abnormal airway histopathology.

References

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