Reactive Airways Dysfunction Syndrome (RADS) & Irritant Induced Asthma (IIA)

Reactive Airways Dysfunction Syndrome (RADS) and Irritant-Induced Asthma (IIA) are both forms of nonimmunological (non-allergic) asthma. Both RADS and Irritant Induced Asthma are caused by inhalation of an irritating substance. Chlorine, ammonia, sulfuric acid are common examples of such irritants, but hundreds more have been identified and, most likely, hundreds are yet to be recognized.) Both RADS and IIA and are characterized clinically by signs and symptoms of asthma including cough, wheezing, chest tightness, and breathlessness.

A major difference between the clinical definition of RADS and IIA is that in the case of RADS, symptoms of asthma appear no later than 24 hours after initial (first) exposure to the causal irritating substance. However, in the case of Irritant Induced Asthma, symptoms (similar to those of RADS) do not appear within 24 hours of the initial exposure, but do appear after repeated, more-or-less tolerable exposures have continued for several days, weeks, or even months. These differences in time from initial exposure to appearance of symptoms have led to the terms “Sudden onset, irritant induced asthma” (RADS) and “Not-so-sudden” irritant induced asthma” (IIA) (Brooks, et al., 1998). Once symptoms do become clinically apparent, both RADS and IIA behave clinically like non-allergic asthma, which, of course is what they are.

It is important to emphasize that symptoms which appear more than 24 hours after exposure to an irritant substance has terminated cannot properly be diagnosed as either RADS or Irritant Induced Asthma. For example, a person who is exposed to irritating substances in the air intermittently for several days (or weeks, months, years), but who remains symptom-free for more than 24 hours after the final exposure, cannot be properly diagnosed as either RADS or Irritant Induced Asthma -- even if asthma symptoms eventually become clinically apparent. To clarify, if the time-interval between exposure and effect exceeds 24 hours, irritation is not likely to have been the causal factor.

RADS and IIA share the following characteristics

Both RADS and Irritant Induced Asthma are considered “new-onset asthma”. That is, by definition, they occur only in persons who have never previously had asthma or been treated for asthma, including childhood asthma. Patients who have preexisting asthma that is worsened by an exposure to an irritating substance do not have RADS (Brooks, 2002). A person with a medical history of asthma can, of course, experience a worsening of preexisting asthma after inhaling an irritant. This is not RADS, but a temporary exacerbation of a preexisting condition (Alberts, WM., 1999).

RADS is not an allergic disorder. However, atopy* has been described (Brooks, et al. 1998) as a risk factor for Irritant Induced Asthma. [Thus, if you are a person with a history of allergies, these allergies will not increase the likelihood that you will develop RADS. However, your preexisting allergic state might place you at a higher risk for developing Irritant Induced Asthma. At the time of this writing, this issue has not been adequately resolved.]
*(the word atopy was coined to describe the phenomenon of allergy and reactivity to certain allergens (Simon, 2000).

RADS v. Irritant Induced Asthma

Undoubtedly, RADS has been with us for a very long time. Reference to occupational respiratory problems in weavers can be found in a citation from an ancient Egyptian papyrus (In: Asthma in the Workplace, 2006. Chapter 2, Pepys, J and Bernstein, IL.) In 1970, a description of this condition (RADS) was published in The Medical Journal of Australia 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 inhalation exposures of the not-so-sudden asthma cases were neither massive nor single and the 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 (timely) related to the irritant exposure, that is, asthma symptoms must become clinically apparent during the period when the irritant exposure is taking place, although this exposure can be intermittent or continuous in nature. Of course, IIA must be differentiated from sensitizer-induced (allergic) 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 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 more recently suggested modifications to these criteria and some comments and clarifications drawn from the literature, which I hope will be useful to the reader.

1. A documented absence of preceding respiratory complaints.
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.
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. This observation is supported in a report by Kern and Sherman (1994), who noted that Brooks, in a personal communication to the authors, informed them that most RADS patients he sees have normal baseline spirometry. Additionally, 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).

7. Nonspecific bronchial hyperresponsiveness may be demonstrated by two laboratory methods.
1.) Significant spirometric response to an inhaled bronchodilator [The Bronchodilator Test] or 2.) A positive nonspecific bronchoprovocation challenge test [the Methacholine Challenge is such a test] (Alberts and Brooks, 1996). 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.
For a superb review of the interpretation of the methacholine challenge test – a test invariable considered in great detail wherein the pros and cons of RADS diagnosis are argued; the reader is referred to Hewitt, DJ (2008).
8. Other pulmonary diseases ruled out.

Diseases most often included in the differential diagnosis of RADS/IIA include vocal cord dysfunction syndrome, gastroesophageal reflux disease (GERD), hypersensitivity pneumonitis, adult onset allergic asthma, acute tracheobronchitis, and organic toxic dust syndrome (Bardana, 1995).

Special Issues

Persistent symptoms, recurrent bouts of acute bronchospasm, and quality-of-life implications

In their exceptionally informative publication, Alberts and do Pico (1996) emphasized that the asthma-like symptoms which characterize RADS are persistent in nature; respiratory symptoms and nonspecific bronchial hyperresponsiveness persist for at least three months and commonly for years -- or even permanently. In contrast, the clinical picture usually seen in individuals who survive a short-term, toxic inhalation exposure is complete recovery without significant sequelae. The authors (Alberts and do Pico) observe that “once RADS is established, the patient is subject to bronchospastic responses from many and varied environmental stimuli, including cigarette smoke, cold air, traffic fumes, and common household chemicals such as hair sprays, perfumes, and bleaches.”

In my professional experience, I have found that RADS patients nearly always find the physically incapacitating and nerve-wracking bouts of bronchospasm which routinely accompany their exposure to countless and inescapable environmental irritants to be a most bedeviling and distressingly-awful drain on their quality of life. To my personal knowledge, it is by no means uncommon for RADS sufferers to become confined to their homes -- virtual shut-ins – as a consequence of their disease.

Diagnosis

In their 1996 publication, Alberts and do Pico wrote: “There is no ‘gold standard’ for the diagnosis of RADS.” They continued, “The diagnosis of RADS is based upon a compatible history and a demonstration of persistent nonspecific bronchial hyperresponsiveness. The latter may be demonstrated by a significant spirometric response to an inhaled bronchodilator or a positive nonspecific bronchial provocation challenge test.”

According to Malo, et al., (2010), the diagnosis of RADS is based upon two findings: (1. History of acute exposure to an irritant material preceding the onset of respiratory symptoms in a subject without prior respiratory symptoms and 2.) Persistence of airway obstruction and/or demonstration of nonspecific bronchial hyperresponsiveness (NBHR). NBHR may be demonstrated by either of two ways: 1). By way of a significant spirometric response to an inhaled bronchodilator [a positive bronchodilator test] or 2). A positive response to a nonspecific bronchoprovocation challenge test [a methacholine challenge is such a test.] I have intentionally included citations from both Alberts and do Pico, (1996) and Malo, et al. (2010), in order to demonstrate that basic diagnostic criteria for RADS remain essentially unchanged over this period of 14 years.

Exposure Assessment. As emphasized in the Consensus Statement “Assessment of Asthma in the Workplace” prepared by the American College of Chest Physicians (accp), Chen-Yeung, M., et al., (1995),

“The assessment of exposure is a critical step in evaluating the contribution of the workplace and environment to a patient's asthma. The goals of the exposure assessment are to identify the causative agents, minimize future exposures, and prevent the development of future cases of occupational asthma. In this context, ‘exposure’ means likely contact of the respiratory system with an airborne chemical or biologic agent [Note: exposure assessment in terms of a quantitative airborne concentration or dose is not included here as a goal by the accp authors].

“Industrial hygiene definition of exposure is not useful in this context because patients with occupational asthma may react to very small quantities of an agent”.

“Practicing clinicians are generally not trained to evaluate occupational and environmental exposures that may be responsible for the development of their patient's disease.”

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.

Inhalation of chlorine gas and chlorine compounds has been reported as the most common cause of inhalation accidents in a review by Brooks (2002). In this same publication, Brooks cited other authors who reported that RADS is less common than allergic-type occupational asthma.

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). Malo, et al. (2010) noted “Some subjects become completely asymptomatic within a few months, while others complain of persistent asthma for years.” 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).

A real clinical entity? Current scientific evidence clearly supports 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, and the legal community (Alberts and do Pico, 1996).

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. Much more has been written on this subject.

Conclusions
Reactive Airways Dysfunction Syndrome (RADS) and Irritant Induced Asthma (IIA) are both forms of non-immunological asthma and both exhibit similar clinical pathological features caused by exposure to an irritating airborne agent and characterized by a negative history of asthma symptoms or treatment with asthma medications prior to exposure, persistence of asthma symptoms for at least three months, objective evidence of nonspecific bronchial hyperresponsiveness, and arguably, abnormal airway histopathology. More details are included in the preceding paragraphs of this review.



Disclaimer: While every effort has been made to ensure the accuracy of this publication, it is not intended to provide legal advice as individual situations will differ and should be discussed with an expert and/or lawyer.For specific technical or legal advice on the information provided and related topics, please contact the author.