Work-Related Asthma

ACOEM PRACTICE GUIDELINES

Work-Related Asthma

Athena T. Jolly, MD, MPH, Julia E. Klees, MD, MPH, Karin A. Pacheco, MD, MSPH, Tee L. Guidotti, MD, MPH, DABT, Howard M. Kipen, MD, MPH, Jeremy J. Biggs, MD, MSPH, Mark H. Hyman, MD, Bruce K. Bohnker, MD, MPH, Matthew S. Thiese, PhD, MSPH, Kurt T. Hegmann, MD, MPH, and Philip Harber, MD, MPH Objective: Summarize developed evidence- includes sensitizer-induced asthma, result- questions developed by the Evidence-based based diagnostic and treatment guidelines ing from sensitization to an antigen in the Work-related Asthma Panel: for work-related asthma (WRA). Methods: workplace, and irritant-induced asthma, Comprehensive literature reviews conducted induced by workplace exposures to irritants 1. Is there evidence on how to identify with article critiquing and grading. Guidelines (Table 1). Each condition has the potential workers who are at higher risk of devel- developed by a multidisciplinary expert panel for considerable acute morbidity, long-term oping occupational asthma? and peer-reviewed. Results: Evidence supports disability, and adverse impact on income 2. What evidence is there for the diagnosis spirometric testing as an essential early test. and quality of life.6–12 of occupational asthma? Serial peak expiratory flow rates measurement The most common form of occu- 3. Is there evidence that different diagnosis moderately recommended for employees diag- pational lung disease in many industrialized tic modalities are needed for workers nosed with asthma to establish work-relatedness. countries, with approximately 10% to 15% with new onset of symptoms or worsen- Bronchial provocation testing is moderately of all prevalent adult cases attributed to ing of previous asthma symptoms? recommended. IgE and skin prick testing for occupational factors,6–8,10,12–14 OA is fur- 4. Are there diagnostic tests that can specific high-molecular weight (HMW) antigens ther classified into OA with latency or OA assist in differentiating occupationally are highly recommended. IgG testing for HMW without latency. OA without latency is less related asthma from nonoccupational antigens, IgE testing for low-molecular weight common, and is believed to represent 5% to asthma? antigens, and nitric oxide testing for diagnosis are 15% of all OA cases.1,15 The percentage of 5. Is there evidence on treatment options not recommended. Removal from exposure is new-onset adult asthma attributable to that differ for occupationally related associated with the highest probability of occupational causes is considered to be asthma from nonoccupational asthma? improvement, but may not lead to complete much higher, up to a third of all cases.16,17 6. What management options are available recovery. Conclusion: Quality evidence sup- The frequency of WEA, defined as preex- for occupational asthma? ports these clinical practice recommendations. isting reactive airways disease that is made 7. Is removal from work necessary in all The guidelines may be useful to providers who temporarily or permanently worse due to cases of occupationally related asthma? diagnose and/or treat WRA. occupational exposures, is substantially The primary target population is more common than OA.18 working-age adults, although the literature The predisposing factors for devel- searches included articles addressing all INTRODUCTION oping OA with latency are not well known. adults. Thus, it is recognized that the prin- sthma is a common, chronic disorder Atopy is the primary established risk factor, ciples may apply more broadly. A of the airways that involves a com- operating largely with respect to high mol- plex interaction of airflow obstruction, ecular weight (HMW) antigens such as GUIDELINE DEVELOPMENT bronchial hyperresponsiveness, and under- animal proteins. It has been proposed that lying inflammation with increased airway PROCESS human leukocyte antigen class-2 alleles A detailed methodology document responsiveness to a variety of stimuli being may be a risk factor for the development typical.1–5 Work-related asthma (WRA) specified evidence selection, scoring, of OA resulting from low molecular weight incorporation of cost considerations, and includes both asthma of an occupational 11,19,20 agents. Medical management and formulation of recommendations.22,23 The origin (occupational asthma [OA]) and compensation decisions require a thorough work-exacerbated asthma (WEA). OA aim was to identify the highest quality assessment of suspected OA, which may be evidence on any given topic. Guidance mistaken for non-OA unless a detailed was drafted using tables that abstracted The ACOEM Practice Guidelines, including the history, including occupational history, the evidence and which were forwarded Work-related Asthma Guideline, is published and appropriate medical tests are performed 21 to the multidisciplinary Panel that reviewed by Reed Group, Ltd. Excerpts from the ACOEM to support an association with work. the evidence and finalized the text and Work-related Asthma Guideline, MDGuide- lines, reproduced with permission from Reed recommendations. Group, Ltd. All rights reserved. The Evidence- GUIDELINE FOCUS/TARGET based Practice Work-related Asthma Panel and POPULATION EVIDENCE REVIEW AND the Research Team have complete editorial independence from ACOEM and Reed Group, The American College of Occu- GRADING neither of which have influenced the recommen- pational and Environmental Medicine All evidence related to WRA in dations contained in this guideline. (ACOEM) created its evidence-based searching four databases (PubMed, Excerpts from the ACOEM Work-related Asthma EBSCO Cochrane Library Scopus Guideline, MDGuidelines, reproduced with per- Work-related Asthma Guideline to primar- , , and ) mission from Reed Group, Ltd. All rights ily address diagnostic options to help deter- was included in this guideline. The com- reserved. mine whether an employee has asthma, and prehensive searches for evidence were The authors declare no conflicts of interest. whether the asthma is related to workplace performed through September 2012 for Address correspondence to: Kurt T. Hegmann, MD, MPH, University of Utah Rocky Mountain exposures (Fig. 1). It was designed to diagnostic studies and February 2014 for Center for Occupational and Environmental present health care providers—who are management studies to help ensure Health, 391 Chipeta Way, Suite C, Salt Lake the primary target users—with evidence- complete study capture. The search strat- City, UT 84108-1294 (Kurt.Hegmann@hsc. based guidance on the evaluation and egies retrieved a total of 10,598 articles that utah.edu). treatment of WRA. This report summarizes were screened, with all potentially appro- Copyright ß 2015 American College of Occu- pational and Environmental Medicine findings from that Guideline (138 pages, priate study abstracts reviewed and eval- DOI: 10.1097/JOM.0000000000000572 497 references) and addresses the following uated against specified inclusion and

JOEM Volume 57, Number 10, October 2015 e121

TABLE 1. Types of Work-Related Asthma

Nomenclature Term Defining Features

Sensitizer-induced OA OA with latency of allergic or presumed Immunological/hypersensitivity component and diagnostic tests include immunological mechanism: not measures of specific sensitization (eg, skin-prick test, serum specific IgE, necessarily IgE circulating IgC against the antigen or skin sensitization) Irritant-induced OA OA without latency No allergic component and worker is not sensitized to an agent; rather, the agent causes inflammatory responses through irritant mechanisms WEA or aggravated WEA or aggravated asthma Worker has prior or concurrent history of asthma not induced by that asthma (no latency period) workplace. The worker is not sensitized to an agent at work, but is irritated by a ‘‘non-massive’’ exposure (eg, cold, exercise, non-sensitizing dust, fumes, or sprays) that provokes an asthmatic reaction

IgE, immunoglobulin E; OA, occupational asthma; WEA, work-exacerbated asthma. Adapted from the American College of Chest Physicians.

exclusion criteria. Searches were supple- synthesis of the evidence plus expert con- by other methods. Six moderate-quality mented with articles from personal files and sensus. These recommendations are for studies support the use of peak expiratory reference reviews. A total of 497 articles practitioners, and decisions to adopt a flow rate for the diagnosis of OA and WRA; were retrieved of which 157 met the particular course of action must be made however, peak expiratory flow rate is heav- inclusion criteria. Of those, 114 were by trained practitioners on the basis of avail- ily dependent upon the worker’s efforts and included as high- or moderate-quality stud- able resources and the particular circum- assumes worker honesty in performing and ies in evidence-based guideline develop- stances presented by the individual patient. recording the test results.33–40 ment. The remaining 43 studies were deemed low-quality and excluded. CLINICAL All included studies were scored for RECOMMENDATIONS NONSPECIFIC BRONCHIAL quality. Recommendations were graded Sixteen diagnostic recommendations PROVOCATION TESTING from (A) to (C) in favor and against the were formulated for diagnostic testing, of Nonspecific bronchial provocation specific diagnostic test or treatment, with which 11 were ultimately recommended testing has been evaluated in quality studies (A) level recommendations having the and five were not recommended (Table that utilized methacholine, histamine, and highest quality body of literature. Quality 2). There were nine recommendations for- mannitol as provocative testing agents. Four evidence was developed into evidence- mulated for the management of WRA, of high-quality and 12 moderate-quality based recommendations. Expert consensus which five were recommended and four studies were used in formulating recommen- was employed for insufficient evidence (I) to were not (Table 3). dations of nonspecific bronchial provocation develop consensus guidance. Recommen- testing as an investigational tool for the 41–57 dations and evidence tables were reviewed SPIROMETRY TESTING diagnoses of OA and WRA. Nonspe- and amended by the multidisciplinary Panel. Spirometry, performed alone or in cific bronchial provocation testing is This guideline achieved 100% Panel agree- conjunction with pre- and postbronchodila- strongly recommended (evidence level A) ment for all developed guidance. tor testing, is an important component of the to diagnose general asthma, and moderately evaluation and management of persons with recommended (evidence level B) to diag- possible WRA.26–32 Spirometry with bron- nose WRA. The Panel supports the Ameri- COMMENTS AND can Thoracic Society’s guideline for MODIFICATION chodilator administration has three distinct potential roles when WRA is a concern: interpreting the methacholine dose that Guidance was developed with suffi- would result in a positive test.58 cient detail to facilitate assessment of com- 1. Determining whether asthma is present; pliance (Institute of Medicine [IOM]) and 2. If asthma is present, helping inform the auditing/monitoring (Appraisal of Guide- SPECIFIC IMMUNOLOGICAL 24,25 conclusion about whether the asthma is TESTING lines for Research and Evaluation). work related; and Alternative options to manage conditions 3. Monitoring response to therapy and Specific immunological testing was are provided in other ACOEM guidelines possible return to work. evaluated separately for HMWand low mol- when comparative trials are available. The Spirometry with bronchodilator is not ecular weight antigens. There were six high- only Appraisal of Guidelines for Research invasive, has few adverse effects, and is low- and 12 moderate-quality studies used in and Evaluation25 and IOM criterion24 not the formulation of recommendations for to-moderate cost and high in yield for com- 50,51,57,59–73 followed was incorporation of the views of plications and other respiratory problems. specific immunological testing. the target population. In accordance with As its value lies in correlation with clinical The Panel evaluated the difference between the IOM’s Trustworthy Guidelines, this information and observation, spirometry immunoglobulin E (IgE) and IgG tests. IgE guideline underwent external peer review with bronchodilator is a recommended inte- testing for HMWantigens is strongly recom- by four external reviewers, and subsequent gral part of the evaluation of WRA. mended (evidence level A) when specific revisions to the guidance, and detailed testing reagents have been validated and are records of the peer-review processes have commercially available. Testing of IgG for been kept, including responses to external PEAK EXPIRATORY FLOW HMW antigens is not recommended (evi- peer reviewers.24 RATES dence level C) for use as a diagnostic tool; This guideline is updated at Serial peak expiratory flow rate however, this test may be efficacious as a least every 3 years or more frequently monitoring is moderately recommended marker for exposure to the antigen. IgE should evidence require it. All treatment (evidence level B) to diagnose WRA in testing to low molecular weight antigens is recommendations are guidance based on patients already diagnosed with asthma not recommended (evidence level I).

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Copyright © 2015 American College of Occupational and Environmental Medicine. Unauthorized reproduction of this article is prohibited JOEM Volume 57, Number 10, October 2015 ACOEM Practice Guidelines: Work-Related Asthma

Consider specific inhalation challenge testing (SICT) – highly specific use. (In the absence of ongoing suspect exposure, the relationship between airway reactivity and the suspect agent can only be confirmed with SIC; this may be the only absolute indication for performing a specific bronchial provocation challenge with a diisocyanate and is justified if the result will have an impact on future health and economic outcomes.)

FIGURE 1. Diagnostic evaluation of occupational asthma with continuing exposure.

SKIN-PRICK TESTING high- and 12 moderate-quality studies used level A) for allergens that are commercially Skin-prick testing (SPT) was eval- to formulate recommendations for available and validated. Current commer- uated separately for HMW and low mol- SPT.50,51,53,62,73–88 SPT for HMW aller- cially available validated extracts include ecular weight allergens. There were eight gens is strongly recommended (evidence some for natural rubber latex, wheat flour,

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TABLE 2. Summary of Recommendations for Diagnostic Testing for Asthma

Test Recommendation(s)

Peak expiratory flow rates Serial peak expiratory flow measurements as an initial evaluation method for diagnosing work-related asthma, in patients already diagnosed with asthma by other methods—Moderately Recommended, Evidence (B) Nonspecific bronchial Nonspecific bronchial provocation testing (eg, methacholine) for use in diagnosing asthma, if the clinical history is provocation testing compelling, and other tests (spirometry and bronchodilator responsiveness) are unhelpful—Strongly Recommended, Evidence (A) Nonspecific bronchial provocation testing (eg, methacholine) for use in diagnosing WRA, as other steps are required to establish the work-relatedness of the asthma—Moderately Recommended, Evidence (B) Mannitol bronchial provocation testing for use in diagnosing WRA; other steps are required to establish the work- relatedness of the asthma—Recommended, Evidence (C) Specific immunological Specific immunological testing (IgE) for workers with symptoms consistent with OA to certain HMW specific allergens testing and when standardized antigens and assay protocols exist—Strongly Recommended, Evidence (A) Specific immunological testing (IgG) as a diagnostic tool for select workers with symptoms consistent with OA to HMW specific allergens—Not Recommended, Evidence (C) Specific immunological testing (IgE) for workers with symptoms consistent with OA to low molecular weight specific allergens due to low sensitivity and specificity and lack of method validation—Not Recommended, Insufficient Evidence (I) Skin-prick testing Skin-prick testing for HMW allergens for select workers with symptoms consistent with OA to specific allergens and where validated, commercial skin testing extracts are available—Strongly Recommended, Evidence (A) Skin prick testing for low molecular weight allergens for select workers with symptoms consistent with OA to specific allergens, and where skin testing extracts are available—Moderately Recommended, Evidence (B) Skin-prick testing for allergens not covered above—Not Recommended, Insufficient Evidence (I) Specific inhalation Specific inhalation challenge testing for use in diagnosing WRA with latency for highly select cases, where the diagnosis of challenge testing OA is highly suspected, but has not been established by less invasive means—Recommended, Evidence (C) Nitric oxide testing Nitric oxide testing for the diagnosis of OA, as it cannot differentiate between, eg, OA and other eosinophilic lung inflammatory conditions—Not Recommended, Insufficient Evidence (I) Exhaled nitric oxide testing for establishing a diagnosis of asthma when more objective evidence is needed such as in litigated cases—Recommended, Evidence (C) Exhaled nitric oxide testing for selective use in monitoring airway inflammation in patients with moderate and severe asthma—Moderately Recommended, Evidence (B) Nasal lavage testing Nasal lavage for select workers with symptoms consistent with occupational airways allergy to specific allergens— Recommended, Evidence (C) Nasal lavage fluid analysis after challenge with the allergen for the diagnosis of OA—Not Recommended, Insufficient Evidence (I)

IgE, immunoglobulin E; HMW, high molecular weight; OA, occupational asthma; WRA, work-related asthma.

rye flour, grain dust, alpha-amylase, bovine fatalities. Facilities must have the techno- conditions such as eosinophilic inflammatory danders, and other animal antigens. SPT to logical equipment and ability to control conditions. FENO is recommended (evi- low molecular weight antigens is moder- exposures, as well as monitor and resusci- dence level C) for diagnosis when more ately recommended (evidence level B) for tate patients, and few such facilities exist. objective evidence is needed such as in liti- allergens that have a commercially avail- Thus, specific inhalational challenge test- gated cases. FENO is recommended (evi- able validated test including some available ing is recommended only under highly dence level B) in monitoring airway for reactive dyes, halogenated platinum select circumstances at appropriately inflammation in patients with moderate and salts, and trimellitic anhydride. All other equipped facilities that include direct severe asthma as evidence indicates it corre- SPT for allergens not specifically men- medical supervision throughout the test- lates with the disease activity.104,107,115 tioned are not recommended (evidence ing. The highly limited availability of Additional guidance regarding criteria for level I). facilities as well as adverse effects caused clinically meaningful change and timing the Panel to reduce this recommendation for FENO was abstracted from the evi- SPECIFIC INHALATIONAL from strongly recommended (evidence dence.102,118,120–122 It is recommended that CHALLENGE TESTING level A) to recommended (evidence level a change of 20% in the value is clinically Specific inhalational challenge test- C). significant and should be measured every 2 ing is often considered the gold standard to 4 weeks while the treatment plan is being test for diagnosing sensitizer-induced NITRIC OXIDE TESTING modified and finalized.104,122,123 OAandisusedwhenothermethodshave Nitric oxide testing—also known as failed to establish the diagnosis. It is also fractional exhaled nitric oxide (FENO)—was NASAL LAVAGE TESTING used as a reference standard, as there is evaluated as a diagnostic tool for all asthma Eight moderate-quality studies were no other definitive diagnostic test. Four including OA, and for selective monitoring of used in formulating recommendations for high- and 16 moderate-quality studies asthma treatment and progression. Two high- nasal lavage.63,93,124–129 Nasal lavage is were used to formulate this recommen- and 20 moderate-quality studies were recommended (evidence level C) for select dation.11,42,46–50,62,63,89–99 However, spe- used to formulate recommendations for workers with symptoms consistent with cific inhalational challenge testing is FENO.45,100–119 FENO is not recommended occupational upper airway allergy to highly technical and costly and has poten- to diagnose OA (evidence level I) as it cannot specific allergens. The testing supports tial for severe adverse effects, including differentiate between asthma and other a diagnosis of occupational allergy, but

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TABLE 3. Summary of Recommendations for Management of Work-Related Asthma

Recommended Not Recommended

Patients, physicians, and employers be informed that persistence of Reduction of exposure as a strategy for certain low molecular weight exposure to the causal agent is likely to result in deterioration of asthmagens (diisocyanates). (I) As an alternative to complete asthma symptoms and airway obstruction. (I) elimination of exposure, continued low-level exposure with use of Patients and their physicians be made aware that complete avoidance of personal protective equipment has been associated with adverse exposure is associated with the highest probability of improvement, health outcomes including reports of death. but may not lead to a complete recovery from asthma. (I) Reducing exposure to the causal agent as a strategy in the management For irritant-induced asthma, exposure reduction to the lowest levels of sensitizer-induced asthma, as available evidence indicates that possible and careful medical monitoring should be performed to most asthma will worsen in continued exposure. (I) However, it is ensure early identification of worsening asthma. (I) recognized that some workers will insist on remaining in their jobs Pharmacological treatment of WRA follows general recommendations for social, economic, and professional reasons, despite counseling on for asthma (C). Current ERS/ATS recommendations for treatment of the adverse health consequences. Continued exposure, even at low severe asthma should be followed. levels, may result in worsening asthma. If such patients remain in Immunotherapy may be considered in settings where OA due to a exposure, documentation of the recommendation regarding removal specific HMW allergen has been established, when only one or a is recommended. (I) Required close and careful medical monitoring few allergens have been linked clinically to disease, when there is a of such patients is recommended (I) to ensure early identification of standardized commercial allergen extract available for treatment, worsening asthma. Reducing exposure to the causal agent in addition good control with pharmacotherapy cannot be established and the to providing immunotherapy and other asthma management, where causative agent cannot be completely avoided for economic, applicable, may be recommended (I), and will depend on the professional, or other reasons. (I) asthmagen, level of exposure, severity of asthma, and the clinical judgment of the physician. Use of respiratory protective devices as a safe approach for managing asthma, especially in the long-term and in patients with severe asthma. (I) Anti-asthma medications as a reasonable alternative to environmental interventions such as exposure reduction or medical removal. (I)

HMW, high molecular weight; ERS/ATS, European Respiratory Society/American Thoracic Society; OA, occupational asthma; WRA, work-related asthma.

other tests are required to establish a diag- surveillance to detect asthma deterioration. of anti-asthma medications in patients who nosis of WRA; however, nasal lavage Reducing exposure to the causal agent remain exposed to the causal agent has not following nasal provocation testing is not in addition to providing immunotherapy been specifically addressed in previously recommended (evidence level I) for and other asthma management, where published guidelines,12,131 or in the Agency diagnosing OA. applicable, depends on the asthmagen, level for Healthcare Research and Quality sys- of exposure, severity of asthma (Table 4), tematic review.1 MANAGEMENT OF WORK- and the clinical judgment of the physician. If RELATED ASTHMA disease progression is documented, then SUMMARY This guideline addresses manage- removal from the exposure is strongly This is the first WRA guideline to be ment of WRA once it is diagnosed (Table recommended. An exception is isocyanate- published that is based on IOM-compliant 3). There are 11 studies incorporated into induced OA. This requires removing the 1,12,43,81,130–137 criteria including systematic literature this analysis, although none worker from exposure, as there have been reviews, literature grading, expert panel con- met high- or moderate-quality criteria. reported deaths in patients on medication 24 138–143 sensus, and peer-review. It is designed to Thus, the panel reached the following con- and using respiratory protection. be a resource for primary care providers, clusions regarding management of WRA Studies have found that continued toluene occupational medicine specialists, and pul- on the basis of consensus. diisocyanate exposure has been associated monary/allergy specialists whodiagnose and Early diagnosis and early avoidance with increasingly persistent and severe manage occupationally related asthma. of further exposure, either by relocating the respiratory symptoms.137,144–146 Personal worker or substituting the hazard, offer the protective equipment is not recommended best chance of complete recovery. Patients as the only treatment option for managing RESEARCH with sensitizer-induced OA should be OA. RECOMMENDATIONS removed from further exposure to the caus- Very few studies have specifically Research into primary and secondary ative agent in addition to providing other examined pharmacologic treatment in the prevention is indicated to reduce the inci- asthma management,12 and it is recom- management of WRA. The pharmacologic dence of WRA. Also recommended is inves- mended to educate all parties that complete treatment of OA and WEA does not differ tigation to improve diagnostic methodology avoidance of exposure to the identified from the treatment of asthma that is not leading to earlier detection of sensitizer- antigen is preferred; however, complete work related12; it relies on a stepwise induced OA, before progression to perma- removal is not always possible, for approach according to the severity of nent asthma, and preventing further cases of example, because of economic constraints asthma and asthma control. Treatment for sensitizer-induced OA. Management with of job change or loss, as well as patient patients with a diagnosis of severe asthma pharmacological treatment options should preferences to continue in the same occu- has been recommended by the European be studied to identify treatments specific pation. In that instance, the Panel recom- Respiratory Society and the American to OA and WEA, and to more specifically mends transfer to low levels of exposure Thoracic Society, but these recommen- evaluate pharmacotherapy for different to the asthmagen and frequent monitor- dations did not exclude or specifically agents, for example, HMW versus low mol- ing with questionnaire and spirometry address OA or WEA.147 The effectiveness ecular weight antigens.

TABLE 4. Medical Removal Considerations

Workplace Exposure Low Severity OAy Moderately Severe OAy Severe OAy

Low Remove worker or reduce exposure; frequent Remove worker. Selectively consider low exposure, Remove worker surveillance with symptom questionnaire and with monthly surveillance with symptom spirometry. Remove worker if progression of questionnaire and spirometry. Remove if disease progression Medium Remove worker or reduce exposure; frequent Remove worker Remove worker surveillance with symptom questionnaire and spirometry. Remove worker if progression of disease High Removal of worker best option as exposure predicts Remove worker Remove worker progression

OA, occupational asthma. Workplace exposure is defined as follows: (1) Low exposure—when regular airborne exposure to the causative agent is not expected. (2) Moderate exposure—when airborne exposures at or below the level of the occupational exposure limit (OEL) of the causative agent are expected. (3) High exposure—when airborne exposures above the level of the OEL of the causative agent are expected. (4) The OEL selected should be a recent, scientifically reviewed, widely used guideline designed for use by industrial hygienists in making decisions regarding safe levels of exposure to various chemical substances and physical agents found in the workplace, such as the American Conference of Governmental Industrial Hygienists Threshold Limit Values1. yAsthma severity is defined as follows: (1) Severe—having abnormal FEV1 (<70%) and requiring use of high-dose inhaled corticosteroids and long-acting inhaled beta-agonists for symptom control. (2) Moderately severe—having abnormal FEV1 (<70%) and symptoms that are well-controlled with low dose inhaled corticosteroids and long-acting inhaled beta-agonists. (3) Low severity—having normal FEV1 and symptom control by as-needed beta-agonist rescue or with low-intensity controller treatment such as low-dose inhaled corticosteroids, leukotriene receptor antagonists, or cromoglycates.

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