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INTRODUCTION — Reactive airways dysfunction syndrome (RADS) and irritant-induced asthma (IrIA) are closely related forms of asthma that result from the nonimmunologic provocation of prolonged bronchial hyperresponsiveness and airflow obstruction by inhaled irritants [1,2]. Irritant-induced respiratory problems were initially described among industrial workers and World War I combatants in the early part of the 20th century [3,4]. These reports focused on acute effects such as pulmonary edema and death, but also described chronic respiratory sequelae of intense, brief exposure to inhaled irritants .
Subsequently, bronchitic symptoms, such as cough and wheezing, were described following a chlorine spill in 1969, although bronchial responsiveness was not assessed . Persistent airway hyperresponsiveness was noted in five of seven subjects four years after an acute exposure to sulfur dioxide . Further studies have led to a growing awareness and understanding of reactive airways dysfunction syndrome and irritant-induced asthma, especially in firefighters, rescue personnel, and people living in the vicinity of the World Trade Center site in September 2001 [1,7,8].
The diagnosis and management of RADS and IrIA will be reviewed here. The diagnosis of asthma and the causes, evaluation and management of occupational asthma are discussed separately. (See "Diagnosis of asthma in adolescents and adults" and "Occupational asthma: Definitions, epidemiology, causes, and risk factors" and "Occupational asthma: Clinical features and diagnosis" and "Occupational asthma: Management, prognosis, and prevention".)
DEFINITIONS — Reactive airways dysfunction syndrome (RADS) 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, or smoke; these initial symptoms are followed by asthma-like symptoms and airway hyperresponsiveness that persist for a prolonged period (table 1) . RADS can occur after exposure to a variety of chemicals generated as gas or aerosol, or exposure to high levels of particulates (table 2A-B). Clinical and functional criteria for the diagnosis of reactive airways dysfunction syndrome are listed in the table (table 1) .
Irritant-induced asthma (IrIA) is a more general term to describe an asthmatic syndrome that results from a single or multiple high dose exposures to irritant products . When only a single, high-dose exposure has been responsible, the term RADS is used. IrIA caused by single or multiple exposures to low doses of irritants has been reported, as after the World Trade Center catastrophe [7,8]. Multiple exposures to high concentrations of products, such as chlorine in pulp and paper mills, may be obvious enough for the affected person to identify the timing, nature, and frequency of events [9,10]. When IrIA is caused by workplace exposures, it is considered a type of occupational asthma, the non-immunologic type.
It has been suggested that IrIA also include the situation where multiple exposures to low concentrations of an irritant have led to bronchial mucosal injury and persistent asthma-like symptoms, although this is less well-established . The term "low-dose RADS" has been used to describe individuals in the latter group, although the background of repeated low-dose (as opposed to a single high-dose) exposure means that they do not formally fulfill the original criteria for RADS; we prefer the term IrIA for these patients. 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 irritant-induced asthma" . The term Low Intensity Chronic Exposure Dysfunction Syndrome (LICEDS) has also been suggested to describe this form of IrIA .
EPIDEMIOLOGY — RADS may occur after inhalational accidents at home, in the workplace, or in the general environment. IrIA 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 . 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 RADS in many others [15,16].
Estimating the incidence of RADS 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 IrIA, 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 [17,18]. 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 RADS and IrIA:
CAUSES AND RISK FACTORS — Risk factors for the development of RADS and IrIA are incompletely characterized, but appear to include the chemical and physical nature and concentration of the irritant agent in addition to certain host factors such as atopy and cigarette smoking.
Increased concentrations of offending agents are associated with higher risk, and vapors and wet aerosols generally appear to be more provocative of RADS than dry particulates . Workers exposed to bleaching agents in paper mills (including chlorine)  and cleaning products  are particularly at risk. Excess rates of asthma have been documented in workers exposed to cleaning agents, and RADS/IrIA may explain this phenomenon (table 2A and table 2B) .
Atopy has been described as a risk factor for the occurrence of the not so sudden onset variant of IrIA that develops days after an irritant exposure . In contrast, previously documented bronchial hyperresponsiveness did not predispose to the development of RADS in firefighters at the World Trade Center . It is likely that the preexisting airway hyperresponsiveness was infrequent among these firefighters given that asthma is an exclusion criterion for recruitment.
Smoking is more common among workers with RADS than those with occupational asthma and seems to increase the risk of functional decline in workers repeatedly exposed to puffs of chlorine [21,25].
PATHOLOGIC CORRELATIONS — Serial observations from two cases of RADS illustrate the histopathologic features of the disease (table 3) [32,33]. 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 basement membrane, and regeneration of basal cells are all more striking in RADS than in occupational asthma with a latency period (table 4). In addition, bronchoalveolar lavage reveals neutrophilia in the acute stage of RADS, whereas lymphocytes and eosinophils are more numerous in occupational asthma with a latency period. (See "Occupational asthma: Pathogenesis", section on 'Pathology'.)
The acute changes of RADS have been reproduced by exposing rats to high concentrations of gaseous chlorine . 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 . Similar findings have been described in a mouse model of RADS . The long term (approximately 10 years) pathological abnormalities of RADS have been described . Bronchial biopsies obtained in 10 subjects showed neutrophilic and eosinophilic inflammation. In addition, basement membranes were thicker among patients with RADS than those with mild immunologic OA or healthy controls.
In one patient with irritant-induced asthma secondary to multiple exposures, an inflammatory infiltrate consisting of lymphocytes and polymorphonuclear cells was found on bronchial biopsy . 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 [37,38].
CLINICAL MANIFESTATIONS — The clinical manifestations of RADS and IrIA differ mainly in the rapidity of onset of symptoms. In RADS, the onset of symptoms 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 [10,39]. Patients with multiple exposures to high concentrations of products such as chlorine may be able to identify the timing, nature, and frequency of events [9,10]. However, patients with IrIA 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, subjects with no history of respiratory complaints report a burning sensation in the throat and nose referred to as RUDS (Respiratory Upper Airways Distress Syndrome) , in addition to cough, dyspnea, wheeze, and chest pain [1,19,41]. These symptoms typically develop within 24 hours of the exposure and are severe enough that approximately 78 percent seek emergency room treatment . In most series, cough is the predominant symptom in RADS and IrIA [1,42,43]. (See 'Definitions' above.)
Patients with IrIA due to multiple low level exposures to irritant agents describe essentially the same symptoms as patients with RADS (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 [44,45]. Occupational rhinitis is discussed in greater detail separately. (See "Occupational rhinitis".)
For both RADS and IrIA, physical examination findings are not well described, but have included conjunctivitis, pharyngeal erythema, tearing, tachypnea, and wheezing [20,46]. 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 . Exposure to ammonia may be associated with burns and blisters on exposed skin and damage to the surface structures of the eye. (See "Chemical terrorism: Diagnosis and treatment of exposure to chemical weapons", section on 'Pulmonary irritants'.)
EVALUATION — 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 is performed to determine whether airflow limitation is present and reversible. (See "Evaluation of the adult with dyspnea in the emergency department".)
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 RADS or IrIA, are listed in the table (table 5).
For patients with persistent symptoms due to RADS or IrIA, the evaluation is the same for the two processes. In addition to spirometry, additional tests include 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 RADS or IrIA, either allergy skin testing or immunoassay to a panel of common aeroallergens is appropriate to exclude allergic asthma due to common aeroallergens. (See "Overview of skin testing for 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 RADS associated with high level exposure to formaldehyde, although the significance of this observation is not known .
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 airways hyperresponsiveness. The roles of spirometry and bronchoprovocation challenge in the diagnosis of asthma are discussed separately. (See "Use of pulmonary function testing in the diagnosis of asthma", section on 'Measures of airflow limitation' and "Bronchoprovocation testing".)
Spirometry — Baseline spirometry is obtained in all patients suspected of having RADS or IrIA; bronchodilator reversibility assessed if airflow limitation is present. In a series of 19 patients seen after chlorine exposure, approximately half had airflow limitation when assessed soon after the exposure . Among 10 subjects with RADS due to high level exposures to a variety of agents, four had airflow obstruction with a forced expiratory volume in one second (FEV1) that was less than 80 percent of predicted when assessed in a subspecialty clinic . (See "Office spirometry" and "Use of pulmonary function testing in the diagnosis of asthma", section on 'Measures of airflow limitation'.)
Following baseline spirometry, bronchodilator reversibility is assessed by inhalation of a short-acting beta agonist. In general, reversibility is defined as an increase in FEV1 of 12 percent or more, accompanied by an absolute increase in FEV1 of at least 200 mL. Airflow obstruction is generally less responsive to bronchodilator in RADS than in asthma, although some degree of reversibility may be present. A comparison of 30 subjects with immunologic occupational asthma and 15 subjects with RADS 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 RADS. However, significant heterogeneity was seen among the RADS group:6 of the 15 subjects had a postbronchodilator improvement in FEV1 of more than 15 percent . (See "Use of pulmonary function testing in the diagnosis of 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 (figure 1 and figure 2) . (See "Overview of pulmonary function testing in adults", section on 'Lung volumes'.)
Nonspecific bronchoprovocation challenge — If baseline spirometry shows absent or minimal airflow limitation (eg, an FEV1 of 70 percent of predicted or greater) and no significant bronchodilator reversibility, nonspecific bronchial challenge (eg, methacholine) is performed to assess for bronchial hyperreactivity. The contraindications to bronchoprovocation challenge and adjustments to medications prior to testing are listed in the tables (table 6 and table 7). The performance of bronchoprovocation challenge is 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 "Use of pulmonary function testing in the diagnosis of asthma", section on 'Bronchodilator responses'.)
Specific bronchoprovocation challenge — Specific bronchoprovocation challenge to sensitizing agents in the workplace is occasionally used in the evaluation of immunologic occupational asthma to ascertain the specific causative agent. However, specific challenge with agents that are known to cause IrIA is not performed . (See "Occupational asthma: Clinical features and diagnosis", section on 'Specific bronchoprovocation challenge'.)
As an exception to avoiding specific bronchoprovocation in RADS and IrIA, specific inhalational challenge has been performed in a patient who developed RADS following a high level exposure to diisocyanate . Diisocyanate is a cause of immunologic occupational asthma among workers with frequent low level exposures. Bronchoprovocation challenge was positive, and the patient subsequently developed immunological occupational asthma associated with nonirritant exposures to the same agent. (See "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Low-molecular-weight' and "Occupational asthma: Clinical features and diagnosis", section on 'Specific bronchoprovocation challenge'.)
Imaging — A chest radiograph is typically obtained to exclude noncardiogenic pulmonary edema or pneumonia in patients presenting after an acute irritant exposure or other causes of dyspnea in those presenting later in the course of RADS or after multiple lower dose irritant exposures. The chest radiograph in patients with RADS and IrIA is typically normal or hyperinflated. (See "Evaluation of the adult with dyspnea in the emergency department", section on 'Chest x-ray (CXR)' and "Approach to the patient with dyspnea", section on 'Imaging'.)
High resolution computed tomography (HRCT) is not usually required in the evaluation of RADS or IrIA, 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 .
DIAGNOSIS — The diagnosis of RADS and IrIA is based upon a combination of exposure history (table 5), time course of symptom onset, and evidence of reversible airflow limitation and/or airways hyperresponsiveness.
The diagnosis of RADS is based upon:
The diagnosis of IrIA is often not as straightforward as the diagnosis of RADS 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 irritant-induced asthma with certainty. However, data from epidemiologic studies that have identified occupations with an increased risk of asthma, such as cleaners [30,52] and pulp mill workers , can be used to support a diagnosis of IrIA in a patient with similar exposures . (See 'Epidemiology' above.)
Acute presentation — At the time of an acute presentation with possible RADS, the differential includes underlying asthma that may have been exacerbated by an irritant exposure, acute respiratory infection, noncardiogenic pulmonary edema, and other causes of an acute onset of dyspnea. A careful history provides guidance regarding the severity of the exposure and thus the likelihood of RADS versus an exacerbation of underlying asthma. A conventional chest radiograph can help exclude pneumonia, noncardiogenic pulmonary edema, and acute eosinophilic pneumonia. A complete blood count and differential provides supportive information for or against infectious or eosinophilic pneumonia. (See "Diagnosis of asthma in adolescents and adults", section on 'Diagnosis' and "Acute bronchitis in adults" and "Diagnostic approach to community-acquired pneumonia in adults" and "Evaluation of the adult with dyspnea in the emergency department".)
Persistent symptoms — For patients presenting with persistent symptoms, the differential diagnosis of RADS and IrIA 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.
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.
A number of features are common to IrIA 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 RADS and irritant-induced asthma are 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 IrIA, 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 and diagnosis" and "Occupational asthma: Definitions, epidemiology, causes, and risk factors", section on 'Causative agents'.)
Paradoxical vocal cord motion (PVCM) refers to abnormal closure of the vocal cords, usually on inspiration; it may mimic asthma or accompany asthma. A temporal association of onset of PVCM and irritant exposure has been described, adding to the importance of differentiating these entities . The diagnosis of PVCM 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 "Paradoxical vocal cord motion", section on 'Evaluation' and "Bronchoprovocation testing", section on 'Pharmacologic challenge'.)
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. Nonasthmatic eosinophilic bronchitis has been described in workers exposed to a variety of occupational agents that are associated with IgE-mediated sensitization [2,54,55]. The key differentiating feature is the negative bronchoprovocation challenge among patients with NAEB. Induced sputum shows eosinophils in NAEB. However, induced sputum analysis has not been fully evaluated in RADS and IrIA and is not widely available. (See "Evaluation of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis' and 'Nonspecific bronchoprovocation challenge' above.)
Acute management of RADS — The management of an acute presentation of RADS is essentially the same as the treatment of an acute asthma exacerbation (algorithm 1 and table 8) . Bronchodilator therapy is administered based on the severity of symptoms and response to treatment, even though the response to inhaled bronchodilator may be blunted compared to 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. (See "Treatment of acute exacerbations of asthma in adults" and 'Spirometry' above.)
Treatment of acute RADS 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 RADS, so the use of systemic glucocorticoids for RADS is based upon clinical experience and their well-documented role in asthma [32,33]. Support for systemic glucocorticoid therapy comes from their use in an animal model of RADS. 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 .
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. When systemic glucocorticoids are discontinued, we initiate high-dose inhaled glucocorticoids (eg, beclomethasone 2000 mcg/day or the equivalent) and taper as tolerated. Relatively high doses of inhaled glucocorticoids may be required for long-term treatment as pathological evidence shows the persistence of eosinophils .
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 RADS reflects our experience. In the report, treatment with inhaled glucocorticoids normalized bronchial hyperresponsiveness, but hyperresponsiveness worsened when therapy was stopped .
The initial dose of inhaled glucocorticoids is based on the step-wise approach to asthma outlined in the National Asthma Education and Prevention Program (NAEPP) [56,57]; in our experience the majority of patients require a high dose to control symptoms (table 9 and figure 3 and table 10). (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.)
Management of chronic RADS or IrIA — For patients with RADS or IrIA who require long-term pharmacologic treatment for asthma symptoms, the step-wise approach described in the NAEPP and the Global Initiative for Asthma (GINA) guidelines is followed even though it has not been formally assessed in this setting (table 9 and figure 3) [56,57]. Over time, if the patient’s asthma remains well-controlled, therapy is tapered according to the same guidelines. The long-term treatment of RADS and IrIA is the same, even though the specific timing and pattern of onset differ. (See "An overview of asthma management", section on 'Assessing control to adjust therapy'.)
Nonpharmacologic treatment of RADS and IrIA has not been studied directly; however, based on clinical experience patients are advised to avoid exposure to other respiratory irritants, including cigarette smoke . 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 — Complete exposure avoidance is the preferred option for workers with IrIA. While low dose exposures to irritant agents appear less likely to cause an increase in symptoms, compared with immunologic inciting agents, the exact risk is not known. On the other hand, workers whose asthma symptoms and physiology have normalized may find it necessary to return to work. The risk of a high-level exposure to appropriate engineering controls and respiratory protective devices should be in place to minimize the risk of worsening IrIA . Ongoing monitoring of symptoms and respiratory physiology is key to early identification of any deterioration.
PROGNOSIS — The long-term outcome of acute RADS and irritant-induced asthma 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 [36,42,44,45,58-60]. As examples:
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