Evaluation of wheezing illnesses other than asthma in adults

INTRODUCTION — Wheezing is a common manifestation of respiratory illness in adults. While wheezing typically brings to mind airway obstruction from bronchoconstriction or excessive mucus production and/or poor clearance due to asthma or chronic obstructive pulmonary disease (COPD), wheezing is also caused by a spectrum of other processes that cause airflow limitation [1-4]. These processes may be present on their own or may coexist with asthma or COPD, contributing to difficult to control symptoms. When evaluating wheezing, it may be helpful to recall the adage, "All that wheezes is not asthma [or COPD]; all that wheezes is obstruction."

An overview of wheezing illnesses in adults, other than asthma or COPD, is presented here. The diagnosis of asthma, COPD, and wheezing illnesses in children are discussed separately. (See "Asthma in adolescents and adults: Evaluation and diagnosis" and "Epidemiology of asthma" and "Chronic obstructive pulmonary disease: Diagnosis and staging" and "Evaluation of wheezing in infants and children".)

WHEEZE AND STRIDOR — A wheeze is a continuous musical sound that can be produced by oscillation of opposing walls of an airway that is narrowed almost to the point of closure [5-7]. Wheezes are usually high pitched, consist of single or multiple notes, occur during inspiration or expiration (more commonly expiration), and originate from airways of any size, from the large extrathoracic upper airway to the intrathoracic small airways. Stridor refers to a monophonic, harsh, and grating sound that is loudest over the anterior neck and is typically high-pitched and predominantly inspiratory [4]. Stridor is sometimes characterized as a type of wheeze due to the overlapping sound signal frequencies of wheeze and stridor [4,6]. (See 'Acoustic characteristics of wheeze' below.)

CAUSES — While asthma and chronic obstructive pulmonary disease are the most common causes of wheezing, a variety of other conditions can produce airflow obstruction and thereby expiratory and/or inspiratory wheezing (table 1). Causes of wheezing are generally categorized based on their location in one of the following three anatomic areas:

●The extrathoracic upper airway, which includes the nose, mouth, pharynx, larynx, and extrathoracic trachea

●The intrathoracic central airway, which includes the intrathoracic trachea and bronchi at least 2 mm in diameter

●The intrathoracic lower airways, which include airways narrower than 2 mm in diameter [8]

Extrathoracic upper airway causes of wheeze — Extrathoracic causes of wheeze/stridor are more likely to be associated with a monophonic inspiratory sound (stridor), but are sometimes associated with expiratory wheeze (table 2).

●Anaphylaxis – The abrupt onset of stridor and respiratory compromise, associated with generalized urticaria, pruritus or flushing, swollen lips-tongue-uvula, or hypotension, is a classic manifestation of anaphylaxis triggered by food, insect sting, medication, or radiographic contrast. In the context of anaphylaxis, stridor is caused by laryngeal edema. (See "Anaphylaxis: Emergency treatment".)

●Vocal cord edema or paralysis – Following tracheal extubation, patients may develop vocal cord (also known as vocal fold) edema or paralysis (picture 1). In patients with bilateral vocal cord paralysis, the vocal cords may be adducted to a median position and cause airflow obstruction that is greater during inspiration than expiration. During expiration, the paralyzed cords open due to the force of airflow during exhalation. In adults, bilateral vocal cord paralysis is most often a consequence of neck surgery or translaryngeal tracheal intubation, but can also be a consequence of a broad spectrum of neurologic disorders. (See "Hoarseness in adults", section on 'Neurologic dysfunction'.)

●Paradoxical vocal cord motion – Paradoxical vocal cord motion (PVCM) refers to inappropriate movement of the vocal cords (also called vocal folds), resulting in functional airway obstruction. This condition was previously referred to as the vocal cord dysfunction (VCD) syndrome. PVCM has been associated with psychosocial disorders, stress, exercise, perioperative airway and neurologic injury, gastroesophageal reflux, and irritant inhalational exposures. Patients often present with inspiratory and/or expiratory wheezing. Some patients have concomitant asthma or have been misdiagnosed with asthma. The diagnosis of PVCM is confirmed by laryngoscopy (sometimes following exercise) showing abnormal adduction of the true cords (during inspiration, throughout the respiratory cycle, or rarely just during expiration). The glottic aperture may be obliterated except for a posterior diamond-shaped passage. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

●Laryngeal stenosis – Laryngeal stenosis can result from irradiation, endotracheal intubation, or laryngeal trauma. (See "Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients", section on 'Laryngeal injury' and "Congenital anomalies of the larynx", section on 'Laryngeal atresia' and "Direct laryngoscopy and endotracheal intubation in adults".)

●Laryngocele – A laryngocele is an abnormal dilation of the laryngeal saccule, which rises vertically between the false cord, the base of the epiglottis, and the inner surface of the thyroid cartilage. Swelling may appear in the neck with a Valsalva maneuver. (See "Congenital anomalies of the larynx", section on 'Laryngoceles and saccular cysts'.)

●Tonsillar hypertrophy – The association of tonsillar hypertrophy with wheezing has largely been reported in children and adolescents [9].

●Goiter – A large goiter can cause compression of the extrathoracic airway (image 1). (See "Clinical presentation and evaluation of goiter in adults", section on 'Obstructive symptoms'.)

●Postnasal drip syndrome – Postnasal drip syndrome, due to a variety of rhinosinusitis conditions, was the most common cause of wheeze in a small series of 34 patients referred to a pulmonary outpatient clinic for evaluation of presumed difficult to control asthma (figure 1) [1]. Sixteen patients had a negative methacholine inhalation challenge and improved with treatment of postnasal drip. The expiratory wheeze associated with the postnasal drip syndrome is thought to originate in the extrathoracic airway, most likely at the level of the vocal cords [2,10].

Intrathoracic central airway causes of wheeze — A variety of processes can cause wheezing due to obstruction of the intrathoracic trachea and mainstem bronchi (table 3). These processes include the following:

●Tracheal stenosis – Tracheal stenosis can be caused by processes such as scarring from endotracheal intubation, prior tracheostomy, granulomatosis with polyangiitis, tracheobronchopathia osteochondroplastica, gastroesophageal reflux disease with aspiration, and cicatricial pemphigoid. (See "Malignant tracheal tumors" and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults".)

●Tracheal and bronchial tumors – The majority of tracheal tumors in adults are malignant with about 50 to 75 percent being squamous cell carcinomas, 10 to 15 percent adenoid cystic carcinomas, and the rest a variety of rarer tumors. Benign tracheal tumors include hemangioma, hamartoma, neurogenic tumors, granular cell tumor, and squamous papillomas. Bronchial tumors of the central airways include adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors, such as typical and atypical carcinoids and small cell carcinomas. Some extrathoracic carcinomas metastasize to the airway (eg, hypernephroma, breast, thyroid, colon, melanoma). (See "Malignant tracheal tumors" and "Clinical manifestations of lung cancer", section on 'Intrathoracic clinical manifestations' and "Pathology of lung malignancies" and "Overview of the initial treatment and prognosis of lung cancer", section on 'Histopathology'.)

●Respiratory papillomatosis – Respiratory papillomatosis, a consequence of neonatal human papillomavirus infection, typically presents in infancy, but may recur in adulthood. (See "Common causes of hoarseness in children", section on 'Papillomatosis'.)

●Tracheomalacia, tracheobronchomalacia, and hyperdynamic airway collapse – Tracheomalacia refers to focal or diffuse loss of structural integrity of the tracheal cartilage rings (figure 2). Hyperdynamic airway collapse (HDAC) involves invagination of the posterior membranous wall of the trachea into the tracheal lumen due to tissue redundancy or loss of the longitudinal smooth muscle fibers that support the posterior wall [11]. Congenital causes of TBM/HDAC include Mounier-Kuhn syndrome and Ehlers-Danlos syndrome; acquired causes include intrinsic or extrinsic pressure (eg, endotracheal tube balloons, mediastinal masses, or aneurysms), inflammation (eg, tobacco smoke, acid aspiration, asthma), and chronic infection (eg, cystic fibrosis). (See "Tracheomalacia in adults: Clinical features and diagnostic evaluation".)

●Relapsing polychondritis – Relapsing polychondritis is an immune-mediated condition associated with inflammation of cartilaginous structures. Involvement of the larynx, trachea, and bronchi can lead to areas of stenosis (eg, subglottic stenosis) or loss of cartilaginous support (tracheobronchomalacia) with dynamic laryngeal collapse during forced inspiration and/or tracheal collapse during expiration. (See "Clinical manifestations of relapsing polychondritis", section on 'Large airway involvement' and "Diagnostic evaluation of relapsing polychondritis".)

●Tracheobronchial amyloid – Tracheobronchial amyloid is a rare, localized form of amyloidosis that can cause plaques in the central airways and resultant airflow obstruction [12-14]. (See "Overview of amyloidosis".)

●Mucus plugs – Mucus plugs can cause intermittent airway obstruction in patients with pneumonia, non-cystic fibrosis bronchiectasis, cystic fibrosis, asthma, allergic bronchopulmonary aspergillosis, or bronchocentric granulomatosis. When inspissated mucus plugs are seen on chest radiograph as v- or y-shaped or cluster-of-grapes densities and/or lead to airway collapse or pneumonia, they are referred to as mucoid impactions of the bronchi [15].

●Vascular rings and aneurysms – Vascular rings (eg, double aortic arch, right aortic arch with aberrant left subclavian artery) and aneurysms can cause extrinsic tracheal compression and dyspnea. (See "Vascular rings and slings".)

●Mediastinal mass – Mediastinal masses that cause extrinsic compression of the airway (eg, thymoma, germ cell tumors, lymphoma), lymphadenopathy (eg, sarcoid), or substernal goiter can result in wheezing. (See "Clinical presentation and evaluation of goiter in adults", section on 'Obstructive symptoms'.)

●Herpes simplex virus (HSV-1) tracheobronchitis – While tracheobronchitis due to HSV-1 is a well-recognized finding in patients with burns, debilitation, or immunosuppression, it can also present with wheezing and bronchoconstriction in immunocompetent patients [16]. Skin and oral mucosal lesions heighten suspicion for HSV-1 but may be absent. Bronchoscopic examination of the airway reveals erythematous, friable tracheal and/or bronchial mucosa. HSV polymerase chain reaction (PCR) or viral culture can confirm the diagnosis.

Although uncommon, particularly in immunocompetent patients, HSV-1 tracheobronchitis is important to consider, as antiviral therapy may be beneficial [16,17]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Respiratory tract infections' and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

Intrathoracic lower airway causes of wheeze — Wheezing in asthma and COPD is largely due to airway narrowing by mucosal inflammation, bronchial smooth muscle constriction, and intraluminal secretions (table 4). Diseases such as reactive airways dysfunction syndrome, infectious bronchitis, and infectious bronchiolitis can also cause diffuse or scattered airflow limitation and wheeze.

●Bronchiectasis due to recurrent infections or parenchymal fibrosis with traction – Wheezing in patients with non-cystic fibrosis bronchiectasis and cystic fibrosis can be caused by secretions in the airways, and thus come and go, or be due to airway collapse from scarring and loss of cartilaginous support (image 2). (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

●Bronchiolitis ─ Adults with acute bronchiolitis due to respiratory syncytial virus infection can present with wheezing, although lower respiratory tract symptoms are less common in adults than children. Patients frequently have concomitant symptoms of fever, coryza, rhinorrhea, and conjunctivitis. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Older children'.)

●Bronchiolitis obliterans – Bronchiolitis obliterans may develop as a result of viral infection, rheumatic disease, toxic exposures, or graft-versus-host-disease (eg, post lung transplant or hematopoietic cell transplant). Wheezes and/or end-inspiratory squeaks may be heard. (See "Overview of bronchiolar disorders in adults" and "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Pulmonary complications after allogeneic hematopoietic cell transplantation: Causes", section on 'Airflow obstruction and bronchiolitis obliterans'.)

●Cardiac asthma – Episodic wheezing and dyspnea are occasionally described in patients with heart failure in the absence of asthma or COPD. It is thought that vascular congestion and perivascular edema within the bronchovascular bundles cause narrowing of the bronchi and thereby wheezing. (See "Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)

●Carcinoid tumors – Carcinoid tumors can cause a focal wheeze via obstruction of the airway or diffuse wheezes due to release of neuropeptides that cause bronchoconstriction as part of the carcinoid syndrome. Carcinoid syndrome due to bronchial carcinoid tumors is rare and usually associated with large tumors (>5 cm). (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging".)

●Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) – This is a rare disease that occurs most commonly in nonsmoking, middle-aged women. It should be considered in patients with wheezing and shortness of breath in patients with severe airflow obstruction not due to asthma or COPD who have high-resolution computed tomography (HRCT) scans showing mosaic attenuation due to constrictive bronchiolitis and small (4 to 10 mm) randomly distributed pulmonary nodules. This condition also is considered a precursor of peripheral carcinoid tumors [18]. (See "Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis" and "Pathology of lung malignancies", section on 'DIPNECH'.)

●Occupational causes of nonasthmatic wheeze – Farmers with silo-filler's disease due to inhalation of a high concentration of nitrogen dioxide can develop acute lung injury, sometimes associated with wheezing. Wheezing has also been reported in arc welders.

●Parasitic infection ─ Parasitic infections, such as Ascaris, Strongyloides, and/or filaria, in patients who visited or reside in endemic areas can lead to wheezing from visceral larva migrans (eg, Ascaris lumbricoides, hookworms, and Strongyloides stercoralis) or the burden of bloodborne microfilaria. Peripheral blood eosinophilia is common. (See "Overview of pulmonary eosinophilia", section on 'Helminth infections'.)

●Reactive airways disease syndrome – Reactive airways disease syndrome is considered a form of asthma, in which inhalation of a high concentration of an irritant causes nonimmunologic provocation of prolonged bronchial hyperresponsiveness. (See "Irritant-induced asthma".)

●Airway distortion – Diseases such as sarcoidosis and tuberculosis can cause sufficient lung parenchymal scarring to result in airway distortion and wheezing (image 3).

●Focal wheeze – A number of localized lower airway processes can cause focal wheezing, including a foreign body lodged in a bronchus, bronchial tumors, extraluminal compression (eg, lymphadenopathy, bronchogenic cyst), and congenital anomalies (eg, tracheal bronchus).

EVALUATION OF ACUTE WHEEZE AND RESPIRATORY DISTRESS — Our first step in evaluating a patient with wheezing is to determine the severity of respiratory compromise and the rapidity of worsening of any associated shortness of breath. For patients with rapid onset of respiratory distress associated with wheezing or stridor, the key initial steps are to ensure adequate oxygenation and ventilation based on pulse oximetry and arterial blood gas measurement. Supplemental oxygen is administered, and a rapid assessment made to determine the most likely cause. If asthma and chronic obstructive pulmonary disease (COPD) are likely, nebulized bronchodilator treatment is immediately given. If there is evidence of anaphylaxis, subcutaneous epinephrine should be given.

For patients with impending respiratory failure and suspicion of central airway obstruction (eg, due to stridor, tachypnea, lack of response to inhaled bronchodilator), endotracheal intubation by an experienced clinician may be necessary prior to a diagnostic evaluation if the initial measures have failed to improve the situation. If endotracheal intubation cannot be performed immediately, inhalation of a helium-oxygen mixture with a helium concentration of at least 40 percent may allow temporary stabilization of respiratory status. (See "Physiology and clinical use of heliox", section on 'Clinical applications'.)

For severe tracheal obstruction, use of an open ventilating rigid bronchoscope may be necessary. At the time of intubation, the larynx and vocal folds are examined for evidence of mass or paralysis. After intubation, the intrathoracic airway can be examined by flexible bronchoscopy through the endotracheal tube. Resolution of wheeze with intubation suggests that the area of obstruction is in the upper airway and may be extrathoracic. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Follow-up'.)

For patients not needing emergent intubation, a high resolution chest computed tomography (CT) with three-dimensional airway reconstruction can help identify and characterize any central airway obstruction. Direct visualization of the airway is often needed to diagnose the specific cause. The diagnosis and management of central airway obstruction are discussed separately. (See 'Imaging' below and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults", section on 'Follow-up'.)

Paroxysmal vocal cord dysfunction can sometimes present with acute respiratory distress and stridor, but does not require intubation. The management of these patients is discussed separately. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Acute management'.)

EVALUATION OF STABLE PATIENTS WITH WHEEZE — When evaluating patients who are not in respiratory distress, the selection of diagnostic tests is directed by the clinical suspicion for a given diagnosis based on the history and physical examination (table 2 and table 3 and table 4). For most patients, the initial evaluation will include pulmonary function testing and a conventional chest radiograph. Based on knowledge of the differential diagnostic possibilities, especially those that have been shown to be the most common, the history, physical examination, lung function studies, chest imaging, and direct visualization are used to narrow down the possibilities (table 1). The severity of respiratory impairment guides the sequence, selection, and location of diagnostic testing.

History — The history is directed towards eliciting symptoms and disease patterns that distinguish the various conditions (other than asthma or chronic obstructive pulmonary disease [COPD]) that can cause wheezing.

●Asthma should be considered likely when patients present with episodic wheezing and other symptoms, such as cough and dyspnea, that respond favorably to conventional asthma medications (eg, inhaled bronchodilators). However, partial clinical improvement after bronchodilators is not always indicative of asthma. (See "Asthma in adolescents and adults: Evaluation and diagnosis".)

●Incomplete or absent response to conventional asthma medications should raise the possibility of wheezing conditions other than asthma [19-21].

●Historical findings that may suggest that wheezing is NOT due to asthma or COPD include a history of sore throat, hoarseness, heartburn, sour taste and regurgitation, flushing, foreign body aspiration, hemoptysis, and peripheral edema. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Approach to diagnosis and evaluation of acute decompensated heart failure in adults", section on 'Clinical manifestations'.)

●The onset and rate of progression of symptoms may be helpful; foreign body aspiration often has an acute onset of symptoms, while a goiter compressing the airway or endobronchial tumor typically cause slowly progressive dyspnea.

●A history of neck or thyroid surgery may direct attention to possible vocal cord paralysis. (See "Surgical management of hyperthyroidism", section on 'Complications' and "Overview of the management of postoperative pulmonary complications".)

●Prior intubation raises concern for possible vocal fold trauma or paralysis, tracheal stenosis, or tracheomalacia.

●The combination of dyspnea, wheeze, intractable (often barking) cough to the point of syncope, and recurrent pulmonary infections is typical of tracheobronchomalacia and hyperdynamic airway collapse. (See 'Intrathoracic central airway causes of wheeze' above.)

●Cigarette smoking more than 10 pack years increases the possibility that wheezing is due to COPD, but also increases the risk of other causes of wheeze such as laryngeal or bronchogenic cancer.

●The development of respiratory symptoms (eg, wheeze, dyspnea, cough) in the minutes or hours after a single accidental inhalation of a high concentration of irritant gas, aerosol, or smoke raises the possibility of reactive airways dysfunction syndrome (RADS). (See "Irritant-induced asthma", section on 'Clinical manifestations'.)

●Wheezing associated with a chronic or recurrent cough productive of purulent sputum may suggest bronchiectasis. (See "Clinical manifestations and diagnosis of bronchiectasis in adults".)

Physical examination — Physical examination should initially focus on vital signs, assessment of oxygen saturation, and evidence of respiratory distress (eg, tachypnea, diaphoresis, intercostal retractions, use of accessory muscles). Chest and neck auscultation are used to differentiate stridor from expiratory wheezing or wheezing in both phases of the cycle.

Acoustic characteristics of wheeze — Wheezes are defined as high-pitched, continuous sounds lasting for at least 250 msec. They generally are louder than normal breath sounds. The acoustic characteristics of the wheeze, such as timbre and the timing of the wheeze in the respiratory cycle, may provide some helpful information about potential causes, although none of these characteristics reliably distinguishes asthma from other conditions.

●Polyphonic versus monophonic wheezing – The timbre of the wheeze may provide a clue to its location [6,7].

•A polyphonic wheeze, consisting of multiple musical notes beginning and ending at the same time is typically produced by dynamic compression of the large, more central airways.

•Monophonic wheezes, consisting of single musical notes, typically reflect disease in small airways and are suggestive of asthma, especially if multiple monophonic wheezes are heard. However, monophonic wheezes can also be produced by disorders involving the extrathoracic large airways. Stridor is also a monophonic sound, but its intensity over the upper airway and occurrence during inspiration help distinguish it from lower airway monophonic wheezing [6].

●Inspiratory versus expiratory wheezing – The timing of wheezing in the inspiratory or expiratory phases of the respiratory cycle sometimes helps to locate wheezing to an extra or intrathoracic source, but not always.

Expiratory wheezing, appreciated either by history or physical examination, is neither sensitive nor specific for asthma [1,22-24]. As an example, symptomatic asthma can present without wheeze, while wheezing associated with other conditions can mimic asthma. In a small prospective study that evaluated patients referred to a pulmonary clinic because of wheezing, the physical finding of scattered expiratory monophonic wheezes was predictive of asthma only 43 percent of the time [1].

Inspiratory wheezing on physical examination is neither a sensitive nor a specific sign of extrathoracic upper airway disease or obstruction. Inspiratory wheezing heard over the lungs frequently accompanies expiratory wheezing during acute asthma; in some patients with asthma, wheezing may only be heard during inspiration [22]. However, stridor (monophonic inspiratory wheeze heard loudest over the neck) is a worrisome sign of upper airway obstruction. When a patient presents with stridor, urgent airway evaluation is indicated and should be performed by clinicians with substantial experience in airway management. Upper airway obstruction due to tumor or stenosis with an airway diameter <8 mm usually causes dyspnea on exertion; when the diameter is <5 mm, stridor is usually evident [25,26]. (See "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "Physiology and clinical use of heliox".)

Location of the wheeze — In a given patient, certain characteristics may help identify the area of narrowing that is giving rise to the sound, such as whether wheezes are focal or diffuse, or are heard loudest over the anterior neck or the posterior or anterior chest. However, transmission of the wheeze sound is better through airways than through lung parenchyma and the chest wall, so wheezes may sound louder over the anterior neck than the chest wall even though they originate in the lower airway [27]. A focal wheeze that is persistently located in one area may be due to abnormalities such as a foreign body in a segmental airway, endobronchial tumor, or a congenital anomaly (eg, tracheal bronchus). (See 'Intrathoracic lower airway causes of wheeze' above.)

Extrapulmonary findings — Tonsillar hypertrophy is typically visible on oral exam. Occasionally, a clue to the cause of airway obstruction is found on physical examination of the neck, when lymphadenopathy, thyroid enlargement, or a surgical scar is identified. Inflammation of the cartilage of the nose or ears may alert the clinician to possible airway narrowing or collapsibility due to relapsing polychondritis. Stigmata of rheumatoid arthritis might suggest bronchiolitis or cricoarytenoid joint arthritis with airway obstruction.

Pulmonary function testing — The initial pulmonary function test for evaluating a wheeze in stable patients is spirometry before and after administration of inhaled bronchodilator. For patients who will go to a pulmonary function laboratory for spirometry, it is helpful to obtain an inspiratory and expiratory flow volume loop at the time of spirometry.

Spirometry pre and post bronchodilator — For patients with expiratory airflow limitation on spirometry that reverses completely with inhaled bronchodilator, the diagnosis is most likely asthma. COPD is diagnosed in adults with a history of cigarette smoking or exposure to indoor smoke and expiratory airflow obstruction that persists despite inhaled bronchodilator. (See "Pulmonary function testing in asthma" and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Diagnosis' and "Chronic obstructive pulmonary disease: Diagnosis and staging", section on 'Diagnosis'.)

Flow volume loop — For patients who do not meet criteria for asthma or COPD or do not respond to a trial of bronchodilator and anti-inflammatory medication, a careful examination of the flow volume loop is in order. The upper airway is divided into intra and extrathoracic components by the thoracic inlet, which is about 1 cm above the suprasternal notch on the anterior chest. During the respiratory cycle, the intrathoracic airway diameter is affected by changes in pleural pressures across the airway (figure 3B), while the extrathoracic airway is more affected by changes in intraluminal pressure (figure 3A). Lesions that are fixed are not affected by these changes in pressure and affect flow during inspiration and expiration. Thus, the flow volume loop can be used to help determine whether airflow obstruction is caused by an intrathoracic or extrathoracic obstruction and also distinguish whether the obstructing lesion is variable or fixed (ie, the severity of obstruction changes during inspiration and expiration) based on the following features (see "Flow-volume loops"):

●Variable obstruction – It is possible to distinguish extrathoracic from intrathoracic upper airway lesions if the obstruction is variable (ie, the obstructing process responds to the normal transmural pressure changes). A variable extrathoracic obstruction (eg, vocal cord paralysis) is typically apparent only during a maximal inspiratory effort (figure 4 and figure 5 and figure 6). The maximal expiratory flow-volume curve and expiratory spirometry are usually normal in this setting, because the extrathoracic airway will be pushed open during expiration. In contrast, a variable intrathoracic obstruction (eg, distal tracheomalacia) is most apparent during maximal expiratory effort (figure 4), and spirometry reveals values consistent with expiratory airflow obstruction.

In addition to visual inspection of the graph, the ratio of inspiratory to expiratory flow rates can help distinguish variable extrathoracic from intrathoracic upper airway lesions [28]. Inspiratory flow rates are normally greater than expiratory flow rates when compared at lung volumes in the lower two-thirds of the vital capacity. When a variable extrathoracic lesion is present, inspiratory flow rates are lower than expiratory, such that the ratio of forced inspiratory flow at 50 percent of vital capacity (FIF50)/forced expiratory flow at 50 percent of vital capacity (FEF50) is less than one. (See "Flow-volume loops", section on 'Variable extrathoracic obstruction'.)

●Fixed lesions – It is difficult to localize fixed upper airway obstruction to an extrathoracic (eg, laryngeal tumor) or intrathoracic (eg, tracheal stenosis due to well-formed scar) location because fixed lesions do not allow the airway to respond to normal transmural pressure changes (figure 4). However, fixed central airway obstructions give the flow-volume loop a characteristic box shape (flow limitation during inspiration and expiration) that suggests the obstruction is in the large rather than small airways. Airflow is uniformly impeded during inspiration and expiration, causing flattening of both the maximum inspiratory and expiratory curves because there is no difference between the amount of narrowing in inspiration and expiration [29].

●Tracheal lesions – In general, spirometric values cannot distinguish large from small intrathoracic airway disease, because the forced expiratory volume in one second (FEV₁) and FEV₁/forced vital capacity (FVC) are reduced in both situations. However, sometimes variable tracheal obstruction may be manifest as a horizontal line in the middle portion of a maximum expiratory effort (instead of the normal gradual descent), as airflow is likely to remain constant when there is only one site of obstruction (figure 4 and figure 6). This sign is helpful when present but is not always detected.

●Mainstem bronchial obstruction – Unilateral mainstem bronchial obstruction can cause several different patterns on the flow-volume loop, including restriction (when occlusion is complete), mixed obstruction and restriction, a biphasic expiratory loop, or flattening of the initial portion of the expiratory flow curve. (See "Flow-volume loops", section on 'Mainstem bronchial obstruction'.)

The results of the flow volume loop can help guide the next steps in the evaluation. When intrathoracic obstruction of the central airway is suspected, imaging studies (eg, multidetector chest computed tomography [CT]) generally precede direct visualization. As an example, variable central obstruction might lead to inspiratory and expiratory CT imaging to look for tracheomalacia. (See 'Imaging' below.)

On the other hand, when the flow volume loop suggests extrathoracic obstruction, laryngoscopy or bronchoscopy is often the next step. (See 'Direct visualization' below.)

Bronchoprovocation challenge — For patients with a normal flow volume loop in whom asthma and reactive airways dysfunction syndrome (RADS) have not been definitively excluded, bronchoprovocation challenge testing can be helpful. A negative methacholine challenge test in a symptomatic patient not on bronchodilator or anti-inflammatory medication (eg, inhaled glucocorticoids or antileukotriene agents) is strong evidence against asthma or RADS. (See "Bronchoprovocation testing".)

Performing flow volume loops (instead of expiratory spirometry alone) during bronchoprovocation challenge testing may provide a clue to possible paradoxical vocal cord motion (PVCM). While patients with PVCM may develop flattening of the inspiratory portion of the flow volume loop in response to pharmacologic bronchoprovocation challenge, direct laryngoscopy is required to confirm the diagnosis. (See 'Extrathoracic upper airway causes of wheeze' above and "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Evaluation'.)

Gas transfer — The pulse oxygen saturation is routinely obtained in patients complaining of dyspnea. Other tests of gas transfer such as the diffusing capacity (DLCO) and the alveolar-arterial oxygen tension difference (P[A-a]O₂ gradient) are usually reserved for patients with a low pulse oxygen saturation, dyspnea that is greater than would be predicted by the degree of wheezing, or abnormal lung parenchyma on imaging studies.

Central causes of airway obstruction usually do not impair the transfer of oxygen and carbon dioxide at the alveolus. Thus, the P(A-a)O₂ gradient on arterial blood gases typically remains normal. In fact, a normal P(A-a)O₂ gradient is good evidence in favor of an upper airway cause of wheezing in a patient with wheezing and respiratory distress. On the other hand, an increased P(A-a)O₂ gradient or a reduced DLCO suggest small airway disease or lung parenchymal involvement (eg, bronchiolitis, bronchiectasis, COPD, lymphangioleiomyomatosis, proximal airway obstruction with atelectasis). (See "Arterial blood gases", section on 'Interpretation' and "Diffusing capacity for carbon monoxide", section on 'Interpretation'.)

Imaging — A conventional chest radiograph is appropriate in most adults with new onset or refractory wheezing. Conventional chest radiographs, with particular attention to the trachea and central airways, should be performed in all patients with the combination of wheezing, acute respiratory distress, and lack of response to inhaled bronchodilator therapy. In addition, a chest radiograph is obtained in patients with a focal persistent wheeze or persistent/recurrent wheezing that is not clearly due to asthma or COPD.

The conventional chest radiograph is generally insensitive for central airway lesions, although it can sometimes identify central airway narrowing involving long segments of the trachea (eg, relapsing polychondritis, tracheobronchopathia osteochondroplastica, amyloidosis, granulomatosis with polyangiitis, tumors). Narrowing of short segments of the trachea (eg, malignant and benign tumors, extrinsic compression, and granulomatous processes) is difficult to identify on the conventional chest radiograph. Similarly, the chest radiograph is not a good screening test for bronchiectasis or bronchiolitis in adults, although increased bronchovascular markings and "tram tracks" may be seen in bronchiectasis. The imaging characteristics of tracheal lesions, bronchiectasis, and bronchiolitis are discussed separately. (See "Radiology of the trachea" and "Evaluation of diffuse lung disease by conventional chest radiography", section on 'Bronchial' and "Overview of bronchiolar disorders in adults", section on 'Chest imaging'.)

Additional imaging studies of the chest, such as computed tomography (CT), high-resolution CT, or dynamic CT are ordered based on the results of the chest radiograph and pulmonary function tests. Chest CT with contrast can identify vascular rings, aneurysms of the major vessels, mediastinal masses, or lymphadenopathy that compress the trachea extrinsically. Axial CT can often identify long segments of tracheal stenosis, but short segments of tracheal stenosis can be missed. Two and three dimensional reconstruction of the central airway images from high-resolution multidetector CT (MDCT) has been reported to identify airway lesions missed on standard chest and tracheal CT images [30]. (See "Principles of computed tomography of the chest", section on 'Two-dimensional and three-dimensional rendering'.)

Paired end-inspiratory and expiratory MDCT views (dynamic CT) of the trachea can be used to detect tracheomalacia and hyperdynamic airway collapsibility. Tracheal collapsibility is assessed based on changes in the shape and cross-sectional area of the trachea between full inspiration and forced exhalation. Flattening of tracheal rings due to tracheomalacia gives a crescent shape to the trachea, while hyperdynamic airway collapse has intact tracheal rings with bulging of the posterior tracheal wall into the airway lumen (figure 2). In general, the cross-sectional area of the trachea is measured at a defined level (eg, 1 cm above the main carina and 1 cm above the aortic arch) to allow comparison between full inhalation and exhalation. A reduction in cross-sectional area of 50 percent or greater during normal, nonforced breathing is consistent with tracheomalacia [30]. However, a broad range of forced expiratory tracheal collapse such as during the expiratory phase of coughing has been noted among normal individuals. (See "Tracheomalacia in adults: Clinical features and diagnostic evaluation", section on 'Dynamic airway CT'.)

High-resolution CT of the smaller airways and lung parenchyma can detect bronchiectasis and sometimes will identify mosaic ground glass attenuation suggestive of constrictive bronchiolitis. A focal area of bronchiectasis may reflect recurrent aspiration and lead to evaluation for impaired swallowing or gastric reflux with aspiration. (See "High resolution computed tomography of the lungs", section on 'Airways diseases'.)

Direct visualization — Direct visualization of the airway is often necessary to make a definitive diagnosis of the various causes of wheeze suspected on the basis of pulmonary function testing and imaging. At the time of visualization, biopsies can be obtained of intraluminal masses and plaques (eg, tumor, amyloid, respiratory papillomatosis).

●When the flow volume loop suggests extrathoracic obstruction, laryngoscopy is often the next step. Laryngoscopy can identify abnormalities such as vocal fold paralysis, paradoxical vocal cord motion (figure 7), and laryngeal masses. (See "Hoarseness in adults" and "Inducible laryngeal obstruction (paradoxical vocal fold motion)", section on 'Laryngoscopy'.)

●Flexible or rigid bronchoscopy may be necessary to confirm a diagnostic suspicion of a tracheal or bronchial mass, foreign body, or tracheomalacia. During bronchoscopy, biopsy samples can be obtained and foreign bodies can be removed. The decision about whether to use flexible or rigid bronchoscopy usually depends on the anticipated location and severity of tracheal lesions, and also whether a therapeutic intervention (eg, stent, laser resection) is planned. (See "Flexible bronchoscopy in adults: Indications and contraindications" and "Flexible bronchoscopy in adults: Overview" and "Rigid bronchoscopy: Intubation techniques" and "Bronchoscopic laser in the management of airway disease in adults".)

SUMMARY AND RECOMMENDATIONS

●Differential diagnosis of wheezing – While asthma and chronic obstructive pulmonary disease (COPD) are the most common causes of wheezing, a variety of other conditions can produce airflow obstruction, and thereby expiratory and/or inspiratory wheezing (table 1 and table 2 and table 3 and table 4). (See 'Causes' above.)

●Initial assessment and treatment of wheezing patients in respiratory distress – For patients with rapid onset of respiratory distress associated with wheezing or stridor, the key initial steps are to ensure adequate oxygenation and ventilation based on pulse oximetry and arterial blood gas measurement, followed by a rapid assessment made to determine the most likely cause. (See 'Evaluation of acute wheeze and respiratory distress' above.)

•Suspected asthma or COPD – If asthma and COPD are likely, nebulized bronchodilator treatment is immediately given.

•Suspected anaphylaxis – If there is evidence of anaphylaxis, subcutaneous epinephrine should be given immediately.

•Suspected central airway obstruction – For patients with impending respiratory failure (ie, impaired oxygenation by pulse oximetry, increased arterial tension of carbon dioxide), endotracheal intubation by an experienced clinician should precede a diagnostic evaluation. If endotracheal intubation cannot be immediately performed, inhalation of a helium-oxygen mixture may provide temporary stabilization of respiratory status. For severe tracheal obstruction, use of an open ventilating rigid bronchoscope may be necessary. In these patients, the diagnostic evaluation proceeds concomitantly with steps to provide adequate ventilation. (See 'Evaluation of acute wheeze and respiratory distress' above and "Clinical presentation, diagnostic evaluation, and management of malignant central airway obstruction in adults" and "Management of non-life-threatening, nonmalignant subglottic and tracheal stenosis in adults" and "Physiology and clinical use of heliox".)

●Clinical manifestations, in stable patients – For patients with a stable respiratory status, a careful history and physical examination may narrow down the potential causes of wheeze not due to asthma or COPD (table 2 and table 3 and table 4). (See 'History' above and 'Physical examination' above.)

●Pulmonary function testing – For most stable patients, the initial pulmonary function test is spirometry before and after inhaled bronchodilator. For patients who do not meet criteria for asthma or COPD or do not respond appropriately to a trial of bronchodilator and anti-inflammatory medication, a careful examination of the flow volume loop is in order. The flow volume loop can be used to help determine whether the obstruction is fixed or variable and whether it is likely to be intrathoracic or extrathoracic (figure 3A-B). (See 'Pulmonary function testing' above.)

●Imaging studies – Imaging of the neck and chest (eg, conventional chest and neck radiographs, computed tomography [CT], three-dimensional reconstruction CT, end-inspiratory and expiratory CT) plays an important role in the evaluation of wheezing due to structural lesions in the central airways. (See 'Imaging' above.)

●Direct visualization of the airways – Direct visualization of the airways is often necessary to make a definitive diagnosis of the causes of wheeze that are suspected on the basis of pulmonary function testing and imaging. At the time of visualization, biopsies can be obtained of intraluminal masses and plaques (eg, tumor, amyloid, respiratory papillomatosis). (See 'Direct visualization' above.)