Evaluation of wheezing in infants and children

INTRODUCTION — Wheezing is a common presenting symptom of respiratory disease in infants and children. One in three children experience at least one acute wheezing illness before the age of three years [1,2]. A nationwide survey performed in the United States between 1988 and 1994 showed that the prevalence for wheezing amongst 2 to 3 year olds was 26 percent and amongst 9 to 11 year olds was 13 percent [3-5]. Subsequent reports continue to show similar prevalence. In a 2007 survey in the US and Europe, a total of 9490 children aged one to five years were screened for respiratory symptoms [5]. Overall, 3077 (32 percent) reported recurrent cough, wheeze, or breathlessness in the preceding six winter months. The prevalence of these symptoms varied from 29 percent in Northern Europe to 48 percent in Southern Europe. The overall prevalence in the US was 27 percent. A large worldwide study looking at older children showed a global prevalence of wheezing of 11.6 percent in children aged 6 to 7 years and 13.7 percent in children between 13 to 14 years of age [4].

Wheezing may be either a benign, self-limited process or the presenting symptom of a significant respiratory disease. The role of the treating clinician is to try to reach the most likely diagnosis as quickly and efficiently as possible so that therapy, if necessary, can be instituted and caregiver concerns can be addressed.

A diagnostic approach to wheezing in childhood is presented in this topic review. Other topics that cover related areas include:

●An overview of recurrent wheezing phenotypes in children (see "Wheezing phenotypes and prediction of asthma in young children")

●The diagnosis and management of childhood asthma (see "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies")

●Virus-induced wheezing (see "Role of viruses in wheezing and asthma: An overview" and "Treatment of recurrent virus-induced wheezing in young children")

●The emergency evaluation of children with acute respiratory distress (see "Acute respiratory distress in children: Emergency evaluation and initial stabilization")

DEFINITION AND PHYSIOLOGY OF WHEEZING — Wheezing is probably the most easily recognized adventitious sound [6]. Its long duration, typically more than 100 msec, allows its musical quality to be discerned by the human ear. In sound analysis, the wheeze appears as sinusoidal oscillations with sound energy in the range of 100 to 1000 Hz and with harmonics that exceed 1000 Hz on occasion (figure 1) [7]. A wheeze is produced by the oscillation of opposing walls of an airway narrowed almost to the point of closure [6]. It can be high pitched or low pitched. The pitch of an individual wheeze is determined not by the diameter of the airway but by the thickness of the airway wall, bending stiffness, and longitudinal tension [8]. A wheeze can consist of single or multiple notes and occur during inspiration or expiration or can be biphasic. Some experts distinguish between wheezes and rhonchi based upon the dominant frequency, or pitch, of the sound. Wheezes have a dominant frequency greater than 400 Hz, whereas rhonchi are of lower frequency, approximately 150 Hz, and lower pitch, which is responsible for its resemblance to the sound of snoring on auscultation [6,9,10]. However, the clinical significance of this distinction, if any, is not well defined [9].

Wheezes can originate from airways of any size throughout the proximal conducting airways. Wheezing requires sufficient airflow to generate airway oscillation and produce sound in addition to narrowing or compression of the airway. Thus, the absence of wheezing in a patient who presents with acute asthma may be an ominous finding, suggesting impending respiratory failure.

Wheezing caused by a fixed large or central airway obstruction or tracheomalacia tends to be low in pitch and has a constant acoustic character throughout the lung (homophonous wheezing) but varies in loudness depending upon the distance from the site of obstruction. In contrast, the degree of narrowing varies from place to place within the lung in the setting of small airway obstruction. As a result, the sounds generated also vary in quality and acoustic character and are described as heterophonous wheezes [11].

Stridor refers to a monophonic sound that is loudest over the anterior neck. Stridor can be heard during inspiration, expiration, or throughout the respiratory cycle, depending on the location and severity of air flow limitation. In general, inspiratory stridor is prominent in the setting of extrathoracic obstruction, whereas expiratory stridor suggests intrathoracic obstruction, and, if the obstruction is fixed and severe, then stridor can be biphasic regardless of its location. (See "Assessment of stridor in children".)

CAUSES — The most likely diagnosis in children with recurrent wheezing is asthma, regardless of the age of onset, evidence of atopic disease, precipitating causes, or frequency of wheezing [12]. However, other diseases can present with wheezing in infancy and childhood, and patients with asthma may not wheeze. The differential diagnosis of wheezing includes a variety of congenital and acquired conditions (table 1).

Wheezing can be divided clinically according to the acuity of its onset and the mechanism of airway narrowing. In addition to asthma, new-onset acute wheezing suggests infection or sudden airway narrowing, whereas chronic or recurrent wheezing may be caused by congenital abnormalities, cardiac disease, aspiration syndromes, impaired immunologic defenses, or underlying pulmonary disease. The age of onset of wheezing can also help determine the etiology. Certain diseases most commonly present in infancy, while other are seen more often in older children (table 1).

Acute wheezing (hours to days) — In addition to acute exacerbations of asthma, acute onset of wheezing in a child is most often caused by an infectious process or foreign body aspiration (FBA).

Infection — The most common cause of acute wheezing in infants under two years of age is viral bronchiolitis, usually due to infection with respiratory syncytial virus (RSV). Rhinovirus and paramyxoviruses, including parainfluenza virus and metapneumovirus, can also result in wheezing. A typical history is a prodrome of rhinorrhea, cough, and intermittent fever followed by wheezing and tachypnea. Physical examination usually reveals nasal congestion, tachypnea, increased work of breathing, and polyphonic wheezes throughout the lungs. (See "Bronchiolitis in infants and children: Clinical features and diagnosis" and "Human metapneumovirus infections" and "Parainfluenza viruses in children", section on 'Clinical presentation' and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Clinical manifestations'.)

Wheezing can also occur with laryngotracheobronchitis. Less commonly, acute wheezing is associated with atypical pneumonia such as Mycoplasma pneumonia, especially in older children. Patients with bacterial tracheitis can also have wheezing, but other symptoms such as toxic looking, high fever, and severe distress will typically guide the diagnosis. (See "Mycoplasma pneumoniae infection in children", section on 'Pneumonia'.)

Foreign body aspiration — FBA should be suspected in any patient who presents with wheezing of sudden onset, even in the absence of a clear history of a choking episode. In addition, FBA should be suspected in any child with a unilateral wheeze or unequal breath sounds. In children, unlike adults, the foreign body can lodge in any bronchus, without predilection for the right side. Patients can also present with chronic symptoms if FBA is not recognized in the acute setting. (See "Airway foreign bodies in children" and 'Structural causes' below.)

Esophageal foreign body also can present with acute wheezing secondary to compression of the airways. A history of feeding and swallowing difficulties and the presence of dysphagia are important clues to the diagnosis. (See "Foreign bodies of the esophagus and gastrointestinal tract in children".)

Chronic or recurrent wheezing — The differential diagnosis of chronic or episodic wheezing is broad and includes structural abnormalities of the tracheobronchial tree or other thoracic structures. Nonstructural causes of chronic wheezing include asthma, aspiration syndromes, bronchopulmonary dysplasia, vocal cord dysfunction, and other disorders (table 1).

Structural causes — Structural abnormalities, including anomalies of the tracheobronchial tree and vascular rings or slings, are among the most common etiologies for persistent wheezing that presents early in life (typically in the first few months) and are not responsive to asthma therapies.

●Anomalies of the tracheobronchial tree – Congenital tracheomalacia and bronchomalacia can present with noisy breathing early in life. Wheezing can present at birth but more commonly becomes apparent in the first two to three months after birth. The wheezing usually has a constant acoustic character throughout the lung but varies in loudness depending upon the distance from the site of obstruction and becomes more pronounced with activity or in the setting of upper respiratory tract infections. Other symptoms can include a croup-like cough or stridor, depending upon the location of the lesion. The severity can range from a thriving child with noisy breathing to a child with severe respiratory distress.

In a study of 124 children ages 7 to 14 months with poor response to asthma therapy, 46 percent of those children were found to have malacia of the central airways [13]. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula" and "Acute events in infancy including brief resolved unexplained event (BRUE)".)

Vascular rings or slings can cause compression and narrowing of large airways and may result in wheezing or stridor [14-17]. These include complete rings (eg, double and right aortic arches) and incomplete rings, also called slings (eg, pulmonary artery sling). (See "Vascular rings and slings".)

Signs and symptoms of congenital vascular compression of the airways commonly appear early in life. Biphasic stridor is a common sign in these patients, but wheezing, respiratory distress, recurrent respiratory infections, and apnea also may be presenting findings. Patients may also have symptoms related to esophageal compression by vascular structures, including feeding difficulty and vomiting.

Fistulas between the tracheobronchial tree and other anatomical structures can cause wheezing. Tracheoesophageal fistulae, including laryngotracheobronchial clefts, are the most common of these conditions. Some infants with rare H-type fistulas are not typically diagnosed in the immediate postnatal period. These infants can present with chronic cough and recurrent pneumonia as well as wheezing. Symptoms such as coughing and choking are increased with feeding. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula" and "Approach to chronic cough in children".)

●Mediastinal masses – Tumors, thymic lesions, bronchogenic cysts, angiomatous lesions, and enlarged lymph nodes can cause compression of the trachea or bronchi, resulting in chronic cough and persistent or progressive wheeze. The anatomic location of the mass within the mediastinum provides some clues to the underlying diagnosis (figure 2). (See "Overview of common presenting signs and symptoms of childhood cancer", section on 'Mediastinal masses' and "Approach to chronic cough in children".)

●Foreign body aspiration – FBA typically presents with the abrupt onset of wheezing. However, patients may present with chronic cough, wheezing, or postobstructive pneumonia if the diagnosis is not recognized initially and the foreign body is retained (algorithm 1). (See 'Foreign body aspiration' above and "Airway foreign bodies in children".)

●Cardiovascular disease – A range of cardiovascular diseases can present with wheezing:

•Cardiac conditions that result in pulmonary artery dilation, such as large left-to-right shunts (eg, ventricular septal defect [VSD], atrial septal defect [ASD], pulmonary artery stenosis, pulmonary hypertension, absent pulmonary valve) and/or left atrial enlargement (eg, mitral valve stenosis), can compress large airways and cause wheezing. In addition to compression of the mainstem bronchi by markedly enlarged central pulmonary arteries, compression of intrapulmonary bronchi by abnormally branching pulmonary arteries has been reported in patients with absent pulmonic valves [14,18]. (See "Pathophysiology of left-to-right shunts", section on 'Clinical manifestations'.)

•However, overcirculation and pulmonary venous congestion are probably the most common cardiac causes of wheezing. This can occur due to poor left ventricular function and, less commonly, due to pulmonary venous outflow obstruction. These conditions can result in distension of the pulmonary vascular bed, bronchiolar wall edema, increased airway resistance, and wheezing [12]. Inflammatory mediators such as transforming growth factor (TGF) beta may also play a part in airway remodeling. In addition, airway hyperactivity has been reported in patients with congestive heart failure [19]. Cardiac findings including cardiomegaly and murmurs may be absent in some infants with obstructed venous return; therefore, a high index of suspicion is required to make the diagnosis. As an example, wheezing was reported as the only presenting symptom in cases of isolated cor triatriatum [20]. (See "Epidemiology, pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults".)

Functional (nonstructural) causes — Functional causes of chronic or intermittent wheezing aside from asthma include aspiration syndromes, inducible laryngeal obstruction (ILO; historically known as paradoxical vocal fold movement [PVFM]), bronchopulmonary dysplasia, and rare disorders such as primary ciliary dyskinesia and bronchiolitis obliterans (BO).

Common causes of functional wheezing in children include:

●Aspiration syndromes – Aspiration syndromes are important and often unrecognized causes of recurrent wheezing in young children. In many cases, these patients are misdiagnosed with difficult-to-control asthma. Aspiration syndromes are associated with a variety of anatomic and functional disorders. FBA and aspiration associated with fistulas are reviewed above (see 'Foreign body aspiration' above and 'Structural causes' above). The two most common categories of functional disorders leading to aspiration are gastroesophageal reflux (GER) and swallowing disorders:

•GER seldom involves aspiration of large amounts of gastric contents. However, chronic microaspiration can cause significant mucosal edema and inflammation and may result in chronic cough and wheezing. Infants who take a bottle to bed are at increased risk of both wheezing and asthma during the first five years of life, probably because of recurrent microaspiration [21]. Children with GER do not always report symptoms of reflux, such as heartburn or vomiting, but may present with more subtle findings, including nocturnal symptoms, hoarseness, or recurrent croup. (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents".)

•Swallowing disorders related to neurologic or muscular dysfunction of the pharynx and/or larynx can result in weakness and impaired swallowing, incomplete closure of the glottis, depressed cough reflex, and recurrent episodes of aspiration. Anatomic abnormalities, such as laryngeal clefts and vocal cord paralysis, can also cause swallowing dysfunction leading to aspiration, which may be "silent" (ie, not associated with coughing or choking events). These infants may present with difficulty sucking or swallowing, drooling, fatigue, loss of interest in oral feeding, tachypnea, or apnea during feeding. The classic finding of coughing with feeding may be absent because of depression of the cough reflex caused by repeated stimulation of the receptors in the larynx and trachea. (See "Neonatal oral feeding difficulties due to sucking and swallowing disorders" and "Aspiration due to swallowing dysfunction in children".)

●Bronchopulmonary dysplasia – Bronchopulmonary dysplasia (BPD), also known as neonatal chronic lung disease or chronic lung disease of prematurity, is an important cause of respiratory illness in preterm newborns, particularly those with a birth weight less than 1250 grams. The etiology of BPD is multifactorial. Most patients have a history of neonatal respiratory distress syndrome. (See "Bronchopulmonary dysplasia (BPD): Clinical features and diagnosis".)

●Inducible laryngeal obstruction – Inappropriate upper-airway obstruction can be caused by adduction of the true vocal folds during inspiration, although false vocal folds and supraglottic tissue may also dynamically constrict the airway. ILO can be triggered by a variety of stimuli including exercise, stress, and others. Exercise-induced laryngeal obstruction (EILO) is ILO restricted to exercise. Most studies note a female predominance, but it is also documented in males. This condition is typically seen in older children, usually teenagers, and adults. The clinical presentation can range from signs mimicking asthma or croup to total upper airway occlusion [22]. The stridor resolves completely when the patient is asleep or immediately after endotracheal intubation or tracheotomy. Patients may complain of dyspnea, throat tightness, a choking sensation, dysphonia, and cough. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)" and "Exercise-induced laryngeal obstruction".)

Less common causes of wheezing in children include disorders leading to recurrent infection/bronchiectasis:

●Cystic fibrosis – Cystic fibrosis (CF) is the most common autosomal recessive disease among White populations, with a frequency of 1 in 2000 to 3000 livebirths. The usual presenting symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and elevated sweat chloride levels. Airway hyperreactivity is a common finding in CF patients. In one study of young children with CF (mean age 16 months), 50 percent had wheezing [23]. (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Respiratory tract involvement' and "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●Primary ciliary dyskinesia – Primary ciliary dyskinesia is a rare disease (prevalence 1 in 10,000 to 30,000 individuals) that typically presents with wet cough. However, some children may have associated wheezing. This diagnosis should be considered in patients who present with recurrent severe upper respiratory tract infections, suppurative otitis, and chronic sinusitis. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)".)

●Inborn errors of immunity – Recurrent viral infections of the lower respiratory tract can present with intermittent episodes of wheezing. In addition, chronic and/or recurrent pyogenic lung infections in patients with inborn errors of immunity (also known as "primary immunodeficiencies") can result in bronchiectasis, permanent tissue destruction, and chronic pulmonary disease if unrecognized or inadequately treated. Wheezing is due to damaged airways in these patients. Immunodeficiency syndromes, especially those involving immunoglobulin G (IgG) and/or immunoglobulin A (IgA) deficiency, are among the most common abnormalities that can cause recurrent bacterial respiratory infections. Both the upper and the lower respiratory tract can be involved and may result in recurrent otitis, pharyngitis, or pneumonia. Complement deficiency, T cell abnormalities, and defects in leukocyte phagocytic and chemotactic activity can result in recurrent upper and lower respiratory tract infection but are less common. (See "Pulmonary complications of primary immunodeficiencies" and "Approach to the child with recurrent infections" and "Laboratory evaluation of the immune system".)

●Bronchiolitis obliterans – BO is a rare disease caused by epithelial injury to the lower respiratory tract that results in obstruction and obliteration of the distal airways [24]. BO may occur after chemical, infectious, or immunologic injury but can be idiopathic. Postviral bronchiolar damage is the most common cause of BO in the nontransplant population. Adenovirus is the most likely virus to cause BO, but other pathogens, including influenza, measles, and Mycoplasma, have also been identified in association with BO [25].

BO is a prominent manifestation of chronic lung transplant rejection and can occur in children following hematopoietic cell transplantation [26-28]. Patients with BO usually present with tachypnea, dyspnea, persistent cough, and wheezing that is unresponsive to bronchodilator therapy. Hypoxemia is present in more severe cases, either at rest or only with exercise and/or during sleep. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome" and "Pulmonary complications of primary immunodeficiencies", section on 'Bronchiolitis obliterans' and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

EVALUATION — Clinical history and physical examination often allow accurate diagnosis. A therapeutic trial of bronchodilators is appropriate to evaluate reversible airway obstruction. Most patients who respond will have asthma. However, a bronchodilator response can also be seen with other conditions that may lead to inflammation and bronchoconstriction, such as bronchopulmonary dysplasia (BPD), cystic fibrosis (CF), and aspiration. Radiographic examination, pulmonary function testing (PFT), bronchoscopy, sweat chloride concentration, and selective laboratory studies are helpful tools in establishing the underlying etiology of wheezing when used appropriately [12,29].

Criteria for the diagnosis of asthma and initiation of treatment are discussed in detail separately (table 2 and table 3). Prompt institution of timely and appropriate pharmacotherapy, education, and prevention strategies are appropriate in children who meet these criteria. (See 'Response to treatment' below and "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies".)

Clinical history — Key parts of the clinical history include determining whether the symptom really is wheezing and inquiring about details of the onset, course over time, and whether it is persistent or intermittent. Also, it is important to inquire about other associated symptoms.

Is it wheezing? — When a patient presents with a history of wheezing, it is crucial to ask the patient or the caregiver(s) to describe what they are experiencing or hearing (or demonstrate it with a home video or audio recording taken on a mobile phone). On many occasions, the word "wheezing" is used as a general term to describe noisy breathing that is primarily due to upper airway noises, including snoring, congestion, rattling, gurgling noises, or stridor [30,31]. It is essential to try to validate the symptom of wheezing if caregiver report is the only source of information and no wheezing is heard on examination of the child. (See "Asthma in children younger than 12 years: Initial evaluation and diagnosis".)

Age at onset — Structural abnormalities (such as tracheomalacia/bronchomalacia, vascular compression/rings, tracheal stenosis/webs), virus-induced wheezing (bronchiolitis and laryngotracheitis), and foreign body aspiration (FBA) are typically seen during infancy and early childhood (table 1). Other disorders, such as inducible laryngeal obstruction (ILO), tend to present in later childhood to adolescence.

Speed of onset and persistence — Two important aspects of the medical history include whether the onset of wheezing was acute or gradual and whether the wheezing is intermittent or persistent.

Acute onset of wheezing (apart from acute exacerbation of asthma) raises the possibility of FBA, particularly if there is a history of choking. Persistent wheezing presenting very early in life suggests a congenital or structural abnormality. In contrast, paroxysmal or intermittent wheezing is a characteristic finding in patients with asthma. Persistent wheezing with sudden onset is consistent with FBA, whereas the slowly progressive onset of wheezing may be a sign of extraluminal bronchial compression by a growing mass or lymph node. Less frequently, patients with interstitial lung disease (ILD) may occasionally present with persistent wheezing. (See "Classification of diffuse lung disease (interstitial lung disease) in infants and children" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

Association with viral respiratory infections — Virus-induced wheezing is common in the first few months to years of life. Among children younger than two years of age, the incidence of wheezing with respiratory illnesses is approximately 30 percent and peaks between two and six months [32,33]. Typically, these infants present with classic coryzal symptoms that progress to coughing, wheezing, and, occasionally, respiratory distress over a period of three to five days. Resolution is gradual over approximately two weeks. These episodes are variably responsive to bronchodilators and systemic glucocorticoids but not antibiotics, expectorants, or antihistamines. A symptom-free period typically ensues, followed by recurrent wheezing with subsequent viral illnesses in up to 50 percent of these infants. While most of these young children will not have virus-induced wheezing after three years of age, some will go on to develop asthma. (See "Role of viruses in wheezing and asthma: An overview" and "Treatment of recurrent virus-induced wheezing in young children".)

Associated cough — Cough is a symptom commonly associated with wheezing [34]. The nature of the associated cough (wet versus dry) may be helpful in determining the underlying etiology. Wet cough typically results from excessive mucus production, mostly due to infection or inflammation (eg, bronchiectasis, CF, primary ciliary dyskinesia, and chronic aspiration). In contrast, pure bronchoconstriction or structural causes for airway narrowing (eg, airway malacia or compression, foreign body, vascular ring) are usually associated with a dry cough. However, the underlying etiology of a dry cough can be complicated by a secondary process, making this distinction difficult (eg, mechanical obstruction can lead to impaired mucus clearance resulting in infection and a wet cough). Asthma can present with either a dry or wet cough depending upon the degree of airway obstruction and the amount of mucus produced (mucus production can vary from one patient to another and can vary at different times in the same patient).

Differentiating asthma from other causes of wheezing — Features in the history that favor the diagnosis of asthma include:

●Intermittent episodes of wheezing that usually are the result of a common trigger (ie, upper respiratory infections, weather changes, exercise, or allergens)

●Seasonal variation

●Family history of asthma and/or atopy

●Good response to asthma medications (see 'Response to treatment' below)

●Positive asthma predictive index (see "Wheezing phenotypes and prediction of asthma in young children", section on 'Asthma Predictive Index (API)')

Clinical features that suggest a diagnosis other than asthma include the following (table 4):

●Poor response to asthma medications, including inhaled bronchodilators, inhaled glucocorticoids, or systemic glucocorticoids. (See 'Response to treatment' below.)

●A history of neonatal or perinatal respiratory problems and wheezing since birth, which suggests a congenital abnormality. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula".)

●Wheezing associated with feeding or vomiting, which can result from gastroesophageal reflux (GER), impaired swallowing, or laryngeal cleft complicated by aspiration. (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Neonatal oral feeding difficulties due to sucking and swallowing disorders".)

●A history of choking, especially with associated coughing or shortness of breath. These findings suggest FBA, even if it does not immediately precede onset of wheezing symptoms. (See "Airway foreign bodies in children".)

●Wheezing with little cough. This finding suggests a purely mechanical cause of obstruction, such as small airways or a vascular ring, rather than asthma, in which cough is a prominent component in children.

●Symptoms that vary with changes in position, which may be caused by tracheomalacia, bronchomalacia, or vascular rings. (See "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula".)

●Poor weight gain and recurrent ear or sinus infections, which suggest CF, immunodeficiency, or ciliary dysfunction. (See "Approach to the child with recurrent infections" and "Cystic fibrosis: Clinical manifestations and diagnosis".)

Physical examination — General examination including measurement of weight and height, vital signs, oxygen saturation, a complete lung and chest examination, and digital inspection for the presence of cyanosis or clubbing. The last two findings suggest a diagnosis other than asthma (table 4).

Chest examination should focus on the following features:

●Inspection for the presence of respiratory distress, tachypnea, retractions, or structural abnormalities. Pertinent findings include an increased anteroposterior (AP) diameter associated with chronic hyperinflation, pectus excavatum caused by chronic airway obstruction and exaggerated swings in intrathoracic pressure, or scoliosis complicated by airway compression. (See "Pectus excavatum: Etiology and evaluation" and "Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis", section on 'Clinical presentation'.)

●Palpation to detect lymphadenopathy or tracheal deviation.

●Percussion can help define the position of the diaphragm and detect differences in resonance among lung regions.

●Auscultation to identify the characteristics and location of wheezing, as well as variations in air entry among different lung regions. A prolonged expiratory phase suggests airway narrowing. Wheezing caused by a large or central airway obstruction (eg, vascular ring, subglottic stenosis, tracheomalacia) has a constant acoustic character throughout the lung but varies in loudness depending upon the distance from the site of obstruction. In contrast, the degree of narrowing varies from place to place within the lung in the setting of small airway obstruction (eg, asthma, CF, primary ciliary dyskinesia, aspiration). The presence of persistent focal wheezing is usually indicative of a localized and mostly structural airway abnormality, and, therefore, airway evaluation by imaging or bronchoscopy is warranted. (See 'Radiography' below.)

Crackles can be present in conjunction with wheezing in asthma and in a variety of other conditions, such as those leading to bronchiectasis (eg, CF, primary ciliary dyskinesia, immunodeficiency). Early inspiratory crackles are often present in patients with asthma due to air flowing through secretions or slightly closed airways during inspiration. Late inspiratory crackles are usually associated with ILD and early congestive heart failure. Thus, the presence of crackles does not exclude the diagnosis of asthma [35].

●Assessment of response to therapy. Marked improvement in wheezing immediately (within a few minutes) after bronchodilator therapy is suggestive of asthma but does not rule comorbid conditions if clinically suspected. (See 'Response to treatment' below.)

The exam should also focus on extrapulmonary findings that suggest an etiology for wheezing. The cardiac examination includes auscultation for murmurs and evaluation for signs of heart failure. Examination of the skin for eczema (common in atopic patients) or other cutaneous lesions may assist in diagnosis. Nasal examination may reveal signs of allergic rhinitis, sinusitis, or nasal polyps. The presence of nasal polyps in children necessitates an evaluation for CF. (See "Approach to the infant or child with a cardiac murmur" and "Heart failure in children: Etiology, clinical manifestations, and diagnosis" and "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis" and "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis" and "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Acute bacterial rhinosinusitis' and "Cystic fibrosis: Clinical manifestations and diagnosis".)

Radiography — A chest radiograph (AP and lateral films) should be obtained in children with new-onset wheezing of undetermined etiology or chronic, persistent wheezing not responding to therapies. It is not necessary to obtain a chest radiograph with every exacerbation in children with asthma, unless there is a specific indication. (See "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Indications for chest radiograph'.)

In most cases, a plain chest radiograph provides a good image of the large airways, including the tracheal air column and main stem bronchi. Plain films can also help differentiate between diffuse and focal disease. The presence of generalized hyperinflation suggests diffuse air trapping and airway disease, seen in asthma, CF, primary ciliary dyskinesia, bronchiolitis obliterans (BO), and aspiration. In contrast, localized findings suggest structural abnormalities or FBA. A chest radiograph can also detect parenchymal lung disease, atelectasis, and, in some cases, areas of bronchiectasis.

In addition, chest radiographs may reveal cardiomegaly, enlarged pulmonary vessels, pulmonary edema, or other signs of cardiac failure. Plain radiographs also are helpful in detecting mediastinal masses or enlarged lymph nodes and may suggest the presence of vascular rings (eg, right aortic arch). (See "Vascular rings and slings".)

Other radiologic studies may be helpful in selected cases (table 5):

●Chest computed tomography (CT) can provide detailed anatomy of the mediastinum, airways, and lung parenchyma.

●Magnetic resonance imaging (MRI) with contrast (magnetic resonance angiography [MRA]) or multidetector computed tomography (MDCT) [15] is the study of choice when a vascular ring or sling is suspected.

●Barium swallow may help in identifying vascular rings, swallowing dysfunction, aspiration syndromes including GER, and some cases of tracheoesophageal fistula and is indicated only when these conditions are suspected. (See "Vascular rings and slings", section on 'Evaluation' and "Gastroesophageal reflux in infants" and "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents" and "Congenital anomalies of the intrathoracic airways and tracheoesophageal fistula", section on 'Diagnosis' and "Aspiration due to swallowing dysfunction in children".)

●A videofluoroscopic swallowing study (also called a modified barium swallow) is suggested in children under two years of age who have recurrent wheezing that is unresponsive to bronchodilators or inhaled or systemic glucocorticoids to identify possible swallowing dysfunction [36]. (See "Aspiration due to swallowing dysfunction in children", section on 'Videofluoroscopic swallow study'.)

Pulmonary function tests — PFTs are an important component of the diagnostic evaluation of a wheezy child. (See "Overview of pulmonary function testing in children".)

In older children who are cooperative, PFT with inspiratory and expiratory flow-volume loops is helpful in determining the presence, degree, and location of airway obstruction, as well as the response to bronchodilators (figure 3). Methacholine challenge testing and exercise testing can confirm airway hyperreactivity in patients for whom the diagnosis of asthma still is in question. Exercise testing with laryngoscopy is helpful to confirm the diagnosis of ILO if suspected. (See "Overview of pulmonary function testing in children" and "Bronchoprovocation testing" and "Flow-volume loops".)

Infant PFT, if available can help in assessing airway obstruction and can be used to quantify the response to bronchodilators [12,37,38]. This test requires sedation and therefore is reserved for selected patients for whom this information may help with diagnosis and management.

Response to treatment — For patients with diffuse wheezing, a trial of inhaled bronchodilators can be used to confirm the presence of reversible airway disease. However, a partial or negative response may not rule out asthma. Inflammation and airway swelling may contribute to wheezing in addition to bronchoconstriction, especially in infants and young children. Thus, if asthma is still suspected in a patient with chronic or persistent symptoms, the combination of inhaled glucocorticoids and bronchodilators for at least two weeks (or five to seven days of oral glucocorticoids if the patient has more severe symptoms) may result in significant improvement in symptoms and help in making the diagnosis of asthma. Further work-up is indicated if the response to this therapy is inadequate or if a comorbid condition is still suspected in a patient who had a positive response to bronchodilator. (See "Asthma in children younger than 12 years: Initial evaluation and diagnosis".)

Laboratory studies — There are few laboratory investigations that are useful in the initial evaluation of the wheezy child. In most cases, the probable diagnosis is suspected based upon the clinical history and physical examination. The role of laboratory tests, when indicated, is either to confirm the diagnosis or to rule out other less likely diagnoses [29]. Complete blood counts are important in patients with chronic or systemic symptoms and may reveal anemia, leukocytosis, or leukopenia. Eosinophilia in this setting supports an underlying allergic process or possible parasitic infection. Further studies should be obtained based upon the suspected diagnosis (table 5).

Infectious work-up — Viral infection is an important cause of wheezing in children and is mediated through numerous mechanisms. Viruses in the Paramyxoviridae family (eg, respiratory syncytial virus and parainfluenza virus) and picornavirus family (eg, human rhinovirus) are important precipitants of wheezing in young children. Metapneumovirus, another member of the Paramyxoviridae family, can result in upper and lower respiratory tract infection and may present with wheezing [39,40]. Thus, viral studies can be helpful in confirming the etiology of wheezing in infants and young children presenting with symptoms suggestive of bronchiolitis. However, they are not routinely recommended. Testing is reviewed in greater detail separately. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Viral testing' and "Human metapneumovirus infections" and "Role of viruses in wheezing and asthma: An overview" and "Parainfluenza viruses in children", section on 'Diagnosis' and "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children", section on 'Diagnosis'.)

Sputum Gram stain and cultures may be useful in a setting suggestive of bacterial infections, including atypical infections (eg, mycobacterial or fungal infections). Tuberculin skin testing and specific serologic assays can be helpful if these infections are suspected. Serologic testing for Mycoplasma may be performed if such an infection is suspected since Mycoplasma is an increasingly recognized cause of wheezing and may predispose children to the subsequent development of asthma [41,42]. (See "Overview of nontuberculous mycobacterial infections" and "Clinical manifestations and diagnosis of allergic bronchopulmonary aspergillosis" and "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Pulmonary tuberculosis' and "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'Laboratory evaluation' and "Mycoplasma pneumoniae infection in children", section on 'Approach to testing'.)

Immunologic evaluation — Assessment of immunoglobulin levels can be used to screen for humoral immunodeficiencies. If there is a high suspicion of immunodeficiency, then a more detailed immunologic work-up is appropriate (table 5). Elevated immunoglobulin E (IgE) can be indicative of an allergic process. Skin prick testing (or in vitro testing) may be helpful in the patient with signs and symptoms suggestive of environmental allergies. (See "Approach to the child with recurrent infections" and "Laboratory evaluation of the immune system" and "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis", section on 'Allergen-specific testing'.)

Sweat chloride test — There should be a low threshold to obtain a sweat chloride test in a patient with persistent or recurrent pulmonary symptoms who does not improve on asthma therapies, especially when wheezing is associated with a chronic, productive cough, since identifying a patient with CF has major implications for the patient, the family, and future reproductive decisions. The sweat chloride test should be undertaken at a facility with substantial experience, and clinicians interpreting the results should be aware of other conditions that result in elevated sweat chloride concentrations. (See "Cystic fibrosis: Clinical manifestations and diagnosis".)

Primary ciliary dyskinesia work-up — Evaluation for primary ciliary dyskinesia can include genetic testing, nasal nitric oxide, and ciliary motion and ultrastructural analysis, especially if the patient presents with a wet, chronic cough; chronic sinusitis; and recurrent otitis media. (See "Primary ciliary dyskinesia (immotile-cilia syndrome)".)

Endoscopy — Bronchoscopy is indicated in patients with suspected FBA, persistent symptoms, or inadequate response to therapy. Rigid bronchoscopy is used in patients with sudden onset of wheezing and suspected FBA. Flexible bronchoscopy can identify structural airway abnormality, including airway malacia (best evaluated during spontaneous breathing when performed under conscious sedation). A structural abnormality was identified in up to 33 percent of infants with chronic wheezing not responsive to asthma therapies by bronchoscopy [36]. Obtaining bronchoalveolar lavage cytology can help in identifying phenotype of asthma (eosinophilic versus neutrophilic) and also can help when infection or aspiration is suspected. However, the recommendation for bronchoscopy and bronchoalveolar lavage (BAL) in infants with chronic or recurrent wheezing is conditional with low quality of evidence [36]. (See "Airway foreign bodies in children" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Aspiration due to swallowing dysfunction in children", section on 'Evaluation of airway anatomy'.)

Esophageal pH and impedance monitoring — GER is common among children under two years of age with recurrent wheezing. Thus, 24-hour esophageal pH monitoring is suggested in infants and children with recurrent wheezing, particularly in children under two years of age with recurrent wheezing who are unresponsive to bronchodilators or inhaled or systemic glucocorticoids, since GER symptoms may be subtle in this age group [36]. Evaluation for GER is also suggested for older children with poor response to asthma therapies, especially if they have any suggestive symptoms. Presenting symptoms may include excessive burping or emesis, coughing after meals, and nocturnal cough or wheeze along with discomfort indicated by crying and/or arching of the back. A positive response to empiric therapy (acid suppression) may be used to support a presumed diagnosis of GER [29]. (See "Clinical manifestations and diagnosis of gastroesophageal reflux disease in children and adolescents".)

Twenty-four-hour esophageal pH monitoring is preferred over an upper gastrointestinal series or gastroesophageal scintigraphy for the diagnosis of GER. Multichannel intraluminal impedance (MII) monitoring is a technique that permits measurement of all reflux episodes, including those that are weakly acidic or alkaline. It is usually used in combination with pH monitoring. In a trial comparing the two techniques, combined MII-pH monitoring detected reflux events that caused symptoms twice as often as pH monitoring alone [43].

SUMMARY AND RECOMMENDATIONS

●Definition and physiology of wheezing – A wheeze is a continuous musical sound heard during chest auscultation that lasts longer than 250 msec. It is produced by the oscillation of opposing walls of an airway narrowed almost to the point of closure. It can be high pitched or low pitched, consist of single or multiple notes, occur during inspiration or expiration or biphasic, and originate from airways of any size. (See 'Definition and physiology of wheezing' above.)

●Causes – Wheezing is a common presenting symptom of respiratory disease in children. It may be either a benign, self-limited process or the presenting symptom of a significant respiratory disease (table 1). (See 'Causes' above.)

•Acute-onset wheezing – In addition to asthma, acute onset of wheezing in a child is most often caused by infection or foreign body aspiration (FBA). (See 'Acute wheezing (hours to days)' above.)

•Chronic or recurrent wheezing – The most likely diagnosis in children with recurrent wheezing is asthma. However, not all patients with asthma wheeze, and other diseases can present with chronic or episodic wheezing. The differential diagnosis is broad and includes structural abnormalities of the tracheobronchial tree or other thoracic structures (eg, vascular rings and slings, mediastinal masses). Nonstructural (functional) causes include aspiration syndromes (from gastroesophageal reflux [GER] and dysphagia), bronchopulmonary dysplasia, vocal cord dysfunction (including inducible laryngeal obstruction [ILO; historically known as paradoxical vocal fold movement (PVFM)] in older children), abnormal immunologic defense mechanisms, bronchiolitis obliterans (BO), and interstitial lung disease (ILD). (See 'Chronic or recurrent wheezing' above.)

●Evaluation – Clinical history and physical examination often allow accurate diagnosis (table 5). Additional diagnostic tools are helpful in establishing the underlying etiology of wheezing in select patients. (See 'Evaluation' above.)

•Clinical history – When a patient presents with a history of wheezing, it is crucial to ask the patient or the caregivers to describe what they actually are experiencing or hearing (or demonstrate it with a home video or audio recording taken on a mobile phone). On many occasions, the word "wheezing" is used as a general term to describe noisy breathing, including snoring, congestion, gurgling noises, or stridor. Two important aspects of the medical history include the patient's age at the onset of wheezing and the course of onset (acute versus gradual). Certain clinical features favor the diagnosis of asthma or suggest another diagnosis (table 4). (See 'Clinical history' above.)

•Physical exam – General examination of a wheezy child should include measurement of weight and height; vital signs including oxygen saturation; digital inspection for the presence of cyanosis or clubbing; a complete chest examination; and cardiac, skin, and nasal examinations. (See 'Physical examination' above.)

•Imaging – Anteroposterior (AP) and lateral chest radiographs are suggested in children with new-onset wheezing of undetermined etiology or chronic, persistent wheezing not responding to therapies. Other radiologic studies such as computed tomography (CT) scan and magnetic resonance angiography (MRA) may be helpful in selected cases (table 5). (See 'Radiography' above.)

•Pulmonary function testing – Pulmonary function tests (PFTs) are an important component of the diagnostic evaluation of a wheezy child. In older children who are cooperative, PFT with inspiratory and expiratory flow-volume loops is helpful in determining the presence, degree, and location of airway obstruction, as well as the response to bronchodilators (figure 3). (See 'Pulmonary function tests' above.)

•Endoscopy – When suspected, endoscopy can help identify FBA or structural abnormalities. (See 'Endoscopy' above.)

•Response to treatment – For patients suspected of having asthma, a trial of inhaled bronchodilators with or without glucocorticoids can be used to confirm the diagnosis prior to initiating a more extensive work-up. Further work-up is indicated if the response to therapy is inadequate. (See 'Response to treatment' above.)

•Laboratory studies – There are few laboratory investigations that are useful in the initial evaluation of the wheezy child. Any studies obtained beyond chest radiographs and PFTs should be based upon the suspected diagnosis (table 5). These studies include tests to examine for viral, bacterial, or fungal infections; sweat chloride test to diagnose cystic fibrosis (CF), work-up for primary ciliary dyskinesis, evaluation for immunodeficiency or allergy, and work-up for GER if indicated. (See 'Laboratory studies' above.)