Differential Diagnosis of the Wheezing Child: Part I, Infants
Authors: Richard M. Ruddy, MD, Division Chief, Pediatric Emergency Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, Division of Pediatric Emergency Medicine; Michael A. Gittelman, MD, Fellow, Pediatric Emergency Medicine, Children's Hospital Medical Center, Cincinnati, Ohio, Division of Pediatric Emergency Medicine
Peer Reviewer: Steven Krug, MD, Associate Professor of Pediatrics, Northwestern University Medical School; Head, Division of Pediatric Emergency Medicine, Children's Memorial Medical Center
Another wheezing child. It seems that this time of year we see more children presenting with wheezing than any other condition. And then it hits again from January through April. That type of repetitive pattern makes it easy to miss a child who may not have a common disease such as asthma or bronchiolitis.
What makes us experts on wheezing in pediatric emergency medicine? The discipline to comprehensively evaluate every child who presents with this common problem and mentally confirm to ourselves that this child does not have significant underlying pathology. Most of the time, this does not involve extensive laboratory or radiographic testing, but instead a focused history and physical that identifies children who require further evaluation. Because of the detailed nature of this article, and the desire to provide our readers with the most comprehensive, up-to-date coverage, we have divided it into two parts. The first part focuses on children younger than 1 year, while the second part will focus on older children. The authors provide an excellent, thorough analysis of each disease process and then present a simple approach to identifying children who may have uncommon pathology.
-The Editor
Introduction
The complaint of wheezing in children accounts for a great number of ill visits to physician offices and emergency departments (ED). In the authors' ED, more than 5% of visits are found to have wheezing on history or physical exam. Most of us have heard repeatedly "all that wheezes is not asthma,"1 nevertheless, we need to carefully avoid the tunnel vision of diagnosing every wheezing child with bronchiolitis or asthma. It is important to remember to look for the diagnostic clues that will assist the clinician to complete this task. What separates the patient with the more common causes of wheezing, such as viral small airway disease or asthma, from the more unusual or critical diagnosis, such as a tumor or foreign body? This article will review the definition and pathophysiology of wheezing, present several illustrative cases that emphasize important differential diagnosis elements, and outline a specific diagnostic work-up and management for each of the problems associated with wheezing.
Definitions
Under most circumstances, breathing is effortless and silent. If a child's breathing pattern becomes audible, it is considered abnormal and is often brought to the attention of a health care provider. Besides nasal congestion, a harsh or continuous low pitched sound, the two most commonly heard abnormal noises during breathing are stridor and wheezing.
Stridor is a harsh, high-pitched respiratory sound that is often present during inspiration. It is generated by increased turbulent airflow through an obstructed extra-thoracic trachea.2 As this narrowed portion of the trachea compresses slightly during inspiration secondary to the natural higher pressures outside compared to inside the airway, turbulent flow and a higher pitched noise is produced.3 Some authors have even shown that the degree of obstruction and the different air speeds through the narrowed region will cause differences in the pitch of the stridor.4 Stridor is most commonly associated with laryngeal and tracheal abnormalities such as croup or laryngomalacia.
Wheezing is a musical, high-pitched, continuous respiratory sound commonly heard during expiration; it may be appreciated occasionally during inspiration. This sound is produced as turbulent airflow passes through the large or medium-sized narrowed or blocked intra-thoracic airways.2 Wheezing is commonly not heard as air passes through the smallest or peripheral airways because typically air does not move rapidly enough through this region to generate noise.5 Homophonous or monophonic wheezing is associated with obstruction in the larger, more central airways. This type of wheezing produces a constant pitch heard equally throughout all of the lung fields. Heterophonous or polyphonic wheezing, on the other hand, is the result of an obstruction in the smaller airways. Because the airway narrowing or mucous plugging is not uniform in these smaller airways, different pitches of wheezing would be expected in each of the different lung fields. Diagnostically, one might associate heterophonous wheezing with the asthmatic with bronchoconstriction of the smaller airways, while homophonous wheezing may be present in a patient with a structural lesion like a foreign body within the right main bronchus.
Pathophysiology
Wheezing is a common symptom in infants, and the incidence is estimated to be 10%.6 A variety of anatomic or physiologic features of the infantile lung predisposes young children to intra-thoracic obstruction and the symptom of expiratory wheezing.
Anatomically, it is obvious that the infant's peripheral airways are smaller in radius and shorter in length compared to an adult. Poiseulle's law of gas flow through a tubular structure states that resistance to flow is related to the length of the tube and inversely proportional to the fourth power of the radius of the tube. Thus, with any obstruction, resistance to airflow in an infant is more evident than in an adult mainly because of the smaller airway radius. With an increase in resistance, one might expect an increase in turbulent flow and a greater propensity for wheezing.
Besides a smaller airway size, infant's also have other anatomic differences from the adult population. As expected, newborn's require a compliant thoracic cavity to enable them to pass easily through the birth canal during delivery. At times of respiratory distress, the increase in pressures to ventilate causes a paradoxical movement of the thoracic cavity (i.e., the chest collapses inward during times of respiratory distress as opposed to outward to increase the lung volume).6 Along with the more submissive thoracic walls, the diaphragmatic attachment in the infant is more horizontal and not oblique like in an older child.7 Because of this different attachment site, the diaphragm descends less and expands the rib cage less. Thus, the combination of a more compliant thorax and a decreased abdominal expansion secondary to a different diaphragmatic attachment, result in less chest wall expansion in times of increased respiratory effort.
Other developmental aspects of infants make them more susceptible to respiratory problems. Non-ambulatory infants tend to be in the supine position more of the time than older children. When supine, diaphragmatic excursion cannot transmit pressure to the abdominal surface as well, resulting in a decrease in lung volume. A difference in functional residual capacity of up to 15% has been shown between the supine and upright positions in adults.8 Also, infants tend to sleep more frequently. Infants may sleep up to 16-20 hours a day, while adults may sleep an average of 8 hours a day. During this restful period, infants can spend the majority of their sleep state in REM sleep, unlike an adult who may spend only one-fifth of their sleep in the REM state. While in REM sleep, there is a loss of tonic activity among the intercostal muscles and the diaphragm.7 This change in tone can lead to a 30% fall in functional residual capacity.7
Finally, there are biochemical differences in the younger patient compared to the adult. Elastin, a protein that has contractile properties and serves to keep an airway open, is relatively deficient in an infant.6 Over the first few years of life, elastin gradually increases along with airway patency. The cartilaginous support within the airway is weaker and more compressible in the infant than the adult patient. Thus, this increased compliance within the airway increases the child's chances of obstruction in response to negative pressure within the respiratory tract. This collapsibility could predispose infants to atelectasis or abnormal airway sounds such as wheezing.
In summary, younger infants have multiple factors that predispose them to respiratory difficulties.
Table 1. Causes of Wheezing in Children Divided by Age and Rapidity of Onset
Wheezing in Children < 1 year |
Wheezing in Children > 1 Year | |
Acute Onset |
*Bronchiolitis/Viral Pneumonia Bronchopulmonary Dysplasia Aspiriation Events Tracheoesophageal Diseases Neuromuscular Diseases *Gastroesophageal Reflux |
Asthma *Anaphylaxis Infections *Viral Atypical/Typical bacterial Parasites Irritants Cigarette Smoke Air Pollutants Chemical Exposures Hydrocarbons Hypersensitivity Pneumonitis |
Chronic Onset |
Asthma Cardiovascular Anomalies Vascular Rings/Slings Double Aortic Arch Defective Host Defenses Immotile Cilia Syndrome Immotile Deficiencies Congenital Structural Anomalies Tracheal/Bronchial Stenosis Tracheo-/Bronchomalacia Lobar Emphysema Pulmonary Sequestration |
Asthma Neoplastic Diseases Primary Pulmonary Tumors Mediastinal Tumors Metastatic Tumors Enlarged Lymph Nodes Neoplasms (i.e., Lymphoma) Tuberculosis Sarcoidosis Autoimmune Diseases Lipid Storage Diseases Pulmonary Hemosiderosis Alpha-1-Antitrypsin Deficiency |
Some manifestations may appear as chronic, yet could have an acute presentation if diagnosed early in its course.
*Common causes of wheezing
Differential Diagnosis
Although the majority of children who present to the ED secondary to wheezing will suffer from asthma or bronchiolitis, it is important to consider a broad differential diagnosis. In order to facilitate recollection of this detailed list, numerous classifications have been used based on the type of lesion, the location of the obstruction, the physiologic changes noted, and by the organ systems involved. One way to categorize the potential causes of wheezing is by the child's age and the time of onset of the symptoms. Table 1 manifests a specific classification system for the wheezing child that excludes some of the causes of wheezing and respiratory distress in the immediate newborn period like hyaline membrane disease. Using this table, four cases are presented to display the varied presentations and the different diagnoses associated with a wheezing child.
Acute Causes of Wheezing in Children Younger than 1 Year
Case #1. A 6-month-old male was in his usual state of good health during the month of February, until three days prior to his ED visit when he developed significant rhinorrhea, cough, and low grade fevers (Tmax = 101°F). His parents noted that his respiratory rate increased, his lips turned a bluish hue, and he had an episode where he stopped breathing completely for 15-20 seconds. As a result, the child was referred to the Ed by his primary physician. No one else in the home was ill and he has had a mild decrease in his oral intake over the past 24 hours.
His birth history was significant for gestation at 34 weeks by spontaneous vaginal delivery. The patient went home with mom without any complications.
Initial physical exam revealed an alert, generally healthy appearing child who was in mild to moderate respiratory distress. Vital signs included a temperature of 100.8°F; heart rate, 120 beats/min; respiratory rate, 56 breaths/min; blood pressure, 78/42; and pulse oximetry 92% in room air. Lungs had crackles with heterophonous wheezing scattered throughout all lung fields. He had significant subcostal and suprasternal retractions with nasal flaring. Cardiac exam was unremarkable.
Table 2. Criteria for Hospital Admission in the Child with Bronchiolitis
· < 2 months of age
· Respiratory rate > 70 bpm
· Respiratory distress
· Pulse oximetry < 92%
· High risk for worse infection
· Poor feeding
· Poor potential follow-up
A capillary blood gas (CBG) was obtained along with a CBC and blood culture. CBG showed the pH to be 7.32, with a PACO2 of 54, and PAO2 of 82. WBC count was 12,500 cells/mm3; Hgb, 10.8 g/dL; Hct, 33%; and platelets, 320,000. The chest radiograph manifests hyperinflation and peribronchial thickening. (See Figure 1.)
Bronchiolitis/Viral Pneumonia. The acute onset of wheezing in an otherwise healthy child younger than one year of age, especially during the winter months, is most commonly caused by bronchiolitis. Bronchiolitis is an acute, self-limited disease of the lower respiratory tract in infants resulting from inflammatory obstruction of the small airways.9 Reports indicate the incidence of bronchiolitis in the first year of life to be 11.4 cases per 100,000 children, leading to approximately 100,000 hospitalizations in the United States per year.10,11 There is a mortality rate of 1-3% in the hospitalized patient and up to a 20-40% in the patients with underlying cardiac disease and pulmonary hypertension. The major causative agent is respiratory syncytial virus (RSV), which is responsible for 60- 90% of the cases; however, parainfluenza virus, adenovirus, rhinovirus, and Mycoplasma pneumoniae may produce a similar clinical syndrome.12
RSV is a single-stranded, medium-sized RNA virus of the paramyxovirus family. The virus causes annual epidemics world-wide. Most commonly, infection occurs during the winter months; however, in the tropical regions, the disease occurs during the rainy season.11 By 2 years of age, 80-95% of children have been infected by RSV. The peak incidence of hospitalization occurs in infants 2-6 months of age and the infection does not provide immunity. In older children and adults, infection often only involves the upper respiratory tract. Most children acquire the disease through direct contact with secretions and not by aerosolized particles. Therefore, the larger the family size, the more likely the incidence of disease.13
After inoculation of the virus, RSV invades the epithelial cells of the nasopharynx. As the infection spreads along the mucosa towards the lower respiratory tract, mucosal inflammation, cell death, and sloughing results. This necrotic epithelium along with airway edema causes narrowing of the smaller airways, resulting in, significant turbulent flow and the classical expiratory wheezing. Eventually, the bronchi become obstructed, causing hyperinflation and atelectasis that is evident on physical exam and chest radiograph.
Similar to the patient in case one, children with RSV present with a 1-4 day history of profuse, clear rhinorrhea, congestion, and a low-grade fever. As the virus transcends the lower respiratory tract, subsequent symptoms of cough, tachypnea, wheezing, and retractions develop. Because of their nasal congestion and increased respiratory effort, many infants feed poorly and may even be irritable on presentation. Their physical exam is often significant for tachycardia, tachypnea, retractions, rhonchi throughout most of the lung fields , and a prolonged expiratory phase with an expiratory heterophonous wheeze. Cyanosis, hypoxia, and a weak respiratory effort are late findings and often signify impending respiratory failure. Complications of RSV, such as apnea, bacterial superinfection, pneumothorax, and dehydration may also be present and may cloud the underlying diagnosis. The severity and the duration of the illness is highly variable ranging from a mild upper respiratory infection lasting 4-5 days to respiratory failure that requires prolonged mechanical ventilation. Children at a higher risk for a worse infection include infants: born prematurely; younger than 2 months of age; with congenital heart disease; with bronchopulmonary dysplasia (BPD); with cystic fibrosis; or with immunosuppression.
The diagnosis of bronchiolitis is mainly based on the patient's history and physical exam; laboratory data rarely facilitate the diagnosis. The WBC count may be normal or elevated and is non-specific. The electrolytes may be abnormal if the child is clinically dehydrated. Since pulse oximetry is a useful and non-invasive tool to approximate arterial oxygenation, an arterial blood gas (ABG) is unnecessary unless the patient has significant respiratory distress. In the children with severe disease, the ABG will show a low serum pH and an elevated PCO2 indicating respiratory acidosis. Chest radiographs are usually not helpful unless complications of bronchiolitis need to be excluded; like pneumothorax, pneumonia, severe atelectasis, or if other diagnoses are still in question. Most often the CXR shows nonspecific findings, such as hyperinflation, peribronchial thickening, and subsegmental atelectasis. The gold standard for the detection of RSV remains the viral cultures of the nasopharynx. Unfortunately, study results return 5-7 days after the child's illness has almost resolved and, therefore, this test is not very practical. As a result, the rapid fluorescent antibody test and the enzyme linked immunosorbant assay technique for the detection of RSV antigen are commonly used to obtain a more rapid diagnosis. Both tests have a sensitivity and specificity of 90% for detecting RSV.14
Two common questions that are often asked in the ED when assessing a child with bronchiolitis are: Do children with bronchiolitis and a fever require more of a diagnostic work-up? And, when does a child with bronchiolitis get admitted to the hospital? Kuppermann et al helped to answer the first question in a recent study.15 Often children younger than 3 months of age, with a fever greater than 100.5°F, and no source for infection, will receive blood, urine, and CSF cultures; while children between 3 and 24 months of age, with a fever greater than 102.5°F, and no source for infection, will receive a blood culture and a urine culture (males usually only get urine cultures when less than 6 months of age). Can bronchiolitis count as a source for infection? Kuppermann et al showed that children younger than 2 years of age with bronchiolitis and a fever were unlikely to have a concomitant bacteremia or UTI. They concluded that routine cultures in these patients are "unnecessary." When to admit a patient with bronchiolitis, on the other hand, is a more difficult question and mainly depends on the general physical appearance of the child. Table 2 offers some guidelines for which children with bronchiolitis should be considered for admission.16 These criteria, however, are mainly suggestions and the overall picture of the patient and the situation must be considered before making the final decision.
In managing the child with bronchiolitis, oxygen suctioning and supportive care continue to be the mainstay of therapy. The value of bronchodilators remains questionable. Some studies have shown children with wheezing to clinically improve after the use of albuterol.17,18 Others have shown albuterol to have no clinical effect on bronchiolitic patients.19,20 Most authors agree that patients who respond to bronchodilators have significant bronchoconstriction as part of their disease. During the stage with mucosal sloughing as the major component causing the wheezing, bronchodilators will usually add little benefit. Because of these controversial results, investigators have tried other techniques to clinically improve the child with bronchiolitis. Racemic epinephrine or l-epinephrine has been attempted because of its alpha and beta adrenergic effects and has proven to be beneficial in three recent studies.21-23 Ipratropium bromide, dexamethasone, antibiotics, and vitamin A have been employed to treat bronchiolitis, without clinical benefit.24-27 Finally, ribaviran, a synthetic nucleoside with virostatic activity against RSV, has been used to treat children with severe disease. Although no study indicates that it will expedite recovery or decrease complications in the previously well child with bronchiolitis, the American Academy of Pediatrics does recommend its use for certain high-risk infants with RSV infection. These patients include infants with congenital heart disease (particularly any at risk for pulmonary hypertension), chronic lung disease, immunosuppressive diseases, preterm infants, younger than 6 weeks of age, or severe disease requiring mechanical ventilation.28
Most recently, RSV immune globulin (RSV IVIG or Respigam) has been instituted in order to prevent RSV infection in the high-risk population. This preventative measure has been instituted for patients with prematurity and BPD, yet has not been employed for any of the other high risk groups. Two independent studies have shown that the immune globulin does decrease hospitalizations and length of hospital stay secondary to RSV.29,30 Currently, a humanized monoclonal antibody that targets the RSV protein or "F" protein is being studied. Both preventative measures should help prevent RSV infection and future wheezing episodes. As most studies report, residual parenchymal damage may cause recurrent wheezing in the infant exposed to RSV with a prevalence of up to 69-75%.31,32
Asthma. Overall, asthma is the most common cause of wheezing in all aged children; however, we will not concentrate on asthma in depth in this article because it was already covered in the May 1998 issue of Pediatric Emergency Medicine Reports.33 Although asthma is greatly prevalent in our society, it is uncommonly diagnosed in the first few months of life. One reason for this phenomenon is that asthma refers to a disease that causes recurrent episodes of reversible airway obstruction. When an infant presents to the ED with his or her first episode of wheezing, it is difficult to label the infant as an asthmatic; even if he or she responds to bronchodilator therapy. If it is not determined that the problem is most consistent with bronchiolitis or viral pneumonia, the patient may be determined to have reactive airways disease (RAD). Another reason younger children may not readily be diagnosed with asthma is that it is often difficult in the acute setting to distinguish from bronchiolitis or other viral pneumonias. Viral illnesses, like RSV, may precipitate an asthma exacerbation and some of the children with a lower respiratory tract infection respond to bronchodilator therapy. Also, an asthmatic may have crackles from atelectasis on physical exam that could be misconveyed as the crackles associated with the mucosal sloughing of bronchiolitis. Thus, in order to declare a patient as an asthmatic, it is often helpful to demonstrate that the patient had multiple episodes of wheezing with no symptoms between attacks; has a family history of atopy or asthma (one parent with asthma = 25% chance child will have asthma; both parents = 50% chance);34 shows symptoms of atopy (usually eczema); responds to bronchodilators; and has been ruled out for other chronic diseases, such as cystic fibrosis or gastroesophageal reflux.
The onset of asthma may be acute or insidious. Acute episodes are often secondary to irritants or allergens, while the insidious presentations are usually associated with viral infections. The cardinal symptoms of children with asthma are a tight cough, often worse at night, heterophonous wheezing with a prolonged expiratory phase, tachypnea, and dyspnea. Crackles may be appreciated in isolated regions of the chest secondary to atelectasis, yet they are usually not heard throughout the chest as in the bronchiolitic patient. As the degree of bronchospasm and airway inflammation increases over time, the child develops more respiratory distress with poorer gas exchange. Little to no air movement may be heard, the child's accessory muscles aid his or her work of breathing, and his or her chest is hyperexpanded due to air trapping. Eventually, the child cannot maintain this excessive effort to breathe and tires. Clubbing is a rare finding in the asthmatic patient, and if present, should encourage the physician to search for another possible diagnosis causing respiratory distress, such as cystic fibrosis or other chronic lung diseases.
Similar to bronchiolitis, the diagnosis of asthma is not based on any particular laboratory test. Children with asthma may have eosinophilia in their blood or sputum signifying an allergic component to their respiratory symptoms. Exercise testing often elicits bronchoconstriction from the stimulus of dry, cool air. Finally, pulmonary function testing can be helpful in the patient with asthma by demonstrating the degree of obstruction, showing the lungs response to particular allergens, and assessing the use of bronchodilators to improve the patient's forced expiratory volume. Again, chest radiographs are not critical for the asthmatic patient, even if it is a first attack.35 The indications to obtain a CXR in asthmatic patients is to search for possible complications of asthma-atelectasis, pneumonia, pneumothorax, or pneumomediastinum. Other etiologies of wheezing, such as cardiopulmonary disease, may be suggested on the CXR. Thus, if an asthmatic patient has subcutaneous emphysema, a high fever, or significant desaturations on pulse oximetry unexplainable by physical exam, there is a greater chance that the chest x-ray will be abnormal.
The mainstay of treatment for the asthmatic child is directed towards prevention, by relieving exposure to the triggers of asthma (i.e., allergens, irritants), and supportive care to combat the bronchoconstriction and inflammation that result in the lower airways. In order to prevent an asthma exacerbation, it is first important to determine the triggering agent. Detecting IgE antibodies to specific allergens by skin testing or by radioallergosorbent testing (RAST) may provide specific sensitivities. Also, cromolyn sodium (a mast cell stabilizer) and inhaled steroid agents by metered-dose inhalers (MDI) have proven to be effective in preventing significant attacks. Supportive care during an asthma exacerbation, on the other hand, is started with oxygen to reverse hypoxia and decrease bronchospasm and beta-agonists to enhance bronchodilation. Inhaled bronchodilators, such as Albuterol, are usually given by nebulization or MDI. Both techniques have been shown to be equally effective in children older than 6 years of age in mild to moderate disease.36 If the child's bronchoconstriction is severe and the inhaled bronchodilator is not able to reach the lower airways, IV or IM beta agonists, like terbutaline and epinephrine can be given to improve the narrowing within the airways. Recently, anticholinergic agents, such as ipratropium bromide or atropine, have been employed in order to reduce vagal tone and inhibit mast cell mediator release.37 Steroids are often initiated if the child is not responding to bronchodilator therapy or if significant inflammation is suspected within the lower airways. Steroids may be delivered by IV, IM, PO, or even nebulization, however, no study has clearly resolved which method is the most effective. Finally, other treatment methods have been studied to relieve a patient with severe asthma. These include magnesium for its bronchodilatory effect;38,39 helium-oxygen mixtures to reduce turbulent flow within the airways;40,41 and inhalational anesthetics to relax the constricted smooth muscles. Admission criteria for the severe asthmatic child can be simplified to any patient who is hypoxic (pO2 < 60 torr), hypercapnic (pCO2 > 40 torr), in significant respiratory distress after a trial of beta agonists, not able to take medicines at home, failed outpatient therapy, not able to follow-up with a physician if the child's condition worsens, or has any of the complications of asthma (i.e., pneumothorax, pneumomediastinum).16
Bronchopulmonary Dysplasia. Because of the advances in neonatology and the increased survival rate of very low birth weight (VLBW) infants, more emergency physicians are seeing children with chronic lung diseases, like bronchopulmonary dysplasia (BPD). BPD is the result of unresolved or abnormally repaired lung damage in the premature infant from high concentrations of oxygen or prolonged mechanical ventilation. These children require oxygen after their first month of life and have a physical exam and chest radiograph consistent with BPD. A strong risk factor for BPD is a birth weight lower than 1500 g.42 Because gestational age is closely related to birth weight, premature infants younger than 32 weeks are also closely associated with BPD.
The pathologic findings in BPD are often extensive. The airway becomes overdistended secondary to the barotrauma from positive-pressure ventilation and sheering of the epithelium results.43 Inflammatory cells then invade the airway causing inflammation, interstitial edema, and squamous metaplasia. Eventually, fibrosis occurs as the fibroblasts attempt to repair the injured lung tissue and the normal architecture of the lung gets altered. Along with the pulmonary changes, these children also suffer from other consequences of prematurity. Many have retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhages, gastroesophageal reflux, and neurologic impairments. In recent years, the severity of initial lung insult has been reduced with the use of surfactant and increasingly sophisticated newborn intensive care.
Most infants with BPD present to the emergency room secondary to excessive heterophonous wheezing often with crackles during a subsequent viral infection. RSV tends to be the most common culprit with one study showing 59% of children on home oxygen developing RSV by two years of age.44 Those children who demonstrate significant hypoxia over a prolonged interval may also develop cor pulmonale. Children with BPD are often on home oxygen to avoid growth impairment, diuretics to decrease interstitial edema, and tube feedings to ensure an adequate caloric intake. Bronchodilator therapy in some cases controls the baseline wheezing, however exacerbations can occur, requiring steroids to decrease parenchymal inflammation. Their chest radiograph often shows hyperinflation and interstitial changes. As the child grows and matures, the airway enlarges and these children often have improvement in their pulmonary function tests.45
Aspiration. Any anatomical or functional disorder that may cause a foreign material to be inhaled, and results in obstruction and inflammation of the airways, is reviewed in this section. Three separate causes of aspiration will be discussed tracheoesophageal fistulas, neuromuscular diseases that may involve the swallowing mechanism, and gastroesophageal reflux. Foreign body aspirations will be covered later in this paper, since most commonly it occurs in children older than 1 year of age.
Tracheoesophageal Fistula. The tracheoesophageal fistula (TEF) group of anomalies is characterized by a congenital communication between the esophagus and some part of the tracheobronchial tree below the glottis. Many types of these fistulous tracts may occur, yet the most common is esophageal atresia or an esophageal pouch with a connection between the distal, unattached portion of the esophagus and the trachea. This anomaly is often diagnosed in the newborn nursery as the infant has difficulty feeding and a nasogastric tube is seen curled in the esophageal pouch on chest radiograph. (See Figure 2.) H-type fistulas, on the other hand, are connections between the esophagus and the tracheobronchial tree without any atresia. These communicating tracts are less common and are only seen in approximately 6% of all TEFs.46 Because both the esophagus and trachea are patent and the condition is rare, these communications are easily missed early in life and are not diagnosed until the infant is older. One study, by Karnak et al, showed that 58% of the cases they reviewed had a delay in diagnosis ranging from 26 days to four years.47
Children with TEF often present with complaints of choking and coughing during feeding that has plagued them since birth. They also suffer from intermittent and chronic wheezing from the repetitive transfer of secretions causing airway inflammation. Multiple bouts of aspirations can result in persistent pulmonary infections. Occasionally, if the fistula connects the trachea to the distal esophagus, the stomach can appear distended and it may be tympanitic on physical exam. Some children with TEFs will have other anomalies along with their pulmonary problems. Skeletal malformations, like vertebral and radial anomalies, renal problems, cardiovascular malformations, and anal atresia have all been associated with TEF, and these grouped anomalies are given the acronym, VATER syndrome.
Even if an H-type fistula is suspected by clinical history and physical exam, the diagnosis is still difficult. Chest radiographs may only show recurrent infiltrates suggestive of pneumonia. Occasionally air may be visualized within the esophagus on the lateral view. Nasogastric tubes have been placed into the distal esophagus with the open end under water. As the catheter tip passes the fistulous tract, air bubbles can be noted in the water.47 Other radiographic and visual images are also used to demonstrate the anomaly. A barium swallow can show the defect, but the dye may miss the fistulous tract if it has an unusual angle. Cine-esophagography has been shown to improve the chances of finding the aberrant tract since it demonstrates momentary filling and emptying more readily. Direct visual examination of the fistula endoscopically or by bronchoscopy is often recommended to confirm the diagnosis. Some investigators encourage placing methylene blue dye in the trachea by an endotracheal tube prior to endoscopy in order to better visualize the connection. No matter how the diagnosis is made, surgical correction is the definitive therapy.
Neuromuscular Diseases. Many children with systemic, neurologic, or muscular anomalies may suffer from a swallowing dysfunction that increases their risk for aspiration. They may not be able to protect their airway secondary to a poor cough reflex or because of an ineffective glottis. Also, some of these infants have difficulty with the coordination of swallowing and the routine process of breathing. As a result, they may present with multiple bouts of pneumonia frequently with chronic, heterophonous wheezes. On suctioning of their secretions, formula may be recovered from their trachea; this would assure the diagnosis. A diagnostic barium swallow may visualize the barium entering the airway during the swallowing mechanism. Often, treatment is supportive, with upright feeding of small amounts of formula. Occasionally, corrective surgery may benefit these children (i.e., in the case of a child with cleft palate), or a tracheostomy is required if the problem is severe.
Gastroesophageal Reflux. Gastroesophageal reflux (GER) is the passive backflow of gastric contents into the esophagus secondary to an underdeveloped or relaxed lower esophageal sphincter. A study by Nelson et al showed the prevalence of GER, in children younger than 1 year of age, to be as high as 67%, with the peak at 4 months of age.48 Most of these children have a self-limited course without medical problems, while others may suffer from significant pulmonary and gastrointestinal symptoms. Parents of children with GER often complain that their child has excessive vomiting or they exhibit pain after feeding. When the reflux is severe, children may have a persistent cough, an expiratory wheeze, or recurrent bouts of pneumonia from aspiration. The exact mechanism for how GER induces pulmonary symptoms, like wheezing, is still unclear. However, two major hypotheses are currently in debate: 1) stimulation of vagal nerve endings from the reflux of acid may induce bronchoconstriction; and 2) small aspirations of gastric contents into the lung can cause significant mucosal inflammation.49
Most often, radiographic techniques are used to diagnose the symptomatic patient with gastroesophageal reflux. If a child has symptoms suggestive of GER and the conservative management is not helping, the first study to obtain is a barium swallow. The barium study is not required to actually diagnose GER, but it is used to evaluate the anatomy of the upper gastrointestinal tract. It excludes other causes of vomiting such as intestinal malrotation and gastric outlet obstruction. Medical therapy should not be started unless the barium swallow excludes other causes and the history is highly suggestive of GER. Other tests may be preferred to confirm the diagnosis of reflux, such as a radionuclide scintigraphy or pH probe monitoring. These are more sensitive studies since they reveal gastroesophageal function over time, while the barium swallow does not. Finally, bronchoscopy is recommended when the more sensitive tests are questionable for GER and the patient is still symptomatic on conservative therapy.
The treatment of GER is a three-stage process. First, when the history and physical exam strongly suggest reflux, it is reasonable to start conservative treatment measures. These techniques include smaller amounts of feeding more often, always feeding upright, and prone angled positioning for sleep. Often, these maneuvers alone will relieve the symptoms until the child is able to outgrow the problem. If symptoms persist and the anatomy of the child's GI tract is confirmed to be normal by barium swallow, it is reasonable to start medical management. This treatment includes a medicine to decrease gastric acid production and one to either increase the rate of gastric emptying or speed the process of peristalsis. If medical management fails and the patient is still symptomatic (i.e., failure to thrive or multiple cases of pneumonia), surgical correction of the lesion by a Nissen Fundoplication is warranted.
The patient in case # 1, had no response to bronchodilator therapy and their RSV antigen test was positive. Thus, the patient was diagnosed with bronchiolitis. Because the patient was hypoxic, hypercarbic, and in respiratory distress, he was admitted to the hospital for supportive care. He was admitted to a monitored bed as his initial blood gas showed early evidence of respiratory failure with a pCO2 of 54. He was discharged two days later without any complications.
Chronic Causes of Wheezing Children Younger than 1 Year
Case #2. An 11-month-old, white female presents to the ED because of coughing, fever (Tmax=103°F), and shortness of breath for one day. The parents thought the patient must have pneumonia, since this is the way she acted the last two times she was diagnosed with pneumonia. She was well until yesterday when she was noted to have clear rhinorrhea, a worsening cough, and an increase in her baseline wheezing. On the day of presentation, her symptoms worsened and her fever was not controlled by home antipyretics, so her parents brought her to the ED.
Birth history is unremarkable; her birth weight was 3.5 kg (50%). Her medical history is only significant for two previous bouts of pneumonia: the first at 4 months of age and the other at 7 months. The mother also noted that the pediatrician was concerned that the child was not growing as well as the other children in the office, but the doctor wanted to get one more growth point before working up this problem.
Physical exam revealed a small, slightly dehydrated, white female in mild to moderate respiratory distress and non-toxic appearing. Vital signs included a temperature of 102.1°F; heart rate, 130 beats/min; respiratory rate, 36 breaths/min; blood pressure, 90/40; pulse oximetry on room air, 94%; and weight of 7.0 kg (< 5%). Mild subcostal retractions were seen, yet grunting or flaring was not evident. Her lungs had crackles appreciated primarily in the right upper lobe. A diffuse, end expiratory, heterophonous wheeze was heard throughout all of the lung fields with a prolonged expiratory phase (ratio of 1:3 for inspiratory:expiratory). Cardiac exam was unremarkable. Peripheral pulses were strong in all four extremities. The child had slight curving of her nails consistent with early digital clubbing.
Initial laboratory data demonstrated a WBC of 21,000 cells/mm3, with 70% neutrophils and 12% bands. The hemoglobin was 9.8 g/dL; hematocrit, 30%; and platelets, 280,000. Electrolytes were normal except for a sodium of 134 mEq/L, a chloride of 92 mEq/L, and a bicarbonate of 28 mEq/L. Chest radiograph (see Figure 3) was interpreted as having overaeration, peribronchial thickening, and right upper lobe cystic changes.
Cystic Fibrosis. Cystic fibrosis (CF) is a disease of the exocrine glands that causes the production of a thick mucous that obstructs glandular function. It has an autosomal recessive inheritance pattern and is estimated to effect approximately 1 in 2000 live births.50 Recently, the gene for CF was located on the seventh chromosome with more than 240 different mutations of this gene resulting in clinical symptoms. Because of the gene mutation, a transport protein, conductance fibrosis transmembrane regulator (CFTR), is not produced causing chloride to be retained in epithelial cells and sodium to be absorbed.51 As a result, organs lined with epithelial cells become dehydrated and have an abundance of mucous.
Most commonly, the gastrointestinal and sinopulmonary systems are affected in patients with cystic fibrosis. Recognition of the disease may first be noted during the neonatal period as the child might present with bowel obstruction secondary to a meconium ileus. As they get older, the parents will state that the stools appear bulky and greasy and the infant may have rectal prolapse. The child may have failure to thrive as a manifestation. Eventually, maldigestion occurs due to pancreatic insufficiency. Other less common presentations of cystic fibrosis may include electrolyte depletion secondary to sweating, males with infertility and sinusitis, or patients with localized respiratory problems and nasal polyposis. Predominantly, children with cystic fibrosis usually present with frequent bouts of pneumonia and healthy periods in between episodes. Early in the disease, Staphylococcus aureus is the organism usually cultured. Pseudomonas aeruginosa is found as the disease progresses with Pseudo-monas cepacia present in the later stages. Children may complain of a constant, dry cough that, as they age, usually progresses to be productive and loose. This reflexive cough is due to significant mucus plugging and small airway hyperreactivity. As a result, heterophonous wheezing can commonly occur along with localized crackles.
If this diagnosis is suspected, a sweat chloride determination at a cystic fibrosis center is the test recommended. The child is considered to have CF if the chloride content in his or her sweat is higher than 60 mEq/L (between 40-60 mEq/L is unequivocal and repeat testing is required) and they have one or more of the symptoms suggestive of cystic fibrosis.52 Besides sweat testing, other tests may be offered to help make the diagnosis. This includes testing for evidence of malabsorption, visualizing the classic findings on chest radiograph, and culturing the common organisms from the sputum.
The treatment of cystic fibrosis is beyond the scope of this paper. However, it is geared toward supportive care and anticipation of expected problems. The goal is to prevent nutritional failure and to control respiratory infections. Reversible airway obstruction in patients with cystic fibrosis often improves with bronchodilator therapy. This makes it common for children with cystic fibrosis to be on bronchodilators.
Cardiovascular Anomalies. In children with congenital heart disease, wheezing may be the result of pulmonary vascular congestion. This problem may be caused by large left-to-right shunts, such as in a patient with an atrial septal defect and left ventricular heart failure, or from aberrent vessels causing an overflow of cardiac output to the right heart, as in total anomalous pulmonary venous return. Obstruction of the left heart, such as in mitral stenosis or rarely cor triatriatum, may also be associated with wheezing. Cough, tachypnea, and heterophonous wheezing tend to occur due to mucosal edema and secretions within the smaller airway.53 Infants may only present with poor feeding and decreased activity. Many of these patients are misdiagnosed as having bronchiolitis or asthma initially, especially if no murmur is appreciated. A chest radiograph often demonstrates cardiomegaly, vascular congestion, and other signs of heart failure. If bronchial compression results from an enlarged pulmonary artery, atelectasis may be observed on the chest x-ray and could lead one to misdiagnose the problem as a primary pulmonary disease. Surgical correction of the aberrant lesion is necessary.
Any anomalous vessel in the thoracic cavity may also cause wheezing due to tracheobronchial compression and the obstruction of air flow; as in the case of an anomalous inominate artery or a right aortic arch with a ligamentum arteriosum. Most commonly tracheal obstruction from a vessel is the result of a double aortic arch. In this situation, the aorta bifurcates around the trachea and/or esophagus. As a result, tracheal compression occurs and the child tends to present with a homophonous wheeze that may be appreciated on inspiration as well as expiration. Children will often be noted to sit with their neck extended and no murmurs are heard on exam. The diagnosis is made by barium swallow showing tracheal compression, by bronchoscopy displaying a pulsating object compressing the trachea, by MRI, or by angiography. Surgical treatment is recommended, but the procedure may not be urgent if the child is asymptomatic or if the impingement is mild. Even after surgical correction, children may continue to wheeze as a result of defected cartilage, which occurred during fetal development, leaving persistent tracheomalacia or bronchomalacia.5
Defective Host Defenses. Children with various defects in host defense mechanisms often present with intermittent wheezing and recurrent pulmonary infections. These defenses can range from a defect in the antibodies and cells needed to fight infection, as in the case of humoral or cellular-mediated deficiencies (i.e., hypogammaglobulinemia or DiGeorge Syndrome), or in the actual defenses within the lungs, as in immotile cilia syndrome. With repeated infections, bronchiectasis, a dilatation of the bronchi due to defects in the supporting structures of the lungs, can result and cause focal wheezing due to obstruction from permanent lung damage.
Immotile Cilia Syndrome. Ciliary and goblet cells line the respiratory epithelium and both work to produce mucociliary transport or clearance of secretions from inside the lung.54 Two mechanisms may cause a defect in this transport system: a genetic error that could lead to an abnormal ciliary structure and ineffective function; or an environmental stimulus that may damage the necessary cilia. Immotile cilia syndrome (or sometimes referred to as primary ciliary dyskinesia) is a congenital defect of the cilia. As a result, children with this problem are at increased risk for recurrent respiratory tract infections that could lead to bronchiectasis. Other associations have also been shown to occur with ciliary disease, including recurrent otitis media, nasal polyps, chronic sinusitis, and reduced male fertility. Approximately half of these patients suffer from situs inversus as well; this inclusion with the other symptoms has been termed Kartagener's Syndrome.
Children with immotile cilia syndrome may present early in life with a continuous purulent rhinorrhea, persistent otitis media, and multiple bouts of bacterial pneumonia often associated with wheezing and crackles. They also complain of a nocturnal, dry cough and varying degrees of wheezing. These lower respiratory symptoms are the result of poor mucous clearance and airway obstruction. Usually, their upper respiratory symptoms, like sinusitis and otitis media, are worse than their lower tract disease. Recurrence of infection after a course of antibiotics is common.
Because this disease is rare, with only 1 in 16,000 children affected, many fail to search for this diagnosis.50 If suspected by history or physical exam, bronchoscopy could be performed showing a decreased ciliary movement. Ultimately, biopsy of the ciliary bronchial mucosa will display the defect in the structure of the cilia under electron microscopy. Chest radiograph, if obtained, may show nonspecific findings, such as atelectasis, pneumonia, or possibly bronchiectasis. A proportion will have a rotational abnormality on chest x-ray, such as dextrocardia. Treatment is geared towards relieving acute exacerbations with antibiotics and aggressive chest physiotherapy. Some authors have even advocated for prophylactic antibiotics in these patients. Without adequate treatment of pulmonary disease, the lungs will show a progressive, rapid deterioration.
Immune Deficiency Syndromes. Similar to primary ciliary dyskinesia, patients with congenital immunodeficiency states also develop multiple sinopulmonary infections during their infant years. Cellular and humoral immunity is basically dependent on two cell lines, T and B lymphocytes. Both of these lymphocytes originate from a common bone marrow stem cell. Patients with B cell deficiencies, such as congenital hypogammaglobulinemia, often present after 6 months of age when the mother's transferred immune protection from IgG dissipates. Most commonly they have absent lymphoid tissue and multiple bouts of sinopulmonary infections from pyogenic and enteric organisms. T lymphocyte deficiencies, like DiGeorge Syndrome, often present with recurrent opportunistic infections (i.e., fungi, P. carinii), growth retardation, and a family history of early sudden death. With multiple upper and lower respiratory tract infections comes increased mucus production in the lungs and more bronchial obstruction. Some patients will develop bronchiectasis, while others may just suffer from bronchoconstriction in response to the recurrent infections. In either case, these patients are more apt to have a heterophonous wheeze.
Once the diagnosis is suspected, specific laboratory tests should be ordered. Serum immunoglobulins (IgA, IgG, and IgM) and specific antibody titers to recognizable antigens, such as tetanus, must be quantitated in order to rule out a B lymphocyte deficiency. To test for T lymphocytes, skin testing for tuberculosis and an anergy panel may be placed and read in 48 hours. Treatment is centered on appropriate antibiotics to combat the confirmed infection. Immunoglobulin therapy in B cell disease has been shown to be valuable.
Structural Defects Within the Airway. Although uncommon, congenital anomalies within the airways may cause wheezing in infancy. This etiology often produces a homophonous wheeze since the central airways are usually affected. Bronchial stenosis, for example, is the narrowing of the bronchi secondary to a congenital anomaly or sometimes as a result of a thoracic surgical procedure. These patients will present with a persistent homophonous wheeze isolated to the affected side because of increased turbulence within the larger airway. Tracheal stenosis, on the other hand, often presents with stridor as most of the trachea is located outside the thoracic cavity; however, if the intrathoracic trachea is constricted, wheezing may result. Similar to stenosis, tracheomalacia and bronchomalacia, also causes a narrowing of the larger airways. In these children, the airway is more collapsible. Thus, high pressures produced during coughing or crying, results in increased expiratory wheezing. Conversely, during restful periods, the wheezing tends to lessen. Cystic anomalies or bronchial obstructions resulting in airway distension, like congenital lobar emphysema, may place a child in respiratory distress with wheezing, cough, and dyspnea as the presenting signs.55 They are often unresponsive to the traditional medical management for wheezing and then other diagnoses are considered. Pulmonary sequestration (lung tissue aberrantly receiving systemic circulation) has been known to present during infancy as a persistent, localized wheeze, unresponsive to medical therapy. These patients may have dullness to percussion, decreased breath sounds in the affected lobar region, and may be asymptomatic or have frequent pulmonary infections. Associated anomalies, such as diaphragmatic hernias and pericardial defects have been noted.
All of the congenital airway defects tend to be challenging to diagnose partly because they are rare and often not suspected. A chest radiograph may show a cystic lesion or hyperlucency isolated to one lobe, if congenital lobar emphysema is present. These patients are treated conservatively and the airway usually resolves over time. However, if symptoms are severe or other structures become displaced, surgical management is warranted. For patients with pulmonary sequestration, chest radiograph often demonstrates a triangular opacity with occasional bronchovascular marking displacement.1 Aortography is the diagnostic method of choice. (See Figure 4.) Finally, tracheal or bronchial stenosis or malacia are mainly diagnosed by clinical suspicion. Endoscopy is the only definitive way to make the proper diagnosis.
The child in case #2 had normal immunoglobulins and a normal PPD. She was treated with beta agonist therapy in the ED with minimal relief. The child was discharged home with steroids and beta agonists and she was to follow-up with pulmonology in 1 week. At her scheduled appointment, her sweat test showed a chloride content of 100 mEq/L and the diagnosis of cystic fibrosis was confirmed.
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