Wheezing in infants is a common and challenging problem. The significance of wheezing can range from a benign nuisance to that of a harbinger of a serious or fetal illness. Most of the time wheezing represents a significant symptom to an infant who is a fragile host. Thus, evaluation of an infant with wheezing requires an experienced physician with a thorough knowledge of the pathophysiology of the many different mechanisms which may cause the infant to wheeze.
The infant represents a particularly fragile host to airway disease because of the size of the airways. Since wheezing represents airway narrowing it is a more significant symptom in infants who already have small airways. The resistance to flow of air through a tube is inversely proportional to the fourth power of the diameter of the tube. Thus, a 16% reduction in the diameter of the rube doubles the resistance. A small additional narrowing of the airway is enough to cause respiratory failure in an infant whose airways are already small and whose compensatory mechanisms, such as control of breathing, ventilatory muscles, and ability to cough, are weaker than adults. The progression from health to respiratory failure can occur very rapidly in infants, particularly if subtle early warning signs are missed. In addition, the differential diagnosis of wheezing in infants is quite broad. Thus, wheezing in infancy presents a major clinical challenge.
Wheezing is a musical, high-pitched sound on exhalation, which generally comes from small airways as they partially collapse. Wheezing occurs on exhalation because that is when small airways collapse. During inhalation the negative pressure in the chest rends to hold the airways open. However, during exhalation positive pressure in the alveoli is conducted from the outside of the small airways and tends to collapse them. This is exaggerated during active exhalation when these pressures may be even higher. Usually wheezing is polyphonic. This means that multiple, slightly different high-pitched sounds are heard at the same time. This is because most of the etiologies which cause wheezing affect many small airways at the same time, and each one collapses at a slightly different time and creates a slightly different tone. The presence of monophonie or single tone wheezing suggests a single area of blockage, such as an isolated area of bronchomalacia or a foreign body. Wheezing is usually accompanied by an increase in the expiratory time. Normally, exhalation takes about Wi times longer than inhalation. However, during wheezing it is not uncommon for exhalation to take 2Vi to 4 times as long as inhalation. Thus, recording of the inspiratory/ expiratory ratio is an important observation in the wheezing infant. Wheezing is also frequently accompanied by an increase in respiratory rate. Young infants compensate for airway obstruction by increasing their rate more than older patients who are more likely to increase their tidal volume. Thus it is not uncommon for the wheezing infant to be breathing 80 EO 100 times per minute.
DIFFERENTIAL DIAGNOSIS OF WHEEZING IN INFANTS
MECHANISMS CAUSING WHEEZING
The small airways in infants may become narrowed by four general mechanisms. The airways may become obstructed by accumulation of mucous. Edema fluid around the small airways may narrow them. Peribronchial smooth muscle may contract, decreasing the diameter. Structural abnormalities may result in narrow segments.
Airway narrowing may be due to accumulation of mucous and airway secretions. Airway mucous glands hypertrophy and increase in number in response to chronic or recurrent irritation or infection. Mucous is cleared in the small airways by the action of the cilia, and in both the large and small airways by cough. The quantity of mucous can be increased by expectorants such as glyceryl guaiacolate, the active component in most over-the-counter cough medicines. Mucous may become more viscous and sticky during extreme dehydration, but mucous does not become less viscous by administration of excess fluids. The therapeutic approach to the infant with excess mucous secretions consists of removal of irritating factors, maneuvers which stimulate cough such as percussion and drainage, correction of dehydration, and avoidance of cough suppressants.
The tissues around the airway may become edematous and compress the airways. This is called peribronchial cuffing. Therapy of wheezing due to interstitial edema consists of avoidance of administration of excessive fluids, or sodium, which increase the interstitial space. Diuretics such as furosemide or chlorothiazide, which decrease interstitial fluid and stimulate pulmonary lymphatic flow are also quite helpful.
The airways may be narrowed' by contraction of bronchial smooth muscle. Normal infants who die have very little peribronchial smooth muscle at autopsy. However, it is now clear that infants with chronic lung disease rapidly develop large peribronchial smooth muscles which may contract and cause bronchospasm. Thus, while normal infants may not be responsive to bronchodilators, infants with persistent lung disease have peribronchial smooth muscle which is responsive to bronchodilators.
Finally, some infants have anatomic areas of narrowing or collapse of the airways. Abnormalities of the bronchial tree or abnormal structures such as blood vessels passing near the trachea may result in malformation or absence of trachea! or bronchial cartilage in a segment. This floppy segment may then be the source of persistent and intractable wheezing in a child who is otherwise happy and growing well.
The table outlines several common etiologies of wheezing in infants. Some of these, such as bronchopulmonary dyspJasia, may be easily ruled in or out by the history. Others, such as bronchomalacia, may require advanced techniques such as fiberoptic bronchoscopy to diagnose.
Infectious etiologies are the most common cause of wheezing in infants. Bronchiolitis is a major cause of morbidity and mortality in young infants every year. Respiratory syncytial virus is the most common etiology. It occurs in epidemics in winter months. Young infants frequently have fever, coryza, tachypnea, cough, and wheezing. Some develop complications such as atelectasis, apnea, or respiratory failure. Respiratory syncytial virus is a frequent cause of nosocomial infections. The mechanism of wheezing in respiratory syncytial virus includes excessive airway mucous; peribronchial edema; and in chronic cases, particularly in the infant with underlying lung disease, bronchial smooth muscle contraction. Other agents which may cause a similar picture include the influenza viruses, adenovirus, chlamydial pneumonia, and the other respiratory viral infections.
Asthma may cause wheezing in infants. However, the diagnosis of asthma may be difficult. The definition of asthma is recurrent episodes of airway obstruction. Thus it may be difficult to know whether an infant experiencing wheezing for the first time during a respiratory infection is merely wheezing in response to the infection or is experiencing the first of many bouts of asthma. In fact, Frick et al suggested that early viral respiratory infections incite the development of reactive airways in genetically susceptible hosts. ' Kattan et al found an increased incidence of reactive airways years following an episode of severe respiratory infection during infancy. 2 The differential between recurrent infection and asthma may become even more difficult in the infant exposed to multiple infections such as infants exposed to large numbers of children. Often the physician must take a wait-and-see position while attempting to minimize exposure to recurrent infection.
Bronchopulmonary dysplasia is now a common cause of wheezing during infancy. Bronchopulmonary dysplasia is the chronic lung disease which develops in infants with respiratory failure. Because these infants are frequently hospitalized and therefore easier to study, bronchopulmonary dysplasia represents the best understood model of wheezing in infancy. A history of neonatal lung disease causing respiratory failure with radiographie changes and oxygen dependency beyond 1 month of age are accepted as the criteria for diagnosing bronchopulmonary dysplasia. Infants with bronchopulmonary dysplasia may have increased mucous, peribronchial edema, bronchial smooth muscle, and cartilaginous damage all contributing to their wheezing.
Cystic fibrosis is a rare but significant cause of wheezing in infants. It should be considered in infants with recurrent or persistent wheezing, cough, recurrent pneumonia, poor weight gain, chronic diarrhea, or a history of hypochloremic dehydration. Cystic fibrosis may be diagnosed by a sweat chloride obtained by iontophoresis in a laboratory proficient in performing this exacting test. Infants with cystic fibrosis have wheezing due to accumulation of mucous in the airways. Other mechanisms are being investigated.
Recurrent aspiration may cause recurrent wheezing in infants. Many infants spit up some of the time and have gastroesophageal reflux demonstrated on barium esophogram. However very few of those wheeze because of recurrent aspiration. More commonly, recurrent aspiration is seen in the infant with neurologic problems who is unable to prevent aspiration during swallowing, or who aspirates during episodes of reflux. Clues to the diagnosis are the appearance of clubbing, a chest x-ray which shows hyperinflation and wandering infiltrates, the presence of fat-laden macrophages in a tracheal aspirate, and a positive esophageal pH study. If the aspiration is due to gastroesophageal reflux then a trial of Meclopromide and/or a fundoplication may be indicated. Since recurrent episodes of reflux cause further lung damage and make the infant a more risky candidate for surgery, judicious consideration on the indications and timing of surgery should be exercised.
Bronchomalacia is the presence of defects or excessive collapsibility of the cartilages of the bronchi. Children with bronchomalacia are often characterized as "happy wheezers. " They gain weight well and thrive and seem in no distress but always have prominent wheezing which is refractory to all therapy. This diagnosis may be made by visualizing the floppy segments during fiberoptic bronchoscopy. The treatment then is to allow the infant to grow so that the airways become larger and less prone to collapse.
Infants with tracheomalacia may have wheezing, or inspiratory or expiratory "honks. " This depends on the exact placement of the collapsible segment in the trachea. If it is high in the trachea and includes the extrathoracic segment the infant will have more problem with inspiration. If it is lower, the trachea will collapse during exhalation. Since this segment often interferes with cough, these infants are prone to recurrent pneumonias as well. Often a segment of tracheomalacia is present because of a vascular ring placing pressure on the trachea and interfering with the development of the normal trachea! cartilages. Usually the diagnosis of a vascular ring can be made on barium esophagram. An astute radiologist will also notice tracheomalacia during a cine-esophagram by noting the variable size of the trachea. Fiberoptic bronchoscopy makes the diagnosis definitive.
Foreign body aspiration is a rare cause of wheezing in the first 6 months of life but becomes increasingly common thereafter. The typical history is the sudden onset of wheezing, respiratory distress, or intercurrent fevers in a previously healthy infant without signs of a respiratory infection. A clear-cut history of choking, gagging or aspiration is obviously helpful. However, it is not uncommon to receive referrals of children who have been having symptoms for several months because of aspiration of a foreign body.
An important differential in approach to the wheezing infant is stridor. Physicians not accustomed to dealing with infants may mistake stridor for wheezing. Stridor occurs during inspiration because of collapse of the upper airway. Parents may describe the noise as wheezing or noisy or rattly breathing. Some lesions can cause both stridor and wheezing, such as one infant recently referred to the author. This 9-monthold infant had a sudden onset of respiratory distress, intermittent wheezing and stridor, and failure to gain weight for 3 months. A chest x-ray demonstrated a penny lodged in the esophagus at the thoracic inlet, causing intermittent compression of the extrathoracic trachea, giving stridor and also causing the infant to aspirate and wheeze.
APPROACH TO TREATMENT OF THE WHEEZING INFANT
The most important aspect of treatment of wheezing infants is an accurate diagnosis. Once the diagnosis is established and the mechanism identified, successful therapy is much more likely. Each etiology of wheezing has different components of the four mechanisms mentioned. The approach cannot be "shotgunned" because some treatments appropriate for some mechanisms may make other problems worse. For example, treatment with theophylline of an infant with wheezing due to gastroesophageal reflux and aspiration may transiently improve the wheezing but provoke more episodes of aspiration and wheezing. Because of the multitude of etiologies, treatment of the wheezing infant is controversial. However, with improvement and more widespread use of diagnostic techniques, the treatment of wheezing in infants is becoming more scientific. Specifically, in the past there have been no good objective tests to demonstrate the degree of airway obstruction or response to it in infants. The development of reproducible techniques to measure pulmonary function in infants in the last few years has made the possibility of scientific therapy a reality. So far, the best studies of these questions have been done in infants with bronchopulmonary dysplasia. Insofar as they pertain to the underlying mechanisms of wheezing, the principles established in the treatment of infants with bronchopulmonary dysplasia apply to infants with wheezing for other etiologies.
Infants who die with bronchopulmonary dysplasia often have marked hypertrophy of their bronchial smooth muscle. Therefore, clinicians began empirically using bronchodilators in infants with bronchopulmonary dysplasia. Kao et al using an infant body plethysmograph were able to demonstrate that inhalation of Isoproterenol was followed by a dramatic decrease in airway resistance which lasted several hours.4 In a subsequent study Kao demonstrated that infants with bronchopulmonary dysplasia have both a decrease in airway resistance and an increase in flow at functional residual capacity in response to Aminophylline as well. Treatment of infants with other etiologies of wheezing is more controversial. Spier et al were unable to demonstrate an increase in flow at functional residual capacity in infants with bronchiolitis. 5 Further studies are required to determine which infants with bronchio.Iitis have an improvement of their pulmonary function following either oral or aerosolized bronchodilators.
If the mechanism for wheezing is due to peribronchial cuffing and interstitial pulmonary edema, then one would expect that diuretics that decrease interstitial fluid and increase pulmonary lymphatic flow would be the treatment of choice. Again, Kaos studies in bronchopulmonary dysplasia have demonstrated that both Lasix and Diuril will decrease airway resistance and decrease compliance.6 Thus in the wheezing infant with bronchopulmonary dysplasia, diuretics can be quite helpful. However, diuretics are controversial in infants with bronchiolitis in whom the presence of interstitial pulmonary edema is less clear or in infants with bronchiolitis who may have copious airway secretions. Excessive use of diuretics may result in inspiration and decreased clearance of these secretions.
If the wheezing is due to excess secretions in the airways, then clearance of these secretions is the prime goal of therapy. In infants with cystic fibrosis, treatment with percussion and drainage may provoke cough and clearance of secretions and can be efficacious in clearing wheezes. Sometimes clearance of secretions is improved after usage of bronchodilators prior to percussion and drainage. However, in the infant prone to gastroesophageal reflux, percussion and drainage treatments may provoke more episodes and worsen the problem.
Only a small fraction of infants have wheezing due to structural abnormalities such as bronchomalacia. In this case the wheezing is usually refractory to all of these therapies and none are indicated.
Empiric trials of bronchodilators, diuretics, and percussion and drainage are warranted in well-defined groups of infants to determine their likelihood of efficacy. The astute clinician can note the effect of various therapies before and after treatment. The infant's mental status and degree of agitation and respiratory distress, respiratory rate, inspiratory/expiratory ratio should all be noted in addition to the presence or absence of wheezing. In most infants the clinician will be able to determine, using these signs, whether a particular therapy is helpful or not.
In summary, wheezing in infants is a common problem which represents considerable challenge in diagnosis and treatment. There are many different etiologies of wheezing in children. Viral infections are the most common, but the clinician should consider asthma, cystic fibrosis, aspiration, bronchopulmonary dysplasia, and structural abnormalities of the airways. The four mechanisms causing wheezing in infants are excessive mucous in the airways, peribronchial edema, contraction of peribronchial smooth muscle, and structural collapse of the airways. The optimal treatment modality depends on the etiology and the mechanisms involved. The best studied etiology of wheezing in infants is bronchopulmonary dysplasia. Studies have demonstrated that infants with bronchopulmonary dysplasia improve their pulmonary function following aerosolized bronchodilators, oral theophylline, intravenous furosemide, and oral chlorothiazide. Infants with wheezing due to other etiologies should be carefully evaluated for theit response to specific therapies.
1. Frick OL. German DF, Mills J: Development of allergy in children: Association with viral infections. ) Atkrgy CIm Immunol 1979: 63:228.
2. Kattan M. Keens TC, LaPierre JG. et al: Pulmonary (unction abnormalities m symptom-free children after broncholitis, Pediatrics 1977, 59;683-688.
3. Nickercnn BG: Bronchopulmonary dysplasia: Chronic pulmdnarv disease following neonatal respiratory failure. Chest 1985; 87:528-515.
4. Kao L(J. Warborton D. Platrker ACG. et al: Eflect ot isnpnneienol inhalation un Jirway resistance in chronic hronchopulmnnary dvsplasia. nriiimnts 1984; 7):W9-5H.
5. Spier S, LaPierre JG, Lamarre A: Response to salKitamol during a but tit second episode rf wheezing in infancy. Am Rev Respir Du f)8S; 131:A259.
6. Kao LC, VCarburton ?. Chene MH, et al: Effect tit' ural diuretics on pulmonary mechanics in infants with chronic hninchopulmonarv dysplasia: Results of a doubleHind crossover sequential mal. Pediatrics 1984: 74; '7-44
DIFFERENTIAL DIAGNOSIS OF WHEEZING IN INFANTS