Bronchiolitis

OVERVIEW: What every practitioner needs to know

Bronchiolitis is a common clinical syndrome of infants and young children involving infection of the lower respiratory tract, typically by seasonal viruses such as respiratory syncytial virus (RSV). Bronchiolitis affects up to one third of children in the first 2 years of life and is the leading cause of hospitalization among infants in the United States. Although hospitalization rates and medical expenditures due to bronchiolitis have increased over recent decades, mortality remains low.

Most children with bronchiolitis can be diagnosed based on clinical findings alone, and additional laboratory or radiology testing adds little to management and is not recommended for routine care. Atypical or severe presentations should prompt consideration of the differential diagnosis, since other conditions can present with respiratory distress during the winter viral season.

Recommended therapy for bronchiolitis has been controversial, and currently no treatment beyond routine supportive care has been shown to improve long-term outcomes. Bronchodilators may have a short-term benefit in selected children with bronchiolitis, although this must be weighed against their adverse effects and costs. Current guidelines recommend against regular use of these agents. Epinephrine may be more effective than albuterol but is generally limited to a role as a rescue agent in the hospital setting.

For inpatients, nebulized hypertonic saline may shorten the length of hospitalization. Limited data suggest that patients with severe disease may benefit from treatment with high flow nasal cannula oxygen, helium-oxygen mixtures or nasal continuous positive airway pressure. Corticosteroids have not been found to be beneficial for routine treatment of infants with bronchiolitis. Further evidence is required to verify the potential benefit of combination therapies such as epinephrine and dexamethasone.

Are you sure your patient has bronchiolitis? What are the typical findings for this disease?

The definition of bronchiolitis varies in research studies and clinical practice guidelines. This may relate to the specificity required in distinguishing cases caused by primary viral infection (classically with RSV in a healthy infant) from viral-induced wheezing in a young child with chronic asthma (typically due to rhinovirus). The presentations of these different causes can overlap substantially and confound simplistic approaches to diagnosis and therapy. In addition, there is variability internationally in the definition of bronchiolitis, with more specific definitions proposed in the United Kingdom compared with the United States, where wheeze is generally considered the hallmark finding in association with a variety of other symptoms.

Combining these definitions, the most typical findings include:

• a child less than 2 years old presenting with onset of wheezing and signs of a concomitant upper respiratory tract infection such as rhinorrhea and cough;

• coarse rales on examination, typically heard bilaterally in the lung fields;

• signs of respiratory distress, including intercostal and/or suprasternal retractions, nasal flaring, or breathing with abdominal muscles;

• fever may be present or absent.

What other disease/condition shares some of these symptoms?

The differential diagnosis for bronchiolitis includes:

• Nonviral lung infections

  Bacterial pneumonia

  Mycoplasma pneumonia

  Chlamydia trachomatis

  Mycobacterium tuberculosis

• Gastroesophageal reflux

• Anatomic abnormalities

• Airway or esophageal foreign body

• Laryngeal or tracheomalacia

• Vascular ring or sling

• Tracheoesophageal fistula

• Bronchogenic cyst

• Mediastinal mass

• Congestive heart failure

• Allergic reaction

• Cystic fibrosis

What caused this disease to develop at this time?

Pathophysiologic characteristics: Bronchiolitis occurs when a respiratory virus descends from the upper airway to the bronchioles, causing airway inflammation and obstruction with mucus and fibrin. The role of bronchospasm is debated but does not appear to play an important part in young infants with classic presentation. Bronchiolitis can occur in healthy infants, but underlying conditions such as chronic lung disease, immunosuppression, or impaired airway clearance due to exposures (e.g., tobacco smoke) or underlying neuromuscular disease can worsen the process. Underlying cardiovascular disease may be worsened by hypoxemia due to ventilation-perfusion mismatch, increased pulmonary vascular pressures, or other effects of bronchiolitis. Genetic variation may play a role, but at this time polymorphisms have only been associated without clear causality.

Epidemiologic features: Bronchiolitis is estimated to occur in up to one third of children during the first 2 years of life, with about 3% of all infants in the United States requiring hospitalization. Rates of hospitalization doubled over the 1980s and 90s, although it is unclear whether this is due to a change in the severity of disease or the threshold for hospitalization caused by the advent of new technology such as pulse oximetry. Recent estimates show mild declines in hospitalizations. Mortality is estimated at about 2/100,000 live births.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Laboratory studies can be used to identify the viral infection causing bronchiolitis or to detect complications of bronchiolitis such as concomitant bacterial infections. In general, identification of the virus does not provide information that is useful in guiding the management of an individual patient and is not recommended for routine care of bronchiolitis. Viral testing can be useful for epidemiologic purposes to identify the onset of RSV season or as part of a program to prevent spread of nosocomial infection in a hospital setting. However, programs developing cohorts of patients using symptoms alone without viral testing have also been successful in reducing nosocomial spread.

Viral testing

Testing is performed on respiratory specimens, typically obtained by suction or swabbing of secretions from the upper respiratory tract:

Viral culture has been the traditional gold standard for virus identification, although it requires several days for results to obtained.

Molecular techniques such as polymerase chain reaction have high sensitivity and specificity and can be batched for turnaround within hours. The high sensitivity of these tests has been reported to exceed that of culture because of the low quantity of virus required to produce positive results. This can also cause potential confusion if a virus from a prior infection causes a positive result. Studies have found that up to 40% of asymptomatic infants may test positive by PCR for some respiratory virus, in particular rhinovirus.

Rapid viral antigen tests have varying sensitivity and specificity depending on the test used and the quality of respiratory specimen that is provided. Immunoassay tests generally have poorer test characteristics than direct fluorescence tests. Interpretation of any test with limited accuracy needs to be adjusted based on the expected prevalence of the disease. In periods of peak viral prevalence, the predictive value of a positive test result is generally good, but in times of low prevalence, false-positive results may be more common than true-positive results.

Concomitant bacterial infection

An important consideration for any viral test is the fact that respiratory viruses such as RSV can be shed for weeks after an acute infection. Therefore a viral test performed on a febrile child may represent an earlier infection rather than the cause of the acute fever. This has been a limitation of studies attempting to use testing for common respiratory viruses as a screen for bacterial infection in febrile infants. In general, studies using clinical criteria of bronchiolitis rather than viral testing alone have had low rates of concomitant bacterial infection.

For febrile infants with clinical symptoms of bronchiolitis during the first 2 months of life, rates of serious bacterial infection have been significantly lower than the rates reported for febrile infants in general, in particular for meningitis and bacteremia. Rates of occult urinary tract infection are also lower but remain common enough (5%-6%) to warrant routine investigation. Evaluation for bacterial infection in older infants should be based on specific signs or symptoms. Acute otitis media has been reported as a complication in as many as 60% of cases of bronchiolitis although the need for treatment with antibacterials is unclear.

Would imaging studies be helpful? If so, which ones?

Imaging modalities such as chest radiography can be used to rule out other potential causes of respiratory distress, evaluate the extent of pulmonary disease, or detect potential complications such as bacterial pneumonia. In general, for typical cases of bronchiolitis, routine chest radiography provides little information to guide management and is not recommended. In one study of 265 children younger than 2 years of age with a typical onset of bronchiolitis presenting as a first episode of viral-associated wheezing in an otherwise healthy child with a non-toxic appearance, none of the radiographs influenced acute management, and the rate of antibiotic use increased because of inappropriate interpretation of radiographs with a viral pattern.

Radiography is indicated in children with atypical presentations or severe symptoms. The degree of atelectasis and other typical findings of bronchiolitis on radiographs have been associated with the severity of the disease course, but it is unclear if this adds information to clinical examination findings.

If you are able to confirm that the patient has bronchiolitis, what treatment should be initiated?

Supportive care is the mainstay of treatment for bronchiolitis. Parents should be instructed in assessment and provision of basic supportive measures, as symptoms may progress over the course of the illness.

Assessment and clearance of the upper airway using suction can improve respiratory distress, particularly in young infants who are obligate nasal breathers.

Oxygenation should be assessed using pulse oximetry, and oxygen should be provided to keep saturation levels greater than 90%. Arbitrary higher thresholds for initiating oxygen may result in unnecessary hospitalization, as was documented in a recent randomized trial. Transient episodes of hypoxemia may resolve with positioning and suctioning. A recent study using home saturation monitoring identified that these events occur commonly in infants with bronchiolitis managed as outpatients and are not associated with progression of disease. Use of continuous pulse oximetry can detect self-limited hypoxemic episodes that may result in prolongation of hospital stay; continuous monitoring can be discontinued as an infant improves. Studies of home oxygen for stable infants with bronchiolitis have demonstrated safety in high-altitude locales.

Hydration status should be assessed and appropriate intervention provided. Most infants with bronchiolitis can continue to feed by mouth. For severely ill infants, fluid can be provided by the nasogastric or intravenous route. Intake and output should be assessed, as free water retention can be a complication of bronchiolitis and other pulmonary disorders.

Routine chest physiotherapy was not demonstrated to be beneficial in one small study.

Bronchodilators: Use of bronchodilators such as albuterol has not been found to improve outcomes in infants with a typical presentation of bronchiolitis. Most of these studies were limited to infants under a year of age with a first presentation of wheeze associated with a viral respiratory infection. In older children or those with recurrent episodes of wheezing a trial of albuterol may be considered using a nebulizer (usually at a dose of 2.5 mg in 3 mL saline) or metered dose inhaler (two puffs) with a spacer and face mask. Epinephrine may be more effective (see discussion in the section discussing evidence) but is generally limited to the hospital setting and given by nebulizer (3 mL of 1:1000 L-epinephrine solution or 0.5 mL of 2.25% racemic epinephrine diluted with 2.5 mL saline). Assessment of response to bronchodilators should be conducted in an objective fashion to determine if there has been a response, and treatment should be continued only in patients in whom a benefit has been observed.

Hypertonic saline: Limited evidence suggests that use of repeated doses of nebulized hypertonic saline (usually 3%) given to children hospitalized with bronchiolitis may reduce length of stay. Since bronchospasm is a potential complication of hypertonic saline, some studies have given it with a bronchodilator. Studies in the outpatient setting have found varying results and use is not recommended in recent treatment guidelines.

What are the adverse effects associated with each treatment option?

Bronchodilators can cause a variety of potential harms, including tachycardia, hypoxemia, hypertension, pallor, vomiting, and tremor. Systematic reviews of studies using bronchodilators have not found significant adverse effects in standard use for healthy infants. Hypertonic saline can cause bronchospasm although this does not appear to be a clinically important effect when given with a bronchodilator.

What are the possible outcomes of bronchiolitis?

Prognosis

Outcomes for infants with bronchiolitis are generally good, although the short-term burden on the child and family can be significant. About 1 in 10 infants with bronchiolitis are hospitalized for supportive care. Risk for severe disease, such as the need for mechanical ventilation, is increased among infants with underlying cardiopulmonary disease, immunodeficiency, prematurity, and young age (<2-3 months). Mortality from bronchiolitis has remained low over recent decades at about 2.2/100,000 live births.

Recovery from bronchiolitis can require weeks; the median duration of symptoms has been estimated at 12 days, but up to 20% of children continued to have intermittent cough at 3 weeks after onset of illness. A long-term association with increased risk for asthma in later childhood has been demonstrated for infants with severe bronchiolitis requiring hospitalization, although it is unclear if this is a complication of bronchiolitis or an underlying characteristic of the child.

Treatment options such as bronchodilators are generally safe but have limited short-term efficacy and should be continued only when they demonstrate benefit after a trial of therapy. Therapies such as leukotriene-receptor antagonists intended to speed recovery and reduce long-term effects of bronchiolitis have not been found to be effective.

What causes this disease and how frequent is it?

Epidemiologic features

Bronchiolitis is caused by a variety of infectious agents but most typically by respiratory viruses common during the winter season.

These viruses include the following:

RSV is a paramyxovirus that circulates in annual epidemics during the winter months and accounts for 50%-80% of bronchiolitis cases. RSV is a ubiquitous agent during this season, infecting 90% of children during the first 2 years of life, a third of whom experience lower respiratory tract infection. Reinfections with RSV occur throughout life but generally are limited to the upper airway in healthy individuals. RSV spreads by large droplet transmission directly from patient to patient or by contact with viral particles on surfaces, which remain infectious for several hours.

Human metapneumovirus (HMPV) is another paramyxovirus that has infectious characteristics similar to those of RSV in regard to seasonal characteristics and mode of infection. HMPV was relatively recently described, but studies of banked specimens show it consistently has accounted for 3%-19% of bronchiolitis cases. The clinical course of HMPV and RSV appear to be similar.

Rhinovirus has an emerging role as a cause of bronchiolitis and is more common in children older than 6 months of age. Rhinovirus is known as a common trigger of wheezing in older children with chronic lung disease and asthma. Rhinovirus is a common coinfecting agent with RSV or HMPV.

Parainfluenza (especially type 3)

Influenza

Coinfection with multiple viral agents is seen in 10%-30% of children hospitalized with bronchiolitis. The impact of infection with multiple viruses on the risk for severe disease is unclear, with varying results across different cohorts.

The genetics of bronchiolitis is an evolving area of research. Various single-nucleotide polymorphisms have been associated with an increased risk for severe disease, but they are not clearly established.

How do these pathogens/genes/exposures cause the disease?

Infection with respiratory virus descends from the upper airway, typically over several days, causing inflammation of the epithelium of the bronchioles, accompanying edema, and peribronchial infiltration by mononuclear and other white blood cells. The airways can become plugged with mucus, necrotic epithelium, and fibrin, leading to atelectasis and air trapping distal to the obstruction. Ventilatory-perfusion mismatch can lead to hypoxemia. Airway inflammation can cause smooth muscle constriction, although bronchospasm appears to play little role in producing symptoms for typical cases of bronchiolitis in young infants. Exposures or underlying conditions, such as immunodeficiency or neuromuscular disease, that impair airway clearance can lead to more severe disease.

Other clinical manifestations that might help with diagnosis and management

In outpatient studies, hypoxemia in the mild range (<94%-95%) has been associated with an increased need for hospitalization and progression to severe disease. This concern may play a role in increased hospitalization rates for bronchiolitis over recent decades with the availability of pulse oximetry, since this level of hypoxemia is not detectable on physical examination alone. A recent trial suggests that mild hypoxemia may contribute to unnecessary hospitalization, as infants for whom the pulse oximetry reading was artificially raised were more frequently discharged without an increase in return visits (see discussion in the evidence section).

Studies assessing inpatients with bronchiolitis have demonstrated prolongation of hospital stay resulting from the use of continuous pulse oximetry and detection of transient hypoxemia.

In general, mild hypoxemia should be a consideration in decision making and level of monitoring of infants with bronchiolitis, but oxygen should be initiated only when clearly indicated (typically at a saturation <90%), and continuous monitoring should be discontinued as the infant improves.

What complications might you expect from the disease or treatment of the disease?

Acute complications from bronchiolitis include respiratory failure and apnea requiring mechanical ventilation. Risk for respiratory failure has been consistently associated with the presence of underlying chronic illness, including prematurity, congenital heart disease, chronic lung disease, and immunodeficiency, although it also occurs in healthy infants. Apnea occurs in fewer than 5% of infants hospitalized with bronchiolitis and has been associated with age less than 1 month or a postconceptual age of less than 48 weeks for premature infants.

How can bronchiolitis be prevented?

Prevention of bronchiolitis is not currently an option because vaccines to prevent infection with common causes such as RSV have not proved to be successful. Interventions to reduce morbidity of bronchiolitis have been focused on high-risk populations, such as premature infants or those with underlying cardiopulmonary disease or immunodeficiency.

Prophylactic therapy with RSV immunoglobulin (palivizumab) has been found to be safe and effective in reducing morbidity from RSV in high-risk infants. Guidelines published by the American Academy of Pediatrics in 2014 recommend therapy for infants with hemodynamically significant heart disease or chronic lung disease of prematurity born before 32 weeks’ gestation and requiring supplemental oxygen for at least the first 28 days of life. Other populations, such as infants with severe immunodeficiency or neuromuscular disease, have not been well studied but may benefit from therapy.

Environmental exposures: Passive exposure to tobacco smoke is known to be a risk factor for many adverse health-related outcomes, although it has not been clearly linked to risk of outcomes in bronchiolitis such as hospitalization. Exposure to other young children in a home or child-care setting is a risk factor for high-risk infants.

Genetic factors: Studies have linked various single-nucleotide polymorphisms with risk for severe bronchiolitis, although these associations are preliminary and not appropriate for clinical use.

Nutritional factors: Breastfeeding has not been shown to reduce risk of hospitalization for bronchiolitis, although guidelines encourage breastfeeding in all infants. Other potential nutritional risk factors such as vitamin D status are under investigation but are not clearly linked to outcomes.

What is the evidence?

Treatment of bronchiolitis has been a topic of controversy and fairly extensive research in comparison with other topics in pediatrics. There are many challenges in assessing the efficacy of therapies for this condition. Infants with bronchiolitis manifest multiple physical findings, such as use of accessory muscles, increased respiratory rate, and other signs of increased work of breathing; findings on lung auscultation, such as rales and wheezes, and abnormalities on physiologic measures such as pulse oximetry. These findings change rapidly from minute to minute in bronchiolitis, in particular with clearance of mucus from the airways that can affect all of these findings. For these reasons it may be difficult to determine whether a change in status was attributable to a therapy.

For short-term improvement there are several bronchiolitis scores (such as the Respiratory Distress Assessment Instrument often used in research studies) that have some evidence for interobserver reliability and limited evidence of validity. A recent trial has called into question the role of mild hypoxemia in driving unnecessary hospitalizations. The investigators randomized otherwise healthy infants with mild to moderate bronchiolitis to receive an altered pulse oximeter that read three points above the true reading. Although infants in the altered oximeter group were less likely to be hospitalized (25% versus 41% for the control group), they were not more likely to return to the hospital for unscheduled care. Another study by this group documented that transient hypoxemia occurs commonly in infants with bronchiolitis managed at home, and these events were not associated with return visits to the hospital or other measures of progression of disease. Longer term outcomes may be assessed by duration of symptoms or requirement for care such as hospitalization, although these also are confounded by the variation in criteria used by different providers. These issues and current recommendations for therapy are summarized in a Clinical Practice Guideline published by the American Academy of Pediatrics and updated in 2014.

“American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Clinical Practice Guideline: Diagnosis and Management of Bronchiolitis”. Pediatrics. vol. 134. 2014. pp. e1474-e1502.

Schuh, S, Freedman, S, Coates, A. “Effect of oximetry on hospitalization in bronchiolitis: A randomized clinical trial”. JAMA. vol. 312. 2014 Aug 20. pp. 712-8.

Principi, T, Coates, AL, Parkin, PC, Stephens, D, DaSilva, Z, Schuh, s. “Effect of oxygen desaturations on subsequent medical visits in infants discharged from the emergency department with bronchiolitis”. JAMA Pediatr.

Many randomized controlled trials have assessed the efficacy of bronchodilators such as inhaled albuterol and epinephrine for bronchiolitis. To assess this literature, it is best to reference a rigorous systematic review of trials as has been published by the international Cochrane Collaboration.

Gadomski, AM, Bhasale, AL. ” Bronchodilators for bronchiolitis”. Cochrane Database of Systematic Reviews. 2014. pp. 6(This review of 30 trials including a total of 1992 infants found no improvement in oxygen saturation, hospitalization rate or duration, or time to resolution of illness attributable to bronchodilators. In outpatient studies there was a statistically significant improvement in clinical scores that was of questionable clinical significance. Results varied across trials, and there was also improvement noted in control patients. The review concludes that given their adverse effects and no proven benefit on outcomes, bronchodilators are not effective in the routine management of bronchiolitis.)

Hartling, L, Bialy, LM, Vandermeer, B. “Epinephrine for bronchiolitis”. Cochrane Database of Systematic Reviews. vol. 6. 2011. pp. CD003123

Hartling, L, Fernandes, RM, Bialy, L. “Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and met-analysis”. BMJ. vol. 342. 2011. pp. d1714

The Cochrane Collaboration review assessed 14 trials comparing epinephrine with either other bronchodilators or placebo. Overall there was some evidence of benefit among children treated with epinephrine as outpatients on short-term measures such as clinical scores and oxygen saturation when compared with placebo. When compared with albuterol, small improvement in short-term measures was also observed. These studies did not demonstrate a reduction in long-term hospitalization rates, and evidence of benefit was limited to a few selected short-term outcomes when assessed for hospitalized children.

The lack of effect of epinephrine in reducing hospitalization rates was also reported in a large recent trial that also assessed corticosteroids (see below). The more recent meta-analysis by the same group included the recent trial and, when all data was pooled, found a reduction in hospitalization rate by 33% when epinephrine was given in the emergency department but no significant difference in hospitalization at 7 days.

Overall, the current evidence on the use of bronchodilators for bronchiolitis supports, at best, a short-term improvement in clinical measures with no demonstrated improvement in long-term outcomes. Epinephrine may be more effective than albuterol, but administration is generally limited to the hospital setting. The AAP guideline recommends against routine use of bronchodilators for all children with bronchiolitis, but epinephrine may be useful as a rescue agent in the hospital setting.

Corneli, HM, Zorc, JJ, Majahan, P. “A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis”. N Engl J Med. vol. 357. 2007. pp. 331-9.

Plint, AC, Johnson, DW, Patel, H. vol. 360. 2009. pp. 2079-89. (These two large multicenter trials based in the emergency department assessed the role of corticosteroids for bronchiolitis. The first, from the Pediatric Emergency Care Applied Research Network (PECARN) network in the United States, found no benefit of a single dose of oral dexamethasone compared with placebo in reducing hospitalization or improving bronchiolitis symptoms.

The second, from the Pediatric Emergency Research Canada (PERC) network in Canada, found similar results using a longer course of dexamethasone, but also explored two other interventions in a factorial trial design. Epinephrine nebulization alone did not reduce hospitalization, but the combination of epinephrine with oral dexamethasone showed a potential benefit, equivalent to a relative reduction of 35% in hospitalization rate over the 7 days after the emergency department visit. Because this interaction effect was not hypothesized in advance, the results needed to be adjusted for multiple analyses and did not reach the level of statistical significance.

Synergy between corticosteroids and beta-agonists is well described in other pulmonary conditions such as asthma, but a definitive recommendation regarding use of these agents for bronchiolitis will await further evidence.

The AAP Bronchiolitis Practice Guideline recommends against routine use of corticosteroids for treatment of bronchiolitis.)

Several trials have assessed the role of nebulized hypertonic saline for treatment of bronchiolitis. This agent may have an effect on clearing mucus and other potential mechanisms and is used in the management of cystic fibrosis.

Zhang, L, Mendoza-Sassi, RA, Wainwright, C, Klasses, TP. “Cochrane Database of Systematic Reviews”. vol. 74. 2013. pp. CD006458(This review of eleven trials found benefit among children hospitalized for bronchiolitis in improving clinical scores and reducing hospital length of stay compared with placebo. Studies in the emergency department have found varying results but no consistent benefit.)

Schuh, S, Lalani, A, Allen, U. “Evaluation of the utility of radiography in acute bronchiolitis”. J Pediatr. vol. 150. 2007. pp. 429-33.

Ongoing controversies regarding etiology, diagnosis, treatment

The current body of evidence regarding treatment of bronchiolitis remains uncertain about the efficacy of combination therapy with corticosteroids and epinephrine (see discussion in the section on evidence above). In addition, evidence is limited regarding the efficacy of therapies for severe bronchiolitis including heliox (helium and oxygen), high flow nasal cannula oxygen, and continuous positive airway pressure, which have been studied in case series and small trials.

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