US Pharm. 2015;40(7):HS5-HS10.

ABSTRACT: Viral bronchiolitis is a common respiratory infection in children. It usually presents as a self-limiting disease; however, severe bronchiolitis can lead to respiratory complications and hospitalization. In 2014, the American Academy of Pediatrics published new treatment guidelines for bronchiolitis. Treatment with ribavirin continues to be reserved for life-threatening situations, while the efficacy of corticosteroids remains questionable. Bronchodilators are no longer a recommended therapy for bronchiolitis; however, there may be a role for inhaled epinephrine. Inhaled hypertonic saline has been endorsed for its advantages in reducing symptoms, hospital admissions, and length of hospital stay.

Viral bronchiolitis, an inflammation of the lower respiratory tract, is a leading cause of acute illness and hospitalization in infants and children aged <2 years. This disease accounts for approximately 150,000 pediatric hospitalizations per year.¹ This paper will present updates on the pharmacotherapy of acute bronchiolitis in pediatric patients.

ETIOLOGY AND PATHOPHYSIOLOGY

The most common etiology of bronchiolitis is respiratory syncytial virus (RSV), followed by rhinovirus, parainfluenza, adenovirus, mycoplasma, metapneumovirus, and human bocavirus. It is estimated that 90% of children aged <2 years are infected with RSV, a negative-stranded RNA virus whose only source of infection is humans. RSV causes bronchiolitis or pneumonia in 25% to 40% of infected infants.²

In bronchiolitis, inflammatory infiltrates of WBCs surround the bronchiolar epithelium, resulting in the buildup of cellular debris and mucus. The buildup of plugs of debris and edema in the necrotic bronchioles can cause airway blockage, leading to airflow obstruction. Because of their smaller airways, young children are at greater risk for complications of bronchiolitis. Acute complications of bronchiolitis include apnea, interstitial pneumonia, atelectasis, and respiratory failure. In children who develop bronchiolitis, 50% will be diagnosed with asthma by age 7 years.¹

In healthy infants and children, bronchiolitis is usually self-limiting and lasts from 7 to 10 days.¹ Risk factors for disease progression include gestational age <34 weeks, chronological age <3 months, and underlying diseases such as cystic fibrosis, congenital heart disease, chronic lung disease, neuromuscular disease, and cardiopulmonary disease.¹ Typically, initial clinical manifestations include upper respiratory tract symptoms such as cough, nasal congestion, and low-grade fever lasting 1 to 3 days, followed by expiratory wheezing, nasal flaring, fine crackles, oxygen saturation on presentation (<94%), tachypnea, increased work of breathing, use of accessory muscles, and retractions in some patients. The need for hospitalization depends on the presence of respiratory symptoms (number of retractions, increased respiratory effort, decreased oxygen saturation), cyanosis, restlessness or lethargy, and underlying disease states, including apnea.³

The development of severe bronchiolitis can result in respiratory failure and subsequent death. However, mortality from RSV-related bronchiolitis is low, estimated at <400 deaths per year.³

DIAGNOSIS

Currently, no routine laboratory or radiologic studies can confirm the diagnosis of bronchiolitis. Diagnosis is based on clinical presentation, patient’s age, seasonal occurrence, and physical examination. A rapid antigen test, if available, is helpful in identifying viral etiology so as to avoid the use of antibiotics. A CBC is obtained to check for possible coinfections in patients presenting with symptoms of bronchiolitis. Chest radiography has not been shown to effectively predict disease progression and should not be used to guide treatment. In the differential diagnosis, asthma exacerbation, foreign-body aspiration, gastroesophageal reflux, pneumonia, and congestive heart failure are ruled out.⁴

PHARMACOTHERAPY

Pharmacotherapy for patients hospitalized with bronchiolitis has included a trial of bronchodilators, corticosteroids in some instances, and ribavirin for severely ill patients. In 2014, the American Academy of Pediatrics (AAP) published guidelines that discourage the use of bronchodilators and newly endorse the use of inhaled hypertonic saline in hospitalized children.^4,5

In healthy infants and children, bronchiolitis resolves with supportive care. The goal of treatment, in addition to supportive care, is symptomatic relief through maintenance of hydration and oxygen saturations. Oxygen supplementation is recommended only if oxygen saturations persistently fall below 90%. Conflicting data from clinical trials on the role of bronchodilators led the AAP to update its guidelines for the management of bronchiolitis in patients aged <2 years.⁵

Bronchodilators

The role of bronchodilators (inhaled beta-adrenergic agonists [albuterol], alpha-adrenergic and beta-adrenergic agonists [inhaled racemic epinephrine]) in the treatment of acute bronchiolitis, once recommended and continued if patients derived benefit, is now highly controversial. The updated AAP guidelines list transient improvements that did not translate to better disease resolution, reduced hospital length of stay (LOS) , or hospitalization rates. Additionally, symptom-scoring methods were based on the observer’s perspective, not on objective assessments. These findings, as well as associated adverse events (AEs) such as tremors and tachycardia, led the AAP to discourage the use of bronchodilators as therapy for bronchiolitis.⁵ Data on bronchodilator use in bronchiolitis are reviewed here.

Albuterol: A 2014 Cochrane review examined the role of bronchodilators in treating bronchiolitis in children aged <1 year.⁶ This meta-analysis included 30 randomized, controlled trials investigating the use of a beta₂-agonist in the management of acute bronchiolitis. Older trials showing a benefit for bronchodilator use included patients with a history of wheezing, which is known to be associated with asthma. The effectiveness of these agents in patients who may have had asthma may have led to a false conclusion that bronchodilators were effective for bronchiolitis.⁶

In later studies, patients with prior wheezing were excluded.⁶ The primary outcome was oxygen saturation; secondary outcomes included clinical scores, hospital admissions, LOS, and time to disease resolution. There was a statistically—but not clinically—significant mean improvement in oxygen saturation of 0.38% compared with placebo. There were no reductions in rates of hospitalization, LOS, or time to disease resolution. Tachycardia and slight tremor were commonly reported. The short-term benefit of using beta₂-agonists was not found to offset costs and associated AEs.⁶

Only one prospective, randomized, controlled trial in a pediatric ICU examined the effect of albuterol, levalbuterol, and epinephrine versus normal saline in 21 pediatric patients with RSV-positive bronchiolitis.⁷ There was a small, statistically significant change of 1 cm in H₂O in peak inspiratory pressure, but no difference in inspiratory system resistance outcome. There was a significant increase in heart rate post bronchodilator use.⁷

Racemic Epinephrine: Epinephrine, an alpha- and beta-adrenergic agonist, has been used to treat symptoms of bronchiolitis. Theoretically, epinephrine, with its alpha-agonist properties of vasoconstriction and reduction in edema combined with beta-agonist properties, should provide a greater benefit than albuterol in reducing mucus production and plugging in patients with bronchiolitis. However, the updated 2014 guidelines recommend against the use of epinephrine, based on inconsistencies in epinephrine’s efficacy in bronchiolitis management in inpatient and outpatient settings. A closer look at clinical trials reveals a niche for racemic epinephrine in these settings.⁵

Two meta-analyses published in 2011 by Hartling and colleagues evaluated the safety and efficacy of epinephrine in the management of bronchiolitis in patients aged <2 years.^8,9 Outcomes included the admission rate for outpatients (N = 526; five trials) and LOS for inpatients (N = 330; two trials). In the outpatient setting, there was a reduction in admission rates on the first day of epinephrine use (risk ratio, 0.67; 95% CI, 0.50-0.89); however, this was based on one study comparing epinephrine and placebo. In the inpatient setting, these reviews found no benefit of epinephrine in reducing LOS.^8,9

A multicenter, randomized, double-blind trial of 203 children in Norway from 2010 to 2011 compared the efficacy of inhaled racemic epinephrine versus inhaled saline in patients aged <1 year.¹⁰ The other aim was to compare the efficacy of “as needed” versus “around-the-clock” inhalations. Results showed no differences between inhaled racemic epinephrine and inhaled saline in terms of LOS, need for oxygen supplementation, ventilation support, or improvement in clinical scores. However, epinephrine administered as needed was associated with a significantly shorter LOS (47.6 hours vs. 61.3 hours; P = .01), less use of oxygen supplementation (38.3% vs. 48.7%; P = .04), and less ventilator support (P <.01) compared with around-the-clock inhalations. No serious AEs were reported, except moderate tachycardia with epinephrine in two children.¹⁰

In summary, epinephrine might play a role in the management of bronchiolitis in the emergency department (ED) by reducing admissions. In inpatients, it may be effective as a rescue medication in reducing LOS, oxygen use, and ventilator support.

Hypertonic Saline

One medication that has demonstrated promising results in the management of acute bronchiolitis is nebulized hypertonic saline (HS) ≥3%. Its hyperosmolarity helps absorb water from the mucosal and submucosal space, thereby increasing mucociliary function by clearing fluids accumulated in the airway and mucus plugs in the lungs. HS can also induce cough to help enhance mucus clearance. The 2014 AAP guidelines recommend administration of HS in hospitalized bronchiolitis patients, but advise against its use in patients in the ED.⁵

A 2013 Cochrane review (N = 1090; 11 trials) evaluated HS versus placebo (normal saline) for mild-to-moderate bronchiolitis in both inpatient and ED settings.¹¹ In the inpatient setting, six trials found a 1.2-day reduction in LOS (P <.00001). The secondary outcome, clinical severity score, was calculated using the sum of four categories, each worth 3 points: respiratory rate, retractions, wheeze, and general condition. Higher scores indicated greater symptom severity. In HS patients, symptom-reduction scores on the first, second, and third days of treatment were 0.88, 1.32, and 1.51 points, respectively, compared with those of patients given 0.9% normal saline (P <.01). No significant AEs were noted.

Another meta-analysis conducted in 2013 (N = 1070; seven trials) found that, compared with normal saline, HS reduced clinical symptoms and LOS by 1 day in hospitalized patients.¹² The effectiveness of HS in nonhospitalized children was not clear. A Cochrane review published in 2008 determined that HS did not significantly reduce hospitalization rates in the outpatient and ED settings.¹¹ However, two recent trials found more evidence supporting the use of HS in the ED. One study found trends toward lower hospitalization rates, and the larger trial demonstrated a 13.7% reduction in admission rates when patients were given HS in the ED (95% CI, 0.28-0.86).^13,14

Evidence suggests that inhaled HS improves symptoms of mild-to-moderate bronchiolitis within 24 hours of therapy initiation and reduces LOS in patients whose duration of stay is expected to exceed 3 days.⁵ There might be a role for HS in reducing ED admission rates. Its role in ICU patients with severe bronchiolitis symptoms has not been studied. With its favorable safety profile and efficacy, HS should be used in the management of mild-to-moderate acute bronchiolitis. The most common dosage studied is HS 3% 4 mL per dose inhaled by nebulizer every 4 to 6 hours, which may take ≥24 hours to work and is typically continued while the child is hospitalized.

Corticosteroids and Ribavirin

Corticosteroids, which are commonly used in asthma, were thought to help reduce edema and lung inflammation in bronchiolitis. However, a Cochrane review from 2013 (N = 2,596; 17 trials) evaluating systemic or inhaled corticosteroids versus placebo found no significant reductions in hospital admission, LOS, clinical-score improvement, oxygen saturation, or respiratory symptoms in inpatient and outpatient settings.¹⁵ In a 2004 meta-analysis of ICU studies (N = 66; three trials), there was no reduction in duration of mechanical ventilation or LOS.¹⁶ With no clear evidence for a benefit from corticosteroids in the management of bronchiolitis, the updated AAP guidelines do not recommend their routine use.⁵

Ribavirin is the only specific antiviral therapy available for the treatment of severe bronchiolitis caused by RSV infections. In otherwise healthy children, ribavirin may slightly improve oxygen saturations; however, it has not been shown to consistently reduce LOS or need for mechanical ventilation. Therefore, ribavirin is reserved as a last-line agent for life-threatening bronchiolitis in patients who are immunocompromised or who have hemodynamically significant cardiopulmonary disease.¹⁷ A 2007 Cochrane review (N = 104; three trials) examined ribavirin versus placebo in infants aged <6 months who were placed on mechanical ventilation in the ICU. There was a mean reduction of 1.8 days of ventilation (95% CI, –3.4 to –0.2) and a reduction of 1.9 days in LOS (95% CI, –4.6 to 0.9)¹⁸; however, trials demonstrating these benefits were not powered to show statistically significant results. According to the AAP Committee on Infectious Diseases, inhaled ribavirin should not be used routinely in RSV because of high cost ($1,100 per day for a 3- to 7-day course of treatment), complicated drug-delivery requirements, and teratogenic risk for healthcare professionals administering the medication, but it can be considered in cases of life-threatening RSV infection.¹⁷

CONCLUSION

Bronchiolitis is a common condition in pediatric patients aged <2 years that is associated with hospital admission and respiratory complications. The management of bronchiolitis remains focused on symptom alleviation in otherwise healthy children; however, based on recent trials, the 2014 AAP guidelines have significantly changed the choice of pharmacotherapy. Given the limited improvement with bronchodilators, as well as their significant AEs, the AAP no longer recommends their routine use even as a trial therapy, as was suggested in the 2006 guidelines.

There is a role for racemic epinephrine in reducing admissions from the ED and improving symptoms when used as needed in hospitalized children. The new therapy recommended by the AAP is HS inhalation. Its benefits include reducing symptoms of bronchiolitis, reducing hospital LOS, and potentially preventing hospital admissions from the ED without causing AEs. There remains no role for routine use of corticosteroids in the treatment of bronchiolitis, and ribavirin is reserved for cases of severe immunosuppression and cardiopulmonary disease. It is hoped that this review helps the pharmacist understand the current guidelines and evidence-based literature in the management of bronchiolitis.

REFERENCES

1. Teshome G, Gattu R, Brown R. Acute bronchiolitis. Pediatr Clin N Am. 2013;60:1019-1034.
2. Centers for Disease Control and Prevention. Respiratory syncytial virus infection (RSV). www.cdc.gov/rsv/clinical/description.html. Accessed March 18, 2015.
3. Zorc JJ, Hall CB. Bronchiolitis: recent evidence on diagnosis and management. Pediatrics. 2010;125:342-349.
4. American Academy of Pediatrics Subcommittee on Diagnosis and Management of Bronchiolitis. Diagnosis and management of bronchiolitis. Pediatrics. 2006;118:1774-1793.
5. Ralston SL, Lieberthal AS, Meissner C, et al. Clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis. Pediatrics. 2014;134:e1474-e1502.
6. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev. 2014;(6):CD001266.
7. Levin DL, Garg A, Hall LJ, et al. A prospective randomized controlled blinded study of three bronchodilators in infants with respiratory syncytial virus bronchiolitis on mechanical ventilation. Pediatr Crit Care Med. 2008;9:598-604.
8. Hartling L, Fernandes RM, Bialy L, et al. Steroids and bronchodilators for acute bronchiolitis in the first two years of life: systematic review and meta-analysis. BMJ. 2011;342:d1714.
9. Hartling L, Bialy LM, Vandermeer B, et al. Epinephrine for bronchiolitis. Cochrane Database Syst Rev. 2011;(6):CD003123.
10. Skjerven HO, Hunderi JO, Brügmann-Pieper SK, et al. Racemic adrenaline and inhalation strategies in acute bronchiolitis. N Engl J Med. 2013;368:2286-2293.
11. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev. 2008;(4):CD006458.
12. Chen YJ, Lee WL, Wang CM, Chou HH. Nebulized hypertonic saline treatment reduces both rate and duration of hospitalization for acute bronchiolitis in infants: an updated meta-analysis. Pediatr Neonatol. 2014;55:431-438.
13. Kuzik BA, Flavin MP, Kent S, et al. Effect of inhaled hypertonic saline on hospital admission rate in children with viral bronchiolitis: a randomized trial. CJEM. 2010;12:477-484.
14. Wu S, Baker C, Lang ME, et al. Nebulized hypertonic saline for bronchiolitis: a randomized clinical trial. JAMA Pediatr. 2014;168:657-663.
15. Fernandes RM, Bialy LM, Vandermeer B, et al. Glucocorticoids for acute viral bronchiolitis in infants and young children. Cochrane Database Syst Rev. 2010;(10):CD004878.
16. Davison C, Ventre KM, Luchetti M, Randolph AG. Efficacy of interventions for bronchiolitis in critically ill infants: a systematic review and meta-analysis. Pediatr Crit Care Med. 2004;5:482-489.
17. Committee on Infectious Diseases, American Academy of Pediatrics. Red Book: 2012 Report of the Committee on Infectious Diseases. 29th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2012.
18. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infection of the lower respiratory tract in infants and young children. Cochrane Database Syst Rev. 2007;(1):CD000181.

To comment on this article, contact rdavidson@uspharmacist.com.