C

Update on management of bron

chiolitisSuzanne Schuha,b,c

aResearch Institute, The Hospital for Sick Children,bDivision of Paediatric Emergency Medicine andcDepartment of Paediatrics, University of Toronto,Toronto, Ontario, Canada

Correspondence to Suzanne Schuh, The Hospital forSick Children, 555 University Ave., Toronto, ON M5G1X8, CanadaTel: +1 416 813 6239; fax: +1 416 813 5043;e-mail: suzanne.schuh@sickkids.ca

Current Opinion in Pediatrics 2011, 23:110–114

Purpose of review

Bronchiolitis impacts millions of infants worldwide. Although several therapeutic options

stem from highly plausible theoretical rationales for success and some may even offer

modest short-term symptom relief, none has been conclusively shown to alter the

course of the disease or its major outcomes. However, several recent papers shed light

on which treatments show promising preliminary evidence and offer insight into future

research endeavors on this topic. This review will summarize bronchiolitis therapy in

view of this recent evidence.

Recent findings

The agents in which theory promises but treatment does not deliver include systemic

corticosteroids alone, inhaled bronchodilators alone and antileukotrienes. The most

promising combination to date appears to be that of oral dexamethasone and inhaled

epinephrine but numerous related issues need to be clarified further. Caretakers need to

be counselled about the usual protracted clinical course of bronchiolitis.

Summary

Because bronchiolitis is a highly heterogeneous entity, future research challenges

should include detailed characterization of infants most likely to benefit from given

interventions. In the meantime, stick with the good old time-honored supportive route!

Keywords

bronchiolitis, dexamethasone, epinephrine, heliox, respiratory distress

Curr Opin Pediatr 23:110–114� 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins1040-8703

IntroductionBronchiolitis is the leading cause of infant hospitaliz-

ations during the first year of life [1]. It is usually defined

as the first viral episode of respiratory distress, accom-

panied by coryza, cough, crepitations and wheezing [2].

The respiratory syncytial virus (RSV) accounts for the

majority of cases [3], although other important viruses

have also been implicated [4–6]. Several excellent

reviews of the etiology and treatment approaches to

bronchiolitis have recently been published [7–11], all

of which highlight importance of oxygenation, hydration

and airway support if necessary [12,13].

However, no single pharmacological agent has been

conclusively found to change the course of the disease.

An important challenge is that bronchiolitis has wide

etiologic heterogeneity, encompassing the only episode

of viral-induced wheezing and the first attack of episodic

wheezing without atopy/interval symptoms as well as the

initial exacerbation of a multitrigger wheeze often associ-

ated with asthma [7]. The bad news is that these wheez-

ing phenotypes respond differently to treatment [7].

Because it is impossible to reliably identify these sub-

groups during their initial presentation, interpretation of

opyright © Lippincott Williams & Wilkins. Unautho

1040-8703 � 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

the results of therapeutic trials of bronchiolitis becomes

challenging [14,15].

In 2006, the American Academy of Pediatrics (AAP)

released a comprehensive evidence-based guideline on

the management of bronchiolitis [16]. Since then, two

large multicenter bronchiolitis trials have shed light on

the management with oral dexamethasone with and

without nebulized epinephrine [17��,18] and raised sev-

eral unanswered questions. Furthermore, several recent

systematic reviews of various other inhaled therapies

guide us when these interventions may be effective

[19–21]. Two recent bronchiolitis papers have clarified

predictors of the return for care after discharge from the

emergency department (ED) [22�] and highlighted the

usual protracted course of this disease [9]. This review

will therefore focus on the update of pharmacotherapy in

bronchiolitis in light of this recent information.

Supplemental oxygenSince the invention of routine transcutaneous oxygen

saturation monitoring two decades ago, the hospitaliz-

ation rate for bronchiolitis has increased 2.5-fold, without

increase in mortality [23]. Several authors postulate the

rized reproduction of this article is prohibited.

DOI:10.1097/MOP.0b013e3283425442

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Management of bronchiolitis Schuh 111

Key points

� Systemic corticosteroids alone, inhaled bronchodi-

lators alone and anti-leukotrienes do not change the

clinical course and outcomes in bronchiolitis.

� The most promising therapeutic combination to

date may be that of oral dexamethasone and inhaled

epinephrine but many issues need to be clarified

further.

� Caretakers need to be counselled about the usual

protracted clinical course of bronchiolitis.

� Future research should focus on characterization of

infants most likely to benefit from given interven-

tions.

use of oximetry is at least in part related to this increase in

admissions [24]. The significance of mild hypoxemia with

saturations below 95% as it relates to bronchiolitis out-

comes has not been specifically studied and the

thresholds for administering supplemental oxygen vary

widely [25–29]. Indeed, a small difference in oximetry of

minimal physiologic significance between 94 and 92% has

been shown on its own to raise postulated hospitalization

rate from 58 to 85% [24]. Another study showed that

approximately 26% of infants with bronchiolitis experi-

ence prolonged hospital stays based on periodic desatura-

tions, despite satisfactory clinical status [30,31]. As a

result of the arbitrary nature of various thresholds for

using supplemental oxygen which are likely not cost-

effective [31–33], the AAP recommends the use of this

intervention in previously healthy infants with satur-

ations below 90% [16]. Further studies of the impact

of desaturations and mild hypoxemia on bronchiolitis

outcomes are needed.

BronchodilatorsBoth nebulized epinephrine and albuterol are commonly

given for bronchiolitis, with highly variable frequency

[34]. The attractive features of inhaled epinephrine in

bronchiolitis include its vasoconstrictive and beta agonist

properties [35,36]. Because patients with bronchiolitis are

a highly heterogeneous group, some of whom may have

their first asthma episode, the AAP guideline recom-

mends that a monitored trial of a bronchodilator may

be given [16]. However, this guideline strongly advises

against routine use of bronchodilators in this disease and

recent evidence outlined below certainly points to

this conclusion.

Of the four studies published since 2003 focusing on short-

term outcomes after nebulized epinephrine versus albu-

terol/placebo in bronchiolitis [37–40], the largest was a

multicenter randomized controlled trial from 2008 which

found no difference between three consecutive doses of

nebulized albuterol and a single dose of epinephrine [40].

Likewise, hospitalized infants given nebulized epineph-

rine appear to derive no added benefit compared with

those treated with albuterol or placebo [33,41]. A systema-

tic review [20] showed four of five inpatient studies

demonstrated no benefit of epinephrine over placebo with

respect to the clinical score [20]. Although the authors

found some evidence of short-term clinical benefit of

epinephrine over albuterol in the four included outpatient

studies, epinephrine inferred no advantage with respect to

hospitalization. They recommend a large randomized

controlled trial comparing epinephrine with placebo and

salbutamol in the outpatient setting.

A recent Canada-wide trial compared the impact of two

doses of nebulized epinephrine, daily oral dexametha-

opyright © Lippincott Williams & Wilkins. Unauth

sone and the combination of both with the use of two

placebos in 800 previously healthy outpatients with

bronchiolitis in the ED [17��]. Although infants in the

epinephrine group had achieved significantly lower

clinical scores during the initial hour of the study com-

pared with those receiving placebo, there was no impact

of epinephrine on hospitalization and this intervention

was accompanied by more side-effects.

CorticosteroidsA recent systematic review of 13 trials of 1198 children

with bronchiolitis given systemic corticosteroids showed

no difference in hospitalization, length of hospital stay,

clinical scores and readmission rates compared with

placebo [42]. The AAP guideline also recommends

against the use of corticosteroids in bronchiolitis [16].

Since then, two large multicenter placebo-controlled

trials have been carried out [17��,18]. The first was a

US trial which found that a single high dose of oral

dexamethasone conveys no benefit compared with

placebo with respect to hospitalizations from the ED,

length of stay, return for care or clinical score [18]. Shortly

thereafter, the aforementioned Canada-wide study by

Plint et al. [17��] used a factorial design to compare the

effect of daily dexamethasone alone, two doses of inhaled

epinephrine in the ED alone and the combination of the

two with using two placebos. Although neither agent

alone produced any benefit, the authors found that the

dexamethasone–epinephrine combination resulted in a

nine-percentage point reduction in hospitalization within

7 days [17��]. The authors postulated this potential

beneficial effect may stem from a synergy between the

two therapeutic agents. Although this difference may

translate into substantial reduction in hospitalizations

in the population as a whole, this effect size is relatively

modest. Because the effects of the high dose of dexa-

methasone used on the brain and lungs of babies are

uncertain [43], this treatment cannot be currently recom-

mended without further evidence. For these reasons, it

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112 Infectious diseases and immunization

seems prudent to investigate a corticosteroid dose con-

siderably smaller compared with that used in the study by

Plint. The optimal treatment duration is also unknown,

and, although a previous small study showed infants

given regular albuterol with a single dose of oral dexa-

methasone achieved outcomes comparable to those given

a longer course of corticosteroids, this needs to be verified

in a large trial [44].

A recent small but worthwhile study clarifies the reasons

for the lack of benefit of isolated steroid therapy in

bronchiolitis [45]. The authors showed that dexametha-

sone fails to produce anti-inflammatory effect in acute

RSV bronchiolitis because it lacks sufficient impact on

the production of inflammatory cytokines which play a

major role in this disease.

Hypertonic salineBoth the hypertonic saline and deoxyribonuclease agents

work by decreasing viscosity of airway mucus [46–

48,49�]. A recently published Cochrane Systematic Reviewof four trials [46,50–52] involving 254 infants with acute

bronchiolitis found that 3% saline results in a significantly

shorter length of hospital stay as well as a lower clinical

score [19]. However, none of these studies involved

infants presenting to the ED. A recent small ED study

of this population using inhaled hypertonic saline and

epinephrine versus normal saline and epinephrine found

no difference between these interventions with respect

to the improvement in the clinical score, oxygen satur-

ation, hospitalization and return for care [53�]. Likewise,

two inpatient studies of the deoxyribonuclease have

demonstrated no benefit [47,48]. Clearly, not enough

compelling evidence currently exists to recommend

the use of mucolytic agents in bronchiolitis and further

research is necessary.

A recent published review article clarifies the postulated

basic science mechanisms of action involving hypertonic

saline in bronchiolitis [49�]. Hypothetically, hypertonic

saline may help reverse some of the pathophysiological

abnormalities in bronchiolitis by increasing airway sur-

face thickness, decreasing epithelial edema, improving

elasticity and viscosity of mucus as well as accelerating

mucus transport rates [49�]. Hopefully, the authors’

highly credible rationale for benefit of this agent on

the inflamed airway will translate into clinical effect on

major outcomes such as hospitalization in a large rando-

mized trial.

HelioxThe mixture of helium and oxygen in an 80 : 20 ratio is

much lighter and less dense than air. Because of associ-

ated greater laminar and lower turbulent flow, less respir-

opyright © Lippincott Williams & Wilkins. Unautho

atory effort should be needed for effective breathing [54].

This may be particularly useful in the ICU setting in

combination with the continuous positive airway pressure

management. However, the evidence to date cannot

recommend this intervention for practice. The four stu-

dies performed in this setting are all small, one has no

control group and two lack blinding [55–58]. Although a

recent Cochrane Systematic Review on the subject suggests

that the addition of heliox may significantly reduce

respiratory distress, heliox appears to show no impact

on the rate of intubation or ventilation or the length of

ICU stay [21].

AntibioticsBacteremia rate in febrile infants with bronchiolitis is

very low, at 0.2% [59] – much superceded by urinary tract

infections and otitis media [60,61]. However, antibiotics

should only be used when specific evidence of coexistent

bacterial infection is present [16].

Interestingly, the macrolides appear to have anti-inflam-

matory and immunomodulating properties in addition to

their antibacterial activity. However, the clinical evi-

dence of benefit of this class of drugs in bronchiolitis

is scarce, with disparate results [62,63]. Infants with

severe bronchiolitis requiring assisted ventilation have

been found to have surprisingly high bacterial co-infec-

tion rate in the tracheal secretions, although to what

degree this finding contributes to the clinical manifes-

tation is currently not clear [64]. Although this may be a

fruitful area of future research in this highly select

population, its results are unlikely to impact the vast

majority of infants with bronchiolitis.

RibavirinAlthough ribavirin produces good in-vitro activity against

the viruses causing bronchiolitis, more recent studies

have failed to show its benefit in either the outcomes

of infants admitted to the ICU or the rate of viral

clearance [65,66]. Because this agent may be teratogenic

and is cumbersome to use, the AAP has recently recom-

mended against its routine use [16]. It may be considered

for immunosuppressed infants and those with hemo-

dynamically significant cardiac disease.

MontelukastThe use of montelukast is another example of where

theory promises but treatment does not deliver. Although

infants with bronchiolitis have high levels of pro-inflam-

matory leukotrienes in their airway, a recent randomized

controlled trial of oral montelukast in infants under

2 years of age with acute bronchiolitis over 6 months

failed to reduce subsequent respiratory symptoms [67].

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Management of bronchiolitis Schuh 113

Continuous positive airway pressureInfants with progressive hypoxemia and increasing

respiratory distress may require continuous positive air-

way pressure support in the ICU setting which constitu-

tes an effective mode of airway support for early venti-

latory decompensation [68,69] and obviates the

complications associated with intubation and sedation

required for children in frank respiratory failure.

Duration of symptoms and return for careRecent evidence suggests that many infants seen in the

ED for bronchiolitis have a protracted clinical course,

with a median disease duration of 15 days, 25% remain-

ing symptomatic after 21 days and 37% experiencing

unscheduled medical visits following the ED visit [70�].

In 2010 Norwood et al. [22�] conducted a study examin-

ing predictors of unscheduled medical visits in infants

with bronchiolitis discharged home from the ED. They

found that the significant independent predictors of this

outcome were age less than 2 months, history of pre-

maturity less than 35 weeks of gestation and history of

hospitalization [22�]. Several years ago, Mansbach et al.[71] also found that the factors associated with a safe

discharge home in bronchiolitis include age 2 months

and older, without prior endotracheal intubation. The

results of these studies are useful in counselling the

parents of this population in the ED prior to discharge

home.

ImmunoprophylaxisPassive immunization with humanized monoclonal anti-

body prophylaxis is recommended for infants 2 years of

age and younger with hemodynamically significant con-

genital heart disease requiring pharmacotherapy, those

suffering from pulmonary hypotension, infants with

chronic lung disease or prematurity who required medical

therapy within 6 months of the start of the bronchiolitis

season and infants born at or before 32 weeks’ gestation,

particularly if they are less than 12 months old during

their first bronchiolitis season [16].

ConclusionThe agents unlikely to impact bronchiolitis outcomes

include systemic corticosteroids alone, inhaled broncho-

dilators alone and antileukotrienes. The most promising

combination to date appears to be that of oral dexametha-

sone and inhaled epinephrine, but numerous related

issues need to be clarified further. These include, among

others, the optimal dose of dexamethasone, duration of

treatment and finding out which subset of babies is the

most likely to respond. Because bronchiolitis is a highly

heterogeneous entity, future research challenges will

include detailed characterization of subjects most likely

opyright © Lippincott Williams & Wilkins. Unauth

to benefit from given interventions. In the meantime,

stick with the good old time-honored supportive route!

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rized reproduction of this article is prohibited.