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Treatment of recurrent virus-induced wheezing in

young children
AUTHOR: Gregory Redding, MD
SECTION EDITOR: Robert A Wood, MD
DEPUTY EDITOR: Elizabeth TePas, MD, MS

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2024.

This topic last updated: Apr 30, 2021.

INTRODUCTION

Viruses are the most common triggers of wheezing in childhood. In some children,
respiratory viral infection will induce transient and episodic wheezing episodes, while, in
others, wheezing with respiratory viruses will also influence future development of asthma.
The heterogeneity in early childhood wheezing phenotypes introduces clinical challenges for
treatment. The optimal management of acute episodes of virus-induced wheezing in infants
and preschool children has yet to be determined [1]. Instituting or escalating asthma
therapies, such as inhaled glucocorticoids, leukotriene modifiers, and bronchodilators, can
be effective in controlling viral-induced wheezing symptoms in some patients. However,
treatment decisions in children with wheezing episodes require an understanding of the risk
factors for severe exacerbations and recurrent wheezing in young children. Therapeutic trials
comparing variable recurrent wheezing phenotypes are ongoing and will be an important
application of precision medicine to determine optimal medication treatments for children
with recurrent virus-induced wheezing. (See "Wheezing phenotypes and prediction of
asthma in young children" and "Risk factors for asthma".)

This topic reviews the treatment of young children with recurrent virus-induced wheezing,
defined as a minimum of three to four wheezing exacerbations a year [2]. Guidelines from
the Global Initiative for Asthma (GINA) [3] and National Asthma Education and Prevention
Program Coordinating Committee (NAEPPCC) [4,5] provide recommendations for children
based upon age and the frequency of viral episodes. Our approach is generally consistent
with these guidelines. Treatment of bronchiolitis in infants and virus-induced asthma
exacerbations in children and adults are discussed separately. The mechanisms by which
viral respiratory infections cause wheezing and asthma exacerbations and the influence of
viral infection on both the development and perpetuation of asthma are also discussed
separately. (See "Bronchiolitis in infants and children: Treatment, outcome, and prevention"
and "An overview of asthma management" and "Role of viruses in wheezing and asthma: An
overview".)

Treatment of asthma in children, both for acute exacerbations and prevention of symptoms,
is discussed in detail separately:

● (See "Asthma in children younger than 12 years: Quick-relief (rescue) treatment for
acute symptoms".)

● (See "Asthma in children younger than 12 years: Management of persistent asthma

with controller therapies".)

● (See "Acute asthma exacerbations in children younger than 12 years: Overview of

home/office management and severity assessment".)

● (See "Acute asthma exacerbations in children younger than 12 years: Emergency

department management".)

● (See "Acute asthma exacerbations in children younger than 12 years: Inpatient

management".)

● (See "Acute severe asthma exacerbations in children younger than 12 years: Intensive
care unit management".)

EPISODIC THERAPY

Episodic therapies are used to treat lower respiratory tract (LRT) symptoms in some young
children with recurrent virus-induced wheezing. Antiinflammatory drugs are rarely used for
acute LRT symptoms in these children.

Symptomatic relief — For symptomatic relief of acute LRT symptoms in children ≤4 years
of age with recurrent virus-induced wheezing, we suggest an as-needed inhaled short-acting
beta agonist (SABA) rather than no symptomatic treatment ( table 1) [3-5]. Nebulized
hypertonic saline in combination with a SABA is typically not used, because it has not
consistently shown a significant advantage over SABA treatment alone.

● Inhaled short-acting beta agonists – Inhaled SABAs (albuterol/salbutamol,

levalbuterol/levosalbutamol) are often first-line therapy for treatment of virus-induced
wheezing. However, response to treatment can differ given the heterogeneity of
 diseases presenting as early childhood wheezing. In children with recurrent wheezing,
SABAs are effective rescue treatments for the quick relief of symptoms ( table 2).
SABAs have not been shown to improve clinical outcomes, decrease the rate of hospital
admission, or decrease the duration of hospitalization in children with bronchiolitis or
acute cough [6,7]. The use of SABAs for acute symptoms and treatment of acute
exacerbations in children with asthma is discussed in greater detail separately. (See
"Beta agonists in asthma: Acute administration and prophylactic use" and "Asthma in
children younger than 12 years: Quick-relief (rescue) treatment for acute symptoms"
and "Acute asthma exacerbations in children younger than 12 years: Emergency
department management", section on 'Inhaled short-acting beta-2 agonists' and
"Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

● Hypertonic saline – Nebulized hypertonic saline combined with a SABA has been
studied but is not used routinely, because it does not have a clear benefit over SABA
alone in patients with acute virus-induced wheezing. Limited data suggest that inhaled
hypertonic saline in combination with a SABA may be effective in treating young
children with acute episodes of virus-induced wheezing. The use of inhaled hypertonic
saline for the treatment of LRT disease is based upon the hypothesis that viral infection,
particularly with rhinovirus, leads to dehydration of the airway surface liquid and
impaired mucus clearance [8-10]. Several randomized trials have reported decreased
rates of hospital admission and decreased length of hospital stay in infants and
children with acute bronchiolitis or acute virus-induced wheezing treated with inhaled
hypertonic saline in addition to SABAs compared with SABAs alone, but other trials
have not detected a significant difference between these treatments [11-15]. In
addition, the studies with positive findings often excluded children with a history of
prior wheezing and/or bronchiolitis, limiting the ability to draw conclusions about this
therapy in children with recurrent wheezing episodes. Further study with randomized,
controlled trials is needed before this treatment can be recommended for clinical use in
young children with recurrent wheeze. (See "Bronchiolitis in infants and children:
Treatment, outcome, and prevention".)

Antiinflammatory therapy — In children ≤4 years of age with recurrent virus-induced

wheezing who have developed LRT symptoms in the setting of a viral infection, we suggest
limiting treatment with systemic glucocorticoids to those who have a history of severe or
refractory disease. This includes children who have a history of severe virus-induced
wheezing exacerbations requiring hospitalization or emergency department (ED) visits, have
not responded to intermittent high-dose inhaled glucocorticoid therapy previously, or have
significant asthma risk factors and are on daily controller therapy. We typically do not use
inhaled glucocorticoids, leukotriene receptor antagonists (LTRAs; montelukast), or macrolide
antibiotics in young children with recurrent virus-induced wheezing who are symptomatic
due to an acute viral infection, because they have not been shown to be effective in most
patients.

● Oral glucocorticoids – The data are mixed regarding the use of oral glucocorticoids to
treat virus-induced wheezing in preschoolers, in part due to the heterogeneity of
studies and outcomes measured, as well as the heterogeneity of diseases leasing to
wheezing in preschool children [16-22]. Overall, this approach does not appear to be
effective in most patients with preschool wheezing. Systemic glucocorticoids may be
beneficial in subgroups of patients (eg, those with recurrent episodes of virus-induced
wheezing, atopic features, and/or family history of asthma) with severe symptoms that
have required hospitalization or frequent emergency department (ED) visits or those
who have failed other approaches such as intermittent high-dose inhaled
glucocorticoids.

Several randomized trials have been conducted that vary in terms of clinical setting,
dose of glucocorticoid administered, and patient population studied. Overall, oral
glucocorticoids do not appear to reduce the need for hospital admission, but they may
modestly shorten hospital length of stay and may reduce the need for SABA rescue
therapy [17-21]. One study that compared the length of hospital stay in wheezing
children 24 to 72 months of age (mean age 41 months) who were started on a three-
day course of oral prednisolone in the ED reported a decreased hospital stay in children
requiring admission for greater than seven hours [21]. A prior study in younger
children (mean age 26 months) with fewer asthma risk factors that did not detect a
significant difference in duration of hospitalization in those treated with a five-day
course of prednisolone compared with those who were not [18,21].

Results from one subgroup analysis suggest that the response to systemic
glucocorticoids during wheezing episodes requiring hospitalization may differ based
upon the type of virus detected [17]. Another subgroup analysis in a multicenter trial
noted lack of benefit of prednisolone treatment in children at high risk for atopic
asthma (history of ≥4 wheezing episodes and a parent with asthma or clinician-
diagnosed eczema) [18]. Additional studies are necessary to better define the
characteristics of children who wheeze severely but intermittently and do or do not
respond to oral glucocorticoid therapy. How glucocorticoid responsiveness relates to
preschool children who will outgrow their asthma-like symptoms and those who will
have asthma diagnosed later also needs to be studied. (See "Natural history of asthma",
section on 'Wheezing during the first six years'.)

The use of systemic glucocorticoids in the treatment of bronchiolitis is reviewed in

detail separately. (See "Overview of bronchiolar disorders in adults" and "Bronchiolitis
in infants and children: Treatment, outcome, and prevention".)
● Inhaled glucocorticoids – Inhaled glucocorticoids do not appear to be effective when
started after the onset of LRT symptoms in the setting of a viral infection. In one
randomized trial of 276 preschool children with recurrent wheezing, there was no
difference in the proportion of symptom-free days in those treated with a combination
SABA and high-dose beclomethasone as needed for symptoms compared with a SABA
alone (64.9 versus 61 percent, respectively) [23]. Similarly, there was no difference in
symptom-free days (83 versus 82 percent, respectively) in another trial of 411 infants
who were treated with a two-week course of low-dose budesonide or placebo started
after a three-day episode of wheezing. The use of inhaled glucocorticoid therapy,
started the first day of viral symptoms, for the prevention of LRT symptoms is
discussed below. (See 'Intermittent preventive therapy' below.)

● Leukotriene receptor antagonists – A couple of randomized trials have examined the

intermittent use of an LTRA, montelukast, to treat acute LRT symptoms in preschool
children with recurrent wheezing [24,25]. Overall, these studies do not favor the use of
intermittent LTRAs for acute wheezing episodes in young children. The first trial, which
included both those treated at the onset of an upper respiratory tract infection (URI)
and those treated for asthma symptoms, found a lower rate of unscheduled health care
utilization for asthma in those treated with montelukast compared with placebo (odds
ratio [OR] 0.65, 95% CI 0.47-0.89) but no significant differences in hospitalizations or
rescue medication use [24]. The other trial, which randomly assigned 1358 children to
intermittent montelukast or placebo at the onset of any subsequent wheezing episode
over a 12-month period, did not find a difference between the groups in the frequency
of unscheduled medical visits for wheezing episodes [25].

● Antibiotics – The potential utility of macrolides as immunomodulatory therapy in the

treatment of recurrent wheezing/asthma has been widely debated given their
antiinflammatory properties and antimicrobial effects against Mycoplasma pneumonia
and Chlamydia pneumonia. One randomized trial provided some evidence for the early
use of azithromycin to shorten the duration of episodes of recurrent wheeze in young
children. In a this trial, 72 children one to three years of age with recurrent asthma-like
symptoms were randomly assigned to oral azithromycin (10 mg/kg once daily for three
days) or placebo for each episode of asthma-like symptoms lasting at least three days
[26]. Treatment with azithromycin significantly decreased the duration of the episode
by 63 percent, with a mean episode duration of 3.4 days in those treated with
azithromycin compared with 7.7 days in those who received placebo. A greater
response was seen with earlier initiation of treatment (83 percent if azithromycin was
initiated before day 6 of symptoms versus 36 percent if initiated after day 6). Adverse
event rates were similar in the two groups. Patterns of bacterial resistance after
treatment were not investigated. However, further study is needed prior to
 recommending widespread use of azithromycin for this indication. (See "Investigational
agents for asthma", section on 'Macrolide antibiotics'.)

PREVENTIVE THERAPY

Preventive therapy includes intermittent antiinflammatory therapy given at the onset of a

viral upper respiratory tract infection (URI) and daily controller therapy.

Intermittent preventive therapy — In children ≤4 years of age with recurrent virus-

induced wheezing who do not meet the criteria for daily controller therapy (see 'Who to
treat' below), we suggest starting a short course of a high-dose inhaled glucocorticoid at the
onset of a viral URI. Low-dose inhaled glucocorticoids have not shown similar efficacy. We
typically do not use a short course of montelukast, oral glucocorticoid, or a macrolide
antibiotic at the onset of a URI in young children with intermittent wheezing, because they
have not been shown to be effective in most patients.

● Inhaled glucocorticoids – Intermittent inhaled glucocorticoids for the prevention of

virus-induced wheezing in young children have been examined in several randomized
trials and two systematic reviews [2,27-33]. These studies are difficult to compare
because of differences in dose of inhaled glucocorticoid used, timing of when the
medication is started in relation to the URI, and primary outcome measured [34].
However, overall, these studies suggest that intermittent high-dose inhaled
glucocorticoids, started at the onset of a URI and continued for up to 10 days, may
decrease asthma-type symptoms and rescue oral glucocorticoid use in preschool
children with virus-associated wheezing who are not on daily inhaled glucocorticoid
therapy. This approach may be particularly effective in patients with asthma risk
factors. There may be slight deficits in growth in some children, although the data are
limited. Growth in children who are prescribed this approach should be carefully
monitored. It is unclear if intermittent high-dose inhaled glucocorticoids are effective if
started after the onset of wheezing in the setting of a URI. Intermittent use of
standard (low to medium) doses of inhaled glucocorticoids does not appear to be
effective in this population, particularly when started after the onset of lower
respiratory tract (LRT) symptoms. (See 'Symptomatic relief' above.)

A systematic review from 2000 identified three trials of preschool children with
recurrent wheeze given episodic high-dose inhaled glucocorticoids for 5 to 10 days
starting at the onset of a URI [28]. Two of these studies showed a reduced requirement
for oral glucocorticoids (risk ratio [RR] 0.53, 95% CI 0.27-1.04), and all showed modest
decreases in symptom scores. Most subsequent larger trials have confirmed these
findings. In one trial of 129 children, a short course of high-dose fluticasone propionate
started at the onset of a URI decreased the use of rescue oral glucocorticoids compared
 with placebo (8 versus 18 percent of URIs required such rescue treatment, respectively)
[29]. However, smaller gains in height and weight were seen in the treatment group
(-0.33 cm and -0.64 kg) compared with placebo over the 6- to 12-month study period. In
another trial of 278 children aged 12 to 53 months with recurrent wheezing and a
positive asthma predictive index, episodic use of high-dose inhaled budesonide started
early in the course of a URI was as effective as chronic daily low-dose budesonide with
respect to frequency of exacerbations requiring oral glucocorticoid therapy [2]. There
were also no significant differences between the two groups in bronchodilator use,
episode-free days, or severity of symptoms during respiratory tract illnesses.
Furthermore, treatment with intermittent high-dose budesonide resulted in a lower
cumulative exposure to budesonide as compared with daily budesonide therapy. In
contrast, another trial using high-dose budesonide at the start of a URI did not find any
difference in rescue oral glucocorticoid use or proportion of episode-free days
compared with intermittent montelukast or placebo in 238 children one to six years of
age with moderate-to-severe intermittent wheezing [30]. Symptom scores for trouble
breathing and interference with activity were moderately decreased in the treatment
groups compared with placebo, particularly during the first few days of treatment.

In one trial of 525 children with history of virus-induced wheezing who presented to
their pediatrician with a URI and were randomly assigned treatment with low-dose
beclomethasone or placebo, no difference was seen in the incidence of wheezing
during the 10-day treatment period [32].

● Oral glucocorticoids – Results from one small observational study suggested that early
treatment with systemic glucocorticoids at the first sign of a URI could reduce the
symptoms of virus-induced exacerbations, emergency department (ED) visits, and
hospitalizations in preschool children with recurrent virus-induced wheezing [35],
although these findings have never been confirmed in a randomized trial.

● Leukotriene receptor antagonists – Several randomized trials have examined the

intermittent use of a leukotriene receptor antagonist (LTRA), montelukast, for
prevention of symptoms in preschool children with recurrent virus-induced wheezing
[24,30,36]. Overall, the studies do not favor the use of intermittent LTRAs for prevention
of acute wheezing episodes in young children. This finding was confirmed in a meta-
analysis, which did not detect a significant difference in the number of episodes
requiring treatment with oral glucocorticoids in those treated with intermittent LTRA
compared with placebo (odds ratio [OR] 0.77, 95% CI 0.48-1.25) [37].

In one of the studies previously discussed, measures of severity of acute illness were
decreased in children treated at the first sign of a URI with high-dose budesonide or
montelukast compared with placebo, but no difference was seen in the proportion of
 episode-free days or rescue oral glucocorticoid use over the 12-month study period
[30]. A similar randomized trial that included older children as well found a modest
reduction in unscheduled visits, symptoms, days off from school/childcare, and
caregiver time off from work in the montelukast group compared with placebo but did
not show a significant difference in rescue medication use or hospitalizations [24].
Another randomized trial found no change in the number of asthma episodes in
children ages six months to five years who were treated with intermittent montelukast
begun at the onset of viral symptoms [36].

● Antibiotics – The potential utility of macrolides as immunomodulatory therapy in the

treatment of recurrent wheezing/asthma has been widely debated given their
antiinflammatory properties and antimicrobial effects against Mycoplasma pneumonia
and Chlamydia pneumonia. One multicenter randomized trial provided some evidence
for the early use of azithromycin in preventing LRT illness (LRTI) in preschool children
with a history of severe recurrent wheezing [38]. Treatment was initiated at the onset of
respiratory illness in conjunction with signs/symptoms that usually preceded the
development of a severe LRTI specific to each child. In this trial, 607 children were
randomly assigned to oral azithromycin (12 mg/kg once daily) or placebo for five days
in addition to albuterol. The risk of progressing to severe LRTI was significantly lower in
the treatment group compared with the control (hazard ratio [HR] 0.64, 95% CI 0.41-
0.98). However, there was no difference in urgent care utilization, ED visits, or
hospitalizations. In addition, the results of the study were not affected by the type of
virus detected during respiratory illness, the presence of a positive asthma predictive
index, age, or sex. Further study is needed prior to recommending widespread use of
azithromycin for this indication. (See "Investigational agents for asthma", section on
'Macrolide antibiotics'.)

Daily controller therapy — An alternative approach to prevention of virus-induced

wheezing is continuous, rather than episodic, therapy.

Who to treat — Initiation of controller medication for children ages zero to four years is
based upon the severity of symptoms and exacerbations, the frequency of exacerbations,
and the risk of development of subsequent asthma ( table 1) [3-5].

We recommend initiating controller therapy in children who have had ≥4 episodes of

wheezing in the past year that lasted more than one day and affected sleep and who have
the following risk factors for persistent asthma [39,40] (see "Risk factors for asthma" and
"Role of viruses in wheezing and asthma: An overview" and "Wheezing phenotypes and
prediction of asthma in young children"):

● One of the following – Parental history of asthma, clinician diagnosis of atopic

dermatitis, evidence of sensitization to aeroallergens
 or

● Two of the following – Evidence of sensitization to foods, ≥4 percent peripheral blood

eosinophilia, wheezing apart from viral URIs

We also suggest the initiation of controller medications for the following children [4]:

● Those aged zero to four years who consistently require quick-relief medications more
than two days per week for a period of more than four weeks.

● Infants and young children experiencing severe exacerbations less than six weeks apart
or those who have two or more exacerbations requiring systemic glucocorticoids within
six months.

● Children with intermittent disease who experience severe exacerbations, especially

during periods when they are likely to be exposed to known triggers, such as seasonal
pollens or respiratory viruses [41].

Chronic controller therapy in children with asthma is discussed in detail separately. (See
"Asthma in children younger than 12 years: Overview of initiating therapy and monitoring
control" and "Asthma in children younger than 12 years: Management of persistent asthma
with controller therapies".)

Choice of treatment — For children ≤4 years of age with recurrent wheezing who meet
the criteria for daily controller therapy, we recommend an inhaled glucocorticoid rather than
montelukast, an oral LTRA. Standard doses of inhaled glucocorticoids given daily are
effective in preventing episodic virus-induced wheezing in young children, particularly in
patients with a clinical diagnosis of asthma, a history of recurrent wheezing with rhinovirus-
induced illness, or other asthma risk factors [39,42-44]. Montelukast may mitigate virus-
induced recurrent wheezing/asthma exacerbations in some children but overall is not as
effective as inhaled glucocorticoids. In addition, montelukast is associated with potential
neuropsychiatric adverse effects, limiting its use for mild asthma. (See "Antileukotriene
agents in the management of asthma", section on 'Adverse effects'.)

● Daily inhaled glucocorticoids – The efficacy of daily inhaled glucocorticoids in young

children with recurrent virus-induced wheezing has been demonstrated in randomized
trials and meta-analyses. In a meta-analysis of 15 trials involving 3278 children with
recurrent wheezing and asthma symptoms, daily inhaled glucocorticoid therapy
reduced exacerbations compared with placebo (13 versus 24 percent, respectively; RR
0.70, 95% CI 0.61–0.79) [44]. An earlier meta-analysis had similar findings and also
reported that while the efficacy of daily inhaled glucocorticoid therapy was higher in
patients with a diagnosis of asthma, the effect size was independent of atopy and age
(infants versus preschoolers) [42].
 Data on the effect of daily inhaled glucocorticoid therapy on linear growth velocity in
this age group are mixed, although the majority of studies show minimal to no effect
[39,45-51]. Results from one study suggest that younger (less than three years old),
smaller preschoolers are at greater risk for growth effects [45]. Further studies are
needed. The potential adverse effects of inhaled glucocorticoids are discussed in
greater detail separately. (See "Major side effects of inhaled glucocorticoids".)

● Daily leukotriene receptor antagonists – Montelukast was studied in a randomized

trial of 549 children aged two to five years of age with intermittent asthma symptoms
[52]. Over 12 months of treatment, montelukast decreased the average rate of
exacerbations by 32 percent and the time to first exacerbations by two months
compared with placebo. However, the need for systemic glucocorticoids was not
significantly different between treatment groups, and the exacerbations studied were
not exclusively limited to virus-induced asthma exacerbations.

Another study investigated the effects of montelukast 4 or 5 mg orally versus

budesonide inhalation 0.5 mg once daily in children two to eight years old with mild
asthma or recurrent wheezing [53]. Subjects were given additional asthma medications,
either twice-daily inhaled budesonide or oral glucocorticoids, for increased asthma
symptoms. No significant difference was found between groups for time to first
supplemental asthma medication use over a 52-week period, the primary outcome of
the study. However, exacerbations rates were lower in the budesonide group versus the
montelukast group. This study was not limited to children who suffered from
intermittent wheezing episodes or virus-induced asthma exacerbations [53].

PREVENTION OF SYMPTOMATIC VIRAL INFECTIONS

Controlling the frequency of symptomatic viral infections is an area of interest. Prevention

strategies include antiviral therapies and therapies to modulate the inflammatory response
to viruses. Efforts to develop antiviral agents for rhinoviruses, the most common cause of
virus-induced wheezing illness, are technically challenging due to the many rhinovirus
subtypes and are not available at this time. Given the role respiratory syncytial virus (RSV)
plays in early childhood wheezing episodes, palivizumab, a monoclonal antibody that
prevents RSV infection in infants and preschool children, has been widely studied. Its use is
associated with a decrease in the subsequent rate of recurrent wheezing compared with
untreated controls [54-56]. Although palivizumab is not indicated for treatment of
bronchiolitis in the acute setting, it may be useful in the prevention of subsequent recurrent
wheezing in young children, particularly preterm infants. (See "Respiratory syncytial virus
infection: Prevention in infants and children".)
An alternative investigational approach to preventing viral upper respiratory tract infections
(URIs) has centered around altering the early microbiome of children to prevent future
respiratory tract illnesses. In one small randomized trial, a reduction in wheezing episodes
was seen in young children treated with a bacterial extract of eight respiratory tract
pathogens compared with placebo [57], but further therapeutic studies have not been
published, and no US Food and Drug Administration (FDA) approved product for this use is
available.

The use of vitamin D has also been studied since vitamin D may influence responses to
airway pathogens, respiratory system development, and susceptibility to respiratory tract
infections. However, vitamin D regimens used have been variable, and studies have not
demonstrated long-term benefit. One randomized, controlled trial in preterm infants showed
a lowering of recurrent wheezing in children who used sustained vitamin D supplementation
in the first year of life but no difference in the rate of upper or lower respiratory tract
infections or in the development of asthma, eczema, or atopy [58,59].

Observations during the coronavirus disease 2019 (COVID-19) pandemic have shown that
public health and behavioral intervention such as handwashing, the use of masks, and
physical distancing can affect the frequency of wheezing illnesses in children. These
measures enacted to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
transmission were also associated with significantly reduced pediatric respiratory and
asthma exacerbations requiring emergency department (ED) visits and hospitalizations [60-
62]. Future seasonal and targeted use of these infection control measures may be a
beneficial population health intervention for the prevention of recurrent wheezing in
children during peak virus seasons.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Bronchiolitis in
infants and children" and "Society guideline links: Asthma in children".)

SUMMARY AND RECOMMENDATIONS

● Definition – Recurrent virus-induced wheezing is defined as a minimum of three to

four wheezing exacerbations in the setting of a viral upper respiratory tract infection
(URI) within a year. The optimal management of virus-induced wheezing in infants and
preschool children is uncertain, in part because of the heterogeneity of wheezing
phenotypes. The specific therapy for each patient is individualized based upon the
severity of symptoms and prior responses to available treatments. Treatment of infants
 and young children with their first episode of wheezing (eg, bronchiolitis) and therapy
for children with established asthma are discussed separately. (See 'Introduction' above
and "Bronchiolitis in infants and children: Treatment, outcome, and prevention" and
"Asthma in children younger than 12 years: Quick-relief (rescue) treatment for acute
symptoms" and "Asthma in children younger than 12 years: Management of persistent
asthma with controller therapies" and "Acute asthma exacerbations in children younger
than 12 years: Emergency department management".)

● Episodic management – Our approach to managing episodes of recurrent virus-

induced wheezing in children ≤4 years of age is as follows:

• Symptomatic relief – For acute symptomatic relief, we suggest an as-needed

inhaled short-acting beta agonist (SABA) ( table 2) rather than no symptomatic
therapy (Grade 2C). Inhaled SABAs are effective for rescue treatment of acute
asthma symptoms and are likely to provide relief to patients with recurrent episodes
of virus-induced wheezing. However, the response can be variable. SABAs do not
appear to be effective for young children with bronchiolitis. (See 'Symptomatic relief'
above and "Asthma in children younger than 12 years: Quick-relief (rescue)
treatment for acute symptoms", section on 'Short-acting beta agonists (SABAs)' and
"Bronchiolitis in infants and children: Treatment, outcome, and prevention".)

• Acute management of children with a history of severe or refractory symptoms

– For patients with a history of severe or refractory disease who have developed
lower respiratory tract (LRT) symptoms in the setting of a viral infection, we suggest
systemic glucocorticoid therapy rather than no antiinflammatory therapy (Grade
2C). This includes children who have a history of severe virus-induced wheezing
exacerbations requiring hospitalization or emergency department (ED) visits, have
not responded to intermittent high-dose inhaled glucocorticoid therapy previously,
or have significant asthma risk factors and are on daily controller therapy. (See
'Antiinflammatory therapy' above.)

● Preventive therapy – Our approach to preventive therapy in young children ≤4 years

of age with recurrent virus-induced wheezing is as follows:

• Children with intermittent nonsevere episodes – For young children who have
intermittent episodes of virus-induced wheezing that are not severe, we suggest a
short course of high-dose inhaled glucocorticoid initiated at the onset of URI
symptoms (ie, before wheezing has occurred) rather than no preventative therapy
(Grade 2B) and rather than lower doses of inhaled glucocorticoid or other
preventative therapies (eg, montelukast, oral glucocorticoid, or macrolide antibiotic)
(Grade 2C). Children with more frequent or severe episodes are treated with daily
controller medication, as discussed below.
 Intermittent preventative inhaled glucocorticoid is continued for up to 10 days.
Fluticasone propionate 750 mcg inhaled twice daily and budesonide 1 mg nebulized
twice daily have both been studied in this setting and appear to decrease asthma-
type symptoms and need for oral glucocorticoid therapy. It is unclear if this therapy
is effective if started after the onset of wheezing in the setting of a URI. Intermittent
high-dose inhaled glucocorticoid therapy is generally well tolerated, although slight
deficits in growth have been reported in some children. (See 'Intermittent preventive
therapy' above.)

• Daily controller therapy for children with frequent or severe episodes – For
young children with all of the following, we recommend daily controller therapy
(Grade 1B) (see 'Daily controller therapy' above):

- Four or more episodes of wheezing in the past year, and

- Each episode lasted more than one day and affected sleep, and

- Other risk factors for persistent asthma (eg, family or personal history of atopic
disease, wheezing outside the setting of a viral URI) are present

We also suggest daily controller therapy for young children who continue to
experience severe or recurrent episodes of wheezing despite intermittent high-dose
inhaled glucocorticoid therapy and those who are at risk for severe episodes,
including children with any of the following (Grade 2C):

- Intermittent (ie, less than four per year) but severe exacerbations
- Frequent need for quick-relief medications (more than two days per week for a
period of more than four weeks)
- Two severe exacerbations less than six weeks apart
- Two or more exacerbations requiring systemic glucocorticoid therapy within six
months

For daily controller therapy, we suggest a standard dose of an inhaled glucocorticoid

( table 1) rather than high- or low-dose inhaled glucocorticoid or other agents (eg,
montelukast) (Grade 2C). However, daily montelukast is a reasonable alternative for
patients who do not tolerate daily inhaled glucocorticoids. Daily inhaled
glucocorticoid therapy may result in modest decline in growth velocity. Thus, growth
should be monitored regularly in all children receiving this therapy. (See 'Daily
controller therapy' above and "Asthma in children younger than 12 years:
Management of persistent asthma with controller therapies".)

ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Sujani Kakumanu, MD, who contributed to earlier
versions of this topic review.

Use of UpToDate is subject to the Terms of Use.

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Topic 546 Version 34.0
GRAPHICS

Stepwise asthma management in infants and children <4 years of age with
recurrent wheezing *

NAEPP ¶ GINA Our appro

(≤4 years old) (≤5 years old) (<4 years o

Therapy Therapy
Therapy
Asthma (all steps (all step
Asthma symptoms (all steps include
symptoms/impact include SABA include SA
SABA as needed)
as needed) as neede

Intermittent: Step 1 Infrequent Step 1 Step 1

Daytime A short wheezing with viral Preferred: Preferred:
symptoms ≤2 course of infections and little
SABA as A short
days/week a daily ICS to no symptoms
needed course
No nocturnal beginning between illnesses
daily
at the Alternative:
awakenings medium
start of a Short course
No dose IC
respiratory of ICS at
interference beginni
tract onset of viral
with activities at the s
infection respiratory
Exacerbations of a
illness plus
treated with respirat
SABA as
OCS ≤1/year tract
needed
infectio
plus SA
as need

Alternative:
SABA as
needed

Mild persistent: Step 2 Asthma symptoms Step 2 Step 2

Daytime Preferred: that require SABA Preferred: Preferred:
symptoms >2 treatment >2
Daily low- Daily low- Daily low
but <7 times/week on
dose ICS dose ICS dose IC
days/week average for 1
Alternative: month or ≥3 Alternatives: Alternatives:
Nocturnal
awakenings 1 Daily LTRA exacerbations/year Daily LTRA Daily LT
to 2/month or or or
Minor Treated more Short course Intermi
interference often than every 6 of ICS at low-dos
with activities to 8 weeks with onset of viral ICS use
Exacerbations SABA but asthma respiratory whenev
treated with diagnosis is in illness SABA is
OCS ≥2 in 6 question Δ used
months or ≥4
 episodes of
wheezing
lasting more
than a day in a
year plus risk
factors for
persistent
asthma

Moderate persistent: Step 3 ◊ Asthma not well Step 3 § Step 3 §

Daily Daily low- controlled on low- Preferred: Preferred:
symptoms dose ICS- dose ICS
Double daily Daily low
Nocturnal LABA
low-dose ICS dose IC
awakenings 3 or LABA
Alternative:
to 4/month
Daily low- or
Daily low-
Daily SABA use dose ICS
dose ICS plus Daily low
Some activity plus LTRA
LTRA dose IC
limitation or plus LTR
Exacerbations
Daily Alternative:
treated with
medium-
OCS ≥2 in 6 Daily
dose ICS
months or ≥4 medium
episodes of dose IC
wheezing
lasting more
than a day in a
year plus risk
factors for
persistent
asthma

Severe persistent: Step 4 ◊ Asthma not well Step 4 § Step 4

Symptoms Preferred: controlled on Preferred: Preferred:
throughout the doubled low-dose
Daily Continue Daily
day ICS
medium- doubled daily medium
Nocturnal dose ICS- low-dose ICS dose IC
awakenings LABA LABA
and
>1/week
Alternative: Refer to Alternative:
Need for SABA
Daily asthma Daily
several
medium- specialist for medium
times/day
dose ICS evaluation dose IC
Extreme
plus LTRA plus LTR
limitation in Alternatives:
activity Add-on LTRA
Exacerbations or
treated with
Increase
OCS ≥2 in 6
frequency of
months or ≥4
ICS dosing
episodes of
 wheezing or
lasting more
Add
than a day in a
intermittent
year plus risk
ICS for
factors for
exacerbations
persistent
asthma

Step-up therapy Step 5 Step 5

for severe Preferred: Preferred:
asthma that is
Daily high- Daily hi
poorly controlled
dose ICS- dose IC
LABA LABA

Alternative: Alternative:
Daily high- Daily hi
dose ICS dose IC
plus LTRA plus LTR

Step 6 Step 6

Preferred: Preferred:
Daily high- Daily hi
dose ICS- dose IC
LABA plus LABA pl
OCS OCS

Alternative: Alternative:
Daily high- Daily hi
dose ICS dose IC
plus LTRA plus LTR
and OCS and OC

Initial and step-up therapies are noted above. A higher level of initial therapy, with concurrent use of
OCS in some cases, may be chosen if the patient presents with an acute exacerbation. Treatment may
be stepped down if asthma is well controlled for at least 3 months and is stepped up 1 or 2 steps if
asthma is not well controlled or is very poorly controlled. An alternative to stepping up therapy is to
first try one of the alternative options in the same step. Before stepping up therapy, inhaler
technique, adherence, and exposure to potential triggers (eg, allergens, tobacco smoke exposures)
should be assessed along with evaluating for alternative and/or concomitant diagnoses.

NAEPP: National Asthma Education and Prevention Program; GINA: Global Initiative for Asthma; SABA:
short-acting beta agonist; OCS: oral corticosteroid (glucocorticoid); ICS: inhaled corticosteroid
(glucocorticoid); LTRA: leukotriene receptor antagonist; LABA: long-acting beta agonist.

* Dosing is reviewed in other UpToDate topics and tables on the management of asthma in children.

¶ Theophylline, nedocromil, and cromolyn are not included in the table even though they were
included in NAEPP. They are rarely used due to the availability of more effective options.

Δ In these patients, a 3-month trial of therapy is reasonable and will help confirm or refute the
diagnosis of asthma.
◊ For children 4 years of age, refer to steps 3 and 4 in the UpToDate table for stepwise asthma
management in children aged 5 to 11.

§ Step-up therapy.

References:
1. National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. 2020
Focused updates to the asthma management guidelines. National Heart, Lung, and Blood Institute, 2020. Available at:
https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/2020-focused-updates-asthma-management-
guidelines (Accessed on December 16, 2020).
2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. Available at:
www.ginasthma.org (Accessed on October 27, 2022).

Graphic 127785 Version 7.0

Asthma medications for acute symptom relief in children <12 years of age*

0 to <4
Medication Dose form 4 to 11 years Comments
years

Inhaled short-acting beta2-agonists (SABAs)

Metered dose inhaler (MDI)

Albuterol 90 mcg/puff 2 puffs up 2 puffs up to Differences in

(salbutamol) to every 4 every 4 potencies exist,
HFA MDI with hours as hours as but products
spacer (valved needed needed shown are
holding essentially
chamber) comparable on a
per-puff basis.
An increasing us
or lack of
expected effect
indicates
diminished
control of
asthma.
Not
recommended
for long-term
daily treatment.
Regular use
exceeding 2
days/week for
symptom contro
(not prevention
of EIB) indicates
the need for
additional long-
term control
Levalbuterol 45 mcg/puff Safety and 2 puffs up to therapy.
(levosalbutamol) efficacy every 4 Periodically clean
HFA MDI with not hours as mouthpiece as
spacer (valved established needed drug may plug
holding in children orifice.
chamber) <4 years Inhaler should b
administered
using a valved
holding
chamber; add a
mask for children
<4 years of age.
 Instructions for
use, priming, and
cleaning MDI
vary by brand.
For specific
information,
refer to
UpToDate topic
on use of inhaler
devices in
children,
Lexicomp, and
patient leaflet
included with
MDI.
Dry powder inhaler (DPI)

Albuterol 90 Safety and 2 puffs up to DPI alternative

(salbutamol) mcg/inhalation efficacy every 4 for prophylactic
breath-activated not hours as use prior to
DPI established needed exercise in older
in children children who are
<4 years comfortable with
and capable of
properly using a
breath-activated
inhaler
technique.
Use of DPI is not
advised as rescu
therapy in an
acute setting, as
some children
may be unable to
generate
sufficient
inspiratory flow
rate to assure
optimal lung
deposition of
drug.
NOTE: DPIs can
contain lactose
and trace milk
proteins (ie,
potential
allergens).
Also refer to
information
 above on
albuterol MDI.

Nebulizer solution

Albuterol 0.63 mg/3 mL 0.63 to 2.5 1.25 to 5 mg May mix with

(salbutamol) 1.25 mg/3 mL mg up to up to every 4 budesonide
2.5 mg/3 mL every 4 hours, as suspension,
hours, as needed ipratropium
5 mg/mL
needed solution, or
(0.5%)
cromolyn sodium
solution for
nebulization.

Levalbuterol 0.31 mg/3 mL 0.31 to 0.31 to 0.63 May mix with

(levosalbutamol) 0.63 mg/3 mL 1.25 mg up mg up to budesonide
1.25 mg/0.5 to every 4 every 4 suspension for
mL hours, as hours, as nebulization.
needed needed
1.25 mg/3 mL

Combination inhaled rapid-onset long-acting beta agonist and glucocorticoid

Budesonide- Budesonide 80 Safety and 1 to 2 Single

formoterol MDI mcg- efficacy inhalations maintenance and
formoterol 4.5 not every 4 reliever therapy
mcg/puff established hours, as (SMART) is off-
in children needed, in label in the US.
<6 years addition to 2 Studies of SMART
inhalations used DPI, but
daily as only the MDI is
maintenance available in the
therapy US. There is a
(maximum small amount of
total daily variability in the
dose 8 puffs) amount of drug
dispensed with
each MDI
actuation,
whereas the DPI
dosing is
consistent. Thus,
2 puff dosing is
preferred for the
MDI.

Use and dose adjustment of inhaled short-acting beta2-agonists for acute asthma exacerbations
are reviewed separately. Short-acting beta agonists (SABAs) can also be used to prevent exercise-
induced bronchoconstriction, 2 inhalations administered 10 to 20 minutes prior to exercise. In
addition, higher doses of SABAs may be used to treat acute exacerbations, and they may be given
more frequently than every 4 hours when patients are in a medically supervised, urgent-care
 setting. Refer to separate UpToDate topic reviews and tables on recommended doses of
medications to treat children with an acute asthma exacerbation.
Nonselective inhaled agents (ie, epinephrine, isoproterenol, metaproterenol) and orally
administered beta2-agonists are not recommended, due to their potential for excessive cardiac
stimulation, especially in high doses.

DPI: dry powder inhaler; EIB: exercise-induced bronchospasm; HFA: hydrofluoroalkane; MDI: metered-
dose inhaler.

* Doses are provided for those products that have been approved by the US Food and Drug
Administration or have sufficient clinical trial safety and efficacy data in the appropriate age ranges to
support their use. Doses shown and strengths (ie, mcg per puff or inhalation) are based upon product
descriptions approved in the United States, which may differ from how strengths are described for
products available in other countries. Consult local product information before use.

Data from:
1. National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management
of Asthma. NIH Publication no. 08-4051, 2007.
2. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and
Prevention Program Coordinating Committee Expert Panel Working Group. https://www.nhlbi.nih.gov/health-topics/all-
publications-and-resources/2020-focused-updates-asthma-management-guidelines (Accessed on October 18, 2021).
3. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, updated 2021.
https://ginasthma.org/reports/ (Accessed on October 18, 2021).
4. Lexicomp Online. Copyright © 1978-2024 Lexicomp, Inc. All Rights Reserved.

Graphic 59229 Version 23.0

Contributor Disclosures
Gregory Redding, MD No relevant financial relationship(s) with ineligible companies to
disclose. Robert A Wood, MD Grant/Research/Clinical Trial Support: Aimmune [Food allergy]; ALK
[Food allergy]; DBV Technologies [Food allergy]; FARE [Food allergy]; Genentech [Food allergy]; NIAID
[Food allergy]; Novartis [Food allergy]; Regeneron [Food allergy]; Siolta [Food allergy].
Consultant/Advisory Boards: Aravax [Food allergy]. All of the relevant financial relationships listed have
been mitigated. Elizabeth TePas, MD, MS No relevant financial relationship(s) with ineligible
companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these
are addressed by vetting through a multi-level review process, and through requirements for
references to be provided to support the content. Appropriately referenced content is required of all
authors and must conform to UpToDate standards of evidence.

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