infection-induced wheezing in young children
TRANSCRIPT
Maintenance of Certification clinical management series
Series editor: James T. Li, MD, PhD
Infection-induced wheezing in young children
Avraham Beigelman, MD, MSCI, and Leonard B. Bacharier, MD St Louis, Mo
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Copyright Statement: Copyright � 2014-2015. All rights reserved.
Target Audience: Physicians and researchers within the field of allergic
disease.
Accreditation/Provider Statements and Credit Designation: The
American Academy of Allergy, Asthma & Immunology (AAAAI) is ac-
credited by the Accreditation Council for Continuing Medical Education
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List of Design Committee Members:Avraham Beigelman, MD, MSCI,
and Leonard B. Bacharier, MD (authors), and James T. Li, MD, PhD (series
editor)
Activity Objectives
1. To learn about the significance of viral infections in the inception of
wheezing episodes and asthma.
2. To review treatment recommendations for the initial episode of virus-
induced wheeze in children.
3. To review the acute management of recurrent virus-induced wheeze
in children.
Recognition of Commercial Support: This CME activity has not
received external commercial support.
Disclosure of Significant Relationships with Relevant Commercial
Companies/Organizations: A. Beigelman has received research sup-
port from the National Heart, Lung, and Blood Institute (NHLBI)/
Washington University School of Medicine, an American College of
Allergy, Asthma & Immunology (ACAAI) Young Investigator Award,
a KL2 Award, and Washington University’s ICTS award and is em-
ployed by Washington University School of Medicine. L. B. Bacharier
has consultant arrangements with Aerocrine, Boeringher Ingelheim
DBV Technologies, GlaxoSmithKline, Genentech/Novartis, Merck,
Schering, Teva, and Cephalon; has grants/grants pending with the
National Heart, Lung, and Blood Institute/National Institutes of Health;
and has received payment for lectures, including service on speakers’
bureaus, from Aerocrine, AstraZeneca, Genentech, GlaxoSmithKline,
Merck, and Schering-Plough and Teva. J. T. Li has consulted for
Abbott.
CLINICAL VIGNETTEA previously healthy 4-month-old male infant presented to the
emergency department (ED) during the month of January forevaluation of respiratory distress. His parents reported that his6-year-old sister had a ‘‘cold’’ for the preceding 7 days. Threedays before the ED visit, the infant developed a runny nose andcough that worsened over the previous 2 days. On the day of
From the Department of Pediatrics, Washington University and St Louis Children’s
Hospital.
Supported in part by Washington University Institute of Clinical and Translational
Sciences grant UL1 TR000448 from National Center for Advancing Translational
Sciences subaward KL2 TR000450.
Received for publication October 2, 2013; revised November 26, 2013; accepted for pub-
lication December 4, 2013.
Corresponding author: Leonard B. Bacharier, MD, Division of Allergy, Immunology and
Pulmonary Medicine, Department of Pediatrics, Washington University School of
Medicine, 660 S Euclid Ave, Campus Box 8116, St Louis, MO 63110. E-mail:
0091-6749/$36.00
� 2014 American Academy of Allergy, Asthma & Immunology
http://dx.doi.org/10.1016/j.jaci.2013.12.001
evaluation, the infant had ‘‘difficulty breathing’’ and diminishedoral intake.
The infant was born at full term after an uneventful pregnancyand delivery. He does not have a history of eczema. Hisimmunizations were up to date. Family history was notable formaternal asthma. His physical examination was remarkable formoderate respiratory distress with subcostal and intercostalretractions. His vital signs were as follows: temperature,38.38C; heart rate, 150 beats/min; respiratory rate, 75 breaths/min; and room air oxygen saturation, 89%. His weight and heightwere both at the 50th percentile for his age. Crackles andexpiratory wheezes were present in all lung fields, but therest of the physical examination was unremarkable. Chestradiography showed hyperinflated lungs with perihilar infiltrates.A nasophyaryngeal swab (multiplex PCR for respiratorypathogens) was positive only for respiratory syncytial virus(RSV). He was admitted for management of RSV bronchiolitis,which included supplemental oxygen for 2 days until his oxygensaturation on room air was greater than 92%, and intravenousfluids until his respiratory distress improved and he was able to
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resume oral feeding. Initially, he was treated with intermittentinhalation of albuterol by means of nebulization, but this wasdiscontinued for lack of further clinical improvement afteralbuterol inhalations. His clinical status gradually improved,and he was discharged home after 3 days with a recommendationfor follow-up with his primary care physician.
Over the ensuing year, he experienced 5 discrete episodes ofrespiratory distress accompanied by wheeze and cough, including1 episode leading to ED care. These acute episodes lastedapproximately a week and were always in the context of viral
Corrections
With regard to the March 2012 article entitled ‘‘Genetic CD(JAllergy Clin Immunol 2012;129:801-10.e6), coauthor Nadine Vregret the error.
With regard to the February 2012 article entitled ‘‘PGD2 inducesof eosinophilic pustular folliculitis’’ (J Allergy Clin Immunol 20author list. Coauthor Christos C. Zouboulis should have been lislist should read and the article should be cited as follows: NakahigY, Zouboulis CC, Tanizaki H, Egawa G, Miyachi Y, KabashimA possible pathogenesis of eosinophilic pustular folliculitis. J Alleno relevant conflicts of interest. The authors regret the error.
respiratory tract illnesses (RTIs); he did not experience anyrespiratory symptoms outside of these episodes. Inhaled albuterolwas administered during these episodes and provided partialrelief of symptoms; he was prescribed oral prednisolone during3 of the episodes. The parents are asking for advice regarding themanagement of these acute wheezing episodes.
The full version of this article, including a review of relevantissues to be considered, can be found online at www.jacionline.org. If you wish to receive CME or MOC credit for the article,please see the instructions above.
21 deficiency is associated with hypogammaglobulinemia’’€olxen should have been listed as Nadine Voelxen. The authors
eotaxin-3 via PPARg from sebocytes: A possible pathogenesis12;129:536-43), an author was mistakenly excluded from theted as the 7th author, after Yoshihiro Urade, PhD. The authorashi K, Doi H, Otsuka A, Hirabayashi T, Murakami M, Uradea K. PGD2 induces eotaxin-3 via PPARg from sebocytes:rgy Clin Immunol 2012;129:536-43. C. C. Zouboulis declares
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REVIEW
OverviewWheezing during early childhood is a common and heteroge-
neous clinical condition, with approximately 50% of childrenexperiencing at least 1 wheezing episode before the age of 6years,E1 and with evidence of viral infection in 80% to 90% ofthese episodes.E1 In addition to serving as the most commontrigger for wheezing episodes, viral RTIs early in life have beenassociated with the inception of recurrent wheezing and theeventual development of asthma.E2 The presentation ofinfection-induced wheezing in childhood is influenced by age,previous RTIs, genetic background, sensitization to aeroaller-gens, environmental factors, and interactions between thesefactors. Infection-induced wheezing in children represents aspectrum of clinical manifestations that often evolve over time:acute viral bronchiolitis is the prototypical initial manifestationof virus-induced wheezing, which is a frequent antecedent torecurrent infection-induced wheezing episodes. Recurrentwheezing in the setting of viral RTIs can progress to asthma,which is often accompanied by infection-induced asthma exacer-bations. In this review we will summarize the significance of andtreatment recommendations for initial and recurrent infection-induced wheezing presentations; the management of childhoodasthma exacerbations has been discussed elsewhere.E3
The inception of recurrent wheezing and asthma:
Role of viral bronchiolitisThe term viral bronchiolitis describes the initial episode of
virus-induced lower RTI in a child younger than 1 to 2 years.The 2 major respiratory tract viruses associated with viralbronchiolitis are RSV and human rhinovirus (HRV); however,other viruses, including human metapneumovirus and para-influenza virus, have been reported as causative pathogens.E2
RSV-induced bronchiolitis is the leading cause of hospitaliza-tion during thewinter months among young children in the UnitedStates and has a major role in the inception of wheezing andasthma as up to 50% of the children hospitalized for RSV-inducedbronchiolitis are given a diagnosis of asthma during the first 6years of life.E4 The likelihood of recurrent wheezing or asthma af-ter bronchiolitis is directly associated with the severity of theinitial illness because children who require hospitalization aremore likely to have these long-term outcomes comparedwith children who experience milder cases of bronchiolitis.E5,E6
Moreover, RSV-induced bronchiolitis requiring hospitalizationremains a risk factor for asthma at least until the age of 18 years,whereas the risk after nonhospitalized RSV-induced bronchiolitismight abate by the age of 13 years.E2
Advances in viral detection methodologies have led to theidentification of HRV and other viruses as important triggers foracute wheezing illnesses in early life and as antecedents for futureasthma. The Childhood Origins of Asthma (COAST) birthcohortE7 of infants at high risk for allergic diseases, asthma, orboth demonstrated that outpatient wheezing illnesses associatedwith HRV infection during the first 3 years of life were the mostsignificant predictor of asthma at age 6 years. Thus althoughRSV and HRV infections early in life are both associated withfuture asthma, these 2 pathogens can exert their effects onsubsequent respiratory tract disease through different pathways,which might differ in terms of the severity of the initialillness (hospitalized RSV-induced bronchiolitis vs outpatient
HRV-induced wheezing), and/or genetic predispositions (foratopy, susceptibility to specific viral infections, or both).E2
It remains uncertain whether severe early-life bronchiolitisrepresents the cause of future asthma by serving as the initialevent (‘‘the first hit’’) in creating airway allergic inflammation orwhether it serves as a marker for asthma susceptibility in childrenwith a predisposition for asthma.E2 Two recent reports provideenhanced understanding of this complex relationship. Treatmentof late preterm infants with the anti-RSV mAb palivizumabduring the RSV season resulted in a significant reduction inwheezing days during the first year of life, with effects thatpersisted after the end of the treatment period, suggesting thatthe occurrence of RSV-induced bronchiolitis has a majorcausative role in the pathogenesis of recurrent wheezing.E8
Second, among participants of the COAST cohort, sensitizationto aeroallergens preceded and served as a significant risk factorfor HRV-induced wheezing. In contrast, having HRV-inducedwheezing did not increase the risk of allergic sensitization,suggesting that at least in this high-risk cohort, HRV-inducedwheezing was a consequence rather than the cause of atopictendency.E9 The progression from a single episode of early-lifevirus-induced wheeze to recurrent wheeze is also related tointeractions between host genetic background and the virusbecause, among the COAST cohort, genetic variants in anasthma-associated gene locus on chromosome 17 (17q21) wereassociated with future asthma diagnosis, although only amongchildren who experienced HRV-induced wheezing in earlylife.E10
The first episode of infection-induced wheezing in
young children: Acute managementDespite the conduct of numerous studies examining the
efficacy of various asthma-related therapies in patients with acutebronchiolitis, recent evidence-based recommendations favorsupportive therapy for viral bronchiolitis because inhaledbronchodilators, corticosteroids (systemic or inhaled), mon-telukast, and antibiotics have failed to show consistent andmeaningful clinical benefits.E11,E12
Recently, 2 interventions have been demonstrated to provideclinical benefit among patients with severe bronchiolitis andmight become considerations for incorporation into clinicalguidelines. The combination of nebulized epinephrine with oraldexamethasone administered in the EDwas superior to placebo inpreventing hospital admission.E13 However, there was no clinicalbenefit for either medication administered alone, and the effect ofthe combined intervention became nonstatistically significantafter adjustment for multiple comparisons, suggesting that thepotential benefit of this combination must be confirmed inadditional studies before it is recommended for patient care.A recent systematic review concluded that nebulized 3% salinesignificantly reduced the duration of hospitalization amonginfants hospitalized with viral bronchiolitis but was notassociated with a reduction in the rate of hospitalization whenadministered in the ED setting.E14
Prevention of subsequent wheezing after an initial
episode of infection-induced wheezing in young
childrenAlthough recurrent wheezing and asthma are frequent
sequelae to bronchiolitis, treatment with asthma controller
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therapy (including corticosteroids and montelukast) during orafter bronchiolitis has not been found to be effective in alteringthe natural history of postviral bronchiolitis wheezing. Onepotential exception to this conclusion is a finding derived froma post hoc analysis of a study that originally investigated theeffect of oral corticosteroid (OCS) therapy during acute viralbronchiolitis. Although OCS treatment was not associated witha protective effect for the development of recurrent wheezingamong the study group as a whole, it was associated with a lowerlikelihood of recurrent wheezing over the following year in thesubgroup of children hospitalized with HRV-induced, but notRSV-induced, bronchiolitis.E15 This finding must be confirmedin prospective studies before systemic corticosteroids shouldbe recommended as a preventative approach for post-HRVwheezing.
Virus-induced recurrent wheezing in early
childhoodRecurrent wheezing among preschool children is a heteroge-
neous disorder with multiple phenotypes, and identification ofthese phenotypes might assist in predicting the progression toasthma in childhood and potentially in predicting treatmentresponse. Commonly, preschool children experience the majorityof their wheezing activity during acute episodes triggered by viralupper respiratory tract infections (URIs; typically HRV) whileexperiencing minimal to no symptoms between these episodes.E1
The terms episodic viral wheeze and severe intermittent wheezinghave been proposed to describe the phenotype of children whowheeze exclusively during viral infections. In contrast, the termmultiple-trigger wheeze has been suggested for children whowheeze when exposed to multiple triggers (including allergens,exercise, and viruses) rather than with viral infections only.However, the classification of episodic and multiple-triggerwheeze appears to be unstable over time because many childrenwill commonly switch between these 2 categories.E3
Most of the children who wheeze during early life do notcontinue to wheeze at school age.E3 Models that includeindicators of subsequent asthma risk have been developed tohelp the clinician identify children at greatest risk for continuedwheezing (and presumably asthma) into older childhood. Oneof these models is the modified Asthma Predictive Index(mAPI), which includes a combination of risk factors in additionto recurrent wheezing: parental history of asthma, personalhistory of atopic dermatitis, allergic sensitization to inhalant orfood allergens, peripheral blood eosinophilia, and wheezing notrelated to a cold. The clinical utility of identifying children athigh risk for recurrent wheezing by using the mAPI issupported by a study demonstrating significantly fewer wheezingexacerbations requiring OCSs among children with positivemAPI results receiving daily low-dose inhaled corticosteroids(ICSs) compared with placebo.E3 A detailed assessment of therelative benefits of daily controller therapy regimens (which caninclude ICSs,montelukast, or both) for the prevention of recurrentwheezing episodes is beyond the scope of this review and isdiscussed elsewhere.E3
Acute management of recurrent virus-induced
wheezing episodes in childrenAs in bronchiolitis, the management of acute virus-associated
wheezing illnesses in young children has traditionally consisted
of asthma medications, such as inhaled bronchodilators,corticosteroids (systemic or inhaled), and/or montelukast.E1
Inhaled b2-agonists are recommended for short-term relief ofacute wheezing symptoms,E16 although the efficacy of thisapproach during confirmed virus-induced wheezing episodeshas not been studied outside the context of viral bronchiolitis.Intermittent montelukast given at the first sign of a URI hasnot been effective in preventing the progression to severeexacerbation requiring OCSsE17 but has been associated withattenuation of clinical severity of the acute episodes measuredby symptom severityE17 and health care useE18 and is an approachrecommended by the European Respiratory Society for episodicviral wheeze.E16 The beneficial effects of intermittent montelu-kast on symptomatology during acute RTIs in this wheezingphenotype have been demonstrated among children with positivemAPI results,E17 further emphasizing the need to customizetreatment according to disease phenotype.
Given the episodic nature of this condition, the role ofintermittent high-dose ICS therapy among children with recur-rent, but not persistent, wheezing has been a topic of recentresearch. Intermittent high-dose fluticasone propionate (750 mgadministered twice daily) beginning at the onset of a URI amongpreschool children with histories of recurrent wheezing triggeredby viral infections was associated with a 50% reduction in the rateof exacerbations requiring OCSs.E19 However, the clinicalapplicability of this specific approach was limited by significantlysmaller gains in height and weight among patients treated withthis specific high-dose ICS regimen.E19 In preschool childrenwith episodic wheeze and positive mAPI results, intermittenthigh-dose ICS treatment (1 mg of budesonide administered twicedaily for 7 days), when started at the earliest signs of an RTI, wascomparable with daily low-dose ICS treatment (0.5 mg ofbudesonide administered once daily) in the prevention ofprogression from early RTI symptoms to severe exacerbationrequiring OCSs.E20 Taken together, these studies suggest thatintermittent treatment with high-dose ICSs or montelukast mighthave a role early in the manifestations during acute wheezingepisodes in preschool children, particularly those with asthmarisk factors (ie, positivemAPI result). However, additional studiesare required to maximize the efficacy of these treatments, toprevent side effects, and to identify the children who will benefitthe most from these treatments.
OCSs are recommended as a treatment for acute asthmaexacerbations by asthma guidelines.E21 However, despite thesubstantial body of evidence supporting the efficacy of thistreatment for asthma exacerbations among school-age childrenand adolescents, evidence supporting the benefits of OCSs forvirus-induced wheeze among preschool-age children is verylimited.E22 A recent large placebo-controlled clinical trialinvestigated the efficacy of OCSs among 700 preschool childrenhospitalized with clinically suspected (but not confirmed)virus-induced wheeze.E23 This study did not show a significantdifference in the duration of hospitalization or rate of symptomresolution after discharge among children treated with OCSsversus placebo,E23 nor was there a difference in OCS responseamong those with asthma risk factors. A recent post hoc analysisin 2 independent outpatient cohorts of preschool children withepisodic wheeze, including more than 1500 RTIs, also revealedthat OCSs did not reduce symptom severity during theseepisodes.E24 The lack of OCS response among preschoolchildren with virus-induced wheezing might be related to the
E5. Escobar GJ, Masaquel AS, Li SX, Walsh EM, Kipnis P. Persistent recurring
wheezing in the fifth year of life after laboratory-confirmed, medically
attended respiratory syncytial virus infection in infancy. BMC Pediatr 2013;
13:97.
E6. Carroll KN, Wu P, Gebretsadik T, Griffin MR, Dupont WD, Mitchel EF, et al.
The severity-dependent relationship of infant bronchiolitis on the risk and
morbidity of early childhood asthma. J Allergy Clin Immunol 2009;123:
1055-61, 61.e1.
E7. Lemanske RF Jr. The Childhood Origins of Asthma (COAST) study.
Pediatr Allergy Immunol 2002;13(Suppl 15):38-43.
E8. Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A,
Kimpen JL, et al. Respiratory syncytial virus and recurrent wheeze in healthy
preterm infants. N Engl J Med 2013;368:1791-9.
E9. Jackson DJ, Evans MD, Gangnon RE, Tisler CJ, Pappas TE, Lee WM, et al.
Evidence for a causal relationship between allergic sensitization and rhinovirus
wheezing in early life. Am J Respir Crit Care Med 2012;185:281-5.
E10. Caliskan M, Bochkov YA, Kreiner-Moller E, Bonnelykke K, Stein MM, Du G,
et al. Rhinovirus wheezing illness and genetic risk of childhood-onset asthma.
N Engl J Med 2013;368:1398-407.
E11. Diagnosis and management of bronchiolitis. Pediatrics 2006;118:1774-93.
E12. Wainwright C. Acute viral bronchiolitis in children—a very common condition
with few therapeutic options. Paediatr Respir Rev 2010;11:39-45.
E13. Plint AC, Johnson DW, Patel H, Wiebe N, Correll R, Brant R, et al. Epinephrine
and dexamethasone in children with bronchiolitis. N Engl J Med 2009;360:
2079-89.
E14. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulised hypertonic
saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev
2013;(7):CD006458.
E15. Lehtinen P, Ruohola A, Vanto T, Vuorinen T, Ruuskanen O, Jartti T.
Prednisolone reduces recurrent wheezing after a first wheezing episode
associated with rhinovirus infection or eczema. J Allergy Clin Immunol 2007;
119:570-5.
E16. Brand PL, Baraldi E, Bisgaard H, Boner AL, Castro-Rodriguez JA, Cus-
tovic A, et al. Definition, assessment and treatment of wheezing disorders
in preschool children: an evidence-based approach. Eur Respir J 2008;32:
1096-110.
E17. Bacharier LB, Phillips BR, Zeiger RS, Szefler SJ, Martinez FD, Lemanske RF Jr,
et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist
in preschool children with moderate-to-severe intermittent wheezing. J Allergy
Clin Immunol 2008;122:1127-35.e8.
E18. Robertson CF, Price D, Henry R, Mellis C, Glasgow N, Fitzgerald D, et al. Short
course montelukast for intermittent asthma in children: a randomised controlled
trial. Am J Respir Crit Care Med 2007;175:323-9.
E19. Ducharme FM, Lemire C, Noya FJ, Davis GM, Alos N, Leblond H, et al.
Preemptive use of high-dose fluticasone for virus-induced wheezing in young
children. N Engl J Med 2009;360:339-53.
E20. Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD, Lemanske RF
Jr, et al. Daily or intermittent budesonide in preschool children with recurrent
wheezing. N Engl J Med 2011;365:1990-2001.
E21. National Asthma Education and Prevention Program. Expert panel report III:
guidelines for the diagnosis and management of asthma. Bethesda: US Depart-
ment of Health and Human Services; 2007.
E22. Grigg J. Role of systemic steroids in acute preschool wheeze. Arch Dis Child
2010;95:491-2.
E23. Panickar J, Lakhanpaul M, Lambert PC, Kenia P, Stephenson T, Smyth A, et al.
Oral prednisolone for preschool children with acute virus-induced wheezing.
N Engl J Med 2009;360:329-38.
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heterogeneity of wheezing phenotypes in early life, a lesserextent of eosinophilic airway inflammation (which is steroidresponsive), or both among most of these young children. Thesestudies and accompanying editorials suggest reconsideration ofOCSs in preschool-age virus-associated wheeze, with addedconsideration of avoidance of using OCSs for outpatientwheezing illnesses while reserving this treatment to theseriously ill hospitalized children.E22,E25 Additional prospectiverandomized controlled trials are required to confirm this findingin outpatient episodes before abandoning this longstandingtherapy.
THE CASE REVISITEDThe patient has a history of severe RSV-induced bronchiolitis
in infancy, which is a known independent risk factor forsubsequent wheezing episodes and eventually asthma. Indeed,over the year after the initial RSV-induced bronchiolitis, thepatient experienced multiple discrete episodes of respiratorydistress accompanied bywheeze and cough that were triggered byviral illness. Although the patient experienced significantmorbidity during these lower RTIs, he did not have respiratorysymptoms outside of these episodes. The parents were advisedthat inhaled albuterol should be provided for short-term relief ofthese acute respiratory symptoms. In addition, early intermittenttreatment with a high-dose ICS or oral montelukast could be givento reduce clinical symptoms during these acute illnesses given thepatient’s high likelihood of response to this approach based on hispositive mAPI result (maternal history of asthma). The parentswere informed that recent studies and expert opinions questionedthe beneficial effects of OCSs. On the basis of this uncertainty, thedecision of whether to start OCS treatment should be determinedbased on the severity of symptoms during future episodes, as wellas consideration of not using OCSs duringmilder episodes that donot require inpatient care. The current data and recommendationsregarding the acute management of infection-induced wheezingin young children are summarized in Table E1.E11,E14,E16-E28
This case highlights many of the aspects associated with thecomplex interaction between respiratory viral infections early inlife and asthma. Viral infections are the dominant triggerof wheezing illnesses during early childhood. Despite theremarkably high prevalence of these illnesses and their attendantmorbidity, the optimal treatment strategies remain undefined formanagement of acute episodes and prevention of recurrentepisodes. Future research should focus on expanding the currentlylimited evidence base for decision making in these clinicalsituations.
REFERENCES
E1. Bacharier LB. Viral-induced wheezing episodes in preschool children:
approaches to therapy. Curr Opin Pulm Med 2010;16:31-5.
E2. Beigelman A, Bacharier LB. The role of early life viral bronchiolitis in the
inception of asthma. Curr Opin Allergy Clin Immunol 2013;13:211-6.
E3. Bacharier LB, Guilbert TW. Diagnosis and management of early asthma in
preschool-aged children. J Allergy Clin Immunol 2012;130:287-98.
E4. Bacharier LB, Cohen R, Schweiger T, Yin-Declue H, Christie C, Zheng J, et al.
Determinants of asthma after severe respiratory syncytial virus bronchiolitis.
J Allergy Clin Immunol 2012;130:91-100.e3.
E24. Beigelman A, King TS, Mauger D, Zeiger RS, Strunk RC, Kelly HW, et al. Do
oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in
preschool children with recurrent wheezing? J Allergy Clin Immunol 2013;131:
1518-25.
E25. Bush A. Practice imperfect—treatment for wheezing in preschoolers. N Engl J
Med 2009;360:409-10.
E26. Bush A, Thomson AH. Acute bronchiolitis. BMJ 2007;335:1037-41.
E27. Gadomski AM, Brower M. Bronchodilators for bronchiolitis. Cochrane Database
Syst Rev 2010;(12):CD001266.
E28. Corneli HM, Zorc JJ, Mahajan P, Shaw KN, Holubkov R, Reeves SD, et al.
A multicenter, randomized, controlled trial of dexamethasone for bronchiolitis.
N Engl J Med 2007;357:331-9.
TABLE E1. Management of infection-induced wheezing in young children
Setting of the wheezing episode Intervention
Current evidence on efficacy of the intervention and/or
whether the intervention is recommended by clinical guidelines
The first episode of virus-induced
wheezing: ‘‘viral bronchiolitis’’
Supportive treatment,
including supplemental
oxygen
Bronchodilators
Corticosteroids
Nebulized 3% saline
d Supportive treatment is recommended for viral bronchiolitis.E11,E26
d Bronchodilators produce small short-term improvements in clinical scores among some
children.E27
d Bronchodilators have not been shown to affect major clinical outcomes, such as the rate
of hospital admission or the duration of hospitalization.E27
d Bronchodilators could be given as a trial to evaluate treatment response but should not
be used routinely in the management of bronchiolitis.E11,E26
d Corticosteroids (oral or inhaled) do not affect bronchiolitis clinical outcomesE28 and are
not recommended in the management of acute bronchiolitis.E11,E26
d Nebulized 3% saline produces a modest reduction in the duration of hospitalization but
is not associated with a reduction in the rate of hospitalization when administered in the
ED setting.E14
Recurrent virus-induced
wheezing episodes
Inhaled b2-agonists
Intermittent montelukast
Intermittent high-dose ICSs
OCSs
d Inhaled b2-agonists are recommended for short-term relief of acute wheezing
symptoms.E16
d Administered at the first sign of URI, intermittent montelukast has been associated with
attenuation of clinical severity of the acute wheezing episodes measured on the basis of
symptom severityE17 and health care use.E18
d Intermittent montelukast represents a recommended approach by the ERS for episodic
viral wheeze.E16
d Treatment at the onset of a URI has been associated with a reduction in the rate of
exacerbations requiring OCSs.E19
d The specifics of intermittent high-dose ICS treatment still need to be determined to
avoid potential side effects that have been shown in one study.E19
d In preschool children with episodic wheeze and positive mAPI results, intermittent
high-dose ICS treatment at the earliest signs of an RTI was comparable with daily
low-dose ICS treatment in prevention of progression from early RTI symptoms to severe
exacerbations requiring OCSs.E20
d OCSs are a recommended treatment for acute asthma exacerbations by asthma
guidelines.E21
d OCS treatment compared with placebo, among preschool children hospitalized with
clinical virus-induced wheeze did not result in a significant difference in the duration of
hospitalization or in the rate of symptom resolution after discharge.E23
d Recent post hoc analysis in 2 independent outpatient cohorts of preschool children with
episodic wheeze concluded that OCSs did not reduce symptom severity during these
episodes.E24
d Recent editorials suggest reconsideration of OCS use in preschool-age virus-associated
wheeze, with added consideration of avoidance of using OCSs for outpatient wheezing
illnesses while reserving this treatment to the seriously ill hospitalized children.E22,E25
ERS, European Respiratory Society.
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