Wheezing Infant Guideline

:
AMERICAN THORACIC SOCIETY

DOCUMENTS
Ofcial American Thoracic Society Clinical Practice Guidelines:

Diagnostic Evaluation of Infants with Recurrent or
Persistent Wheezing
Clement L. Ren*, Charles R. Esther, Jr.*, Jason S. Debley, Marianna Sockrider, Ozge Yilmaz, Nikhil Amin,
Alia Bazzy-Asaad, Stephanie D. Davis, Manuel Durand, Jeffrey M. Ewig, Hasan Yuksel, Enrico Lombardi, Terry L. Noah,
Peggy Radford, Sarath Ranganathan, Alejandro Teper, Miles Weinberger, Jan Brozek, and Kevin C. Wilson; on behalf
of the ATS Ad Hoc Committee on Infants with Recurrent or Persistent Wheezing
THIS OFFICIAL CLINICAL PRACTICE GUIDELINE OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, MARCH 2016
Background: Infantile wheezing is a common problem, but there are and imprecise estimates. The committee made conditional
no guidelines for the evaluation of infants with recurrent or persistent recommendations to perform bronchoscopic airway survey,
wheezing that is not relieved or prevented by standard therapies. bronchoalveolar lavage, esophageal pH monitoring, and a swallowing
study. It also made conditional recommendations against empiric food
Methods: An American Thoracic Societysanctioned guideline
avoidance, upper gastrointestinal radiography, and gastrointestinal
development committee selected clinical questions related to
scintigraphy. Finally, the committee recommended additional
uncertainties or controversies in the diagnostic evaluation of
research about the roles of infant pulmonary function testing and food
wheezing infants. Members of the committee conducted
avoidance or dietary changes, based on allergy testing.
pragmatic evidence syntheses, which followed the Grading of
Recommendations, Assessment, Development, and Evaluation
Conclusions: Although infantile wheezing is common, there is a
(GRADE) approach. The evidence syntheses were used to inform
paucity of evidence to guide clinicians in selecting diagnostic tests
the formulation and grading of recommendations.
for recurrent or persistent wheezing. Our committee made several
Results: The pragmatic evidence syntheses identied few studies conditional recommendations to guide clinicians; however, additional
that addressed the clinical questions. The studies that were identied research that measures clinical outcomes is needed to improve our
constituted very low-quality evidence, consisting almost exclusively condence in the effects of various diagnostic interventions and to
of case series with risk of selection bias, indirect patient populations, allow advice to be provided with greater condence.
Overview for further evaluation and treatment. knowledge gap and interest, the ATS
Guidelines for diagnostic testing exist for convened a committee of pediatric
Wheezing occurs commonly during infancy older children with asthma (4), but such pulmonologists with clinical and research
(1). In most cases, wheezing episodes are guidelines are lacking for wheezing infants. experience in infantile wheezing to develop
mild and easily treated (2). However, In a 2009 survey of Assembly on Pediatrics evidence-based guidelines for the diagnostic
some infants will develop persistent or members of the American Thoracic Society evaluation of infantile wheezing.
recurrent wheezing, which is often severe (ATS), infantile wheezing was one of the For these guidelines, the committee
(3). These infants are frequently referred highest ranked topics for which members dened infantile wheezing as recurrent or
to pediatric pulmonology specialists desired a guideline. To address this persistent episodes of wheezing in infants
*These authors contributed equally to this work.

ORCID ID: 0000-0003-4431-0644 (C.L.R.).
Correspondence and requests for reprints should be addressed to Clement L. Ren, M.D., Indiana University School of Medicine, Riley Hospital for Children,
705 Riley Hospital Drive/ROC4270, Indianapolis, IN 46202. E-mail: clren@iu.edu
This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org
Am J Respir Crit Care Med Vol 194, Iss 3, pp 356373, Aug 1, 2016
Copyright 2016 by the American Thoracic Society
DOI: 10.1164/rccm.201604-0694ST
Internet address: www.atsjournals.org
356 American Journal of Respiratory and Critical Care Medicine Volume 194 Number 3 | August 1 2016
AMERICAN THORACIC SOCIETY DOCUMENTS
Contents Bronchodilators, Inhaled Treatment with Bronchodilators,

Overview Corticosteroids, or Systemic Inhaled Corticosteroids, or
Introduction Corticosteroids Be Managed Systemic Corticosteroids Undergo
Use of These Guidelines according to the Results of an Upper Gastrointestinal Series
Methods Infant Pulmonary Function Rather Than 24-Hour Esophageal
Denition Testing Using the Raised-Volume pH Monitoring?
Process Rapid Thoracoabdominal Question 7: Should Infants
Results Compression Technique or with Persistent Wheezing
Question 1: Should Infants with Clinical Assessment Alone? That Is Not Relieved by
Persistent Wheezing despite Question 4: Should Infants without Bronchodilators, Inhaled
Treatment with Bronchodilators, Eczema Who Have Persistent Corticosteroids, or Systemic
Inhaled Corticosteroids, or Wheezing despite Treatment with Corticosteroids Undergo
Systemic Corticosteroids Undergo Bronchodilators, Inhaled Gastroesophageal
Airway Survey via Flexible Corticosteroids, or Systemic Scintigraphy Rather Than
Fiberoptic Bronchoscopy? Corticosteroids Undergo Empiric 24-Hour Esophageal
Question 2: Should Infants with Food Avoidance? pH Monitoring?
Persistent Wheezing despite Question 5: Should Infants Question 8: Should Infants without
Treatment with Bronchodilators, with Persistent Wheezing despite Neurologic Pathology with
Inhaled Corticosteroids, or Treatment with Bronchodilators, Persistent Wheezing That Is Not
Systemic Corticosteroids Inhaled Corticosteroids, or Relieved by Bronchodilators,
Undergo Bronchoalveolar Systemic Corticosteroids Undergo Inhaled Corticosteroids, or
Lavage? 24-Hour Esophageal pH Systemic Corticosteroids
Question 3: Should Infants Monitoring? Undergo a Swallowing Function
with Persistent Wheezing Question 6: Should Infants Study?
despite Treatment with with Persistent Wheezing despite Limitations and Future Directions
less than 24 months old (herein referred to corticosteroids, or systemic corticosteroids, recommendation, very low quality of
as infants with persistent wheezing). The which compare clinical outcomes among evidence).
guidelines address diagnostic tests that those who are managed according to 6. For infants with persistent wheezing
are frequently considered by pediatric results of infant pulmonary function despite treatment with bronchodilators,
pulmonologists and other clinicians when testing using the raised-volume rapid inhaled corticosteroids, or systemic
evaluating infantile wheezing, but are either thoracoabdominal compression (RVRTC) corticosteroids, we suggest 24-hour
controversial or a frequent source of method versus those who are managed esophageal pH monitoring rather than
uncertainty. Diagnostic tests that are upper gastrointestinal radiography
according to clinical assessment alone.
generally considered standard of care (e.g., (conditional recommendation, very low
4. A. For infants who do not have eczema
chest radiography) were not addressed. quality of evidence).
but have persistent wheezing despite
The committee performed a pragmatic 7. For infants with persistent wheezing
treatment with bronchodilators,
evidence synthesis and then used the despite treatment with bronchodilators,
inhaled corticosteroids, or systemic inhaled corticosteroids, or systemic
Grading of Recommendations, Assessment,
corticosteroids, we suggest that corticosteroids, we suggest 24-hour
Development, and Evaluation (GRADE)
approach (5) to formulate and grade the clinicians and caregivers not use esophageal pH monitoring rather
following recommendations: empiric food avoidance or dietary than gastrointestinal scintigraphy
changes (conditional recommendation, (conditional recommendation, very low
1. For infants with persistent wheezing very low quality of evidence). quality of evidence).
despite treatment with bronchodilators, B. We recommend research studies that 8. For infants with persistent wheezing
inhaled corticosteroids, or systemic determine whether food avoidance or despite treatment with bronchodilators,
corticosteroids, we suggest an airway inhaled corticosteroids, or systemic
dietary changes guided by food allergy
survey via exible beroptic bronchoscopy corticosteroids, we suggest performing
testing improves clinical outcomes
(conditional recommendation, very low video-uoroscopic swallowing studies
quality of evidence). in infants who do not have eczema
but have persistent wheezing despite (conditional recommendation, very low
2. For infants with persistent wheezing despite quality of evidence).
treatment with bronchodilators, inhaled treatment with bronchodilators,
corticosteroids, or systemic corticosteroids, inhaled corticosteroids, or systemic
we suggest bronchoalveolar lavage (BAL) corticosteroids. Introduction
(conditional recommendation, very low 5. For infants with persistent wheezing
quality of evidence). despite treatment with bronchodilators, Wheezing during infancy is a common
3. We recommend research studies in inhaled corticosteroids, or systemic clinical problem. In the Tucson Childrens
infants with persistent wheezing despite corticosteroids, we suggest 24-hour Respiratory Study, a longitudinal birth
treatment with bronchodilators, inhaled esophageal pH monitoring (conditional cohort study of healthy full-term infants,
American Thoracic Society Documents 357

34% of children had at least one episode of the specic clinical situation and parent Results
wheezing before age 3 years (1). In some preferences.
infants, this is a sign of early-onset asthma Question 1: Should Infants with
(6), whereas other infants may wheeze Persistent Wheezing despite
because of diminished airway function or Methods Treatment with Bronchodilators,
innate immune responses (7, 8). For the Inhaled Corticosteroids, or Systemic
majority of infants, these wheezing episodes Denition Corticosteroids Undergo Airway
are mild, episodic, and easily treated. For these guidelines, the committee Survey via Flexible Fiberoptic
However, some infants will develop severe dened infantile wheezing as recurrent or Bronchoscopy?
recurrent or persistent wheezing. Guidelines persistent episodes of wheezing in infants
for the evaluation and treatment of asthma less than 24 months old (herein, referred to Summary of evidence. Our literature search
in older children and the general approach as infants with persistent wheezing). did not identify any studies that compared
to the evaluation of infantile wheezing have This cutoff was chosen for two reasons: wheezing infants undergoing airway survey via
been published (4, 9), but no guidelines exist previous documents have addressed bronchoscopy with wheezing infants who did
for the use of more specialized testing, such wheezing in preschool-aged children not undergo airway survey. Therefore, our
as exible beroptic bronchoscopy, in the (35 yr old) (10), and wheezing on the basis recommendation is based on 10 case series
evaluation of infants with persistent of diminished airway function tends to that collectively included 1,364 patients and
wheezing. Recognizing the need for clinical improve by age 3 years (1). The population reported that 452 of the 1,364 patients (33%)
guidance on the diagnostic evaluation of was further limited to infants with who underwent airway survey for respiratory
wheezing infants, the ATS convened a persistent wheezing despite treatment with symptoms were found to have an anatomic
guideline development committee of recommended rst-line therapies of abnormality known to cause wheezing
pediatric specialists to conduct pragmatic bronchodilators, inhaled corticosteroids, or (Table 1) (1221). Lesions included
evidence syntheses and then use the evidence systemic corticosteroids (11). tracheomalacia, bronchomalacia,
syntheses as the basis for recommendations tracheobronchomalacia, vascular rings,
for the evaluation of persistent wheezing Process
vascular slings, and airway compression by a
in infancy. The co-chairs (C.L.R. and C.R.E.) were
vascular structure. No major complications
conrmed by the ATS Assembly on
were reported in any of the case series, with
Pediatrics, Program Review Subcommittee,
minor complications such as transient
Use of These Guidelines and Board of Directors. A guideline
hypoxemia described in 510% of subjects.
development committee was then assembled,
Infants with wheezing due to
These ATS guidelines are not meant to which consisted of pediatric clinicians and
tracheomalacia, bronchomalacia, or
establish a standard of care. Rather, researchers with expertise in the evaluation of
tracheobronchomalacia are typically
they represent an effort to summarize wheezing during infancy. All members of the
managed by observation alone if wheezing is
evidence and provide reasonable clinical committee disclosed and were vetted for
the only abnormality or the associated
recommendations based on that evidence. potential conicts of interest according to the
Clinicians, patients, third-party payers, rules and procedures of the ATS. The symptoms are mild, because the vast
other stakeholders, and the courts should committee then developed clinical questions, majority of infants improve over time
never view these recommendations as using the PICO (Patient, Intervention, with conservative therapy (22). Infants
dictates. No guidelines or recommendations Comparator, and Outcomes) framework. with wheezing due to tracheomalacia,
can take into account all of the often Each question was the basis of a pragmatic bronchomalacia, or tracheobronchomalacia
compelling, unique individual clinical evidence synthesis, which consisted of occasionally require an intervention
circumstances. Therefore, no one charged searching the Medline and CINAHL (e.g., positive airway pressure, surgery, or
with evaluating clinicians actions should (Cumulative Index to Nursing and Allied stenting) because of accompanying life-
attempt to apply the recommendations Health Literature) databases on the basis of threatening airway obstruction, respiratory
from these guidelines by rote or in a blanket prespecied search criteria, selecting studies failure, recurrent pneumonias, or failure
fashion. These guidelines are not intended based on prespecied selection criteria, and to thrive. Positive airway pressure
to be a comprehensive review of the appraising and summarizing the evidence immediately decreases respiratory distress,
evaluation of infantile wheezing, but according to the GRADE approach. The restores airway patency, and improves
rather to provide evidence-based evidence syntheses were used as the basis for pulmonary function according to multiple
recommendations for a set of specialized the formulation of recommendations, which small case series and case reports (2330).
diagnostic tests frequently considered in the was based on consideration of the balance of Surgery (most commonly, aortopexy)
evaluation of this patient population. benets versus harms and burdens, quality of relieves obstruction in virtually all patients
Clinicians will be able to use these evidence, patient preferences, and cost and with tracheomalacia, but is less effective in
recommendations when considering resource use. The recommendations were patients with tracheobronchomalacia or
specic diagnostic tests for the evaluation of graded according to the GRADE approach. bronchomalacia according to small case
persistent wheezing. Recommendations The specics of the PICO framework, series (3137). This was illustrated by a case
for order or selection of diagnostic testing outcomes, and other methods are series in which 21 of 21 patients (100%)
are beyond the scope of this document, and described in greater detail in the online had tracheomalacia corrected by aortopexy,
such decisions will vary depending on supplement. but only 1 of 4 patients (25%) with
Table 1. Airway Survey: Quality Assessment and Summary of Findings
Quality Assessment
Quality
Study Publication Importance of of
No. Design Limitations Indirectness Inconsistency Imprecision Bias Outcome Evidence Summary of Findings
Frequency with which bronchoscopy identies an anatomical lesion known to cause wheezing
10* Case series Serious Seriousx None Seriousjj Undetected Not a prespecied Very low The 10 case series collectively
outcome included 1,364 patients.
American Thoracic Society Documents

452 of 1,364 patients (33%) were
found to have anatomical
abnormalities known to cause
wheezing.
The largest series included 885
patients. When this study was
removed, the estimate was
unchanged.
Complications were rarely
reported.
Frequency of wheezing after treatment
27 Case series and Serious** Serious None Serious Undetected Critical Very low 90% of patients with
case reports tracheomalacia, bronchomalacia,

or tracheobronchomalacia
improved with time alone.
88100% of patients with vascular
rings, vascular slings, or vascular
compression of the airways
improved with surgery.
Complications occurred in 10%
and mortality in ,5%.
*References 1221.

No studies included a control group. Therefore, they are all case series.

Limitations were serious because of probable selection bias related to who underwent bronchoscopy and who did not. Most studies did not provide details of how they decided when to
perform bronchoscopy with airway survey and when not to perform bronchoscopy with airway survey.
x
Indirectness was serious because few studies were limited solely to wheezing infants. Most included infants with respiratory symptoms or signs, such as stridor, wheezing, cough, respiratory
distress or failure, or recurrent infections.
jj
Imprecision was serious because sample size was small (,100) in all but one of the studies that were reviewed.

References 2342 and 4450.
**Limitations were serious because of probable selection bias related to who was eventually treated with positive airway pressure, airway stenting, and surgery, as well as which type of
surgery was used.

Indirectness was serious because few studies were limited solely to wheezing infants. Most included infants being treated for a variety of respiratory symptoms or signs (e.g., stridor,
wheezing, cough, respiratory distress or failure, or recurrent infections) caused by anatomical abnormalities.

Imprecision was serious because the sample size was small (,100) in all the studies that were reviewed.
359
tracheobronchomalacia was corrected by relief from the burden, cost, and potential antibiotic therapy, and indirect evidence
aortopexy (31). Airway stenting has been harms of further diagnostic testing; probable from a randomized trial of 50 children with
used to improve airway obstruction in reductions in the use of ineffective productive cough presumed to be caused by
infants (3842), but complications medications (bronchodilators or systemic bacterial bronchitis found that the cough
including formation of granulation tissue, corticosteroids) and the frequency of resolved in 48% of children who received
migration, or erosion occurred in 50% of physician visits; and parental reassurance, antibiotic therapy, compared with only 16%
cases and were potentially associated given the high likelihood that the condition of those who did not receive antibiotics (71).
with death in 2 of 22 infants (39, 40). will spontaneously resolve. Finding The trial likely underestimated the effects
Newer approaches include direct vascular rings, vascular slings, and airway of antibiotics in patients with bacterial
tracheobronchopexy (43). compression by a vascular structure leads to bronchitis because children did not need to
In contrast, wheezing due to vascular surgical therapy with an 88100% success have a conrmed bacterial infection to be
rings, vascular slings, and airway rate. In the judgment of the committee, enrolled in the trial; patients without
compression by a vascular structure is the possibility that approximately 30% of bacterial bronchitis are unlikely to have
unlikely to self-resolve, and surgical infants who undergo airway survey will responded to antibiotic therapy and,
correction is performed for symptomatic benet far exceeds the burdens and cost therefore, their inclusion would have made
patients. According to seven case series, of bronchoscopy, as well as the potential antibiotic therapy appear less effective.
improvement in respiratory symptoms harms (i.e., complications due to On the basis of the rates of BAL
was seen in 88100% of patients, and bronchoscopy are rare and complications due infection (4060%) and symptom
complete resolution was seen in more than to subsequent therapy range from zero for improvement with antibiotic treatment
50% of patients. Recurrent laryngeal nerve conservative management to approximately (48%) described previously, we estimate
injury was the most common surgical 10% for surgery). The recommendation for that 2030% of children with persistent
complication and occurred in less than 10% airway survey is conditional because the low wheezing who undergo bronchoscopy with
of patients. More serious complications such quality of evidence provides little certainty BAL will be found to have a lower airway
as aortoesophageal stula, heart failure, or that the benets of airway survey exceed the bacterial infection and that their symptoms
wound infection associated with mortality burdens, costs, and harms. There are also will improve with antibiotic therapy. The
occurred in less than 5% of patients (4450). emerging data on neurodevelopmental risks committees condence in the estimated
Taken together, the evidence indicates of anesthesia that need to be considered (52). effects of BAL (i.e., the quality of evidence)
that an anatomic abnormality known to In addition, parental preferences regarding is very low because it is based on prevalence
cause wheezing can be identied by airway invasive procedures tend to be highly estimates derived from case series and
survey in approximately 33% of patients individualized. a therapeutic effect estimated from a
with respiratory symptoms, and in the Recommendation 1. For infants with randomized trial, both of which had serious
committees clinical experience more than persistent wheezing despite treatment with limitations. The case series were limited
90% of such patients will improve because bronchodilators, inhaled corticosteroids, or by selection bias, indirectness of the
either their condition is self-limited or systemic corticosteroids, we suggest airway population (children with cough rather
surgery can correct the abnormality. survey via exible beroptic bronchoscopy than infants with wheezing), and small
Thus, about 30% of patients are likely to (conditional recommendation, very low sample sizes with few events. The
benet from an airway survey, either quality of evidence). randomized trial was similarly limited by
through direct intervention (surgery) or by indirectness of the population (children
avoiding unnecessary tests and treatments Question 2: Should Infants with with cough rather than infants with
for a benign, self-limited condition. Persistent Wheezing despite wheezing), indirectness of the outcome
Identication of airway malacia may also Treatment with Bronchodilators, (cure of infection rather than improvement
help in management of infants believed Inhaled Corticosteroids, or Systemic in wheezing), and imprecision (small
to have concomitant asthma, because Corticosteroids Undergo sample size with few events).
b-agonists may adversely affect airway Bronchoalveolar Lavage? Rationale. To conrm or exclude lower
dynamics in these children (51). The airway bacterial infection as the cause of
committee has very low condence Summary of evidence. Our literature search recurrent or persistent wheezing, clinicians
(i.e., quality of evidence) in the accuracy of did not identify any studies that compared have three options: (1) they can perform
these estimated effects, because the case wheezing infants undergoing BAL with BAL and then treat patients with conrmed
series had probable selection bias and most wheezing infants who did not undergo BAL. bacterial infection with antibiotics;
series looked at infants who underwent Therefore, our recommendation is based on (2) they can empirically treat all patients
bronchoscopy for respiratory symptoms, data from 20 case series, identied in our with empiric antibiotics; or (3) they can do
not specically wheezing. literature search, showing that 1480% of neither. The committee judged the balance
Rationale. Bronchoscopy with airway infants (4060% in most studies) with of the benets versus the burdens and
survey that identies an anatomical cause of recurrent or persistent wheezing produce a risks to be greater for the rst option
wheezing confers several potential benets. positive BAL culture (Table 2) (12, 16, 18, (i.e., 2030% children improve after
Finding tracheomalacia, bronchomalacia, or 5370). No complications were reported in treatment of BAL-identied infection) than
tracheobronchomalacia usually leads to any of the case series. for either the second option (i.e., the
conservative management, which has a high Patients with a positive BAL culture same infection cure rate, but 4060% of
success rate and other benets including typically receive a prolonged course of patients receive unnecessary antibiotics
Table 2. Bronchoalveolar Lavage: Quality Assessment and Summary of Findings
Quality Assessment
Study Publication Importance of Quality of

Frequency with which BAL detects infection (dened as a positive culture)
20* Case Serious Seriousx Nonejj Serious Undetected Not a prespecied Very low Among the 20 case series identied, the
series outcome proportion of BAL samplings that
resulted in a positive microbiological
culture ranged from 14 to 80%; however,
most series reported that 4060% of
BAL samplings resulted in a positive
microbiological culture.
None of the series reported complications
from BAL.
Frequency of wheezing after treatment
1** RCT Serious Serious None Serious Undetected Critical Very low 50 children with wet cough due to
presumed bacterial bronchitis were

treated with either antibiotics or no
antibiotics. Among the patients who
were treated, the cure rate was 48%.
Among the patients who were not
treated, the cure rate was 16%.
Definition of abbreviations: BAL = bronchoalveolar lavage; RCT = randomized controlled trial.

*References 6, 10, 12, and 4461.

No studies included a control group. Therefore, they are all case series.

Limitations were serious because of probable selection bias related to who underwent BAL and who did not. Most studies did not provide details of how they decided when to perform
bronchoscopy with BAL and when not to perform bronchoscopy with BAL.
x
Indirectness was serious because few studies were limited solely to wheezing infants. Most included older children and frequently cough overlapped with wheezing.
jj
Inconsistency was not a problem. In most studies, the prevalence of positive BAL cultures was 4060%.

Imprecision was serious because the sample size was small (,100) in all the studies that were reviewed.
**Reference 71.

Descriptions of the concealment of allocation and blinding of the assessors were incomplete.

Indirectness was serious because the population of interest is wheezing infants, but the population studied was children with cough. In addition, the outcome of interest was wheezing, but
the outcome of the studies was cure of infection.
361
with their associated risks, such as fever, responsiveness (BDR) using the RVRTC compare clinical outcomes among infants
rash, anaphylaxis, acquisition of resistance, technique (73, 74). Both studies reported who are managed according to infant PFT
and change in gut microbiome [72]) or third that the presence of BDR identied by the performed using the RVRTC technique
option (i.e., only 6.49.6% infection cure RVRTC technique predicted future acute versus those who are managed according to
rate). The committee recognized that the exacerbations of wheezing requiring clinical assessment alone.
estimated cure rates for lower respiratory treatment with systemic corticosteroids. No
infection likely overestimate the cure rate for studies were identied that compared the Question 4: Should Infants without
wheezing because some infants with lower effects of management according to the BDR Eczema Who Have Persistent
respiratory tract bacterial infection have measured by the RVRTC technique versus Wheezing despite Treatment with
additional or alternative causes of wheezing; management based on clinical assessment Bronchodilators, Inhaled
nonetheless, the committee still thought alone (i.e., no PFTs) on the clinical outcomes Corticosteroids, or Systemic
that the risk of BAL is sufciently small of interest (frequency of wheezing, frequency Corticosteroids Undergo Empiric
that the benets probably outweigh the of doctor visits, frequency of hospitalization, Food Avoidance?
burdens and harms. prescriptions for bronchodilators,
The strength of the recommendation prescriptions for inhaled or systemic Summary of evidence. The National
for BAL is conditional because the corticosteroids, parental stress, additional Institute of Allergy and Infectious Diseases
committees very low condence in the diagnostic testing, and inappropriate has published clinical guidelines on food
estimated effects of BAL made it impossible therapy). Thus, there was no published allergy in children with eczema, including
to be certain that the benets of BAL evidence available to inform the guideline recommendations for food allergy testing
outweigh the risks and burdens in the development committees judgments. and avoidance in infants and children with
majority of patients. Moreover, BAL Rationale. In the absence of published this condition (76). Therefore, we focused
requires bronchoscopy, an invasive evidence, the guideline development our question on the role of food avoidance
procedure requiring sedation, and it is committee turned to its collective clinical in infants without eczema. Our systematic
uncertain that most families would want experience to try to answer the question. review identied four studies that assessed
bronchoscopy performed on their infant, However, despite extensive discussion, the the results of empiric food avoidance
despite persistent wheezing. guideline development committee could (Table 3). All of the studies measured our
Recommendation 2. For infants with not reach consensus on a clinical prespecied outcome of frequency of
persistent wheezing despite treatment with recommendation for or against infant PFTs, wheezing, but none measured any of our
bronchodilators, inhaled corticosteroids, or due to the paucity of evidence. Some other prespecied outcomes, including
systemic corticosteroids, we suggest BAL members of the committee believed that the frequency of doctor visits, frequency of
(conditional recommendation, very low information derived from infant PFTs did hospitalization, prescriptions for
quality of evidence). not justify the burdens and risks involved in bronchodilators, prescriptions for inhaled
performing the test. Among the potential or systemic corticosteroids, parental
Question 3: Should Infants benets of conrming or excluding BDR, stress, additional diagnostic testing, and
with Persistent Wheezing the clinician may be directed away or toward inappropriate therapy. A trial randomly
despite Treatment with Bronchodilators, diagnostic testing that targets anatomical assigned 487 infants to receive either a
Inhaled Corticosteroids, or Systemic causes of wheezing, respectively. Among the cows milkfree diet or a usual diet for at
Corticosteroids Be Managed risks and burdens of such testing are the least the initial 4 months of life and found
according to the Results of Infant need for sedation; the risks associated with no difference in wheezing, eczema, or
Pulmonary Function Testing Using airway occlusion, gastric distention, and nasal discharge at 1 year (77). Four
the Raised-Volume Rapid aerophagia; the additional personnel needed hundred and forty-six of the infants were
Thoracoabdominal Compression to monitor the infant during and after the reassessed 6 years later. There were still
Technique or Clinical Assessment test; and the time and personnel needed to no differences in the incidence of
Alone? set up and conduct the test. Other members wheezing, asthma diagnoses, eczema, or
of the guideline development committee allergic rhinitis (78). Another trial
Summary of evidence. Our literature search believed that there are circumstances in randomly assigned 110 infants to receive
revealed 1,261 studies related to wheezing which infant PFTs are clinically useful. For either a partially hydrolyzed formula or
and pulmonary function tests (PFTs) in example, a restrictive pattern on the PFT standard infant formula for the rst
children. The overwhelming majority (1,226 might lead clinicians to explore interstitial 4 months of life. There was no difference
studies) were excluded because they enrolled lung disease, and marked gas trapping might in the incidence of wheezing at 2 years,
children during later childhood, and the motivate clinicians to evaluate the infant although eczema was more common
guideline development committee believed further for neuroendocrine hyperplasia of among the infants who received a
that such evidence was too indirect to inform infancy, although wheezing is usually not a standard formula (79). Finally, a
judgments for infants. Among the 35 studies common feature of this condition (75). prospective cohort study monitored 6,905
that involved PFTs performed during Recommendation 3. In infants with newborns through preschool age and
infancy, only 2 (from the same cohort of persistent wheezing despite treatment found no relationship between the early
patients at two different time points) with bronchodilators, inhaled introduction of potentially allergenic
described clinical outcomes after corticosteroids, or systemic corticosteroids, foods (e.g., cows milk, egg, nuts, soy, or
the assessment of bronchodilator we recommend research studies that gluten) and either wheezing or eczema at
Table 3. Empiric Food Avoidance: Quality Assessment and Summary of Findings
Quality Assessment
Publication Importance of Quality of
No. Study Design Limitations Indirectness Inconsistency Imprecision Bias Outcome Evidence Summary of Findings
Incidence of wheezing (measured at 1 yr)

1 RCT* Serious Serious None Seriousx None Critical Very low The trial of 487 infants found no
difference in the incidence of
wheezing during the rst year
of life: 84/232 (36%) vs.
80/242 (33%)
Incidence of wheezing (measured at >14 yr)
2 1 RCTjj 1 1 observational Serious** Serious None Seriousx None Critical Very low The randomized trial of 110

study infants found no difference
in the incidence of wheezing
at 2 yr
The prospective cohort study
of 6,905 children found no
wheezing at 2, 3, or 4 yr
among those who were
introduced to cows milk,
nuts, egg, soy, or gluten
earlier or later than 6 mo
Incidence of wheezing (measured at >4 yr)
1 RCT Seriousxx Serious None Seriousx None Critical Very low The trial of 446 infants found no
wheezing during the initial
7 yr of life: 148/215 (69%) vs.
157/231 (68%)
Diagnosis of asthma
1 RCT Seriousxx Serious None Seriousx None Important Very low The trial of 446 infants found no
asthma diagnoses during the
initial 7 yr of life: 60/215
(28%) vs. 81/231 (35%)
Definition of abbreviation: RCT = randomized controlled trial.

*Reference 77.

Concealment was by envelopes containing color-coded cards and the caregivers were not blinded.

The question is about infants without eczema who have refractory wheezing; however, the trial enrolled newborns. In addition, the question asks about general food avoidance, but the trial
employed only cows milk avoidance.
x
The opposite ends of the confidence interval would result in different clinical decisions if real.
jj
Reference 78.

Reference 79.
**The randomized trial did not report concealment and the caregivers were not blinded; the observational study relied on questionnaires that retrospectively assessed the introduction of
certain foods into the diet, creating a risk of recall bias.

The question is for infants without eczema who have refractory wheezing; however, the randomized trial enrolled newborns with a family history of atopy and the observational study
monitored any newborn. In addition, the question asks about general food avoidance, but the trial employed only cows milk avoidance.

Reference 80.
xx
This was a 7-year follow-up of Miskelly and colleagues (77). Thus, it had the same limitations: Concealment was by envelopes containing color-coded cards and the caregivers were not
blinded. In addition, 41 of the 487 patients dropped out of the study between Years 1 and 7.
363
ages 2, 3, and 4 years. The study plans to with standard therapies, we suggest improved in 6 and resolved in 3. The
monitor the participants to adulthood (80). not using empiric food avoidance remaining 13 patients with GER were
None of the studies evaluated the effects of (conditional recommendation, very low treated with medical management; 9 had
empiric food avoidance in a subgroup of quality of evidence). symptomatic improvement and 4 were lost
food antigen IgEpositive infants. B. We recommend research to determine to follow-up. In the second series (84), 12
Taken together, the evidence suggests whether or not empiric food avoidance is infants with persistent wheezing despite
that empiric food avoidance has no effect benecial for the subgroup of infants bronchodilator and antiinammatory
on the frequency of wheezing. However, it who are positive for IgE to food antigens. therapy underwent 24-hour pH
provides very low condence (i.e., quality of monitoring, and all were conrmed to
evidence) in the estimated effects because the Question 5: Should Infants with have GER. They were subsequently treated
randomized trials were limited by risk of bias, Persistent Wheezing despite with prokinetic agents and histamine
indirectness of population and intervention, Treatment with Bronchodilators, receptor blockers; six improved enough to
and imprecision, and the observational study Inhaled Corticosteroids, or Systemic no longer require antiasthma medications,
was limited by possible recall bias. Corticosteroids Undergo 24-Hour two improved enough that they required
Rationale. The guideline development Esophageal pH Monitoring? only intermittent antiasthma medications,
committee chose to include questions and four failed to improve and underwent
regarding food avoidance and allergy testing Summary of evidence. Our systematic review fundoplication. After fundoplication,
because in the collective experience of the did not identify any randomized trials three of the four patients no longer
committee, parents of infants with persistent or controlled observational studies required antiasthma medications. In the
wheezing frequently raise this topic. that compared clinical outcomes among third series (85), 81 children with
Although there is evidence that respiratory those who underwent 24-hour esophageal recurrent pneumonias or chronic asthma
symptoms can be provoked by food antigens pH monitoring versus those who did underwent 24-hour pH monitoring, and
in infants with eczema (81), less is known not. However, we did identify three case 38 (47%) were found to have GER. Forty
about this relationship in infants without series that used 24-hour pH monitoring patients were treated for GER (2 on the
eczema. The guideline development to determine the prevalence of basis of alternative tests). Among the
committees judgments were based on the gastroesophageal reux (GER) among 12 children who underwent medical
impact of empiric food avoidance on children with wheezing and also reported the management, 10 improved (83%). Among
frequency of wheezing, because our other clinical outcomes that followed treatment the 24 children who underwent surgical
prespecied outcomes were not reported. of those with conrmed GER (Table 4) treatment, 22 improved (92%). Four
The lack of benecial effects due to empiric (8284). patients were lost to follow-up. None of
food avoidance in any study, combined The most recent case series (83) the case series reported any adverse effects
with the committees recognition enrolled 25 infants and children with from the 24-hour pH monitoring or
that empiric food avoidance can be asthma (88% had persistent wheezing) subsequent therapy.
burdensome, led the committee to suggest and performed 24-hour pH monitoring Taken together, the evidence indicates
that empiric food avoidance not be used in on all participants. GER was identied in that GER exists in 47100% of infants with
infants without eczema who have persistent 19 of 25 (76%) infants and children. persistent wheezing and, if identied, more
wheezing despite standard therapy. The Participants with GER were treated than 83% (most estimates are in the
strength of the recommendation is with a proton pump inhibitor and 90100% range) will improve with medical
conditional because the very low quality of reassessed at 3 months, at which time or surgical treatment. However, the
evidence prevented the committee from there were statistically signicant evidence provides very low condence in
being certain about its judgments. In other improvements in symptoms (from 2.3 the estimated effects. With respect to
words, although the committee believes to 0.4 symptoms per day), use of indirectness of the population, most studies
that there is no evidence that the desirable bronchodilators (from 8.3 to 1.4 d per included older children with a mix of
consequences of empiric food avoidance patient), use of systemic steroids (from respiratory problems in addition to
outweigh the undesirable consequences in 5.3 to 0.4 d per patient), frequency wheezing (e.g., recurrent pneumonia,
the majority of patients, it recognizes that of exacerbations (from 1.5 to 0.3 apnea, stridor, and cough) and did not
there may be clinical circumstances in exacerbations per patient), and evaluate the wheezing infant subgroup.
which a trial of empiric food avoidance may hospitalizations (from 9.1 to 0.5 d With respect to indirectness of the
be reasonable for a minority of patients per patient) compared with before intervention, there was variability in the
for whom the clinical history strongly treatment. methods used for 24-hour pH monitoring,
correlates respiratory symptoms with food The case series conrmed three earlier including positioning of probes, patient
exposure or in whom respiratory symptoms series. In the rst (82), 36 infants and positioning, dietary restrictions, scoring
are elicited in a double-blind placebo- children with various respiratory disorders criteria, denitions of an abnormal study,
controlled food challenge. underwent 24-hour pH monitoring. GER and use of impedance data. pH probes
was identied in 22 of 36 infants and detect only acid reux unless paired with
Recommendation 4. children (61%) , including 4 of 6 infants impedance; thus, not using impedance
and children (67%) with wheezing. Among data may underestimate episodes of
A. For infants without eczema who have those 22 patients, 9 patients underwent postprandial reux in infants with frequent
persistent wheezing despite treatment fundoplication, after which symptoms feeds and buffering of gastric contents (86).
Table 4. Gastroesophageal Reux: Quality Assessment and Summary of Findings
Quality Assessment
Frequency with which 24-h esophageal pH monitoring (gold standard) identies GER
4 Case Serious Serious None Seriousx None Not a prespecied Very low 24-h esophageal pH monitoring
series* outcome identied GER in 19/25 infants and
children (76%),jj 22/36 infants and
children (61%), 12/12 infants
(100%),** and 38/81 children
(47%).
Wheezing
4 Case Serious Serious None Seriousx None Critical Very low A case series of 25 infants and children
series* with presumed asthma found GER in

19/25 (76%). After treatment of the
GER, symptoms decreased from 2.3
to 0.4 symptoms per day and
exacerbations decreased from 1.5 to
0.3 exacerbations per patient.jj
A case series of 36 infants and children
with recurrent respiratory symptoms
found GER in 22/36 (61%). Among
those with GER, 9/22 (41%)
underwent fundoplication with
subsequent improvement or
resolution in all, and 13/22 (59%)
were medically managed with

improvement in the 9 who were not
lost to follow-up.
A case series of 12 infants with
persistent wheezing found GER in
12/12 (100%); after treatment of the
GER, 6/12 (50%) no longer needed
medications for wheezing, 2/12
(17%) needed medications only
intermittently, and 4/12 (33%)
needed fundoplication, which
eliminated the need for medications
in 3/4 (75%).**
A case series of 81 children with
recurrent pneumonias or chronic
asthma found GER in 38/81 (47%).
Forty patients were treated for GER
(2 on the basis of alternative tests).
Among the 12 children who
underwent medical management, 10
improved (83%). Among the 24
children who underwent surgical
treatment, 22 improved (92%). Four
patients were lost to follow-up.
(Continued )
365
Table 4. (Continued )
366
Quality Assessment
Use of bronchodilators
1 Case Serious Serious None Seriousxx None Important Very low A case series of 25 infants and children
seriesjj with presumed asthma found GER in
GER, use of bronchodilators decreased
from 8.3 to 1.4 d per patient.jj
Use of systemic steroids
Hospitalizations
Definition of abbreviation: GER = gastroesophageal reflux.

*References 8285.

There was no process to ensure that patients were consecutively or randomly included; thus, selection bias in favor of infants clinically suspected of having GER is likely.

The question is specifically about infants with wheezing; however, three of the case series included older children and symptoms other than wheezing.
x
There were only 154 patients in the four case series combined.
jj
Reference 83.

Reference 84.
**Reference 82.

Reference 85.

The question is specifically about infants with wheezing; however, the case series included older children and asthma symptoms other than wheezing.
xx
The case series included only 25 infants and children, of whom only 19 were treated for GER.
American Journal of Respiratory and Critical Care Medicine Volume 194 Number 3 | August 1 2016
Rationale. The guideline development systemic corticosteroids, we suggest 24-hour positive results (one patient did not
committee believed that the balance of esophageal pH monitoring (conditional undergo pH monitoring). On the basis of
benets versus risks, burdens, and cost recommendation, very low quality of these numbers, the sensitivity of a UGI
favors 24-hour pH monitoring in evidence). series would be 75%, compared with 97%
most infants who have persistent for pH monitoring. The sensitivity of a UGI
wheezing despite bronchodilator and Question 6: Should Infants series appears to be similarly poor among
antiinammatory therapy. Specically, with Persistent Wheezing despite children without respiratory symptoms
among such infants who undergo 24-hour Treatment with Bronchodilators, (89).
pH monitoring, 67100% will be found to Inhaled Corticosteroids, or Systemic These accuracy tests constitute very
have GER and nearly all will improve Corticosteroids Undergo an Upper low-quality evidence, meaning that they
substantially with treatment, without Gastrointestinal Series Rather Than provide very low condence in their results.
requiring further diagnostic testing. The 24-Hour Esophageal pH Monitoring? The poor quality of evidence reects the
procedure is well tolerated by the vast fact that the studies did not enroll
majority of patients and, although its Summary of evidence. The guideline consecutive patients, and it was not reported
semiinvasive nature and potential development committee next asked whether whether there was legitimate uncertainty
need for inpatient admission may be an upper gastrointestinal (UGI) series is an about the presence or absence of GER.
concerning to some parents, the acceptable alternative to 24-hour esophageal Rationale. The primary advantages of
committee believed that most families pH monitoring, which we considered the performing a UGI series rather than 24-hour
would be willing to have the test done. reference standard. Our systematic review esophageal pH monitoring are that a UGI
Although combined pH and impedance did not identify any randomized trials or series can be performed less invasively and in
probe monitoring has become the standard controlled observational studies that less time. A less frequent advantage is that
at most centers, the available evidence compared clinical outcomes among those UGI series occasionally demonstrate
largely predates widespread use of who underwent a UGI series with those who pertinent anatomical abnormalities, such as
impedance probes. Therefore, the committee underwent 24-hour esophageal pH hiatal hernias or esophageal indentation
was unable to comment specically on the monitoring. However, it did identify three suggestive of a vascular ring. The
value of impedance monitoring. studies that evaluated the accuracy of a UGI disadvantages of a UGI series include
An alternative to 24-hour pH series in detecting GER in infants and children radiation exposure, the need for patient
monitoring is an empiric trial of antiacid with wheezing (Table 4) (82, 85). cooperation, and its semiinvasive nature.
therapy. However, in up to one-third In the only study that used 24-hour pH The guideline development committee
patients receiving empiric therapy, the monitoring as the reference standard, 79 made the a priori decision that the benets
antiacid therapy is inappropriate and incurs children (age, 217 yr) who had difcult- of a UGI series would outweigh both the
unnecessary cost, burden, and risk. In to-control asthma underwent 24-hour disadvantages of a UGI series and the
addition, the rate of treatment success is esophageal pH monitoring. GER was consequences of incorrect results if
likely to be lower among empirically treated identied in 58 of 79 children (73%). A the false-negative rate was less than 10%
patients because those with GER that barium swallow study was then performed, (i.e., sensitivity greater than 90%) and the
requires fundoplication may be incorrectly which identied GER with a sensitivity false-positive rate was less than 10%
considered nonresponders. In that case, it and specicity of 46 and 82%, respectively (i.e., specicity greater than 90%). In other
may be presumed that GER is not a (88). words, assuming a prevalence of GER of
contributor and the parents may never be The other two studies used various roughly 60%, the committee would accept
offered potentially curative surgical therapy. reference standards, but reported enough 40 false-positive results and 60 false-
Furthermore, studies in older patients data to enable us to estimate the sensitivity negative results for every 1,000 patients
suggest that proton pump inhibitor therapy of a UGI series in the detection of GER tested. The acceptable false-negative and
is linked to increased risk of pneumonia relative to 24-hour esophageal monitoring. false-positive rates are both relatively small
(87). Although a similar risk has not In a study of infants and children (age, because 24-hour pH monitoring is not
been reported in infants, a normal pH- 2 mo10.5 yr) with recurrent respiratory overly risky or burdensome.
monitoring study could potentially reduce disorders (82), 22 of 36 (61%) were found The evidence indicates that the
any risks associated with proton pump to have GER by 24-hour pH monitoring, sensitivity (6879%) and specicity (82%)
inhibitor therapy. and 15 of 35 (42%) were found to have of UGI series are insufcient to warrant the
The strength of our recommendation is GER by UGI series. Assuming that patients use of UGI series as an alternative to
conditional because the very low quality of in whom GER was detected by UGI series 24-hour esophageal pH monitoring. The
evidence provided little condence in the also had GER detected by 24-hour pH recommendation against UGI series is
estimated benets and harms reported by monitoring, the sensitivity of a UGI series conditional because the very low quality of
the case series. As a result, the committee would be 68%. In a study of 82 infants and evidence does not provide sufcient
could not be certain about its judgments children (5 mo16 yr) with recurrent condence in the estimated sensitivity and
regarding the balance of benets versus pneumonia or chronic asthma (85), 40 were specicity to be certain that a UGI series
harms, burdens, and cost. found to have GER on the basis of study is not a worthwhile alternative. The
Recommendation 5. For infants with criteria; of these, 30 of 40 had positive UGI meaning of a conditional recommendation
persistent wheezing that is not relieved by series results and 38 of the 39 infants who is that it is right for most patients, but
bronchodilators, inhaled corticosteroids, or had 24-hour pH monitoring showed may not be right for a sizable minority

in certain situations. As an example, a was used as the reference standard (90). 24-hour esophageal pH monitoring. The
UGI series can be a valuable tool for Finally, two studies did not compare recommendation against scintigraphy is
identifying vascular rings or slings and may gastroesophageal scintigraphy with a conditional because the very low quality
be considered if such malformations reference standard, but rather, reported of evidence does not provide sufcient
are suspected. A UGI series can also be that the technique identied GER in 22% condence in the estimated sensitivity and
considered in circumstances in which of infants and children (age, 3 mo4 yr) specicity to be certain that scintigraphy is
24-hour pH monitoring is not a practical who presented with recurrent wheezing not a worthwhile alternative.
option. or vomiting (91) and in 26% of infants Recommendation 7. For infants with
Recommendation 6. For infants with and children (age, 6 mo6 yr) who persistent wheezing that is not relieved by
persistent wheezing that is not relieved by presented with difcult-to-treat asthma bronchodilators, inhaled corticosteroids, or
bronchodilators, inhaled corticosteroids, (92); these yields were lower than the systemic corticosteroids, we suggest 24-hour
or systemic corticosteroids, we suggest 67100% described previously for 24-hour esophageal pH monitoring rather than
24-hour esophageal pH monitoring esophageal pH monitoring. The sensitivity gastrointestinal scintigraphy (conditional
rather than a UGI series (conditional of gastroesophageal scintigraphy appears to recommendation, very low quality of
recommendation, very low quality of evidence). be similarly poor among infants and evidence).
children without respiratory symptoms
Question 7: Should Infants with (89). Question 8: Should Infants without
Persistent Wheezing That Is Not These accuracy studies constitute very Neurologic Pathology with Persistent
Relieved by Bronchodilators, Inhaled low quality of evidence, meaning that they Wheezing That Is Not Relieved by
Corticosteroids, or Systemic provide very low condence in their Bronchodilators, Inhaled
Corticosteroids Undergo estimated effects. The poor quality of Corticosteroids, or Systemic
Gastroesophageal Scintigraphy evidence reects the fact that the studies did Corticosteroids Undergo a
Rather Than 24-Hour Esophageal pH not enroll consecutive patients, and it was Swallowing Function Study?
Monitoring? not reported whether there was legitimate
uncertainty about the presence or absence of Summary of evidence. Our literature review
Summary of evidence. The guideline GER. Moreover, there was indirectness of did not identify any randomized trials or
development committee next asked whether the population because our focus was on controlled observational studies that
gastroesophageal scintigraphy is an wheezing infants, but many of the studies compared clinical outcomes among
acceptable alternative to 24-hour pH enrolled older children. those who underwent a swallowing function
monitoring, which we considered the Rationale. The primary advantages of study versus those who did not. However, it
reference standard. Our systematic review gastroesophageal scintigraphy rather did identify two case series that reported the
did not identify any randomized trials or than 24-hour esophageal pH monitoring prevalence of aspiration detected by
controlled observational studies that are that scintigraphy can be performed video-uoroscopic swallowing function
compared clinical outcomes among those less invasively and in less time. The studies in infants and children who did
who underwent scintigraphy with those who disadvantages of scintigraphy are not have chronic illnesses but did have
underwent 24-hour esophageal pH primarily radiation exposure (albeit less respiratory symptoms including wheezing
monitoring. However, it did identify four than that required for a UGI series) and (Table 5). Both series also reported the
studies that evaluated gastroesophageal high cost. outcomes of treatment (93, 94).
scintigraphic detection of GER in infants The guideline development committee The rst series enrolled 472 infants
and children with wheezing. made an a priori decision that the advantages (age, ,1 yr) with either respiratory
In the only study that used 24-hour of gastroesophageal scintigraphy would symptoms or vomiting and performed
pH monitoring as the reference standard, outweigh the disadvantages associated with uoroscopic swallowing studies on each.
79 children (age, 217 yr) who had potential incorrect results if the false-negative Swallowing dysfunction was detected in
difcult-to-control asthma underwent rate was less than 10% (i.e., sensitivity greater 63 of 472 infants (13%). Among these
24-hour esophageal pH monitoring. than 90%) and the false-positive rate was less infants, 70% had tracheal aspiration
Gastroesophageal scintigraphy identied than 10% (i.e., specicity greater than 90%). and 30% had laryngeal penetration.
GER with a sensitivity and specicity of In other words, assuming a prevalence of Because the coordination of swallowing
15 and 73%, respectively (88). Another GER of roughly 60%, the committee would improves with age among infants without
study of infants with wheezing used clinical accept 40 false-positive results and 60 false- chronic illnesses, the infants with
history and a response to anti-GER therapy negative results for every 1,000 patients swallowing dysfunction were managed
as the reference standard instead of tested. The acceptable false-negative and by thickening the consistency of their
24-hour pH monitoring. It found that false-positive rates are both relatively small food. Tracheal aspiration or laryngeal
gastroesophageal scintigraphy detected because 24-hour pH monitoring is not overly penetration was seen in 179 swallowing
GER with a sensitivity and specicity of risky or burdensome. studies with thin liquids, 61 studies with
58 and 85%, respectively, when a history The evidence indicates that the thickened liquids, and 14 studies with
compatible with GER was used as the sensitivity and specicity (15 and 73%, pureed food (93).
reference standard, and with a sensitivity respectively) of gastroesophageal The second case series included 112
and specicity of 79 and 50%, respectively, scintigraphy are insufcient to warrant the infants (age, ,1 yr) with wheezing or
when a response to anti-GER therapy use of scintigraphy as an alternative to intermittent stridor and performed video-
Table 5. Aspiration: Quality Assessment and Summary of Findings
Quality Assessment
No. Design Limitations Indirect-ness Inconsistency Imprecision Bias Outcome Evidence Summary of Findings
Frequency with which video-uoroscopic swallowing studies (gold standard) identify aspiration due to swallowing dysfunction
2 Case Serious Serious None Seriousx None Not a prespecied Very low 472 infants (age less than 1 yr) with
series* outcome either respiratory symptoms or
vomiting underwent uoroscopic
swallowing studies; swallowing

dysfunction was detected in 63 of
472 infants (13%)jj
122 infants (age less than 1 yr) with
either wheezing or intermittent
stridor underwent uoroscopic
swallowing studies; swallowing
dysfunction was detected in 13 of
112 infants (12%)
Wheezing (assessed by the surrogate outcome of radiographic tracheal aspiration or laryngeal penetration)
2 Case Serious Serious None Seriousx None Critical Very low In a case series of 472 infants (age
series* less than 1 yr) with either respiratory
symptoms or vomiting, tracheal
aspiration or laryngeal penetration

was seen in 179 swallowing studies
with thin liquids, 61 studies with
thickened liquids, and 14 studies
with pureed food, a risk reduction of
more than 90%jj
In a case series of 122 infants (age
less than 1 yr) with either wheezing
or intermittent stridor, nine infants
with conrmed swallowing
dysfunction were treated with a
thickened diet, while four infants
had their oral feedings stopped and
received nasojejunal or gastrostomy
feedings temporarily. In all of the
infants, the swallowing dysfunction
resolved within 39 mo
*References 93 and 94.

There was no process to ensure that patients were consecutively or randomly included; thus, selection bias in favor of infants clinically suspected of having swallowing dysfunction is likely.

The question is specifically about infants with wheezing; however, both case series included infants with symptoms other than wheezing.
x
There were only 584 patients in the two case series combined.
jj
Reference 93.

Reference 94.
369
uoroscopic swallowing function studies on cooperation, cost, availability of speech based on a positive test would provide
each. Swallowing dysfunction was detected pathologist, and the risk of aspiration therapeutic benet to the patient, but
in 13 of 112 infants (12%). Nine infants during the study. The committee judged this presumption and limited evidence
were treated with a thickened diet, and four that the desirable consequences outweigh reduced our ability to make strong
infants had their oral feedings stopped and the undesirable consequences and, recommendations.
received nasojejunal or gastrostomy therefore, suggests that infants with One clear need for future research is
feedings temporarily. In all of the infants, persistent wheezing that has not to determine whether implementation of
the swallowing dysfunction resolved within responded to conventional therapies these tests actually leads to treatment
39 months (94). undergo a video-uoroscopic swallowing that improves patient-important outcomes.
Taken together, the evidence suggests study. The recommendation is Outcome measures should include both
that swallowing dysfunction, which is conditional because the very low quality clinical responses and parental preferences,
known to cause wheezing, can be identied of evidence provides little certainty that particularly regarding choices between
by video-uoroscopic swallowing studies the benets of a video-uoroscopic diagnostic testing and empiric treatment.
in 1015% of infants who do not have swallowing study exceed the burdens, However, study design is complicated by the
a chronic illness but have respiratory costs, and harms. fact that a substantial fraction of infants with
symptoms. More than 90% of such patients Recommendation 8. For infants persistent wheeze not responsive to standard
will improve with feeding interventions without neurologic pathology with therapies have anatomic abnormalities that
while waiting for the swallowing persistent wheezing that is not relieved by may not respond to any medical therapy.
coordination to improve with age. Thus, bronchodilators, inhaled corticosteroids, or Routine incorporation of bronchoscopy
914% of patients who undergo video- systemic corticosteroids, we suggest a into clinical trials could address this issue, but
uoroscopic swallowing studies may swallowing function study to evaluate for likely would be problematic given the
derive some benet. The committee has aspiration (weak recommendation, very low relatively high costs and risks associated with
very low condence (i.e., quality of quality of evidence). this procedure.
evidence) in the accuracy of these This issue highlights the fact that
estimated effects because the study many current tests involve substantial
designs were case series (i.e., they Limitations and Future costs and/or risks that limit widespread
were uncontrolled); and there Directions use. Further research should address
was risk for indirectness (i.e., most whether diagnosis could be achieved by
series looked at infants who had a A common theme throughout our less invasive tests, radiologic studies in
variety of respiratory symptoms, not guideline development was the striking lieu of bronchoscopy for anatomic
specically wheezing). paucity of data regarding infantile abnormalities, or analysis of exhaled breath
Rationale. A video-uoroscopic wheezing. Despite how widespread and to detect markers of airway infection or
swallowing study confers several potential common this clinical problem is, we were reux. Comparative effectiveness studies
benets. Finding swallowing dysfunction unable to nd any large clinical studies that and the development of clinical
usually leads to feeding modications that used consistent case denitions and pathways would also help clinicians
reduce aspiration by approximately 90%; outcomes. Most of the studies cited were better evaluate infants with persistent
a reduction in aspiration is a surrogate case series, providing the lowest quality of wheezing.
outcome for persistent wheezing, stridor, evidence on the GRADE scale. Given the In summary, this document provides
cough, and pneumonia. Other benets frequency with which infantile wheezing guidelines that further two goals of
include relief from the burden, cost, and occurs, there is an urgent need for more interest to the ATS. First, they will aid the
potential harms of further diagnostic testing; rigorous research to be conducted in this pediatric generalist or respiratory
probable reductions in the use of ineffective eld. specialist in the management of the infant
medications (bronchodilators or inhaled Although we used the GRADE with recurrent or persistent wheeze that
corticosteroids) and the frequency of methodology, we rarely had patient- does not respond to conventional
physician visits; and parental reassurance important outcomes that could be therapies. Second, they will serve to
given the high likelihood that the condition reliably linked to performance of the identify the research needed to improve
will spontaneously resolve. Limitations various diagnostic tests. As a result, diagnosis and treatment of this vulnerable
include the need for infant/child we presumed that treatment strategies population. n
This clinical practice guideline was prepared by an ad hoc subcommittee of the ATS Assembly on Pediatrics.
Members of the subcommittee are as NIKHIL AMIN, M.D. TERRY L. NOAH, M.D.
follows: ALIA BAZZY-ASAAD, M.D. PEGGY RADFORD, M.D.
CLEMENT L. REN, M.D. (Co-Chair) STEPHANIE D. DAVIS, M.D. SARATH RANGANATHAN, M.D.
CHARLES R. ESTHER, JR., M.D., PH.D. (Co-Chair) MANUEL DURAND, M.D. ALEJANDRO TEPER, M.D.
JASON S. DEBLEY, M.D., M.P.H. JEFFREY M. EWIG, M.D. MILES WEINBERGER, M.D.
MARIANNA SOCKRIDER, M.D., M.P.H., D.P.H. HASAN YUKSEL, M.D. JAN BROZEK, M.D., PH.D.
OZGE YILMAZ, M.D. ENRICO LOMBARDI, M.D. KEVIN C. WILSON, M.D.
Author Disclosures: O.Y. received GlaxoSmithKline and Merck Sharp Dohme, M.S., A.B-A., M.D., J.M.E., T.L.N., P.R., S.R.,
conference travel support from Allergopharma and received conference travel support from A.T., M.W., J.B., and K.C.W. reported no
Turkey and GlaxoSmithKline. N.A. was Allergopharma, GlaxoSmithKline, and Nutricia. relationships with relevant commercial
previously employed by MannKind Corp. and E.L. was a speaker and on a data safety interests.
has been an employee of Regeneron and monitoring board for Chiesi, received
Pharmaceuticals since January 2016 conference travel support from Lusofarmaco,
(subsequent to guideline completion). S.D.D. was on an advisory committee and a speaker Acknowledgment: The committee would
was on an advisory committee and a for Novartis, was a speaker for Sigma-Tau, like to acknowledge the invaluable
consultant for Vertex Pharmaceuticals, was and participated in meetings organized efforts of Angela Dixon from the University
a consultant for Eli Lilly and Co., and was a by his institution that were sponsored by of Rochester (Rochester, NY) for her
speaker for ABCOMM in an activity supported CareFusion, Cosmed, Italchimici, Stewart work as the medical librarian on this
by Gilead. H.Y. was a speaker for Italia, and Valeas. C.L.R., C.R.E., J.S.D., project.
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AMERICAN THORACIC SOCIETY

Ofcial American Thoracic Society Clinical Practice Guidelines:

*These authors contributed equally to this work.

Contents Bronchodilators, Inhaled Treatment with Bronchodilators,

American Thoracic Society Documents 357

American Thoracic Society Documents

case reports tracheomalacia, bronchomalacia,

American Thoracic Society Documents

presumed bacterial bronchitis were

Definition of abbreviations: BAL = bronchoalveolar lavage; RCT = randomized controlled trial.

Incidence of wheezing (measured at 1 yr)

American Thoracic Society Documents

Definition of abbreviation: RCT = randomized controlled trial.

American Thoracic Society Documents

were medically managed with

Definition of abbreviation: GER = gastroesophageal reflux.

American Thoracic Society Documents 367

American Thoracic Society Documents

aspiration or laryngeal penetration

*References 93 and 94.

American Thoracic Society Documents 371

American Thoracic Society Documents 373

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