Systematic Review of Evidence-Based Guidelines on

Medication Therapy for Upper Respiratory Tract Infection

in Children with AGREE Instrument
Linan Zeng
1,2,3
, Lingli Zhang
1,2,3
*, Zhiqiang Hu
1,4
, Emily A. Ehle
5
, Yuan Chen
1,2,3
, Lili Liu
1,4
, Min Chen
1,4
1Department of Pharmacy, West China Second University Hospital, Sichuan University, Sichuan, China, 2Key Laboratory of Birth Defects and Related Diseases of Women
and Children, Sichuan University, Ministry of Education, Sichuan, China, 3Evidence-Based Pharmacy Centre, West China Second University Hospital, Sichuan University,
Sichuan, China, 4West China School of Pharmacy, Sichuan University, Sichuan, China, 5Department of Pharmacy, The Nebraska Medical Centre, Omaha, Nebraska, United
States of America
Abstract
Objectives: To summarize recommendations of existing guidelines on the treatment of upper respiratory tract infections
(URTIs) in children, and to assess the methodological quality of these guidelines.
Methods: We searched seven databases and web sites of relevant academic agencies. Evidence-based guidelines on
pediatric URTIs were included. AGREE II was used to assess the quality of these guidelines. Two researchers selected
guidelines independently and extracted information on publication years, institutions, target populations, recommenda-
tions, quality of evidence, and strength of recommendations. We compared the similarities and differences of
recommendations and their strength. We also analyzed the reasons for variation.
Results: Thirteen guidelines meeting our inclusion criteria were included. Huge differences existed among these 13
guidelines concerning the categorization of evidence and recommendations. Nearly all of these guidelines lacked the
sufficient involvement of stake holders. Further, the applicability of these guidelines still needs to be improved. In terms of
recommendations, penicillin and amoxicillin were suggested for group A streptococcal pharyngitis. Amoxicillin and
amoxicillin-clavulanate were recommended for acute bacterial rhinosinusitis (ABRS). An observation of 23 days prior to
antibiotic therapy initiation for mild acute otitis media (AOM) was recommended with amoxicillin as the suggested first
choice agent. Direct evidence to support strong recommendations on the therapy for influenza is still lacking. In addition,
the antimicrobial durations for pharyngitis and ABRS were still controversial. No consensus was reached for the onset of
antibiotics for ABRS in children.
Conclusions: Future guidelines should use a consistent grading system for the quality of evidence and strength of
recommendations. More effort needs to be paid to seek the preference of stake holders and to improve the applicability of
guidelines. Further, there are still areas in pediatric URTIs that need more research.
Citation: Zeng L, Zhang L, Hu Z, Ehle EA, Chen Y, et al. (2014) Systematic Review of Evidence-Based Guidelines on Medication Therapy for Upper Respiratory Tract
Infection in Children with AGREE Instrument. PLoS ONE 9(2): e87711. doi:10.1371/journal.pone.0087711
Editor: Oliver Schildgen, Kliniken der Stadt Ko ln gGmbH, Germany
Received October 28, 2013; Accepted January 2, 2014; Published February 20, 2014
Copyright: 2014 Zeng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the National Natural Science Foundation of China (Project Number: 81373381). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: zhlingli@sina.com
Introduction
Acute respiratory infections (ARIs) are classified as upper
respiratory tract infections (URTIs) or lower respiratory tract
infections (LRTIs) [1]. URTIs include the common cold,
laryngitis, pharyngitis/tonsillitis, acute rhinitis, acute rhinosinusitis
and acute otitis media (AOM) [2]. URTIs in children are a
frequent illness accounting for a high proportion of doctor office
visits [3,4]. A national survey report from the UK showed the
consultation rates of URTIs were 3,103 and 1,002 per 10,000
person years at risk in children aged 04 and 515 years,
respectively [5].
A proliferation of clinical guidelines published in peer-reviewed
journals has been seen due to the high morbidity of URTIs. It is
important that these guidelines provide appropriate guidance for
the treatment of URTIs. Nevertheless, the growing number of
guidelines has been accompanied with a growing concern about
variance and conflicts among guideline recommendations and the
quality of guidelines [18].To date, there have been no systematic
attempts to compare recommendations from available guidelines
for the treatment of children with URTIs.
The aim of this study is to assess the quality of evidence-based
guidelines for drug therapy of URTIs in children and to compare
the recommendations of the existing evidence-based guidelines.
Special attention was devoted to areas of disagreement and
discussion with an ultimate aim to improve the clinical practice in
treatment of URTIs for children. Such an assessment is important
as it may explain some of the variability in guideline recommen-
PLOS ONE | www.plosone.org 1 February 2014 | Volume 9 | Issue 2 | e87711
dations and may assist health care providers in choosing among
available guidelines.
Methods
Data Sources
We searched Pubmed, Guidelines International Network (GIN),
U.S. National Guideline Clearinghouse (NGC) and four Chinese
databases: Chinese Biomedical Literature Database (CBM), China
Knowledge Resource Integrated Database (CNKI), VIP Database
and Wanfang Database for evidence-based guidelines (until March
2013) using the following items: respiratory tract infections,
common cold, laryngitis, pharyngitis, tonsillitis, rhinitis, rhinosi-
nusitis, otitis media, middle ear inflammation, influenza, grippe as
Medical Subject Headings (MeSH) or keywords. The searches
were limited to guidelines published in English or Chinese. We
also searched guidelines at web sites of academic agencies, such as
American Academy of Pediatrics (AAP) and Infectious Diseases
Society of America (IDSA). Retrieved references were considered
if they met our inclusion criteria.
Guideline Selection
Inclusion criteria. Types: evidence-based guideline with
systematic literature review and grading system for quality of
evidence and/or strength of recommendation [6].
Figure 1. Summary of guideline search and review process.
doi:10.1371/journal.pone.0087711.g001
Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 2 February 2014 | Volume 9 | Issue 2 | e87711
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 3 February 2014 | Volume 9 | Issue 2 | e87711
Diseases: URTIs including rhinosinusitis, pharyngitis, laryngitis,
rhinitis, otitis media, tonsillitis, common cold and influenza.
Patients: children ages 018 years old
Interventions: drug therapy
Exclusion criteria. Types: guideline of hospital level; old
version of guideline
Diseases: non-infectious upper respiratory diseases
Interventions: vaccines
Guideline Quality Assessment
Appraisal of guidelines with the AGREE
instrument. Quality of evidence-based guidelines was assessed
by using AGREE II from the following domains: scope and
purpose, stakeholder involvement, rigor of development, clarity of
presentation, applicability, editorial independence and overall
guideline assessment. Each of the AGREE II items and the two
global rating items were rated on a 7-point scale (1-strongly
disagree to 7-strongly agree). A score was assigned depending on
the completeness and quality of reporting. Domain scores were
calculated by summing up all the scores of the individual items in a
domain and by scaling the total as a percentage of the maximum
possible score for that domain. The scaled domain score was
calculated as: (obtained score-minimum possible score)/(maxi-
mum possible score-minimum possible score) [7].
Appraisal of agreement between reviewers. We used the
intraclass correlation coefficient (ICC) as a measure of agreement
between reviewers. The ICC was applied to each guideline.
Calculations were carried out by using SPSS 13.0.
Data Extraction
Two researchers selected guidelines independently and extract-
ed the following information: publication years, institutions, target
populations, recommendations, quality of evidence, and strength
of recommendations. We compared the similarities and differences
of recommendations and their strength and analyzed the reasons
for variation.
Results
Guideline Search and Review Process
A total of 1,785 citations and abstracts were identified in the
initial searches. Finally, 13 guidelines meeting our inclusion
criteria were included, covering a period from 2005 to 2013
(Figure 1). These 13 guidelines focused on drug therapy for
pharyngitis, rhinosinusitis, otitis media and influenza. For the
remaining URTIs (laryngitis, tonsillitis, rhinitis), no guidelines for
children were found.
Characteristics and Quality of Guidelines
Half of the 13 guidelines are from America developed by the
American Academy of Pediatrics (AAP) and the Infectious
Diseases Society of America (IDSA). Five guidelines are developed
specially for children, while the rest are for both adults and
children. All guidelines, except one, announced the conflict of
interests and none were founded by industrial partners. All
guidelines stated the formulation of recommendations was based
on evidence. However, there is a huge variation in the grading
systems of evidence quality and recommendation strength used
(Table 1).
Comparison of the Categorization of Evidence and
Recommendations of the 13 Guidelines (Table 2)
There were huge differences among 13 guidelines concerning
the categorization of evidence and recommendations. Eight
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 4 February 2014 | Volume 9 | Issue 2 | e87711
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 5 February 2014 | Volume 9 | Issue 2 | e87711
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 6 February 2014 | Volume 9 | Issue 2 | e87711
different grading systems were used, two of which failed to give
strength of recommendations. Four guidelines used GRADE [21
25]. One guideline used SIGN [26] and one used CTFPHE [27].
Seven guidelines used other grading systems. The variation in
terms of grading system may decrease the comparability of
guidelines and confuse readers.
Evaluation of the AGREE Domains of Guidelines Analyzed
(Table 3)
Scope and purpose. This domain evaluates the overall
objectives, expected benefit or outcomes, and target population of
guidelines. The medium score for this domain was 90.28%
(76.39%97.22%), indicating that most guidelines satisfied criteria
of this domain.
Stake holder involvement. This domain evaluates the
degree of relevant professional group involvement and whether
the views and preferences of the target population have been
considered and the definition of target users has been clearly
presented. The overall score in this domain was low with a
medium of 61.11% (33.33%83.33%). Most of the guidelines
involved relevant professionals in the development process and
declared the target population. However, the guideline developers
did not seek the preference of target populations sufficiently
resulting in a decrease in score of this domain.
Rigour of development. This domain addresses the method
of evidence search, grading, summarizing and the formulation of
recommendations. The medium score for this domain was 76.04%
(32.81%91.15%), with 1 guideline scoring ,50%. This guideline
failed to demonstrate the link between evidence and recommen-
dations. It was not reviewed externally before its publication
either.
Clarity of presentation. This domain evaluates presentation
and format of guidelines. The medium score was 95.83%
(90.28%98.61%), indicating that all guidelines satisfied criteria
of this domain.
Applicability. This domain evaluates the consideration of
facilitators or barriers to its implementation, as well as monitoring
criteria. The medium score of this domain was 56.25% (10.42%
83.22%), the lowest of all domains. Four of 13 guidelines scored #
50%. Most guidelines failed to consider the applicability
sufficiently in guideline development.
Editorial independence. This domain addresses founding
issues and competing interests of guideline development members.
The medium score was 81.25% (8.33%97.92%), with 3
guidelines scoring,50%.
Agreement among reviewers. Table 3 summarizes the
degree of agreement for 13 guidelines by ICC. The ICC values
indicate overall agreement between reviewers was excellent (80%)
for 8 of 13 guidelines and substantial (70%) for the other 5
guidelines.
Recommendations
Recommendations towards drug therapy of Group A
streptococcal pharyngitis for children (Table 4). Recommenda-
tions on antibiotics fromIDSAand ISCI are consensus. The first choice
was penicillin or amoxicillin. For penicillin-allergic patients, cephalospo-
rins, clindamycin, or macrolides were recommended. Only IDSA,
however, gavearecommendationonthedurationof antibiotics (10days).
In terms of adjunctive therapy, IDSA suggested nonsteroidal anti-
inflammatory drugs (NSAIDs) as adjunct to anappropriate antibiotic for
treatment of moderate to severe symptoms or control fever. Aspirin
should be avoided in children due to the risk of Reyes syndrome [28].
Recommendations towards drug therapy of acute
bacterial rhinosinusitis (ABRS)/sinusitis for children
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 7 February 2014 | Volume 9 | Issue 2 | e87711
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Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 8 February 2014 | Volume 9 | Issue 2 | e87711
(Table 5). All of the 5 guidelines supported the use of antibiotics
in pediatric ABRS. However, AAP emphasized the onset of
antibiotics should be in cases of severe onset or worsening course,
while the other four recommended antibiotics for all clinical
diagnosed ABRS. Guidelines from FSP and SIP recommended
amoxicillin as first-line choice due to the lowrisk of treatment failure
[10]. IDSA, however, suggested amoxicillin-clavulanate rather than
amoxicillin as empiric antimicrobial therapy, considering the
increasing prevalence of H. influenza among URTI of children
and the high prevalence of b-lactamase-producing respiratory
pathogens in ABRS [29,30]. For children with risk factors,
amoxicillin-clavulanate was recommended. For non-type 1 hyper-
tension, both ISCI and IDSA recommended doxycycline as an
alternative for older children. Nevertheless, a variance appeared in
terms of antibiotics for type 1 hypertension patients. ISCI and IDSA
suggested levofloxacin, while AAP recommended cephalosporins
based on recent studies which indicated the risk of a serious allergic
reaction to cephalosporinsin patients with penicillin or amoxicillin
allergy appeared to be nil [3133]. The duration of antibiotic
therapy is still controversial (328) [34]. In addition, all guidelines
consistently deprecated decongestants, antihistamine and systemic
corticosteroids (not local corticosteroids) in pediatric ABRS.
Recommendations towards drug therapy of influenza
(Table 6). H1N1: Both IDSA and WHO recommended
antivirals for confirmed or highly suspected H1N1 infection.
However, IDSA recommended zanamivir rather than oseltamivir,
while WHO recommended oseltamivir for children (.1 year) who
have severe or progressive clinical illness.
H3N2: Only IDSA released a guideline on the treatment of
H3N2 and recommended oseltamivir or zanamivir for laboratory-
confirmed or highly suspectedH3N2. IDSA also warned that
adamantanes should not be used.
H5N1: The recommendations on use of antiviral drugs for H5N1
were based predominantly on studies of infection with human
influenza rather than clinical trials on treatment of H5N1 patients.
Both WHO and IDSA placed a high value on the prevention of
death and relatively lowvalues on adverse reactions, development of
resistance, and costs of treatment. Oseltamivir and zanamivir were
recommended as first-line therapy and amantadine was recom-
mended when neuraminidase inhibitors were not available.
Influenza-like syndrome: The SNLG did not recommend the
routine use of amantadine, rimantadine, oseltamivir or zanamivir
for influenza-like syndrome because of their side effects, the
emerging resistance phenomena, and the irrelevance of the
outcomes considered in the selected studies. Instead, SNLG
recommended the use of oseltamivir in the post-exposure
prophylaxis in non-vaccinated institutionalized patients.
Recommendations towards drug therapy of acute otitis
media (Table 7). SIGN, JOS and AAP all recommended an
observation of 23 days before antibiotic therapy for mild AOM.
AAP recommended amoxicillin as the first choice and an antibiotic
with additional b-lactamase for children with risk factors. SIGN and
JOS recommend amoxicillin, amoxicillin-clavulanic, cephalospo-
rins and macrolides with a statement that cephalosporins and
macrolides can be used but less safe than amoxicillin [35]. Duration
of antimicrobial therapy is still controversial [36]. SIGN recom-
mended a 5 day course according to British National Formulary,
while AAP recommended a 5 to 10 day course based on the age of
children [35,37]. Further, only SIGN evaluated the efficacy and
safety of adjunctive therapies [38].
Discussions
Variation of Evidence and Recommendation Grading
System
CTFPHE was first published in 1979 by Canadian Ministry of
Health. The quality of evidence is based on the study design and
the strength of recommendation depends on sufficiency of
evidence. CTFPHE was the first grading system developed and
is the foundation of many other grading systems. However, the
CTFPHE still has some drawbacks [27]. For instance, a lack of
strong relevance between quality of evidence and strength of
recommendation and lack of consideration of results exist
consistently among studies [39]. Consequently, many other
Table 4. Main Therapeutic Options on Group A Streptococcal Pharyngitis for Children According to Guidelines.
Therapy recommended Shulman 2012,IDSA Snellman 2013,ISCI
Target of population Children .3 years Children
Antibiotics
Onset of antibiotics Diagnosis of pharyngitis Culture positive cases of group A streptococcal
pharyngitis
Type of antibiotics
First-line Penicillin, amoxicillin (strong, high) Penicillin, amoxicillin
Second-line (penicillin allergy) A first-generation cephalosporin
1
, clindamycin,
clarithromycin, azithromycin (strong, moderate)
Cephalosprins
1
, macrolides, clindamycin, amoxicillin-
clavulanate (2 low quality studies; 1 high quality
study)
Duration 10 days
2

Adjunctive drugs
NSAIDs
3
For treatment of moderate to severe symptoms or
control fever (high, strong)

Corticosteroids NR
4
(moderate, weak)
Notes:
1
The first-generation cephalosporins can be used for patients who are not anaphylactically sensitive.
2
Azithromycin should be given for 5 days.
3
NSAIDs: nonsteroidal anti-inflammatory drug.
4
NR: not recommended.
doi:10.1371/journal.pone.0087711.t004
Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 9 February 2014 | Volume 9 | Issue 2 | e87711
organizations developed their own grading systems [40,41]. SIGN
grading system developed by the Scottish Intercollegiate Guide-
lines Network is one of the most-widely used systems [26].
However, it still failed to consider the consistency and indirectness
of study results. In 2000, GRADE working group was founded
based on organizations from 19 countries including WHO. The
aim of this group is to develop a consolidated grading system for
quality of evidence and strength of recommendation. In 2004, the
first edition of this grading system was published and was
recognized by more than 30 organizations including WHO and
Cochrane Collaboration. Although the 13 guidelines included in
our study were published after 2005, only four of them use the
GRADE system. We suggest further guidelines use a comparable
uniform grading system to evaluate the quality of evidence and
strength of recommendations.
Quality of Guidelines
The potential benefits of guidelines are only as good as the quality
of the guidelines themselves. Appropriate methodologies and
rigorous strategies in the guideline development process are
important for the successful implementation of the resulting
recommendations [7]. For these 13 guidelines, two domains are
the main problems which decrease the quality and reliability of
guidelines. The first is a failure to seek patients views and
preferences or fail to report this information. Many methods can
be used to consider patients expectations such as: formal
consultations with patients, participation of patients on guideline
development group or external review group, or a literature review
of patients values. However, these processes were seldom
performed or described in guideline development or the final
reports of guidelines. This problem is also found in other disease
guidelines [42,43,44]. The second problem is a lack of consideration
of applicability of guidelines. How to facilitate the application of
guidelines is as important as howto develop a high quality guideline.
Table 5. Main Therapeutic Options on Acute Bacterial Rhinosinusitis(ABRS)/Sinusitis for Children According to Guidelines.
Therapy recommended
Blomgren 2005,
FSO
Esposito 2008,
SIP Chow 2012, IDSA Wald 2013, AAP
Snellman 2013,
ISCI
Target of population Children .1 year Children .1 year Children Children aged 118 years Children
Antibiotics
Onset of antibiotics Clinical diagnosis of
ABRS (B)
Clinical diagnosis of ABRS
(I,A)
Clinical diagnosis of ABRS
(strong, moderate)
Severe onset or worsening
course ABRS (B, strong
recommendation)
Clinical diagnosis of
ABRS (high quality)
Types of antibiotics
First-line Amoxicillin Mild: Amoxicillin (IV,B) Amoxicillin-clavulanate
(Strong, moderate)
Amoxicillin or
amoxicillin- clavulanate
(B, Recommendation).
Amoxicillin-
clavulanate (high
dose may consider
in children ,2
years) (Guideline).
Second-line
With risk factors
1
Mild: Amoxicillin-clavulanic
or cefaclor (IV, B) Severe:
ceftriaxone, amoxicillin-
clavulanic, ampicillin-
sulbactam (IV, B)
Amoxicillin-clavulanate
(weak, moderate) or third-
generation oral
cephalosporin+clindamycin
(weak, moderate).
Amoxicillin-clavulanate
Hypersensitivity
Non-type I Third-generation oral
cephalosporin+clindamycin
(weak, moderate),
doxycycline (.8 years)
Cefdinr, cefuroxime,
cefpodoxime
Doxycycline (for
older children),
Levofoxacin
Type I Levofloxacin (weak, low). Cefdinir, cefuroxime,
cefpodoxime, or
cefixime +clindamycin
Durations 7days Mild: 1014 days (IV,B)
Severe: 1421 days (IV,B)
1014 days (weak, low-
moderate).
1028 days 314 days (Low
quality evidence)
Adjunctive drugs
Corticosteroids Recommended to
allergic patients
NR (II,A) Recommended to allergic
patients (weak, moderate)
Recommended for
recurrent or allergic
patients (high
quality evidence).
Decongestants NR
2
NR (II,A) NR(strong, low-moderate) NR
Antihistamines NR NR (II,A) NR(Strong, low-moderate) NR
Notes:
1
Risk factors include: previous receive of antibiotic therapy; attendance at school, local or systematic diseases that favor infections due to antibiotic-resistant pathogens;
from geographic regions with high endemic rates of invasive penicillin-nonsusceptible (PNS) S. pneumonia; severe infection; age,2; recent hospitalization;
immunocompromised.
2
NR: not recommended.
doi:10.1371/journal.pone.0087711.t005
Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 10 February 2014 | Volume 9 | Issue 2 | e87711
The facilitators and barriers that may impact the application of
guidelines should be considered when developing the guideline.
Also, there is a need to consider how to disseminate and implement
the guideline effectively using additional materials such as a quick
reference guide, educational tools and patient leaflets. These factors
are important but often ignored by guideline developers. Studies on
the effectiveness of clinical guideline implementation strategies
showed that successful guideline implementation strategies should
be multifaceted, and actively engage clinicians throughout the
process [45,46]. Thus, future guidelines should pay more attention
to the implementation process of guidelines.
Factors Contributing to Inconsistencies of Guidelines
Although an important level of consensus appears throughout
the various guidelines, there are still some conflicts in recommen-
dations for drug choice and durations of therapy. There are three
main reasons contributing to the variances. First, the geographic
difference leads to the variance of pathogens and its drug
resistance. Second, the recommendations of guidelines were based
on different evidence. Recent studies may overturn the results of
previous studies. Thus, the timely updated guidelines are more
reliable. Third, the expectation and preference of guideline
developers and patients may influence the final recommendation.
Therefore, a local guideline is more useful for health professionals
if there is a conflict among guidelines.
Suggestions for Future Research
The durations of antimicrobial therapy for rhinosinustis and
acute otitis media are still controversial. More studies are needed
to compare the different durations of antibiotics in children. In
addition, the antivirials for influenza also lack direct evidence.
Many recommendations are based on indirect evidence. Thus,
more clinical trials or prospective observational studies are needed.
Conclusions
Future guidelines should use a consistent grading system for
quality of evidence and strength of recommendations and seek the
preference of stake holders to improve the applicability of
guidelines. Further, there are still some areas in pediatric URTI
that need more research.
Supporting Information
Checklist S1.
(DOC)
Table 6. Main Therapeutic Options on Influenza for Children According to Guidelines.
Therapy
recommended
H1N1 H3N2 H5N1
Influenza-like
syndrome
Harper 2009,
IDSA
Bautista 2009,
WHO
Harper 2009,
IDSA
Bellamy 2006,
WHO
Harper 2009,
IDSA
Morciano 2009,
SNLG
Target of population Children.1 year Children (#12) and
Adolescents(1318
years)
Children .1 year Children Children .1 year Children
Antivirals
Onset of antivirals Laboratory-
confirmed or
highly suspected
infection (A, II)
Confirmed or strongly
suspected infection
(Low, Strong)
Laboratory-confirmed
or highly suspected
infection (A, II)
Confirmed or
strongly suspected
infection
Laboratory-confirmed
or highly suspected
infection (A, II)
Post-exposure
prophylaxis in non-
vaccinated
institutionalized
patients
Choose of antivirals Zanamivir,
adamantine
(rimantadine)
(A, II)
Pandemic H1N1
with severe or
progressive clinical
illness: oseltamivir
(Low, strong)
Uncomplicated
pandemic H1N1:
oseltamivir,
zanamivir(Low,strong)
Oseltamivir, zanamivir
(A-II)
Oseltamivir (strong,
very low), zanamivir
($7 years) (weak,
very low).
Oseltamivir,
zanamivir (A-II)
Oseltamivir (C/I)
Antibiotics
Severe community-
acquired pneumonia:
follow guidelines
(strong) Mechanical
ventilation:
recommend treatment
or prevention of
ventilator associated or
hospital acquired
pneumonia (strong)
Non-complicated:
NR
1
(E/I) Influenza-
like syndrome-
related sore
throat: NR, unless
symptoms are
complicated by
bacterial
infections(D/I)
NSAIs
Aspirin: NR (strong,
regulatory warning)
Paracetamol,
ibuprofen (B/I)
Notes:
1
NR: not recommended.
doi:10.1371/journal.pone.0087711.t006
Guidelines on URTIs in Children
PLOS ONE | www.plosone.org 11 February 2014 | Volume 9 | Issue 2 | e87711
Acknowledgments
We thank all the anonymous reviewers for invaluable comments on earlier
manuscript drafts.
Author Contributions
Conceived and designed the experiments: L. Zhang. Performed the
experiments: L. Zeng ZH YC LL MC. Analyzed the data: L. Zeng ZH.
Wrote the paper: L. Zeng. Revised the language of the paper: EAE.
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Target of population Children Children ,15 years Children aged 6 months-12years
Antibiotics
Onset of antibiotics Mild: observation for
3 days without use of
antimicrobial agents (1+,B)
Mild: observation for 3 days
without use of antimicrobial
agents (A)
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Types of antibiotics Amoxicillin, amoxicillin-
clavulanic, cefaclor,
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erythromycin (1+,B)
Amoxicillin, amoxicillin-
clavulanate, ampicillin,
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1
: amoxicillin (B,Recommendation). Second-line
2
: an antibiotic
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Duration 5 days (1+, B). ,2 years: 10 days; 25 years: 7 days; .6 years: 57 days
Adjunctive
decongestants NR
3
(1++, A)
antihistamines NR (1++, A)
paracetamol Recommended for
analgesia
4
(1+, D)

Notes:
1
The child does not received amoxicillin in the past 30days or does not have concurrent purulent conjunctivitis or the child is not allergic to penicillin.
2
The child has received amoxicillin in the last 30 days or has concurrent purulent conjunctivitis, or has a history of recurrent AOM unresponsive to amoxicillin.
3
NR: Not Recommended.
4
Parents should give paracetamol for analgesia but should be advised of the potential danger of overuse.
doi:10.1371/journal.pone.0087711.t007
Guidelines on URTIs in Children
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