Community-acquired pneumonia in children:

updated perspectives on its etiology, diagnosis, and

treatment
Ki Wook Yun, MD, PhD
Department of Pediatrics, Seoul National University Children’s Hospital, Seoul National University College of Medicine, Seoul, Korea

Pneumonia is a common pediatric infectious pitalization worldwide. Moreover, considering

disease that is familiar to pediatricians and a that most novel infectious diseases causing
major cause of hospitali- zation worldwide. pandemics, including coronavirus disease 2019
Recent well-designed epidemiologic studies in (COVID-19), are caused by respi- ratory
developed countries indicated that respiratory pathogens, the clinical significance of pneumonia
viruses are detected in 30%–70%, atypical is even greater. Despite its importance,
bacteria in 7%–17%, and pyogenic bacteria in particularly in child- ren, the diagnosis, treatment,
2%–8% of children hospitalized with community- and prevention of pneumonia are based on
acquired pneumonia (CAP). The etiological studies conducted in adults. Thus, clinical
distribution of CAP varies widely by child age studies have been conducted in developing and
and the epidemiological season of the developed countries to improve the diagnosis
respiratory pathogen. Moreover, diagnostic and treatment of pneu- monia in children. This
tests, particularly for the detection of review summarizes the results of major
Streptococcus pneumoniae and Mycoplasma international and Korean studies conducted to
pneumoniae, the 2 major bacterial pathogens date and proposes the most appropriate diagnosis
involved in pediatric CAP, have several and treatment policies accordingly.
limitations. Therefore, mana- gement and
empirical antimicrobial therapy for children
with CAP should be applied in a stepwise
Epidemiolo
manner based on recent epidemiological,
gy

Pneumonia is the leading cause of death in

children aged <5 years worldwide. Estimated
numbers of global deaths by pneumonia were
Key message 0.76 million, while the cause- specific mortality
rate was 5.5 cases per 1,000 livebirths in 2015.1)
· Most commonly confirmed causes of community-
acquired pneumonia (CAP) in children are Although mortality rates in developed countries
Mycoplasma pneumoniae (8%–40%) and respiratory do not reach the levels observed in low- and
syncytial virus (15%–20%). middle-income countries, the morbidity and
· Pyogenic bacteria, most commonly Streptococcus financial burden associated with pneumonia
pneumo- niae (40%–50%) and Streptococcus remain significant. In a recent large
pyogenes (10%–25%), are detected in 2%–5% of epidemiological study in the United States (US),
children hospitalized with CAP. the annual incidence of community-acquired
· CAP should be diagnosed conservatively according
pneumonia (CAP) re- quiring hospitalization was
to clinical and radiological criteria.
15.7 cases per 10,000 children, with the highest
· The etiology should be identified via appropriate
test result interpretation. rate among children younger than 2 years.2) Over
the past 20 years, the incidence of lower
respiratory tract infections (LRTIs) has declined
Introduction worldwide. A total number of episodes of clinical
pneumonia in young children (<5 years of age) in
Pneumonia is a common infectious disease
132 developing countries decreased by 22% from
among child- ren, familiar to pediatricians, and
178×106 in 2000 to 138×106 in 2015.3) There has been
a major cause of hos-
 a substantial decrease in the number of reflects not only economic de- velopment,
deaths and the mortality rate, which improved nutrition, and reduced household
Review article
CEP ChtlitnpsE:x//pdPoei.odriagt/r1V0o.3l.36475,/cNeop..2,08202–.08194,522024
C o r r e s p o n d i ng u th o r : K i W o o k Y u n , M D , P h D . D e p a r tm e nt of Pediatrics, Seoul
M e d i c in e , 1 0 1 Da eh a k - ro , J o n gn o - g u , S eo ul 0E 3 m 0 8
a 0
il ,: pK eo d re
w ail ly @ g m a il .c o m ,
National University Children’s Hospital, Seoul National University College of Re ce iv e d : 1 7 D e c e m b er 2 0 2 2 , R
h tt p s :/ /o r c id . o rg / 0 0 0 0 - 0 0 0 2 - 0 7 9 8 -6 77 9
e v is e d : 1 9 J a n u a r y 2 0 2 3 , A c c e p t e d : 8 F ebruary 2023
T h is is an o p e n - a c c es s a r t ic l e d is t r i b u t e d u n d e r t h e te r m s o f t h e C r e a t i v e
p er m its un r e s tr i c te d n o n - c o m m e r c i a l u s e, d i st r ib u t io n , an d r e p r o d u c t i o n
Copyright
C o m © m 2024
on sby AThe
t Korean
tr ib u Pediatric
ti o n N o n - C m m e r c ia l L ic en s e (h t t p: / / c r e ativecommons.org/licenses/by-nc/4.0/) which
Society
i n a ny m e di u m , p ro v i de d t h e or ig in a l w o r k is p ro p e r ly c i t e d .
 Acute onset of
respiratory/syste Abnormality Evident
mic infectious on infiltrations
symptoms auscultation on CXR
Lobar/lobular Beta-lactam Abx
(add macrolide
consolidation during Mpn
season)
Pleural effusion
Acute onset of respiratory/systemic
Abnormality
infectious
on auscultation
symptoms
Evident infiltrations on CXR High inflammatory
markers2)

Exclusion of Flu Ag (+) Oseltamivir/

HAP
peramivir
Aspiration pneumonia
Bronchiolitis Diagnosis of CAP Initial W/U
Atelectasis SARS-CoV-2 Ag Remdesivir ±
Asthma exacerbation
(+) Dexa
Etiologic W/U
RDV: children (≥3.5 kg) with O2 need, but not MV. 5
days
NPS/A, Sputum Blood PE, BAL Dexa: in high inflammatory state. 0.15 mg/kg/d, 10
days

Pyogenic bacteria by culture

Pyogenic bacteria
Pyogenic
by culture PO AMX±CLV IV AMP±SBT
bacteria by culture, PCR or Ag

CTX

Atypical bacteria by serology

Atypical bacteria by PCR Atypical
1) bacteria by PCR Doxycycline/levofloxacin
Reconsid ± steroid
er Macrolide
etiology
Reconsider etiology Single low titer or IgM positivity only
Supportive care except
Oseltamivir/peramivir
SARS-CoV-2 & Flufor Flu remdesivir ± Dexa for SARS- CoV-2

Viruses by PCR Viruses by PCR

HRV, HCoV, HBoV

Graphical abstract. CCXR, chest radiograph; HAP, hospital-acquired pneumonia; CAP, community-acquired pneumonia;
W/U, work-up; Abx, antibiotics; Mpn, Mycoplasma pneumoniae; Flu, influenza virus; Ag, antigen test; Dexa,
dexamethasone; RDV, Remdesivir; MV, mechanical ventilation; NPS/A, nasopharyngeal swab/aspirate; PE, pleural effusion;
BAL, bronchoalveolar lavage; PCR, polymerase chain reaction; HRV, human rhinovirus; HCoV, human coronavirus; HBoV,
human bocavirus; PO, per oral; AMX, amoxicillin; CLV, clavulanate; IV, intravenous; AMP, ampicillin; SBT, sulbactam; CTX,
ceftriaxone or cefotaxime. 1)4-fold increase in a paired serum sample or a single serologic test (IgG+IgM) titer of 1:640
or higher. 2)C-reactive protein or procalcitonin.

crowding but also the use of pneumonia-specific Departments (EDs) nationwide between 2007 and
interven- tions such as improved case 2014.
management—including em- pirical antibiotic In the last 5 years (March 2015 to February 2020)
treatment—and effective vaccines against leading before the COVID-19 pandemic, the number of
causes of pneumonia in children.4) CAP cases in child- ren in 4 referring hospitals in
While the number of pneumonia cases and the Korean metropolitan area was 1.0/100
death rates have significantly decreased, inpatients in the Department of Pediatrics.
hospital visits and hospitali- zation rates are
increasing
Yun KW. Etiology,in both and
diagnosis, developing and
treatment of CAP de- veloped
in children 81 www.e-cep.org
countries, and the situation in South Korea is no
exception.3,5) According to the National Health
Insurance Corporation database, the number of
hospital visits incre- ased from 9,509 to 12,833 per
100,000 population between 2004 and 2014,
especially for those <10 years of age.5) In an
Asian multinational study, a total of 3,151 CAP
patients <5 years of age were hospitalized in 2011
at 3 Korean hospitals, which accounted for 22.4%
of all hospitalizations during that period. It was
higher than Vietnam (5.4%), Malaysia (2.8%), and
Indonesia (18.2%).6) In another study using
National Emergency Department Information
System data, a total of 329,380 children were
diagnosed with pneumonia at Emergency
It showed the highest incidence in the winter
season, when respiratory syncytial virus (RSV)
and Mycoplasma pneumoniae were prevalent,
and another increasing trend in March and
September with the opening of schools. However,
the COVID-19 pandemic had a significant impact
on the epidemiology of other respiratory viruses,
showing a different epidemiology of pneumonia
from that noted before the pandemic.7)
Nevertheless, the incidence of CAP increased
significantly due to the circulation of RSV-B in
the winter season of 2021 and human
metapneumovirus and RSV-A in the fall and
winter of 2022 (unpublished data).

Etiology

1. Results of recent etiological studies

As mentioned above, the use of effective
vaccines such as pneuococcal conjugate vaccine
(PCV), Haemophilus influenza type b vaccine,
and influenza vaccine, improved hygiene and
living environment, and the efforts of the World
Health Organization (WHO) and each country to
reduce pneumonia have greatly reduced global
morbidity and mortality rates.3,4) At the same
time, changes in the distribution of the
causative pathogens of pneumonia are
expected. To enable the appropriate diagnosis,
treatment,
and prevention of pneumonia, it is important to fluid using both polymerase chain reaction (PCR)
understand the distribution of the causative and con- ventional culture techniques. As a
pathogens. Large-scale epidemiological and result of this compre- hensive etiologic work-up
etiological studies have recently been conducted for CAP in children, pathogens were detected in
to address this urgent and unmet need. 81%, viruses in 73%, pyogenic bacteria in 7%, and
Efforts to enhance our understanding of the atypical bacteria such as M. pneumoniae in 8%.
etiology of pneumonia have been initiated in Similarly, another US study was conducted to get
developing countries. The Drakenstein study was data on the clinical characteristics and etiology
conducted in 2012–2014 by the Bill and Melinda of CAP in both inpatients and outpatients during
Gates Foundation using the South African birth 2015–2018. In this study, except for S.
cohort.8) Two large-scale multicenter prospective pneumoniae, there were no significant differ-
case- control cohort studies of pneumonia ences between inpatients and outpatients in
etiology in children have been conducted: the the propor- tions of children with specific
GABRIEL (Global Approach to Biological pathogens detected.11) The main strengths of
Research, Infectious disease, and Epidemics in these studies include the prospective collection
Low-income countries) in 2010–20149) and the of standardized data using advanced molecular
PERCH (Pneumonia Etiology Research for Child diagnostic techniques.
Health) study in 2011–2014.10) These 2 studies To date, well-designed comprehensive
involved infants and toddlers etiological studies of CAP in children have rarely
<5 years of age who were hospitalized for been conducted in Asia. A Japanese study in 2005–
pneumonia (Table
2006 investigated the detection frequency of
1).
pathogens in nasopharyngeal swabs of child- ren
Among developed countries, the US first
with CAP using real-time PCR and bacterial
conducted a multicenter prospective case-control
culture. S. pneumoniae and M. pneumoniae were
study for pneumonia etiology in children during
the most commonly detected at 24% and 15%,
2010–2012, the well-known EPIC (Etiology of
respectively. Among viruses, rhinovirus was
Pneumonia in the Community) study.2) A total of
detected most commonly at 14.5%.12) This result
2,638 children with CAP requiring hospitalization
showed that S. pneumoniae colonized the
were enrolled in 3 hospitals over 2.5 years. In this
naso- pharynx of children before the introduction
study, 89% of patients had radiographic evidence
of PCV in 2010. However, in a Taiwanese study
of pneumonia, and pyogenic bacterial pathogens
conducted in 2010–2013 at 8 participating medical
were detected only in the blood, pleural effusion,
centers, the prevalence of S.
and bronchoalveolar lavage (BAL)

Table 1. Summary of international studies of etiology of CAP in children

Variable GABRIEL9) PERCH10) EPIC2) CHIRP11)
a) b)
Region/center Multinational (n=8) Multinational (n=7) US (3 hospitals) US (6 hospitals)
Period 2010–2014 2011–2014 2010–2012 2015–2018
Setting Prospective Prospective Prospective Prospective observational
observational case- observational case- observational case- case- control
control control control
Subject Hospitalized Hospitalized Hospitalized Hospitalized and outpatient
clinic
Age 2–60 Months 1–59 Months <18 Years 2 Months–18 years
CAP category Radiologically WHO-defined severe or Radiologically confirmed Radiologically confirmed
included confirmed, primary very severe
end-point pneumonia pneumonia65) with a
(WHO64))c) positive x-ray
Cases (n) 888 1,769 2,222 441
Controls (n) 870 5,102 521 50
Pathogen detected NA 98.2% 81% 64.6%
Virus 78.3% 61.4% 73% 55.6%
HRV (24.9%), RSV (20.0%), RSV (31.1%), HRV (NA), RSV (28%), HRV (27%), HRV/EV (18.6%), RSV (16.8%),
bocavirus (9.2%) HMPV (NA) HMPV HMPV
(13%) (10.0%)
Pyogenic bacteria 15.2% 27.3% 7% 4.3%
Spn (9.9), Hib (2.7), SA NA Spn (4%) Spn (2.3%)
(2.0)
Atypical bacteria 1.9% NA 8% 8.8%
 Mpn (1.5%), Cpn (0.4%) NA Mpn (8%) Mpn (8.2%)
CAP, community-acquired pneumonia; GABRIEL, Global Approach to Biological Research, Infectious disease, and Epidemics in Low-income
countries; PERCH, Pneumonia Etiology Research for Child Health; EPIC, Etiology of Pneumonia in the Community; CHIRP, Conventional Versus
Hypofractionated Radiation in High Risk Prostate Patients; US, United States; WHO, World Health Organization; HRV, human rhinovirus; RSV,
respiratory syncytial virus; HMPV, human metapneumovirus; NA, not available; Spn, Streptococcus pneumoniae; Hib, Haemophilus influenza type b;
SA,
a)
Staphylococcus aureus; Mpn, Mycoplasma pneumoniae; Cpn, Chlamydia pneumoniae.
Cambodia,TheChina, Haiti, India, Madagascar, Mali, Mongolia, and Paraguay. b)Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand,
Zambia. c)
presence
of end-point consolidation (as defined above) or pleural effusion in the lateral pleural space (not just in the minor or oblique fissure) that
was spatially associated with a pulmonary parenchymal infiltrate (including other infiltrates).

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cep.2022.01452
 Table 2. Proportion of viral etiologies among acute lower respiratory tract infections in Korean children in
previous studies
Referenc Period No. Viral testing Total% RSV PIV ADV IFZ HRV
e (viral)
15 2000–2001 796 Culture 26.1 56.3 20.2 10.0 13.5 -
16 2002–2006 3,854 Culture 9.8 29.6 32.3 14.0 - -
17 2005 654 Multiplex RT-PCR 35.8 34.2 21.8 33.8 10.2 -
18 2000–2005 515 Multiplex RT-PCR 60.6 23.7 7.9 6.8 6.4 5.8
19 2005–2006 863 Multiplex RT-PCR 54.9 24.8 13.0 8.0 11.7 9.0
20 2010–2011 1,520 Multiplex RT-PCR 72.5 35.5 13.8 12.8 5.3 25.6
RSV, respiratory syncytial virus; PIV, parainfluenza virus; ADV, adenovirus; IFZ, influenza virus; HRV, human rhinovirus; RT-PCR, reverse
transcription polymerase chain reaction.

pneumoniae was very high despite the introduction commonly detected viruses in some studies. 17,20) These
of PCV in 2005. In this study, respiratory specimens studies are very limited because bronchiolitis was
were excluded from the detection of S. included and bacterial pathogens were not
pneumoniae; however, they incorporated urinary investigated. On the other hand, in a study of 122
antigen test results, which could not differentiate cases of empyema diagnosed in 35 hospitals
between colonization and true infection, nationwide in 1999–2004, S. pneumoniae was the most
particularly in children. The most common common (36.9%), followed by Streptococcus pyogenes
pathogen was S. pneumoniae (31.6%), but it was (6.6%) and Staphylococcus aureus (5.7%).21) Moreover,
detected using only the urinary antigen test in the analysis of 288 cases of lobar/ lobular pneumonia
(83.1%). In addition, they mainly used serological diagnosed at a single institution in 2006–2008,
tests, which have relatively low specificity, to pyogenic bacteria,
detect M. pneumo- niae, the second most
commonly identified pathogen (22.6
%).13)
In China, a multicenter prospective study was
conducted on the etiology of radiologically
confirmed CAP in hos- pitalized children aged 6
months to 14 years in 2015. They tested only 8
respiratory viruses from oropharyngeal swabs
using the direct fluorescent antibody technique,
used an immunoglobulin M (IgM) serologic test
for M. pneumoniae detection, and did not report
the test results for pyogenic bacteria. M.
pneumoniae was the most frequently detected
pathogen (32.4%).14) In the major Asian studies
above, the rates of pyogenic bacteria and M.
pneumoniae were repor- tedly very high,
including culture and/or PCR results from upper
respiratory tract specimens and serological tests,
respectively.

2. Korean etiological studies

In South Korea, there have been no systematic
analyses of the etiology of pneumonia in
children. However, the detection rates of the
respiratory viruses for acute LRTI were studied
by several researchers between 2000 and 2011,
varying from 10% to 73% (Table 2).15-20) The most
commonly detected viruses were RSV and
parainfluenza virus, although adenovirus and
human rhinovirus (HRV) were the second most
83 Yun KW. Etiology, diagnosis, and treatment of CAP www.e-
 which mostly consisted of S. pneumoniae bacteria in only 2.3% of children hospitalized with
(88.9%), were identified in 5.9% of blood and CAP. No pathogens were detected in
respiratory cultures versus approximately half of the children. The most
M. pneumoniae in 50.7% of serologic tests.22) common pathogens were M. pneumoniae (16.8%)
A large-scale multicenter study of CAP and RSV
etiology was recently conducted by a
pediatric research network.23) This was a
retrospective study of 30,994 children with
CAP hos- pitalized in 2010–2015 at 23 hospitals.
This study did not include data on pyogenic
bacteria. The same group recently conducted
a multicenter prospective study of CAP
etiology in 1,023 children in 2018–2020 at 28
hospitals nationwide.24)
M. pneumoniae (41.3%) and viruses (65.7%)
with HRV (30.5%) were commonly detected. A
total of 264 bacterial strains (25.8%), isolated
by culture and/or PCR: S. aureus (13%), S.
pneumoniae (9%), and H. influenzae (2%). The
proportions of M. pneumoniae and pyogenic
bacteria in this study were significantly higher
than those reported in other Asian studies.
These findings may indicate that colonized
pyogenic bacteria might be misidentified as a
pathogen and that the result of the serologic
test with low specificity for
M. pneumoniae was mainly used for the
etiologic diagnosis. To evaluate the etiologic
distribution of CAP in Korean children from a
different perspective, a retrospective multi-
center study was recently conducted by
another group.7) In this study, a rigorous case
definition for CAP was applied with evident
clinical symptoms, physical examination, and
chest radiographic findings corresponding to
pneumonia. In addition, upper respiratory
tract specimens were exclud- ed to detect
pyogenic bacteria and colonization. Serological
test results for M. pneumoniae were
considered positive only when a 4-fold increase
between paired blood samples or a much
higher (usually 10 times) cutoff value with a
single antibody titer was identified. In
addition, HRV, hu- man bocavirus (HBoV), and
human coronavirus (HCoV) were excluded as
pathogens because they are often detected in
the nasopharynx of asymptomatic children
and their etiologic role in CAP is not evident in
children. In the last 5 years (March 2015 to
February 2020) before the COVID-19 pandemic,
respiratory viruses were detected in 31.6%,
atypical bacteria in 17.4%, and pyogenic

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cep.2022.01452 84
 (13.7%), and the most common pyogenic bacterial of some bacterial pneumonias may be missed, even
species were S. pneumoniae (0.6%) and S. in cases of pneumonia for which the causative
pyogenes (0.6%). bacteria have not been identified or respiratory
viruses have been detected.
Therefore, it is common to use empirical antibiotics
Diagnosis based on clinical findings suggesting the possibility
of pyogenic bacterial pneumonia, such as
1. Clinical diagnosis lobar/lobular consolidation, empyema/PE, and high
The diagnosis of pneumonia is based on inflammatory markers (C-reactive protein and
respiratory symp- toms, physical examination, procalcitonin). In particular, if these findings occur
and/or chest radiographic findings. However, in outside the M. pneumoniae epidemic period (which
the absence of clear alveolar consolida- tion and
PE on chest radiography (CXR), it may be difficult
to distinguish other LRTI such as croup,
bronchitis, and bronchiolitis from pneumonia.
The case definitions for pneumonia of the WHO
are mainly used in developing countries, and the
severity is classified by the degree of re-
spiratory distress. Pneumonia is defined as
cough/difficulty breathing and age-adjusted
tachypnea.25) In addition, the etiological
diagnosis of pneumonia is complicated and di-
fficult in typical clinical situations.

2. Pneumococcal pneumonia
In particular, bacterial pneumonia, such as that
caused by S. pneumoniae, the most important
pathogen in CAP because it should be treated
with antibiotics, is difficult to accurately identify
in children.26) A small proportion of cases are
detected by blood and/or PE culture, even under
ideal conditions. Sputum cannot be adequately
produced by young children but can be easily
contaminated by organisms present in the
nasopharynx. In addition, the detection of
pneumococcus in the nasopharynx or positivity
on a uri- nary antigen test may indicate
asymptomatic carriage, which is prevalent even
in healthy young children. When pneumococci
are present in the nasopharynx, genomic
fragments of the bacteria can be detected in the
blood through PCR. Therefore, blood PCR for
pneumococcus has low specificity in children with
CAP.26) Moreover, diagnostic serology is
insensitive in children, and paired samples are
difficult to obtain. BAL or lung biopsy, performed
to avoid contamination with upper respiratory
secretions, is the gold standard diagnostic
technique for pneumonia; how- ever, these
procedures are rarely performed in children with
CAP because of their invasiveness. Thus, even
with a sufficient etiologic work-up, the diagnosis

85 Yun KW. Etiology, diagnosis, and treatment of CAP www.e-

may have similar clinical manifestations) or in antibody test including both immunoglobulin G
children who have not completed PCV (IgG) and IgM was highly concordant with the
immunization, the probability of a positive results of a Mycoplasma PCR test from
pneumococcal etiology of this pneumonia nasopharyngeal aspirates in Korean children.35)
might be high. Recent studies additionally Thus, we may use a high single titer of serologic
suggested that the naso- pharyngeal carriage (IgG + IgM) test for M. pneumoniae to enhance
load of pneumococcus is higher in its specificity, although the sensitivity is probably
pneumococcal CAP than in other etiologic reduced, particularly in school-aged children and
CAP and thus can be used to diagnose adolescents with CAP during the M. pneumoniae
pneumococcal CAP.27-29) epidemic.
As mentioned above, atypical bacterial
3. M. pneumoniae pneumonia, particu- larly M. pneumoniae
Atypical pneumonia pathogens include M. pneumonia, has limitations in clinical diagnosis
pneumoniae, Chlamydophila pneumoniae, because it can present with various symptoms,
Chlamydophila trachomatis, and Legionella severities, and laboratory and CXR findings.
pneumophilia; however, M. pneumoniae However, if a school-aged child who has received
accounts for most of the causes of atypical all PCV doses develops CAP accompanied by
CAP in children. However, in neonates and lobar/lobular consolidation or PE
infants less than 3 months of age,
C. trachomatis can manifest similar to viral
pneumonia such as RSV. A repetitive staccato
cough, tachypnea, and rales are characteristic,
but wheezing is uncommon.30) All atypical
bacteria are usually detected by PCR in
respiratory samples because culturing is
difficult and time-consuming. Recent- ly,
multiplex PCR kits containing major
respiratory viruses and atypical bacteria have
been commercialized and are now frequently
used in clinical settings.31)
However, caution is required for
interpretation as M. pneumoniae may be
detected in nasopharyngeal swabs from
asymptomatic healthy children depending on
the time of prevalence, region, target age,
and race.32) Mycoplasma PCR in sputum
samples show widely distributed sensitivity of
9%–100%, has poor concordance with paired
serology, and does not reliably differentiate
infection from coloniza- tion.33) On the other
hand, serology is among the most widely used
methods for the diagnosis of M. pneumoniae.
A four-fold or higher increase in antibody
levels in acutecon- valescent serum is
considered diagnostic, but it is difficult to
apply in clinical settings. Therefore, a single
IgM titer is usually measured, but it can
remain high for months or pos- sibly years,
may not appear in very young children or
during reinfection, and the positive predictive
value can be as low as 15%.32-34) However, a
single antibody titer of 1:640 or higher in an

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cep.2022.01452 86
 during an M. pneumoniae epidemic, the and assessment of disease severity. This technique
possibility of M. pneumoniae pneumonia may be may open a new era for the identification of potential
high.36,37) therapeutic or preventive targets, if applied in an
appropriate clinical setting.42)
4. Respiratory viruses
The detection of respiratory viruses in patients
with pneu- monia is mainly performed on Treatment
nasopharyngeal aspirate or
swabsamplesusingcommerciallyavailablemultiplexr 1. Empirical antimicrobial therapy
eal-time reverse transcription PCR (RT-PCR) Among children with CAP in developed countries,
Unlike most bacteria, respiratory viruses have a 60%–
low probability of asymptomatic colonization;
therefore, those detected in children and ado-
lescents with pneumonia are generally accepted
as causative agents. However, HRV, HBoV, and
HCoV are the exceptions. Because these viruses
often cause asymptomatic infection or can shed
for a long time after infection, they are detected at
a similar rate in the asymptomatic control group
as in patients with pneumonia.2,10,11,38) Serology can
support RT-PCR, but it is also clinically limited
because of possible false-positive and
-negative results; thus, acute and convalescent
serum should be obtained.39)

5. Novel etiologic diagnostics

Syndromic multiplex PCR panels have been
developed for this purpose. It enables the
detection of viruses, atypical bacteria, pyogenic
bacteria, and antimicrobial resistance marker
genes in respiratory specimens. Semiquantitative
results were also obtained for bacterial targets.
The panel showed a sensitivity of 100% and
specificity of 87.2%.31) Me- tagenomics and pan-
viral group PCR can detect additional viruses,
some of which are known to be pathogenic, in
nasopharyngeal/oropharyngeal specimens from
one-third of children hospitalized with CAP of
unknown etiology. Both broad-range methods
could be useful tools in future epidemiological
and diagnostic studies.40) Cell-free plasma next-
generation sequencing was made available in
2017 to supplement the standard of care
diagnostic techniques. In a previous study in the
US, among 15 children hospitalized with CAP, a
pathogen was identified in 13 of 15 children (86
%) with cell-free plasma sequencing compared
with 47% for those using standard culture and
PCR-based methods alone.41) RNA sequencing
profiles by transcriptional analy- sis of blood from
infants with RSV LRTI allow specific diagnosis,
better understanding of disease pathogenesis,

87 Yun KW. Etiology, diagnosis, and treatment of CAP www.e-

90% might have a viral etiology; thus, they studied and recommended by both 2011 IDSA
would require conservative management with and 2017 KCDC guide- lines.43,44) However, a 5-
symptomatic care during the disease course. day course of high-dose oral amo- xicillin was not
However, children with presumed bac- terial inferior to a 10-day course in 6- to 59-month- old
and influenza virus pneumonia require outpatients with alveolar CAP, which is more
empirical antimicrobial therapy during their likely to have a pyogenic bacterial cause.48) In
initial presentations. The Pediatric Infectious Malawian children, 3-day treatment with
Disease Society and Infectious Disease amoxicillin for chest-indrawing pneu- monia was
Society of America (IDSA) in the US noninferior to 5-day treatment.49) In the United
recommended amoxicillin or ampicillin for Kingdom, among children with CAP discharged
children with presumed pyogenic bacterial from an ED or hospital ward (within 48 hours),
pneumonia, azithromycin for children with lower-dose outpatient oral amoxicillin was
presumed atypical pneumonia, and noninferior to higher-dose amoxicillin and 3-day
oseltamivir or zanamivir for children with duration was noninferior to 7 days in terms of the
presumed influenza pneu- monia.43) The need for antibiotic re-treatment.50) In the SAFER
Korea Centers for Disease Control and Pre- (Short- Course Antimicrobial Therapy for
vention (KCDC) similarly recommended the Pediatric Respiratory Infections) trial in Canada,
2017 guidelines for antibiotic use in children short-course (5-day) antibiotic
with LRTI.44)
However, clinical suspicion of the etiology
of CAP in children is difficult and
inaccurate; therefore, most clini- cians
usually prescribe antibiotics. Thus, unless
pyogenic bacterial pneumonia is carefully
considered, the effect of empirical amoxicillin
administration is generally insignifi- cant.
This has been evidenced by several well-
designed large-scale randomized clinical
trials in developing count- ries. In Malawi
children aged 2–59 months, placebo treat-
ment for nonsevere fast-breathing
pneumonia was signi- ficantly inferior to
amoxicillin treatment in terms of overall
treatment failure. However, by day 4,
approximately 93% of children receiving
placebo did not experience treatment failure,
and there was no significant difference
between groups in treatment failure or
relapse by day 14.45) In Paki- stan, among
children younger than 5 years of age with
nonsevere pneumonia, the frequency of
treatment failure was higher in the placebo
than amoxicillin group, but a difference that
did not meet the noninferiority margin for
placebo.46) Also, in the US, among children
who visited the ED with suspected CAP,
treatment failure or admission within 30 days
was not statistically different between those
who did and did not receive an antibiotic
prescription.47)
In terms of antibiotic treatment duration, 10-
day treat-
ment courses of amoxicillin have been best
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 Diagnosis: all of the following 3
(1) Acute systemic and/or respiratory symptoms
(2) Abnormality on auscultation
(3) Infiltration/consolidation on CXR

Community-acquired pneumonia in otherwise healthy children

Severity: consideration of the followings

Dyspnea/desaturation
High inflammatory markers
Lobar consolidation and/or PE on CXR

Outpatient Inpatient

Bacterial suspecteda)
Flu season Mpn season Bacterial Suspecteda) Flu season Mpn season COVID-19
Others diagnosed Others

Empirical therapy: initial within 48 hours after symptom onset

Empirical therapy: if needed

Oseltamivir Macrolide Amoxicillin 1st-line Ampicillin Oseltamivir Macrolide Remdesivir

Symptomatic Definitive therapy: total duration of 5 days Definitive therapy: total duration of 5 days
care

2nd-line LFX/DOX
Ceftriaxone Peramivir Steroid
Steroid

Duration: according to clinical responsiveness

Symptomatic care
Fig. 1. CXR, chest x-ray; PE, pleural effusion; Flu, influenza; Mpn, Mycoplasma pneumoniae; LFX, levofloxacin; DOX,
doxycycline; COVID-19, coronavirus disease 2019. a)Lobar/lobular consolidation, not fully vaccinated with pneumococcal
conjugate vaccine, or high concentration of inflammatory markers (C-reactive protein >10 mg/dL and/or procalcitonin
>5 mg/dL) during the no Mpn epidemic season.

therapy appeared comparable to standard care pneumoniae pneu- monia can be found in the 2019
(10-day) for the treatment of previously healthy guideline codeveloped by the Korean Society of
children with CAP not requiring hospitalization.51) Pediatric Infectious Disease and the Korean
Academy of Pediatric Allergy and Respiratory
2. Antimicrobial therapy for M. pneumoniae Disease54) and would not be covered here as it is
Macrolides are recommended as first-line beyond the
therapy; how- ever, macrolide resistance rates to
M. pneumoniae among children have been
increasing substantially. Macrolide resistance
does not contribute to the clinical severity of M.
pneumoniae pneumonia; however, it may be an
aggravating factor. Antibiotics may not be
required for treatment in mild cases due to the
self-resolving nature of M. pneumonia infection
regardless of macrolide resistance.52) The clinical
benefit of tetracyclines and fluoroquinolones has
been shown in terms of shortening symptom
duration and ac- hieving rapid defervescence in
some reports. However, due to safety concerns
regarding these 2 alternative anti- biotics,
clinicians should weigh the risks and benefits
when selecting treatment options. Alternative
antibiotics may be considered when patients
remain febrile or when chest x-rays show
deterioration at least 48–72 hours after macro- lide
treatment.53) The detailed recommendations for
the treatment of macrolide-resistant M.

89 Yun KW. Etiology, diagnosis, and treatment of CAP www.e-

scope of this review.

3. Antiviral therapy
Among the viral pathogens that cause CAP
in children, influenza virus and severe acute
respiratory syndrome coronavirus 2 are
currently recommended treatment with
antiviral agents. Early treatment with
oseltamivir reduces the illness and
hospitalization durations for patients with
serious illness or those with ongoing
clinical deteriora- tion.55,56) Zanamivir (in ≥7
years-old) and peramivir (in ≥6 months-old)
could also be administered by inhalation and
parenterally, respectively, for the treatment
of influenza pneumonia.57) Remdesivir is
suggested for children (≥3.5 kg) with severe
COVID-19 including pneumonia who need
supplemental oxygen without mechanical
ventilation. Nirmatrelvir/ritonavir is
considered for adolescents (≥12 years and ≥40
kg) at high risk of progression to severe
disease who do not require supplemental
oxygen and are within 5 days of symptom
onset.58) High risk factors include obesity,
diabetes, heart disease, chronic lung
diseases, sei- zure disorders, and an
immunocompromised status.59) Otherwise, for
the treatment of other common respiratory
viruses causing CAP in children, specific
antiviral therapies including ribavirin for RSV
and cidofovir for adenovirus are not usually
recommended.43)

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 4. Steroids Footnotes
Clinical trials have yielded conflicting data
regarding the benefits of adding systemic Conflicts of interest: No potential conflict of
corticosteroids to CAP treat- ment. Recent interest rele- vant to this article was reported.
randomized clinical trials conducted in adults
indicated that short-term corticosteroid treatment Funding: This study received no specific grant from
reduces the time to clinical stability in patients any funding agency in the public, commercial, or not-
admitted to the hospital for CAP60) or reduces the for-profit sectors.
risk of treatment failure among patients with
severe CAP and a high initial inflamma- tory
response,61) but these effects were not clinically
signifi- cant. Pediatric studies must evaluate the
strengths and weaknesses of steroid therapy in
children with CAP. However, for some pathogens,
the effectiveness of corticosteroids has been
relatively well evaluated and corticosteroids are
recom- mended for treatment in some situations.
First, early cortico- steroid therapy reduces
disease morbidity in children with CAP caused by
M. pneumoniae, particularly macrolide- resistant
M. pneumoniae, without increasing the incidence
of adverse reactions.62,63) In addition,
corticosteroids are recommended for children
and adolescents with severe to critical COVID-19.
This might reduce excessive immune and
inflammatory responses during the severe course
of COVID-19 pneumonia.58)

5. Recommended management of CAP in

children
Regarding the recent epidemiology and
diagnostic and therapeutic advances, we
recommend a management stra- tegy for CAP in
otherwise healthy children (Fig. 1).

Conclusion

CAP is a common infectious disease that can be

easily dia- gnosed and treated by all pediatricians.
However, it results in unnecessary medical
resource waste, excessive antibiotic
administration, and hospitalization because an
accurate diagnosis and appropriate treatment are
frequently lacking. As evidence-based scientific
diagnosis and treatment po- licies have become
the basis for overcoming emerging infec- tious
diseases such as COVID-19, multidisciplinary
clinical studies are needed to better understand
and appropriately diagnose, treat, and prevent
CAP in children.

91 Yun KW. Etiology, diagnosis, and treatment of CAP www.e-

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