STAT E O F T H E A RT R E V I E W

Advances in the diagnosis of pneumonia

in children
Heather J Zar,1 Savvas Andronikou,1 2 Mark P Nicol3 4
1
Department of Paediatrics and
Child Health, Red Cross Children’s A B S T RAC T
Hospital and MRC Unit on Child
and Adolescent Health, University Pneumonia remains a major cause of childhood mortality and morbidity globally.
of Cape Town, Cape Town 7700,
South Africa
Accurate diagnosis and attribution of the causes of pneumonia are important for
2
Department of Radiology, measuring the burden of disease, implementing appropriate preventive or treatment
University of Bristol and the Bristol
Royal Hospital for Children, UK
strategies, and developing more effective interventions. This review summarizes
3
Division of Medical Microbiology, recent diagnostic advances in radiological techniques, specimen collection, and
Department of Pathology, University
of Cape Town laboratory methods. Although chest ultrasound and chest magnetic resonance
4
National Health Laboratory Service imaging are promising modalities for radiological diagnosis, their role in clinical
of South Africa, Johannesburg,
South Africa management and their impact on outcomes need further study. Rapid, highly
Correspondence to: H J Zar
heather.zar@uct.ac.za
sensitive, multiplex laboratory tests performed on upper respiratory tract samples or
Cite this as: BMJ 2017;358:j2739 induced sputum can detect nucleic acid from potential pathogens in most children
doi: 10.1136/bmj.j2739
with pneumonia. However, it may be difficult to attribute causality because it is
Series explanation: State of the
Art Reviews are commissioned often impossible to distinguish between organisms colonizing or infecting the upper
on the basis of their relevance to respiratory tract and those causing pneumonia. Currently available host biomarkers
academics and specialists in the US
and internationally. For this reason lack accuracy for distinguishing bacterial or mixed bacterial-viral infections from
they are written predominantly by
US authors viral infections. New biomarkers derived from host transcriptional profile analysis
may be more accurate but require validation. Prospective studies with appropriate
control populations, including studies of clinical impact, are needed to improve our
understanding of the role of tests. Although progress has been made in radiological
techniques and laboratory testing, current methods for diagnosing and attributing
the causes of pneumonia are suboptimal.

Introduction pathogenesis of pneumonia may be dysbiosis, or imbal-

The incidence and severity of pneumonia in childhood,
and its related mortality, have declined substantially in
the past decade owing to improved socioeconomic con-
ditions; better access to care; wider implementation of
effective management and preventive strategies; and
the development and availability of improved vaccines,
particularly the pneumococcal (PCV) and Haemophilus
influenzae type b (Hib) conjugate vaccines.1 However,
pneumonia remains the leading cause of childhood mor-
tality globally outside the neonatal period and a major
cause of morbidity and hospital admission.2 3 Further-
more, pneumonia or lower respiratory tract infection
(LRTI) in early childhood has increasingly been asso-
ciated with reduced lung function in infancy and the
development of chronic non-communicable respiratory
diseases, such as asthma or chronic obstructive pulmo-
nary disease, in children and adults.4‑7
Pneumonia was formerly thought to occur after inva-
sion of a sterile lower respiratory tract by a single patho-
genic organism. However, recent evidence indicates that
the healthy lung is not sterile and that the normal lung
microbiome exists in a dynamic state.8 A key step in the
ance, in the normal microbial ecology of the respiratory
tract as a result of factors related to the host, environ-
ment, or organism.9 10 Dysbiosis may result in the over-
growth of a single pathogen, or multiple pathogens, as
supported by recent data from studies using sensitive
highly multiplexed diagnostics, which identify multiple
potentially pathogenic organisms from the respiratory
tract of most children with pneumonia.11 12
Accurate diagnosis of pneumonia and the attribution
of its cause are important for measuring the burden of
disease, for implementing appropriate treatment or pre-
ventive strategies, and for developing new more effective
interventions. The availability and increased uptake of
global and national childhood immunization programs of
conjugate vaccines against bacterial pathogens have had
an impact on the causes of childhood pneumonia. The
relative contribution of different pathogens needs to be
re-evaluated to inform the development of modified treat-
ment guidelines, such as the widely used World Health
Organization Integrated Management of Childhood Ill-
ness guideline, and to prioritize vaccine development and
implementation.

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 STAT E O F T H E A RT R E V I E W
Diagnostic advances include the use of new radiologi-
cal methods, better specimen collection, and improved
microbiological tests. Advances in radiological tech-
niques include the use of point-of-care (POC) chest ultra-
sound and chest magnetic resonance imaging (MRI). In
addition, telemedicine enables the remote interpreta-
tion of radiological investigations by expert radiologists.
Improved methods for specimen collection include a bet-
ter understanding of the role of non-invasive specimens
(such as urine or nasopharyngeal samples) and the use
of induced sputum. Laboratory based advances encom-
pass rapid tests for pathogen nucleic acid or antigen,
simultaneous detection of multiple pathogens, and host
transcriptional profile analysis for the identification of
novel biomarkers.
This review summarizes recent advances in the diagno-
sis of community acquired pneumonia in childhood and
focuses on radiological techniques, specimen collection,
and laboratory methods. The impact of these advances on
the current understanding of the pathogenesis of pneu-
monia and the implications for future strategies and
research are discussed.
Incidence of pneumonia in childhood
The incidence of pneumonia in childhood has fallen
substantially in recent decades, but pneumonia remains
the main cause of death in children outside the neonatal
period and of loss of disability adjusted life years in chil-
dren and adolescents.2 3 The Global Burden of Diseases
study, which used many data sources and mathemati-
cal modeling, estimated that pneumonia accounted for
almost 900 000 of the 6.3 million deaths in children in
2013, with the greatest burden occurring in low and mid-
dle income countries.2 The incidence of pneumonia in
children under 5 years of age in high income countries
has been estimated at 0.015 episodes per child year, com-
pared with 0.22 episodes per child year in low and middle
income countries.13
Several case-control or descriptive studies, mainly in
high income countries, have reported that vaccination,
especially with the 13-valent PCV (PCV13), has reduced
the incidence and severity of pneumonia in children and
of complications such as empyema.14‑18 Nevertheless,
the incidence of pneumonia in childhood, even in highly
vaccinated populations, imposes a substantial burden on
healthcare systems. The incidence of pneumonia in chil-
dren participating in a South African birth cohort study in
a peri-urban, poor socioeconomic area was 0.27 episodes
per child year during infancy, with the peak incidence
occurring at 3 months of age19; this occurred despite high
coverage of vaccination, including PCV13.
Specific childhood populations may be especially vul-
nerable to developing pneumonia or severe disease. A
meta-analysis reported that the incidence of and mor-
tality from pneumonia in children infected with HIV is
about six times higher than in those not infected with
HIV.20 Infants who have been exposed to HIV but are not
infected (those born to HIV infected mothers who are HIV
negative owing to effective interventions for preventing
mother-to-child transmission) are also increasingly rec-
ognized as being more vulnerable to pneumonia. These
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infants have a higher risk of severe disease or hospital
admission than children who have not been exposed to
HIV (infants born to HIV negative mothers).21 A meta-
analysis confirmed several other risk factors for pneu-
monia associated mortality including malnutrition, lack
of breast feeding, crowded living conditions, exposure to
indoor air pollution, and low birth weight.22
Sources and selection criteria
This review examines advances in the diagnosis of pneu-
monia in children, focusing on radiological techniques,
specimen collection, and laboratory methods. We iden-
tified references through searches of publications listed
in PubMed from January 2000 to September 2016 using
combinations of medical subject headings (MeSH) that
included child AND (pneumonia OR lower respiratory
tract infection OR pertussis) AND (diagnosis OR chest
radiology OR lung ultrasound OR MRI lung OR induced
sputum OR specimen). We reviewed relevant titles and
abstracts, and we prioritized randomized studies, system-
atic reviews or meta-analyses, and case-control or cohort
studies. Where higher quality evidence was not available,
case series and other observational studies were consid-
ered. Individual case reports were not included. Prefer-
ence was given to publications from the past five years.
Because this was not a formal systematic review, we did
not grade the included studies but summarized key out-
comes or results. We only included articles or abstracts
published in English.
Current guidelines for radiological diagnosis
Chest radiography is often performed for suspected
pneumonia,23 24 which is the most common indication for
imaging of the chest.25 This is despite several guidelines
advising against the routine use of chest radiography25
and the lack of evidence for its impact on clinical out-
comes.26 27 Several international or national guidelines
including those from the British Thoracic Society (BTS)28
and the National Institute for Health and Care Excellence
(NICE) in the United Kingdom,29 the Paediatric Infectious
Diseases Society and the Infectious Diseases Society of
America (IDSA),30 the South African Thoracic Society
(SATS),31 and the International Union against Tubercu-
losis and Lung Diseases32 do not recommend chest radi-
ography in children who are well enough to be treated as
outpatients. Rather, chest radiography is recommended
only in children who are admitted to hospital with severe
symptoms, hypoxia, or suspected complications such as
empyema.
Limitations of chest radiography
Changes seen on chest radiographs may be more spe-
cific for pneumonia than clinical signs, with radiological
signs associated with more severe disease and treatment
failure.33 34 However, the use of chest radiography for
diagnosis has several limitations. The two dimensional
nature of chest radiography may lead to consolidation,
adenopathy, or complications being masked by other
anatomical structures such as the heart, mediastinum,
and diaphragm35 36; it may also lead to the problem
of summation shadows.37 Furthermore, inter-reader
 STAT E O F T H E A RT R E V I E W
agreement in the interpretation of chest radiographs is
poor.23‑38 In a recent review, 10 of 12 pediatric studies
showed only fair to moderate interobserver agreement.38
Agreement is worse for reporting of an “infiltrate” in
children under 5 years,23 and it remains moderate even
when using WHO standardized radiological criteria for
pneumonia.23 39 In addition, the lack of abnormality on
chest radiography does not exclude pneumonia,40 41 and
abnormal chest radiographs may be interpreted as nor-
mal.23 Other limitations include lack of access to basic
radiology services at primary healthcare facilities in many
low and middle income countries; expense; exposure to
radiation (although low at 0.01-0.02 mSv for a standard
chest radiograph)42; and need for specialized equipment,
power source, and trained technologists. Imaging with
computed tomography is more reliable but discouraged
for routine diagnosis because of the resources needed
and the radiation risk,25 despite new dose reduction
techniques.43
New imaging techniques are therefore needed to
increase diagnostic accuracy and improve access. Two
alternative forms of diagnostic imaging have emerged—
POC ultrasound and rapid sequence MRI, which may have
applications across different settings. The use of these
techniques is enhanced by the capacity for remote read-
ing by expert radiologists.
Advances in radiological diagnosis
Clinician led POC ultrasound
It is now feasible for ultrasound to be performed by
non-radiologists with the advent of affordable handheld
machines. Children are ideal candidates for diagnostic
imaging using ultrasound because of their thin chest wall
and small lung mass. Ultrasound has several advantages
over other imaging modalities: it can be performed at
POC, it is feasible and less costly than chest radiography,
it is less affected by movement or crying than other imag-
ing modalities, it can be done in sleeping children,35 and
it is free of ionizing radiation.24‑41 Although ultrasound
performed by non-radiologists is controversial, it has
become a useful tool for physicians, emergency medicine
doctors, and intensivists.44
Lung ultrasound involves scanning a child in the ante-
rior, lateral, and posterior areas of each hemithorax.45‑47
Consolidation is diagnosed as a hypoechoic area with ill
defined borders surrounded by B-lines and loss of or an
irregular shredded border of the pleural line.24‑50 Other
signs include punctate hyperechoic or linear and branch-
ing echogenic structures, reflecting air bronchograms, and
a decrease in lung sliding (fig 1). Lobar involvement pre-
sents as a liver-like area in the thorax or hepatization of
the lung.47 Homogeneous, anechoic, or hypoechoic fluid
in the pleural space indicates a pleural effusion (fig 2).47
Evidence for the use of ultrasound to support the diag-
nosis of pneumonia in children is accumulating. Most
studies have compared POC ultrasound performed by cli-
nicians with chest radiography findings reported by radi-
ologists (table 1). A literature search of lung ultrasound
for pneumonia in children yielded 24 original studies,
11 commentaries, a meta-analysis, and a summary of
evidence.62 Only three studies compared ultrasound
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with a gold standard of pneumonia defined by computed
tomography, and only one study provided the diagnostic
accuracy of ultrasound and chest radiography against
computed tomography for pneumonia. In this last study
the positive predictive values for ultrasound and chest
radiography were 0.61 and 0.71, respectively, whereas
the negative predictive values were 0.86 and 0.8, respec-
tively.58 Four studies provided interobserver agreement,
with three reporting high agreement for consolidation
on ultrasound (κ=0.8-0.9).50‑59 Only one study reported
the interobserver agreement for chest radiography and
ultrasound simultaneously; agreement for ultrasound
was fair (κ=0.55) but better than that for chest radiog-
raphy (κ=0.33).58
The limitations of ultrasound include its inability to
visualize the whole lung at the same time or to identify
consolidation deep within the lung parenchyma.25 In
addition, the spleen or air in the stomach can be misin-
terpreted as lung consolidation with air bronchograms.54
Overall, the use of POC ultrasound as an alternative
to chest radiography in primary screening for triage in
the emergency department or clinic is promising. How-
ever, even though ultrasound has potential as a screening
test, it is not clear whether it affects patient outcome or
management. Further studies are needed to compare the
impact of chest radiography versus POC ultrasound on
patient relevant outcomes and to inform best practice.
Rapid sequence MRI
When cross sectional imaging is needed for the diagno-
sis of severe pneumonia or associated complications, the
possible radiation risks of computed tomography can be
avoided by using MRI.63 64 It can be difficult to achieve
adequate MRI imaging of the lungs owing to low proton
density with signal loss and because cardiac pulsation
and breathing produce strong motion artefacts.37‑66 Fur-
thermore, in children who are too young to cooperate,
sedation or anesthesia is required, and this may cause
dependent atelectasis, which can be misinterpreted
as infection.65 67 Therefore, older children are scanned
awake, and in cooperative children respiratory motion
can be prevented by voluntary breath holding.65
At some facilities MRI has become an established tech-
nique for imaging the lungs using improved sequences
and modern respiratory triggering63 65—a mechanism of
scanning in between breaths. Faster protocols using con-
ventional T2 weighted sequences have been developed
that can be performed with free breathing and completed
in under 10 minutes, enabling imaging in children with
pneumonia.64 66
Disease in the alveolar spaces results in a high intensity
MRI signal that stands out against the low signal of nor-
mally aerated lung (fig 3). A high signal on T2 weighted
sequences is seen in all diseases with alveolar exudates,
making MRI ideal for imaging pneumonia.65 MRI has one
major advantage over chest radiograph—it is a cross sec-
tional imaging technique without the limitations of two
dimensional imaging.37 65 It can also demonstrate com-
plications of pneumonia such as abscess or effusion.65
Evidence for the accuracy of MRI and interobserver
agreement in interpreting pneumonia in children is
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Fig 1 |  Ultrasound of the chest using a linear probe. This figure
shows absence of the pleural line and an underlying wedge
shaped low density lung with linear and branching densities
corresponding to air bronchograms (arrows) consistent with
pneumonia
sparse. Only three studies have compared MRI for the
detection of lung consolidation against computed tomog-
raphy as the gold standard (table 2).64‑71 Other studies
have compared MRI findings with chest radiography;
however, these studies provide weak evidence because
chest radiography is considered an inadequate gold
standard (table 2).
Tele-reading of diagnostic images by expert radiologists
Many low and middle income countries have few or no
radiologists, and even fewer pediatric radiologists, which
hampers the reliable interpretation of chest images.72
However, tele-radiology may overcome the lack of radiol-
ogy expertise through electronic transfer of digital imag-
ing for reviewing remotely.33‑73
Tele-radiology consultation is feasible and may help
obtain a more accurate radiological diagnosis.72 Several
free platforms are available to transfer chest radiographs,
ultrasound scans, or even larger datasets to experts for
interpretation.73 Challenges include generating high qual-
ity images at the source, the digital transfer chain, limited
expertise of the reporting radiologist,73 language barriers,
legal problems, and image transfer sustainability.72
Microbiological diagnosis
Various diagnostic modalities are available to support
the diagnosis of the cause of pneumonia. These include
tests done on respiratory specimens, such as microscopy
(including targeted fluorescence microscopy for specific
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Fig 2 |  Ultrasound of the chest using a linear probe. This figure
shows low echogenicity within the underlying lung with bright
foci representing bronchograms; arrows show septations and
strands within the surrounding pleural fluid in keeping with
empyema
pathogens), microbiological and viral culture, antigen
detection, and molecular testing for nucleic acid from the
pathogen. Some of these tests may be used with other
specimen types—for example, molecular or antigen test-
ing of urine samples. Blood culture remains important
for identifying bacteremic pneumonia, and serological
testing may be useful for specific pathogens or for retro-
spective confirmation of infection.
Improved methods for microbiological diagnosis have
challenged traditional assumptions regarding the causes
of pneumonia and the interpretation of microbiological
results. Multiple potential pathogens are often detected
in respiratory samples from children with pneumonia,
and coinfection may be particularly important in severe
disease. Furthermore, some organisms such as Myco-
bacterium tuberculosis, which were formerly regarded
as causing chronic disease, have been shown to be asso-
ciated with acute pneumonia in tuberculosis endemic
areas.74
Limitations of current microbiological testing methods
Accurate identification of the cause of pneumonia is
needed to guide appropriate treatment, to develop
rational guidelines for empiric treatment, and to evaluate
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Table 1 | Studies of chest ultrasound for diagnosis of pneumonia in children*

Study design and Gold standard Interobserver
Study population US operator andCXR reader details method Results of ultrasound performance agreement
Copetti Prospective; 79 US: 1 sonographerCXR: 2 radiologists Clinical diagnosis US diagnosis of pneumonia: 60/60 (100%)CXR diagnosis of Not done
200845 children pneumonia: 53/60 (88%)
Iuri D 200935 Prospective; 28 US: 2 radiologistsCXR: 2 radiologists CXR US diagnosis of consolidation: 22/28 (79%)Sensitivity 92%; specificity Not done
children 100%; PPV 100%; NPV 85%
Kurian 200951 Retrospective; 19 US: 2 technologistsCXR: 2 CT US similar to CT for consolidation and identified all effusions Not done
children radiologists(1 consultant, 1 resident)
Tsung 201252 Prospective; 20 US: 2 investigator sonographers and CXR N/A US κ=0.82
children 1 reviewerCXR: attending pediatric
radiologist
Caiulo 201353 Prospective; 102 US: 1 expert sonographerCXR: 1 Clinical diagnosis US diagnosis of pneumonia: 88/89 (99%)US consolidation diagnosis: Not done
children radiologist (BTS guidelines) 83/89 (93%)CXR diagnosis of pneumonia: 81/89 (91%)
54
Shah 2013 Prospective; 200 US: 15 sonographersCXR: 15 CXR US consolidation diagnosis: 49/200 (25%)Sensitivity 86%; specificity US κ=0.9
children radiologists 97%CXR consolidation diagnosis: 36/200 (18%)
Esposito Prospective; 103 US: 1 sonographerCXR: 1 radiologist CXR US diagnosis of pneumonia:Sensitivity 97.9%; specificity 94.5%; PPV Not done
201455 children 94%; NPV 98%; concordance κ=0.64
Chavez Prospective; 378 US: 2 general practitioners US N/A US κ=0.79
201556 children (127 controls)
Ho 201557 Retrospective; 163 US: 1 pediatricianCXR: 2 radiologists None US diagnosis of pneumonia: 159/163 (98%)CXR diagnosis of Not done
children pneumonia: 151/163 (93%)
Iorio 201549 Retrospective; 52 US: 1 operatorCXR: radiologist Clinical diagnosis US diagnosis of pneumonia: 28/29 (97%)Sensitivity 86%; specificity Not done
children (BTS guidelines) 96%; PPV 96%; NPV 85%CXR diagnosis of pneumonia: 25/29
(86%)Sensitivity 97%; specificity 96%; PPV 97%; NPV 96%
Urbankowska Prospective; 106 US: 1 sonographer Clinical and US diagnosis of pneumonia: 71/106 (67%)Sensitivity 93%; specificity Not done
201524 children radiology 100%; PPV 100%; NPV 86%CXR diagnosis of pneumonia: 76/106
(72%)US to CXR agreement: κ=0.89
Ambroggio Prospective; 132 US: 1 sonographerCXR: multiple CT US consolidation diagnosis:PPV 61%; NPV 86%CXR consolidation US κ=0.55CXR
201658 children (36 with CT) radiologists diagnosis:PPV 71%; NPV 80% κ=0.36
Guerra 201648 Prospective; 222 US: 3 pediatriciansCXR: radiology None US consolidation diagnosis: 207/222 (93%)CXR consolidation Not done
children experts diagnosis: 197/222 (89%)CXR and US consolidation: 190/222 (86%)
Jones 201659 Prospective RCT; 191 US: 15 sonographers N/A US κ=0.81
children and young
adults
Lovrenski Prospective; 95 US: 1 sonographer None US diagnosis of pneumonia: 67/95 (71%)Auscultation diagnosis of Not done
201660 children pneumonia: 45/95 (47%)
Samson Prospective; 200 US: 1 sonographerCXR: 2 radiologists CXR US for consolidation: sensitivity 87%; specificity 95%; PPV 93%; NPV Not done
201661 children 91%
Varshney Prospective; 95 US performance: 1 novice sonographer Clinical diagnosis For consolidation >1 cm:Sensitivity 25%; specificity 97%For US κ=0.68US
201650 children with 2 days’ trainingUS reading: Expert consolidation <1 cm:Sensitivity 50%; specificity 79% κ=0.88 for
sonographer with 5 years’ experience consolidation >1 cm
*Abbreviations: BTS=British Thoracic Society; CT=computerized tomography; CXR=chest radiography; N/A=not available; NPV=negative predictive value; PPV=positive predictive value; RCT=randomized controlled
trial; US=ultrasound.

the impact of preventive interventions, such as vaccina-
tion. However, it can be difficult to attribute the cause of
pneumonia because disease may be caused by multiple
pathogens, bacteria seldom invade sterile sites (such as
the bloodstream), and it is hard to distinguish colonizing
flora from pathogenic organisms in respiratory samples.
Although there have been important advances in rapid
and accurate identification of potential pathogens using
multiplex molecular methods or rapid antigen detection,
the evaluation of novel diagnostic tests is hampered by
the lack of an accurate reference standard test for assign-
ing the cause of pneumonia or for distinguishing between
bacterial and viral pneumonia.
Current guidelines for microbiological diagnosis
Given the difficulties associated with the interpretation
of etiologic diagnostics and lack of data on their impact
on management, BTS guidelines for community acquired
pneumonia (CAP) recommend microbiological testing
only in children with severe pneumonia who need to be
admitted to intensive care or those with complications.28
In such cases, a variety of diagnostic tests are suggested
including blood culture; nasal specimens for viral detec-
tion; acute and convalescent serology for viruses and
atypical organisms; and pleural fluid (if present) for
microscopy, culture, antigen detection, and polymerase
chain reaction. These guidelines are similar to the South
African Thoracic Society guidelines, which recommend
etiologic diagnostic testing only in children who are
admitted to hospital; tests include blood culture, pleu-
ral fluid testing, possible viral testing on nasal samples,
and microbiologic testing for tuberculosis when clinically
suspected using induced sputum or other specimens.31
However, these guidelines differ substantially from those
of the Pediatric Infectious Diseases Society and the Infec-
tious Diseases Society of America (IDSA), which include
rapid diagnostic testing for influenza virus and other
respiratory viruses in children with CAP who are being
treated in the community or in hospital.30 For children
with CAP who are in hospital, IDSA guidelines further rec-
ommend blood culture in those with complicated or mod-
erate to severe disease and sputum for Gram stain and
culture in those who can produce a specimen.30 Tracheal
aspirates for culture and detection of viral pathogens
are recommended in children who have been intubated,
whereas bronchoscopy, bronchoalveolar lavage, or lung

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tinguish live pathogenic organisms from those that are

colonizing or infecting the upper respiratory tract or
nucleic acids left over from previous infections.

Respiratory samples
A range of specimens may be useful for investigating the
causes of pneumonia, and the diagnostic utility varies
with specimen type and specific organism (table 3).75 76
Nasopharyngeal samples, swabs or aspirates, have tradi-
tionally been used for the detection of most viruses and
for pertussis. Flocked nasopharyngeal swabs provide a
similar yield to aspirates, are simpler to obtain than aspi-
rates,77 78 and may provide a better yield than other swab
types.79‑81 Studies are inconsistent regarding the relative
yield of nasopharyngeal versus oropharyngeal specimens
for the detection of viruses; there may be incremental
yield from testing of both specimen types for specific
viruses such as influenza A or adenovirus.82‑85 Naso-
pharyngeal specimens may also be useful for the diag-
Fig 3 |  Axial short tau inversion recovery (STIR) magnetic resonance imaging performed without
nosis of tuberculosis using the polymerase chain reaction
anesthesia or contrast showing high signal in the right posterior alveolar spaces (arrow) in
(PCR) in children from whom it is not possible to obtain
keeping with pneumonia
more representative lower respiratory tract samples.86
biopsy are recommended only in those with severe pneu- Although sputum induction has been shown in many
monia who have negative diagnostic tests.30 In addition to studies to be safe and to provide an effective specimen
testing children with severe disease, targeted testing may for microbiologic diagnosis of pulmonary tuberculosis
be warranted in outbreak situations, or if infection with in children of all ages, there are relatively few studies of
specific pathogens, such as M tuberculosis or Bordetella its use in acute pneumonia. Recent data suggest that the
pertussis, is suspected. diagnostic yield of induced sputum may be greater than
for nasopharyngeal samples for specific organisms. In a
Value of different specimen types and associated multicenter case-control study of children in hospital for
diagnostic tests severe or very severe pneumonia, the use of induced spu-
Optimal specimen collection is key to accurate identifica- tum samples increased the detection of B pertussis using
tion of the cause of pneumonia. Diagnostic yield depends PCR by 48% compared with the use of a combined naso-
on the type and quality of the specimen collected, timing pharyngeal and oropharyngeal swab.87 Two South Afri-
of collection, previous use of antimicrobials, transport, can studies also found an increased yield of B pertussis on
storage, and laboratory processes for testing. It may be PCR with induced sputum,11 88 although no difference was
difficult to obtain a representative sample from the lower shown in another hospital based study.89 Several stud-
respiratory tract, and contamination with organisms such ies have shown good agreement between PCR testing of
as Streptococcus pneumoniae or Haemophilus influenzae, induced sputum and nasopharyngeal swabs for viruses;
which colonize the upper airways but are also important the yield is highest when both sample types are tested.11‑90
pathogens, is likely. This may lead to overestimation or The use of induced sputum has also been reported to be
underestimation of the contribution of these bacteria to helpful for microbiologic confirmation of Pneumocystis
pneumonia. Similarly, although molecular diagnostics jirovecii pneumonia in HIV infected children when using
enable the detection of many respiratory viruses and PCR for diagnosis.91 However, as with nasopharyngeal
bacteria that are not easy to culture, it is difficult to dis- samples, induced sputum samples are likely to be con-
taminated with upper respiratory tract flora, so it may be
Table 2 | Studies of chest MRI for diagnosis of pneumonia in children* difficult to interpret results.
Gold standard Nasopharyngeal and induced sputum samples may
Study Study design Study population method* Results of MRI performance be cultured for bacteria and fungi, although culture is
Peltola 200836 Retrospective 24 children with suspected CXR MRI detection of cases with increasingly being replaced (or supplemented) with
lung infection alveolar and interstitial
disease=100% nucleic acid amplification tests for a range of microbes,
Yikilmaz 201168 Prospective 40 children CXR MRI v CXR:Consolidation or by rapid viral antigen detection. If samples are tested
κ=0.78Effusion κ=0.30 for a wide variety of micro-organisms using multiplex
Peprah 201269 Retrospective 6 children with TB air space CT MRI detection of air space assays, a potential pathogen may be identified in almost
disease disease and lung necrosis=100%
all children with pneumonia. For example, a Finnish
Gorkem 201370 Prospective 71 children CT MRI overall=97%MRI
consolidation=100%
study reported that a potential bacterial or viral pathogen
Ozcan 201671 Prospective 17 children with CT MRI overall=81%MRI was detected by PCR in 97% of children in hospital with
neutropenia consolidation=100% pneumonia using an adequate induced sputum sample,12
Sodhi 201664 Prospective 75 children with suspected CT MRI v CT for consolidation and and in a South African study, both bacteria and viruses
infection effusion:Agreement κ=1 were detected in nasopharyngeal samples from 87% of
*Abbreviations: MRI=magnetic resonance imaging; CT=computed tomography; CXR=chest radiography; TB=tuberculosis.
children with pneumonia.11

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Table 3 | Summary of specimen types and laboratory tests for the causes of pneumonia in children
Relevant laboratory tests Advantages Disadvantages
Nasopharyngeal swab or aspirate
Bacterial culture, molecular or antigen detection of bacteria Ease of collection, relatively good correlation of results with sputum Colonization or infection of the upper airways does not imply
and viruses testing, method of choice for some viruses (eg influenza virus) that organisms are causing pneumonia
Sputum or induced sputum
Bacterial culture, molecular or antigen detection of bacteria Relative ease of collection; more representative of organisms in lower Induced sputum collection requires expertise; samples are
and viruses respiratory tract; incremental yield over testing of upper respiratory contaminated by upper respiratory tract organisms, so may also
samples alone detect organisms colonizing or infecting upper airways
Bronchoalveolar lavage or aspirate
Bacterial culture, molecular or antigen detection of bacteria More representative of organisms in lower respiratory tract; less likely Few comparative studies versus other sample types; costly,
and viruses to be contaminated by upper respiratory tract flora invasive, requires expertise
Transthoracic lung aspirate
Bacterial culture, molecular or antigen detection of bacteria Most representative of lower respiratory tract, least contamination Useful mainly for peripheral infective foci in the lung; costly,
and viruses with upper airway respiratory tract flora invasive, requires expertise; small risk of serious complications
Blood
Culture for bacterial pathogens Relative ease of collection; positive culture with a known pathogen Low yield from bacterial culture, therefore high cost per case
has high specificity detected
Molecular testing More sensitive than blood culture for some targets, eg pneumococcal Lacks specificity for disease (eg lytA positive with
lytA nasopharyngeal carriage)
Serology Useful for epidemiological studies and for specific pathogens, eg Usually requires acute and convalescent sera, so not useful for
pertussis treatment decisions
Biomarker detection Potential to discriminate bacterial versus viral infection Accuracy for distinguishing bacterial versus viral pneumonia is
suboptimal for available biomarkers
Urine
Antigen detection Ease of collection; high sensitivity of pneumococcal capsular Poor specificity for pneumococcal disease (positive with
polysaccharide detection for invasive pneumococcal disease nasopharyngeal carriage)

However, this high yield of apparent pathogens should
be interpreted with caution. Most studies reporting on the
use of molecular testing of respiratory tract samples have
been case series without relevant matched controls. A
large meta-analysis of case-control studies of viral detec-
tion in children with LRTI reported that respiratory syn-
cytial virus (RSV) was most strongly associated with LRTI
(odds ratio 9.8), whereas influenza virus (5.1), parain-
fluenza virus (3.4), and human metapneumovirus (3.8)
were less strongly associated. Rhinovirus was only weakly
associated with LRTI (1.4), whereas no association was
found for adenovirus, bocavirus, or coronaviruses.92
A Dutch study found that Mycoplasma pneumoniae
DNA was not detected any more often in children with
any respiratory tract infection than in control children.93
Two recent studies, a birth cohort in South Africa11 and
a multicenter study in the US,94 have reported similar
findings. RSV, influenza virus, and B pertussis have been
consistently and strongly associated with pneumonia in
many studies. However, there is considerable heterogene-
ity with regard to the causative role of many other viruses
and bacteria detected in respiratory samples, which may
relate to case definitions, sampling, and the inclusion of
a relevant control group.92
Few studies have evaluated the impact of rapid viral
diagnostics on patient outcomes or healthcare utiliza-
tion. A randomized controlled trial (RCT) of 418 patients
(2-21 years of age) presenting to an emergency depart-
ment with influenza-like symptoms randomized patients
to groups where physicians did or did not receive results
of rapid influenza viral testing.95 The number of ancillary
investigations (P<0.001 for complete blood count and
blood culture; P=0.011 for urine analysis and urine cul-
ture) and chest radiographs performed (P=0.001) were
significantly reduced in patients who tested positive.
These patients were also prescribed fewer antibiotics
(P<0.001) and had a shorter length of stay (P<0.001). A
second study randomized 204 children (3-36 months of
age) presenting with febrile acute respiratory illness at
an emergency department to rapid viral testing or routine
care (which included rapid viral testing if specifically
requested by the physician).96 No difference was seen
in length of visit, rate of ancillary testing, or prescrip-
tion, although the number of post discharge antibiotic
prescriptions was reduced in the group who had viral
testing (relative risk 0.36; 95% confidence interval 0.14
to 0.95). Two retrospective record review studies showed
a reduction in antibiotic usage in children who received
rapid viral testing.97 98 No large studies have evaluated
the impact of rapid viral testing and the associated
reduction in antibiotic use on patient outcomes. Given
that bacteria and viruses are often detected at the same
time, and that children admitted to intensive care with
severe disease and RSV infection may have concomitant
bacterial infection,99 rapid viral testing cannot be used
alone to rule out bacterial infection, particularly in chil-
dren with severe pneumonia.
Overall, these results call into question the routine use
and interpretation of costly, multiplex detection assays
and suggest that more limited assays that target specific
pathogens that are strongly associated with pneumo-
nia, such as influenza, RSV, and pertussis, may be more
appropriate (table 4).
Real time PCR assays can often estimate the density
of colonization (pathogen load) in the upper respiratory
tract, which may be associated with the likelihood of
infection. For example, the pneumococcal colonization
density has been associated with respiratory virus infec-
tion and invasive pneumococcal pneumonia.100 How-
ever, pathogen density in the upper respiratory tract was
not associated with pneumonia in a recent case-control
study.11

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 STAT E O F T H E A RT R E V I E W

Table 4 | Laboratory tests in children with ambulatory or severe pneumonia: indications and limitations*
Test
Children with mild or ambulatory pneumonia
Serum for C reactive protein or procalcitonin
Upper respiratory tract samples for rapid viral detection of influenza,
for example
Children with severe disease, complications, and those in hospital
Blood culture
Upper or lower respiratory tract samples for rapid viral testing (PCR or
antigen detection)
Induced or expectorated sputum for mycobacterial culture and PCR
(Xpert MTB/RIF) for Mycobacterium tuberculosis
Induced or expectorated sputum or upper respiratory tract sample for
PCR for Bordetella pertussis
Induced or expectorated sputum for PCR for Pneumocystis jirovecii
Acute and convalescent serum for respiratory pathogens and
mycoplasma and chlamydia
Pleural fluid microscopy, culture, and pneumococcal antigen
detection or PCR
Tracheal aspirate for bacterial culture; PCR for pneumocystis and viral
pathogens
Bronchoscopy, bronchoalveolar lavage, or lung biopsy for bacterial
culture; PCR for pneumocystis and viral pathogens; culture and PCR
for M tuberculosis (in epidemiological context)
*Abbreviations: PCR=polymerase chain reaction; RSV=respiratory syncytial virus.
Indications
Limited evidence that use in an algorithm for children with
mild or uncomplicated pneumonia may reduce antibiotic
exposure
During outbreaks of viral illness, rapid testing may reduce
antibiotic prescription; guidelines differ on recommendation
All children
Children with severe or complicated pneumonia
Children in whom pulmonary tuberculosis is clinically
suspected
Children in whom pertussis is suspected
Children in whom pneumocystis pneumonia is suspected
Children with severe or complicated pneumonia
If pleural effusion present
Intubated children
Children with severe illness in whom no pathogen has been
detected or those who have not responded to treatment
Limitations
Data are very limited; studies include longitudinal monitoring of
kinetics of response to treatment; requires a blood specimen;
not currently recommended to distinguish bacterial disease
Bacterial coinfection cannot be excluded; vigilance for
coexisting bacterial disease required
Low yield but higher in HIV infected children; cost effectiveness
questionable
Difficult to infer causality for many pathogens; most useful for
influenza virus and RSV
Repeated specimens needed to optimize microbiologic yield
Upper respiratory samples have a lower yield than sputum
May not distinguish colonizing from disease causing organisms
Clinical utility questionable, given need for comparison of acute
and convalescent sera
May not distinguish colonizing from disease causing organisms
Invasive and requires specific expertise

Reducing contamination of samples c­ollection of blood cultures in ambulatory children; blood

Samples that are less likely to be contaminated by upper
respiratory flora may be less prone to problems of inter-
pretation. Bronchoscopy with bronchoalveolar lavage
(BAL) or aspirate may provide a representative sample
from the lower respiratory tract but it is invasive and
requires specialized skill and sedation of the child. Few
studies have compared the viral yield from BAL with that
from upper respiratory samples, but the results seem to
be similar.101 BAL is mainly used in patients with hospital
acquired infections, immunocompromised patients, and
those with severe or refractory disease when other speci-
mens have not been able to identify the causative agent.
Transthoracic lung aspiration provides a representative
specimen, uncontaminated by the upper airway flora, when
pneumonia is peripheral and accessible to needle aspira-
tion; however, it is invasive and requires expertise. Recent
studies and a review have provided reassuring data on the
safety of this procedure.76 In a report from the Gambia, the
diagnostic yield depended on the method of testing, with a
potential pathogen identified by a combination of culture
and molecular testing in 53 of 56 samples (including 47
lung aspirates and nine pleural fluids).102Streptococcus
pneumoniae was identified in 91% of samples by molecu-
lar testing, but only 25% of samples by culture.102 Because
case-control studies are not possible with this specimen
type, inferences regarding causality are not straightforward.
It seems probable that contamination with upper respiratory
tract flora is less likely with lung aspirates; however, highly
sensitive nucleic acid amplification assays may detect very
small amounts of nucleic acid and do not necessarily imply
the presence of viable organisms in large numbers.
Blood
Because the yield from blood culture is typically low, both
BTS and IDSA guidelines recommend against routine
culture is indicated only in children who are in hospital,30
in intensive care,28 or have complicated pneumonia.28 30
Most studies have not evaluated the yield of systemati-
cally collected blood cultures from all children presenting
with pneumonia but have been retrospective studies of
existing practice, which may be biased by collection in
sicker children.
Two recent multicenter studies of children in hos-
pital with pneumonia in the US that were performed
after implementation of PCV, documented notably dif-
ferent rates of bacteremia—1.5% (6/390)103 and 7%
(26/369)104—with S pneumoniae the predominant patho-
gen in both. Collection of a blood culture was associated
with increased time to discharge, even after matching
on propensity scores based on clinical factors.103 105 Cost
effectiveness modeling predicts that, in the US, blood
cultures would need to be drawn from 118 children in
hospital to identify one child with bacteremia in whom
the result would lead to a meaningful change in antibiotic
treatment.106 It may be more cost effective to target testing
to children at higher risk of bacteremia, such as those
less than 6 months of age with fever; those admitted to
intensive care; immunosuppressed patients; those with a
central line in place; or those with chronic medical condi-
tions, effusion, or empyema.106
Several studies have described substantially enhanced
detection of S pneumoniae in blood samples using real
time PCR targeting the lytA gene of the pneumococcus,
compared with blood culture. 107‑109 However recent
results from the multicenter Pneumonia Etiology
Research for Child Health (PERCH) study showed both
poor sensitivity (64%; 36/56 microbiologically confirmed
pneumococcal pneumonia cases were PCR positive) and
specificity (5.5%; 273/4987 of non-pneumonia controls
were PCR positive).110 These results illustrate the need for

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 STAT E O F T H E A RT R E V I E W
well controlled studies of the cause of pneumonia, and
the major limitations of studies of case series in correctly
ascribing the cause.
Serological testing of blood specimens may be useful
for epidemiological studies of the cause of pneumonia,
where comparison of acute and convalescent titers may
help identify the causative agent,93‑112 although the diag-
nostic value of a single specimen collected in the acute
phase of the illness is generally limited. Pertussis serol-
ogy may be a useful complementary diagnostic tool in
older children and during the later phases of illness.113 114
Urine
Because urine is relatively easy to obtain from most chil-
dren, pathogen specific nucleic acids or antigens in urine
are attractive diagnostic targets. Several prospective stud-
ies and a systematic review have concluded that a simple
immunochromatographic lateral flow test for pneumococ-
cal C polysaccharide antigens in urine has high sensitiv-
ity (close to 100%) for invasive pneumococcal infection
but lacks specificity (60-80%), particularly in children
with nasopharyngeal pneumococcal carriage.115‑117 More
recently, an immunodiagnostic assay for serotype specific
detection of polysaccharides from 13 different pneumo-
coccal serotypes (those found in PCV13) has been devel-
oped,118 and it has been shown to be sensitive and specific
(98% and 100%, respectively, when using bacteremic epi-
sodes with one of the 13 serotypes included in the test as
the reference) for pneumococcal pneumonia in adults.119
However, this test is likely to also be positive in people
with nasopharyngeal carriage of pneumococci. Urine
lipoarabinomannan testing by lateral flow assay has been
shown to have clinical utility in adults with tuberculosis
and advanced HIV infection, but it lacks both sensitivity
and specificity in children with tuberculosis.120
Host biomarkers for distinguishing between bacterial
and viral infection
In the absence of tests that can identify the specific cause
of pneumonia, a test that could discriminate between
children with bacterial pneumonia, who require antibi-
otics, and those with viral pneumonia, would be a major
advance. Host biomarkers have shown some promise in
this regard; however, their evaluation is complex given
the lack of an accurate reference standard comparator
test.
The most commonly used biomarkers, procalcitonin
(PCT) and C reactive protein (CRP) seem to have subop-
timal sensitivity and specificity for identifying children
with bacterial pneumonia, with no satisfactory cut-off
point on receiver operating characteristic curve analy-
sis.121‑123 The reported performance characteristics of
procalcitonin versus CRP vary, with no clear evidence
that either is superior.121 124
BTS guidelines recommend against the use of acute
phase reactants for distinguishing between bacterial and
viral pneumonia,28 whereas IDSA guidelines recommend
that they are not used as the only distinguishing determi-
nant.30 However, two European RCTs showed a reduction
in antibiotic use in children with lower respiratory tract
infection randomized to a procalcitonin guided algorithm
For personal use only 9 of 13
versus standard of care. One study that randomized 319
pediatric inpatients showed a reduction in the prescrip-
tion of antibiotics (85.8% v 100%; P<0.05) in the proc-
alcitonin group compared with the control group.125 The
other study, which randomized 337 children attending
an emergency department, failed to show differences
in prescribing rates but showed that the mean duration
of antibiotic exposure was reduced in the procalcitonin
group (−1.8 days, 1 to −0.5).126 A recent Vietnamese RCT
compared POC testing for CRP with routine care in of
2037 patients (including 1028 children) with non-severe
acute respiratory tract infection. It found a reduction in
immediate antibiotic use in children (and adults) who
received CRP testing (odds ratio 0.49, 40 to 0.61) with
no increase in adverse events.127
Semi-quantitative POC testing for CRP or procalcitonin
is feasible and available but requires an instrument to
interpret results and, in the case of procalcitonin, remains
relatively costly (even though it may be cost effective
in critically ill adult patients). 128 The safety of such
approaches needs to be established in low and middle
income countries with higher rates of complicated and
severe pneumonia, its cost effectiveness assessed, and
appropriate procalcitonin cut-off values for pediatric
pneumonia identified.
White blood cell indicators are less reliable than pro-
calcitonin or CRP for identifying children with bacterial
pneumonia.122‑129 Several other biomarkers, including
the combination of haptoglobin, tumor necrosis factor
(TNF) receptor 2, or interleukin 10, and tissue inhibitor
of metalloproteinases 1,130 have shown promise for the
classification of children with bacterial pneumonia but
require further evaluation.
Emerging diagnostics
Current research on the respiratory microbiota in health
and during infection is likely to refine our understanding
of how ecological changes in this niche may predispose
to or predict pneumonia. Tests that can identify such
changes may allow us to identify children at risk of pneu-
monia and help discriminate between pneumonia caused
by different classes of pathogens.
Work is needed to clarify the role of infection with mul-
tiple pathogens in the pathogenesis of pneumonia, to
inform the interpretation of multiplex diagnostic assays.
However, reliable evaluation of the accuracy of diagnos-
tics relies on the availability of accurate reference stand-
ard tests for the cause of pneumonia. In the absence of
such reference standards, the development of consensus
guidelines for the interpretation of microbiological test-
ing would be useful, both to guide clinical decision mak-
ing and for studies of the causes of pneumonia.
An increasing area of interest is the use of blood
specimens to identify a host transcriptional signature
associated with specific pathogens. A recent analysis
of transcriptional data from multiple cohorts identified
a transcriptional signature that distinguished influenza
virus infection from bacterial and other viral infections.131
Similarly, a whole blood transcriptional profile that
distinguishes RSV infection from other viral infections
and predicts the severity of disease has been described.132
 STAT E O F T H E A RT R E V I E W
QUESTIONS FOR FUTURE RESEARCH
• What place does chest ultrasound have in the screening
and diagnosis of childhood pneumonia?
• What ultrasound findings are most accurate for the
diagnosis of pneumonia?
• Is ultrasound useful for informing antibiotic treatment for
pneumonia or monitoring treatment response?
• What is the role of magnetic resonance imaging (MRI) for
the diagnosis of pneumonia?
• Can MRI accurately distinguish between lymphadenopathy
caused by tuberculosis and that caused by bacterial or viral
lower respiratory tract infection?
• What is the optimal sampling strategy for the detection of
pathogens in childhood pneumonia?
• What biomarker or biomarker signature accurately
distinguishes bacterial or mixed viral-bacterial pneumonia
from viral pneumonia?
• What is the impact of rapid point-of-care biomarker testing
on antimicrobial prescription rates and clinical outcome
in children with severe pneumonia and children with
pneumonia in lower and middle income countries?
• What role does infection with multiple pathogens play in
the development and severity of pneumonia?
• What is the impact of rapid multiplex testing for respiratory
pathogens on patient and health system relevant
outcomes?
A two transcript signature has recently been identified
which holds promise for distinguishing between febrile
children with bacterial infection and those with viral
infection.133 Although proof of principle has therefore
been established for transcriptional profiles, there are
considerable challenges in translating these findings
to the diagnosis of the cause of pneumonia. Signatures
require validation in different geographic settings with
different co-prevalent illnesses and human populations,
and the considerable technical obstacle of gene expres-
sion analysis on multiple markers in an inexpensive and
portable format must be overcome.
Conclusion
Greater use of POC ultrasound in primary care settings
may offer useful radiological imaging for pneumonia,
particularly when combined with tele-radiology. Fur-
ther study of rapid sequence chest MRI, especially for
the detection of complications, is warranted. Pneumo-
nia occurs because of dysbiosis in the normal microbial
ecology of the respiratory tract in a susceptible child.
Improvements in specimen collection and microbiologi-
cal testing have enabled the detection of many potential
organisms from respiratory specimens, but the under-
standing of how these interact in the pathogenesis of
pneumonia is limited. Many new microbiological tests
have high sensitivity for detecting potential pathogens
but are limited in their ability to attribute causation, par-
ticularly when testing upper respiratory tract specimens.
Targeted testing approaches for specific pathogens that
are strongly associated with pneumonia may offer a more
useful strategy than highly multiplexed testing, particu-
larly in specific patient groups. A rapid, affordable, and
reliable test to distinguish bacterial pathogens in pneu-
monia is urgently needed.
For personal use only 10 of 13
Contributors: All three authors helped in the conception, design, drafting,
final approval, and accountability of this article’s accuracy and integrity. HJZ
serves as the overall guarantor.
Competing interests: All authors have read and understood BMJ policy on
declaration of interests and declare the following interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: No patients were involved in the creation of this
article.
1 Campbell H, Nair H. Child pneumonia at a time of epidemiological
transition. Lancet Glob Health 2015;3:e65-6. doi:10.1016/S2214-
109X(14)70308-0.
2  Global Burden of Disease Pediatrics Collaboration. Global and national
burden of diseases and injuries among children and adolescents between
1990 and 2013: findings from the Global Burden of Disease 2013 Study.
JAMA Pediatr 2016;170:267-87. doi:10.1001/jamapediatrics.2015.4276.
3 Liu L, Oza S, Hogan D, et al. Global, regional, and national causes of child
mortality in 2000-13, with projections to inform post-2015 priorities: an
updated systematic analysis. Lancet 2015;385:430-40. doi:10.1016/
S0140-6736(14)61698-6.
4 Martinez FD. Early-Life Origins of Chronic Obstructive Pulmonary Disease. N
Engl J Med 2016;375:871-8. doi:10.1056/NEJMra1603287.
5 Gray D, Willemse L, Visagie A, et al. Determinants of early-life lung function in
African infants. Thorax 2016;doi:10.1136/thoraxjnl-2015-207401.
6 Svanes C, Sunyer J, Plana E, et al. Early life origins of chronic obstructive
pulmonary disease. Thorax 2010;65:14-20. doi:10.1136/
thx.2008.112136.
7 Chan JY, Stern DA, Guerra S, et al. Pneumonia in childhood and impaired
lung function in adults: a longitudinal study. Pediatrics 2015;135:607-16.
doi:10.1542/peds.2014-3060.
8 Dickson RP, Erb-Downward JR, Huffnagle GB. Towards an ecology of the
lung: new conceptual models of pulmonary microbiology and pneumonia
pathogenesis. Lancet Respir Med 2014;2:238-46. doi:10.1016/S2213-
2600(14)70028-1.
9 Biesbroek G, Tsivtsivadze E, Sanders EA, et al. Early respiratory microbiota
composition determines bacterial succession patterns and respiratory
health in children. Am J Respir Crit Care Med 2014;190:1283-92.
doi:10.1164/rccm.201407-1240OC.
10 Teo SM, Mok D, Pham K, et al. The infant nasopharyngeal microbiome
impacts severity of lower respiratory infection and risk of asthma
development. Cell Host Microbe 2015;17:704-15. doi:10.1016/j.
chom.2015.03.008.
11 Zar HJ, Barnett W, Stadler A, et al. Aetiology of childhood pneumonia in a
well vaccinated South African birth cohort: a nested case-control study of
the Drakenstein Child Health Study. Lancet Respir Med 2016;4:463-72.
doi:10.1016/S2213-2600(16)00096-5.
12 Honkinen M, Lahti E, Osterback R, et al. Viruses and bacteria in sputum
samples of children with community-acquired pneumonia. Clin Microbiol
Infect 2012;18:300-7. doi:10.1111/j.1469-0691.2011.03603.x.
13 Rudan I, O’Brien KL, Nair H, et al. Epidemiology and etiology of childhood
pneumonia in 2010: estimates of incidence, severe morbidity, mortality,
underlying risk factors and causative pathogens for 192 countries. J Glob
Health 2013;3:010401. doi:10.7189/jogh.03.010401.
14 Simonsen L, Taylor RJ, Schuck-Paim C, et al. Effect of 13-valent
pneumococcal conjugate vaccine on admissions to hospital 2 years after
its introduction in the USA: a time series analysis. Lancet Respir Med
2014;2:387-94. doi:10.1016/S2213-2600(14)70032-3.
15 Moore MR, Link-Gelles R, Schaffner W, et al. Effect of use of 13-valent
pneumococcal conjugate vaccine in children on invasive pneumococcal
disease in children and adults in the USA: analysis of multisite, population-
based surveillance. Lancet Infect Dis 2015;15:301-9. doi:10.1016/S1473-
3099(14)71081-3.
16 Waight PA, Andrews NJ, Ladhani NJ, et al. Effect of the 13-valent
pneumococcal conjugate vaccine on invasive pneumococcal disease
in England and Wales 4 years after its introduction: an observational
cohort study. Lancet Infect Dis 2015;15:629. doi:10.1016/S1473-
3099(15)70044-7.
17 Angoulvant F, Levy C, Grimprel E, et al. Early impact of 13-valent
pneumococcal conjugate vaccine on community-acquired pneumonia in
children. Clin Infect Dis 2014;58:918-24. doi:10.1093/cid/ciu006.
18 Greenberg D, Givon-Lavi N, Ben-Shimol S, et al. Impact of PCV7/PCV13
introduction on community-acquired alveolar pneumonia in children <5
years. Vaccine 2015;33:4623-9. doi:10.1016/j.vaccine.2015.06.062.
19 le Roux DM, Myer L, Nicol MP, et al. Incidence and severity of childhood
pneumonia in the first year of life in a South African birth cohort: the
Drakenstein Child Health Study. Lancet Glob Health 2015;3:e95-103.
doi:10.1016/S2214-109X(14)70360-2.
20 Theodoratou E, McAllister DA, Reed C, et al. Global, regional, and national
estimates of pneumonia burden in HIV-infected children in 2010: a
meta-analysis and modelling study. Lancet Infect Dis 2014;14:1250-8.
doi:10.1016/S1473-3099(14)70990-9.
21 Evans C, Jones CE, Prendergast AJ. HIV-exposed, uninfected infants: new
global challenges in the era of paediatric HIV elimination. Lancet Infect Dis
2016;16:e92-107. doi:10.1016/S1473-3099(16)00055-4.
22 Jackson S, Mathews KH, Pulanic D, et al. Risk factors for severe acute lower
respiratory infections in children: a systematic review and meta-analysis.
Croat Med J 2013;54:110-21doi:10.3325/cmj.2013.54.110.
 STAT E O F T H E A RT R E V I E W
23 Elemraid MA, Muller M, Spencer DA, et al. Accuracy of the interpretation
of chest radiographs for the diagnosis of paediatric pneumonia. PLoS
One 2014;9:e106051. doi:10.1371/journal.pone.0106051.
24 Urbankowska E, Krenke K, Drobczynski L, et al. Lung ultrasound in
the diagnosis and monitoring of community acquired pneumonia
in children. Respir Med 2015;109:1207-12. doi:10.1016/j.
rmed.2015.06.011.
25 Toma P, Owens CM. Chest ultrasound in children: critical appraisal.
Pediatr Radiol 2013;43:1427-34, quiz 25-6. doi:10.1007/s00247-
013-2756-4.
26 Nascimento-Carvalho CM, Araujo-Neto CA, Ruuskanen O. Association
between bacterial infection and radiologically confirmed pneumonia
among children. Pediatr Infect Dis J 2015;34:490-3. doi:10.1097/
INF.0000000000000622.
27 Swingler GH, Hussey GD, Zwarenstein M. Randomised controlled
trial of clinical outcome after chest radiograph in ambulatory acute
lower-respiratory infection in children. Lancet 1998;351:404-8.
doi:10.1016/S0140-6736(97)07013-X.
28 Harris M, Clark J, Coote N, et al. British Thoracic Society guidelines
for the management of community acquired pneumonia in children:
update 2011. Thorax 2011;66(suppl 2):ii1-23. doi:10.1136/
thoraxjnl-2011-200598.
29  National Institute for Health and Care Excellence. Fever in under 5s:
assessment and initial management. (Clinical guideline 160.)2013;
https://www.nice.org.uk/guidance/cg160.
30 Bradley JS, Byington CL, Shah SS, et al. The management of community-
acquired pneumonia in infants and children older than 3 months of
age: clinical practice guidelines by the Pediatric Infectious Diseases
Society and the Infectious Diseases Society of America. Clin Infect Dis
2011;53:e25-76. doi:10.1093/cid/cir531.
31 Zar HJ, Jeena P, Argent A, et alDiagnosis and management of community-
acquired pneumonia in childhood—South African Thoracic Society
Guidelines. S Afr Med J 2005;95(12 Pt 2):977-81.
32 Enarson P, Enarson D, Gie R. Management of the child with cough or
difficulty breathing: a guide for low income countries.International
Union Against Tuberculosis and Lung Disease, 2005.
33 Kelly MS, Crotty EJ, Rattan MS, et al. Chest radiographic findings and
outcomes of pneumonia among children in Botswana. Pediatr Infect Dis
J 2016;35:257-62. doi:10.1097/INF.0000000000000990.
34 Simbalista R, Andrade DC, Borges IC, et al. Differences upon admission
and in hospital course of children hospitalized with community-
acquired pneumonia with or without radiologically-confirmed
pneumonia: a retrospective cohort study. BMC Pediatr 2015;15:166.
doi:10.1186/s12887-015-0485-6.
35 Iuri D, De Candia A, Bazzocchi M. Evaluation of the lung in children with
suspected pneumonia: usefulness of ultrasonography. Radiol Med
(Torino) 2009;114:321-30. doi:10.1007/s11547-008-0336-8.
36 Peltola V, Ruuskanen O, Svedstrom E. Magnetic resonance imaging
of lung infections in children. Pediatr Radiol 2008;38:1225-31.
doi:10.1007/s00247-008-0987-6.
37 Puderbach M, Kauczor HU. Can lung MR replace lung CT?Pediatr Radiol
2008;38(suppl 3):S439-51. doi:10.1007/s00247-008-0844-7.
38 Johnson J, Kline JA. Intraobserver and interobserver agreement of
the interpretation of pediatric chest radiographs. Emerg Radiol
2010;17:285-90. doi:10.1007/s10140-009-0854-2.
39 Neuman MI, Lee EY, Bixby S, et al. Variability in the interpretation of
chest radiographs for the diagnosis of pneumonia in children. J Hosp
Med 2012;7:294-8. doi:10.1002/jhm.955.
40 Hendaus MA, Jomha FA, Alhammadi AH. Lung ultrasound for the
diagnosis of childhood pneumonia: a safe and accurate imaging mode.
Ther Clin Risk Manag 2015;11:1817-8. doi:10.2147/TCRM.S96222.
41 Roic G. Lung ultrasound in the diagnosis of pediatric pneumonia: are
we ready for routine use?Acta Med Acad 2016;45:82-3. doi:10.5644/
ama2006-124.163.
42 Andronikou S. Letting go of what we believe about radiation and the
risk of cancer in children. Pediatr Radiol 2017;47:113-5. doi:10.1007/
s00247-016-3697-5.
43 Gorycki T, Lasek I, Kaminski K, et al. Evaluation of radiation doses
delivered in different chest CT protocols. Pol J Radiol 2014;79:1-5.
doi:10.12659/PJR.889952.
44 Chang SD, Munk PL. The changing landscape of radiology: ultrasound
training for nonradiologists. Can Assoc Radiol J 2014;65:1.
doi:10.1016/j.carj.2013.12.001.
45 Copetti R, Cattarossi L. Ultrasound diagnosis of pneumonia in children.
Radiol Med (Torino) 2008;113:190-8. doi:10.1007/s11547-008-
0247-8.
46 Lichtenstein DA, Lascols N, Meziere G, et al. Ultrasound diagnosis
of alveolar consolidation in the critically ill. Intensive Care Med
2004;30:276-81. doi:10.1007/s00134-003-2075-6.
47 Cattarossi L. Lung ultrasound: its role in neonatology and pediatrics.
Early Hum Dev 2013;89(suppl 1):S17-9. doi:10.1016/S0378-
3782(13)70006-9.
48 Guerra M, Crichiutti G, Pecile P, et al. Ultrasound detection of pneumonia
in febrile children with respiratory distress: a prospective study. Eur J
Pediatr 2016;175:163-70. doi:10.1007/s00431-015-2611-8.
49 Iorio G, Capasso M, De Luca G, et al. Lung ultrasound in the diagnosis of
pneumonia in children: proposal for a new diagnostic algorithm. PeerJ
2015;3:e1374. doi:10.7717/peerj.1374.
For personal use only 11 of 13
50 Varshney T, Mok E, Shapiro AJ, et al. Point-of-care lung ultrasound in
young children with respiratory tract infections and wheeze. Emerg Med J
2016;33:603-10. doi:10.1136/emermed-2015-205302.
51 Kurian J, Levin TL, Han BK, et al. Comparison of ultrasound and CT in
the evaluation of pneumonia complicated by parapneumonic effusion
in children. AJR Am J Roentgenol 2009;193:1648-54. doi:10.2214/
AJR.09.2791.
52 Tsung JW, Kessler DO, Shah VP. Prospective application of clinician-
performed lung ultrasonography during the 2009 H1N1 influenza A
pandemic: distinguishing viral from bacterial pneumonia. Crit Ultrasound
J 2012;4:16. doi:10.1186/2036-7902-4-16.
53 Caiulo VA, Gargani L, Caiulo S, et al. Lung ultrasound characteristics
of community-acquired pneumonia in hospitalized children. Pediatr
Pulmonol 2013;48:280-7. doi:10.1002/ppul.22585.
54 Shah VP, Tunik MG, Tsung JW. Prospective evaluation of point-of-care
ultrasonography for the diagnosis of pneumonia in children and
young adults. JAMA Pediatr 2013;167:119-25. doi:10.1001/2013.
jamapediatrics.107.
55 Esposito S, Papa SS, Borzani I, et al. Performance of lung ultrasonography
in children with community-acquired pneumonia. Ital J Pediatr
2014;40:37. doi:10.1186/1824-7288-40-37.
56 Chavez MA, Naithani N, Gilman RH, et al. Agreement between the World
Health Organization algorithm and lung consolidation identified using
point-of-care ultrasound for the diagnosis of childhood pneumonia by
general practitioners. Lung 2015;193:531-8. doi:10.1007/s00408-
015-9730-x.
57 Ho MC, Ker CR, Hsu JH, et al. Usefulness of lung ultrasound in the
diagnosis of community-acquired pneumonia in children. Pediatr
Neonatol 2015;56:40-5. doi:10.1016/j.pedneo.2014.03.007.
58 Ambroggio L, Sucharew H, Rattan MS, et alLung ultrasonography: a viable
alternative to chest radiography in children with suspected pneumonia?J
Pediatr 2016;176:93-98.e7. doi:10.1016/j.jpeds.2016.05.033
59 Jones BP, Tay ET, Elikashvili I, et al. Feasibility and safety of substituting
lung ultrasonography for chest radiography when diagnosing pneumonia
in children: a randomized controlled trial. Chest 2016;150:131-8.
doi:10.1016/j.chest.2016.02.643.
60 Lovrenski J, Petrovic S, Balj-Barbir S, et al. Stethoscope vs ultrasound
probe—which is more reliable in children with suspected
pneumonia?Acta Med Acad 2016;45:39-50. doi:10.5644/ama2006-
124.155.
61 Samson F, Gorostiza I, Gonzalez A, et al. Prospective evaluation of
clinical lung ultrasonography in the diagnosis of community-acquired
pneumonia in a pediatric emergency department. Eur J Emerg Med 2016.
doi:10.1097/MEJ.0000000000000418.
62 Audette LD, Parent MC. BET 3: bedside lung ultrasound for the diagnosis
of pneumonia in children. Emerg Med J 2016;33:589-92. doi:10.1136/
emermed-2016-206047.3.
63 Biederer J, Mirsadraee S, Beer M, et al. MRI of the lung (3/3)-current
applications and future perspectives. Insights Imaging 2012;3:373-86.
doi:10.1007/s13244-011-0142-z.
64 Sodhi KS, Khandelwal N, Saxena AK, et al. Rapid lung MRI in children with
pulmonary infections: time to change our diagnostic algorithms. J Magn
Reson Imaging 2016;43:1196-206. doi:10.1002/jmri.25082.
65 Hirsch W, Sorge I, Krohmer S, et al. MRI of the lungs in children. Eur J Radiol
2008;68:278-88. doi:10.1016/j.ejrad.2008.05.017.
66 Volker M, Ehses P, Weick S, et al. Free breathing 1H MRI of the human
lung with an improved radial turbo spin-echo. MAGMA 2015;28:227-38.
doi:10.1007/s10334-014-0468-x.
67 Boiselle PM, Biederer J, Gefter WB, et al. Expert opinion: why is MRI still
an under-utilized modality for evaluating thoracic disorders?J Thorac
Imaging 2013;28:137. doi:10.1097/RTI.0b013e31828cafe7.
68 Yikilmaz A, Koc A, Coskun A, et al. Evaluation of pneumonia in
children: comparison of MRI with fast imaging sequences at 1.5T
with chest radiographs. Acta Radiol 2011;52:914-9. doi:10.1258/
ar.2011.100429.
69 Peprah KO, Andronikou S, Goussard P. Characteristic magnetic resonance
imaging low T2 signal intensity of necrotic lung parenchyma in children
with pulmonary tuberculosis. J Thorac Imaging 2012;27:171-4.
doi:10.1097/RTI.0b013e318211abfb.
70 Gorkem SB, Coskun A, Yikilmaz A, et al. Evaluation of pediatric thoracic
disorders: comparison of unenhanced fast-imaging-sequence 1.5-T MRI
and contrast-enhanced MDCT. AJR Am J Roentgenol 2013;200:1352-7.
doi:10.2214/AJR.12.9502.
71 Ozcan HN, Gormez A, Ozsurekci Y, et al. Magnetic resonance imaging of
pulmonary infection in immunocompromised children: comparison with
multidetector computed tomography. Pediatr Radiol 2016. doi:10.1007/
s00247-016-3729-1.
72 Griggs R, Andronikou S, Nell R, et al. World Federation of Pediatric Imaging
(WFPI) volunteer outreach through tele-reading: the pilot project in South
Africa. Pediatr Radiol 2014;44:648-54. doi:10.1007/s00247-014-
2948-6.
73 Andronikou S. Pediatric teleradiology in low-income settings and
the areas for future research in teleradiology. Front Public Health
2014;2:125. doi:10.3389/fpubh.2014.00125.
74 Oliwa JN, Karumbi JM, Marais BJ, Madhi SA, Graham SM. Tuberculosis
as a cause or comorbidity of childhood pneumonia in tuberculosis-
endemic areas: a systematic review. Lancet Respir Med 2015;3:235-43.
doi:10.1016/S2213-2600(15)00028-4.
 STAT E O F T H E A RT R E V I E W
75 Hammitt LL, Kazungu S, Morpeth SC, et al. A preliminary study of
pneumonia etiology among hospitalized children in Kenya. Clin Infect Dis
2012;54(suppl 2):S190-9. doi:10.1093/cid/cir1071.
76 Hammitt LL, Murdoch DR, Scott JA, et al. Specimen collection for the
diagnosis of pediatric pneumonia. Clin Infect Dis 2012;54(suppl 2):S132-
9. doi:10.1093/cid/cir1068.
77 Tunsjo HS, Berg AS, Inchley CS, et al. Comparison of nasopharyngeal
aspirate with flocked swab for PCR-detection of respiratory viruses in
children. APMIS 2015;123:473-7. doi:10.1111/apm.12375.
78 Hansen KB, Westin J, Andersson LM, et al. Flocked nasal swab versus
nasopharyngeal aspirate in adult emergency room patients: similar
multiplex PCR respiratory pathogen results and patient discomfort. Infect
Dis 2016;48:246-50. doi:10.3109/23744235.2015.1096956.
79 Waris M, Osterback R, Lahti E, et al. Comparison of sampling methods
for the detection of human rhinovirus RNA. J Clin Virol 2013;58:200-4.
doi:10.1016/j.jcv.2013.06.002.
80 Esposito S, Molteni CG, Daleno C, et al. Comparison of nasopharyngeal
nylon flocked swabs with universal transport medium and rayon-bud
swabs with a sponge reservoir of viral transport medium in the diagnosis
of paediatric influenza. J Med Microbiol 2010;59:96-9. doi:10.1099/
jmm.0.015305-0.
81 Dube FS, Kaba M, Whittaker E, et al. Detection of Streptococcus
pneumoniae from different types of nasopharyngeal swabs in children.
PLoS One 2013;8:e68097. doi:10.1371/journal.pone.0068097.
82 Hernes SS, Quarsten H, Hamre R, et al. A comparison of nasopharyngeal
and oropharyngeal swabbing for the detection of influenza virus by real-
time PCR. Eur J Clin Microbiol Infect Dis 2013;32:381-5. doi:10.1007/
s10096-012-1753-0.
83 Spencer S, Gaglani M, Naleway A, et al. Consistency of influenza A virus
detection test results across respiratory specimen collection methods using
real-time reverse transcription-PCR. J Clin Microbiol 2013;51:3880-2.
doi:10.1128/JCM.01873-13.
84 Kim C, Ahmed JA, Eidex RB, et al. Comparison of nasopharyngeal and
oropharyngeal swabs for the diagnosis of eight respiratory viruses by
real-time reverse transcription-PCR assays. PLoS One 2011;6:e21610.
doi:10.1371/journal.pone.0021610.
85 Hammitt LL, Kazungu S, Welch S, et al. Added value of an oropharyngeal
swab in detection of viruses in children hospitalized with lower respiratory
tract infection. J Clin Microbiol 2011;49:2318-20. doi:10.1128/
JCM.02605-10.
86 Zar HJ, Workman L, Isaacs W, et al. Rapid molecular diagnosis of pulmonary
tuberculosis in children using nasopharyngeal specimens. Clin Infect Dis
2012;55:1088-95. doi:10.1093/cid/cis598.
87 Barger-Kamate B, Deloria Knoll M, Kagucia EW, et al. Pertussis-associated
pneumonia in infants and children from low- and middle-income countries
participating in the PERCH study. Clin Infect Dis 2016;63(suppl 4):S187-
96. doi:10.1093/cid/ciw546.
88 Muloiwa R, Dube FS, Nicol MP, et al. Incidence and diagnosis of
pertussis in South African children hospitalized with lower respiratory
tract infection. Pediatr Infect Dis J 2016;35:611-6. doi:10.1097/
INF.0000000000001132.
89 Nunes MC, Soofie N, Downs S, et al. Comparing the yield of nasopharyngeal
swabs, nasal aspirates, and induced sputum for detection of Bordetella
pertussis in hospitalized infants. Clin Infect Dis 2016;63(suppl 4):S181-6.
doi:10.1093/cid/ciw521.
90 Mermond S, Zurawski V, D’Ortenzio E, et al. Lower respiratory infections
among hospitalized children in New Caledonia: a pilot study for the
Pneumonia Etiology Research for Child Health project. Clin Infect Dis
2012;54(suppl 2):S180-9. doi:10.1093/cid/cir1070.
91 Morrow BM, Samuel CM, Zampoli M, et al. Pneumocystis pneumonia in
South African children diagnosed by molecular methods. BMC Res Notes
2014;7:26. doi:10.1186/1756-0500-7-26.
92 Shi T, McLean K, Campbell H, et al. Aetiological role of common respiratory
viruses in acute lower respiratory infections in children under five years:
a systematic review and meta-analysis. J Glob Health 2015;5:010408.
doi:10.7189/jogh.05.010408.
93 Spuesens EB, Fraaij PL, Visser EG, et al. Carriage of Mycoplasma
pneumoniae in the upper respiratory tract of symptomatic and
asymptomatic children: an observational study. PLoS Med
2013;10:e1001444. doi:10.1371/journal.pmed.1001444.
94 Self WH, Williams DJ, Zhu Y, et al. Respiratory viral detection in children and
adults: comparing asymptomatic controls and patients with community-
acquired pneumonia. J Infect Dis 2016;213:584-91. doi:10.1093/infdis/
jiv323.
95 Bonner AB, Monroe KW, Talley LI, et al. Impact of the rapid diagnosis of
influenza on physician decision-making and patient management in the
pediatric emergency department: results of a randomized, prospective,
controlled trial. Pediatrics 2003;112:363-7doi:10.1542/peds.112.2.363.
96 Doan QH, Kissoon N, Dobson S, et al. A randomized, controlled trial of the
impact of early and rapid diagnosis of viral infections in children brought to
an emergency department with febrile respiratory tract illnesses. J Pediatr
2009;154:91-5. doi:10.1016/j.jpeds.2008.07.043.
97 Byington CL, Castillo H, Gerber K, et al. The effect of rapid respiratory viral
diagnostic testing on antibiotic use in a children’s hospital. Arch Pediatr
Adolesc Med 2002;156:1230-4doi:10.1001/archpedi.156.12.1230.
98 Blaschke AJ, Shapiro DJ, Pavia AT, et al. A national study of the impact of
rapid influenza testing on clinical care in the emergency department. J
Pediatric Infect Dis Soc 2014;3:112-8. doi:10.1093/jpids/pit071.
For personal use only 12 of 13
99 Levin D, Tribuzio M, Green-Wrzesinki T, et al. Empiric antibiotics are
justified for infants with respiratory syncytial virus lower respiratory tract
infection presenting with respiratory failure: a prospective study and
evidence review. Pediatr Crit Care Med 2010;11:390-5. doi:10.1097/
PCC.0b013e3181b809c5.
100 Wolter N, Tempia S, Cohen C, et al. High nasopharyngeal pneumococcal
density, increased by viral coinfection, is associated with invasive
pneumococcal pneumonia. J Infect Dis 2014;210:1649-57.
doi:10.1093/infdis/jiu326.
101 Li L, Zhu T, Chen ZR, et al. Detection of human bocavirus in
nasopharyngeal aspirates versus in broncho-alveolar lavage fluids in
children with lower respiratory tract infections. J Med Virol 2016;88:211-
5. doi:10.1002/jmv.24338.
102 Howie SR, Morris GA, Tokarz R, et al. Etiology of severe childhood
pneumonia in the Gambia, West Africa, determined by conventional and
molecular microbiological analyses of lung and pleural aspirate samples.
Clin Infect Dis 2014;59:682-5. doi:10.1093/cid/ciu384.
103 McCulloh RJ, Koster MP, Yin DE, et al. Evaluating the use of blood cultures
in the management of children hospitalized for community-acquired
pneumonia. PLoS One 2015;10:e0117462. doi:10.1371/journal.
pone.0117462.
104 Myers AL, Hall M, Williams DJ, et al. Prevalence of bacteremia
in hospitalized pediatric patients with community-acquired
pneumonia. Pediatr Infect Dis J 2013;32:736-40. doi:10.1097/
INF.0b013e318290bf63.
105 Leyenaar JK, Lagu T, Shieh MS, et al. Variation in resource utilization for
the management of uncomplicated community-acquired pneumonia
across community and children’s hospitals. J Pediatr 2014;165:585-91.
doi:10.1016/j.jpeds.2014.04.062.
106 Andrews AL, Simpson AN, Heine D, et al. A cost-effectiveness analysis
of obtaining blood cultures in children hospitalized for community-
acquired pneumonia. J Pediatr 2015;167:1280-6. doi:10.1016/j.
jpeds.2015.09.025.
107 De Schutter I, Vergison A, Tuerlinckx D, et al. Pneumococcal aetiology and
serotype distribution in paediatric community-acquired pneumonia. PLoS
One 2014;9:e89013. doi:10.1371/journal.pone.0089013.
108 Elemraid MA, Sails AD, Eltringham GJ, et al. Aetiology of paediatric
pneumonia after the introduction of pneumococcal conjugate vaccine.
Eur Respir J 2013;42:1595-603. doi:10.1183/09031936.00199112.
109 Cvitkovic Spik V, Beovic B, Pokorn M, et al. Improvement of pneumococcal
pneumonia diagnostics by the use of rt-PCR on plasma and respiratory
samples. Scand J Infect Dis 2013;45:731-7. doi:10.3109/00365548.2
013.804631.
110 Morpeth SC, Deloria Knoll M, Scott JAG, et al. Detection of pneumococcal
DNA in blood by polymerase chain reaction for diagnosing pneumococcal
pneumonia in young children from low- and middle-income countries.
Clin Infect Dis 2017;64(suppl 3):S347-56. doi:10.1093/cid/cix145.
111 Tuerlinckx D, Smet J, De Schutter I, et al. Evaluation of a WHO-validated
serotype-specific serological assay for the diagnosis of pneumococcal
etiology in children with community-acquired pneumonia. Pediatr Infect
Dis J 2013;32:e277-84. doi:10.1097/INF.0b013e31828c363f.
112 Chang HY, Chang LY, Shao PL, et al. Comparison of real-time polymerase
chain reaction and serological tests for the confirmation of Mycoplasma
pneumoniae infection in children with clinical diagnosis of atypical
pneumonia. J Microbiol Immunol Infect 2014;47:137-44. doi:10.1016/j.
jmii.2013.03.015.
113 Vaz-de-Lima LR, Martin MD, Pawloski LC, et al. Serodiagnosis as adjunct
assay for pertussis infection in Sao Paulo, Brazil. Clin Vaccine Immunol
2014;21:636-40. doi:10.1128/CVI.00760-13.
114 May ML, Doi SA, King D, et al. Prospective evaluation of an Australian
pertussis toxin IgG and IgA enzyme immunoassay. Clin Vaccine Immunol
2012;19:190-7. doi:10.1128/CVI.05430-11.
115 Anjay MA, Anoop P. Diagnostic utility of rapid immunochromatographic
urine antigen testing in suspected pneumococcal infections. Arch Dis
Child 2008;93:628-31. doi:10.1136/adc.2008.138958.
116 Charkaluk ML, Kalach N, Mvogo H, et al. Assessment of a rapid urinary
antigen detection by an immunochromatographic test for diagnosis
of pneumococcal infection in children. Diagn Microbiol Infect Dis
2006;55:89-94. doi:10.1016/j.diagmicrobio.2005.10.013.
117 Esposito S, Bosis S, Colombo R, et al. Evaluation of rapid assay for
detection of Streptococcus pneumoniae urinary antigen among infants
and young children with possible invasive pneumococcal disease. Pediatr
Infect Dis J 2004;23:365-7doi:10.1097/00006454-200404000-
00021.
118 Pride MW, Huijts SM, Wu K, et al. Validation of an immunodiagnostic
assay for detection of 13 Streptococcus pneumoniae serotype-specific
polysaccharides in human urine. Clin Vaccine Immunol 2012;19:1131-
41. doi:10.1128/CVI.00064-12.
119 Huijts SM, Pride MW, Vos JM, et al. Diagnostic accuracy of a serotype-
specific antigen test in community-acquired pneumonia. Eur Respir J
2013;42:1283-90. doi:10.1183/09031936.00137412.
120 Nicol MP, Allen V, Workman L, et al. Urine lipoarabinomannan testing
for diagnosis of pulmonary tuberculosis in children: a prospective
study. Lancet Glob Health 2014;2:e278-84. doi:10.1016/S2214-
109X(14)70195-0.
121 Giulia B, Luisa A, Concetta S, et alProcalcitonin and community-acquired
pneumonia (CAP) in children. Clin Chim Acta 2015;451(Pt B):215-8.
doi:10.1016/j.cca.2015.09.031
 STAT E O F T H E A RT R E V I E W
122 Elemraid MA, Rushton SP, Thomas MF, et al. Utility of inflammatory
markers in predicting the aetiology of pneumonia in children.
Diagn Microbiol Infect Dis 2014;79:458-62. doi:10.1016/j.
diagmicrobio.2014.04.006.
123 Page AL, de Rekeneire N, Sayadi S, et al. Diagnostic and prognostic
value of procalcitonin and C-reactive protein in malnourished children.
Pediatrics 2014;133:e363-70. doi:10.1542/peds.2013-2112.
124 Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value
of laboratory tests in identifying serious infections in febrile children:
systematic review. BMJ 2011;342:d3082. doi:10.1136/bmj.d3082.
125 Esposito S, Tagliabue C, Picciolli I, et al. Procalcitonin measurements
for guiding antibiotic treatment in pediatric pneumonia. Respir Med
2011;105:1939-45. doi:10.1016/j.rmed.2011.09.003.
126 Baer G, Baumann P, Buettcher M, et al. Procalcitonin guidance to reduce
antibiotic treatment of lower respiratory tract infection in children
and adolescents (ProPAED): a randomized controlled trial. PLoS One
2013;8:e68419. doi:10.1371/journal.pone.0068419.
127 Do NT, Ta NT, Tran NT, et al. Point-of-care C-reactive protein testing to
reduce inappropriate use of antibiotics for non-severe acute respiratory
infections in Vietnamese primary health care: a randomised controlled
trial. Lancet Glob Health 2016;4:e633-41. doi:10.1016/S2214-
109X(16)30142-5.
For personal use only 13 of 13
128 Deliberato RO, Marra AR, Sanches PR, et al. Clinical and economic impact of
procalcitonin to shorten antimicrobial therapy in septic patients with proven
bacterial infection in an intensive care setting. Diagn Microbiol Infect Dis
2013;76:266-71. doi:10.1016/j.diagmicrobio.2013.03.027.
129 Hoshina T, Nanishi E, Kanno S, et al. The utility of biomarkers in differentiating
bacterial from non-bacterial lower respiratory tract infection in hospitalized
children: difference of the diagnostic performance between acute pneumonia
and bronchitis. J Infect Chemother 2014;20:616-20. doi:10.1016/j.
jiac.2014.06.003.
130 Valim C, Ahmad R, Lanaspa M, et al. Responses to bacteria, virus, and malaria
distinguish the etiology of pediatric clinical pneumonia. Am J Respir Crit Care
Med 2016;193:448-59. doi:10.1164/rccm.201506-1100OC.
131 Andres-Terre M, McGuire HM, Pouliot Y, et al. Integrated, multi-cohort analysis
identifies conserved transcriptional signatures across multiple respiratory
viruses. Immunity 2015;43:1199-211. doi:10.1016/j.immuni.2015.11.003.
132 Mejias A, Dimo B, Suarez NM, et al. Whole blood gene expression profiles to
assess pathogenesis and disease severity in infants with respiratory syncytial
virus infection. PLoS Med 2013;10:e1001549. doi:10.1371/journal.
pmed.1001549.
133 Herberg JA, Kaforou M, Wright VJ, et al. Diagnostic test accuracy of a 2-transcript
host RNA signature for discriminating bacterial vs viral infection in febrile
children. JAMA 2016;316:835-45. doi:10.1001/jama.2016.11236.