Systematic Review

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Ventilator-associated pneumonia in
neonates and children: a systematic analysis
of diagnostic methods and prevention
Elias Iosifidis1 , Georgia Pitsava‡ ,1 & Emmanuel Roilides*,1
1
Infectious Disease Unit, 3rd Department of Pediatrics, Medical Faculty, Aristotle University School of Health Sciences, Hippokration
General Hospital, Thessaloniki Greece
*Author for correspondence: Tel.: +30-2310-892444; Fax: +30-2310-992981; roilides@med.auth.gr
‡
Equally contributed

Aim: While ventilator-associated pneumonia (VAP) remains frequent in Pediatric ICU, there is no gold
standard for diagnosis. Methodology: We conducted a systematic PUBMED analysis (January 1990–January
2017) searching original, full-length studies addressing only pediatric patients; for VAP diagnosis, only
those comparing different diagnostic methods and for VAP prevention those implementing preventive
measures. Results: Among 367 articles, 17 and 16 were analyzed for diagnosis and prevention, respectively.
For diagnosis, 13 studies used CDC criteria; whereas, 14 assessed algorithms: clinical pulmonary index
score, ventilator-associated events and biomarkers. Among five randomized trials assessing preventive
strategies one found a role of probiotics. Ventilator-care bundles reduced VAP rates. Conclusion: Absence
of diagnostic gold standard impedes comparison of current approaches and preventive strategies.

First draft submitted: 8 April 2018; Accepted for publication: 25 July 2018; Published online:
26 September 2018

Keywords: critical illness • diagnosis • pediatrics • pneumonia • ventilator-associated

The prevalence of healthcare-associated infections in children remains high and the burden of these infections
is highest in pediatric and neonatal intensive care units [1–3]. Ventilator-associated pneumonia (VAP) constitutes
one of the most common healthcare-associated infections in Pediatric and Neonatal ICU and has been related
to increased morbidity, length of stay and broad-spectrum antibiotic usage [3–7]. However, incidence of VAP in
neonatal and pediatric ICUs vary significantly around the world (between 1 to 63 episodes per 1000 ventilator
days) reflecting different burden of disease but also differences in diagnostic process [3,7,8].
Most of our understanding of VAP in children has derived from data retrieved from research in adults. However,
despite some similarities, in other words, pattern of causative agents isolated (Gram-positive or Gram-negative
pathogens), there are many differences between neonates/children and adults with VAP. Especially in neonates and
infants, there are age-specific comorbidities including bronchopulmonary dysplasia, hyaline membrane disease and
necrotizing enterocolitis, which interfere with clinical and laboratory diagnostic criteria of VAP [4,5]. Furthermore, a
definitive diagnosis of VAP remains controversial even in adult patients. Until now, the Centers for Disease Control
and Prevention (CDC) criteria have been widely acceptable and used for surveillance purposes in both pediatric
and adult populations. However, there are significant difficulties when applying these criteria for VAP diagnosis
including the requirement of radiographic evidence of pneumonia for the final diagnosis as well as the reliance on
subjective clinical signs and symptoms. For this reason, a new algorithm for the diagnosis of ventilator-associated
events including ventilator-associated pneumonia has been developed but is currently used only in adult ICU in
the USA [9].
The lack of a diagnostic gold standard has a negative impact on research for the prompt management of VAP
in the direction of prevention and appropriate antibiotic use. Thus, a better approach than the existing diagnostic
criteria is needed for VAP. The purpose of this systematic analysis was to review and compare old and new diagnostic
as well as preventive modalities for VAP in critically ill children.

10.2217/fmb-2018-0108 
C 2018 Future Medicine Ltd Future Microbiol. (2018) 13(12), 1431–1446 ISSN 1746-0913 1431
Systematic Review Iosifidis, Pitsava & Roilides

Methods
We conducted a systematic review of published articles found in Pubmed. The search strategy was: (‘ventilator
associated pneumonia’ [All fields]) and (’children’ [All fields]). In this systematic review we included studies that:
were original and full articles (not abstracts in conferences), compared different VAP diagnostic approaches or in
case of prevention clear presentation of measures to reduce VAP rates and included only pediatric patients. This
search was conducted from January 1990 until January 2017.
A master excel database with all results was created. All articles found with this strategy were independently
reviewed by two reviewers (E Iosifidis and G Pitsava) and allocated as eligible for VAP diagnosis or for VAP
prevention or not. This allocation was decided based on the title and the abstract or in selected cases on the full
article. Final allocation was reviewed by a third investigator (E Roilides). Eligible articles were further assessed and
all their references were assessed for use as possible source for other eligible studies. During this assessment all review
articles as well as studies, which were conducted in adults or did not have enough data for pediatric patients, were
excluded. Especially for VAP diagnosis, studies concurrently comparing at least two different diagnostic methods
in the same pediatric population were included.
Data were independently extracted by two reviewers (E Iosifidis and G Pitsava). For VAP diagnosis the following
data were extracted: first author, year of publication, journal, number of patients included in the analysis, type
of study, comparison of different VAP approaches and main results. When available, kappa coefficient score was
retrieved or calculated directly from the data provided. For VAP prevention the following data were extracted: first
author, year of publication, country, number of patients included, diagnostic criteria for VAP, type of study and
main results (reduction or not in VAP rates). Especially for studies, which implemented a bundle of actions for
reducing VAP, the exact elements were extracted from these studies.

Results
Overall, 367 articles were found between January 1990 and January 2017. Among them, 83 articles were allocated
as relative to VAP diagnosis (31 articles) and prevention (52 articles) in critically ill pediatric patients. For VAP
diagnosis, 17 studies fulfilled the inclusion criteria, whereas 14 were excluded (seven review/non original articles,
three mixed adult and children data, two only microbiology data, one survey, one without comparing different
approaches). For VAP prevention 16 were further assessed (14 retrieved from Pubmed search and two from
references) as eligible and 36 were excluded (most of them were reviews and some of them guidelines/methodology
or methodology articles) (Figure 1).

VAP diagnosis
Overall, 17 original studies compared at least two different modalities for VAP diagnosis in children (studies
concurrently comparing at least two different diagnostic methods in the same pediatric population were excluded).
In most of them (13 out of 17 articles), the CDC criteria were used for VAP (CDC-VAP) diagnosis (Figure 2).
Other frequent diagnostic criteria included the Clinical Pulmonary Infection Score (CPIS) found in four articles
(Figure 2) or the new CDC definition criteria for ventilator-associated events (VAEs) found in five articles (Figure 3).
New biomarkers for the diagnosis of VAP were used in four articles. In one article genetic markers from peripheral
blood leucocytes were used for the diagnosis of VAP in critically ill children [10].
Different microbiological techniques (invasive such as use of bronchoscopy, or not) were compared most of
the time with traditional CDC criteria. Clinical Pulmonary Infection Score was compared with CDC criteria and
with microbiology. The use of biomarkers was compared with CDC in three articles and with Clinical Pulmonary
Infection Score in one article. VAE definition was also compared with traditional CDC criteria. The only molecular
study of blood RNA expression profiles used CDC criteria for comparison.
Agreement between different approaches varied significantly. All surveillance studies except for one were per-
formed in critically ill patients using CDC VAP criteria. In four of these studies, CDC VAP criteria were compared
with the new CDC VAE criteria. Agreement between these two CDC criteria (CDC VAP and CDC VAE) was
poor (k = 0.16 and k = 0.24) in two studies and moderate (k = 0.43) in one study. One of the four studies [11]
used CDC VAP as the gold standard for VAP diagnosis and found that the new CDC VAE criteria had a very low
sensitivity (18%) for VAP diagnosis, which was increased from 18 to 33% when CDC VAE criteria were modified
for children (Modified Ped VAP, Figure 3). Similar poor concordance was found between traditional CDC VAP
and a new pediatric VAE/VAP definition proposed by Cocoros et al., when these criteria were applied for first
time in 12 pediatric/neonatal intensive care units in six USA hospitals. Agreement was low, and actually among

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 Ventilator-associated pneumonia in neonates & children Systematic Review

Search strategy: “ventilator associated pneumonia in

children”
n = 367 articles

VAP diagnosis VAP prevention

n = 31 n = 51

Excluded Excluded No full text, only

n = 14 n = 34 abstract
n=1
Financial studies
n=2

Fulfilled inclusion criteria Fulfilled inclusion criteria

n = 17 n = 15†

Figure 1. Flow diagram of the study. † 14 articles fulfilled inclusion criteria according to the algorithm plus one
eligible full article retrieved from references of the aforementioned articles.

19 pediatric patients, who fulfilled new pediatric VAE/VAP criteria only three (15.8%) were diagnosed as having
CDC VAP criteria [12].
Association between VAP diagnosis and mortality was assessed in two surveillance studies [13,14]. Iosifidis et al.
found that patients diagnosed with VAP following CDC VAE criteria had higher mortality than patients diagnosed
with VAP according to CDC VAP criteria; whereas, Beardsley et al. found that CDC VAE was not associated
with higher mortality than CDC VAP. Using the proposed pediatric VAE/VAP criteria Cocoros et al. also found a
higher mortality in children with pediatric Ventilator-associated condition (VAC), infection-related VAC (IVAC)
or possible VAP (PVAP) in relation to children without VAE. However, in this study there was no comparison with
mortality in children diagnosed with CDC VAP [12].
Four studies [15–18] compared different sampling from lower respiratory tract of critically ill children for the
diagnosis of VAP. In one study bronchoalveolar lavage (BAL) was compared with nonbronchoscopic (blind)
protected specimen brush (PSB) and the gold standard for VAP diagnosis was based on expert opinion. In this
study, bronchoalveolar lavage had a higher sensitivity than protected specimen brush (48 vs 26%), but was less
specific than protected specimen brush (89 vs 97%) [18]. In another study bronchoscopic BAL, blind BAL and blind
bronchial sampling were compared with tracheal aspirates, and clinical criteria followed by BAL culture were the
gold standard for VAP diagnosis [16]. Blind BAL had the highest sensitivity (96%), blind bronchial sampling (BBS)
had the highest specificity (82%) and tracheal aspirates had a moderate sensitivity (84%) and specificity (77%) [16].
In 2013 Sachdev et al. compared Gram stain with culture in two separate blind bronchial aspirates performed with
a 2-h interval for the diagnosis of VAP based on expert opinion [15]. They found that a positive culture had a good
agreement (K = 0.65 and 0.68) with polymorphonuclear neutrophils and presence of bacteria in Gram stain. In
addition, Gauvin et al. found that bacterial index in BAL had a good agreement with VAP diagnosis made by an
expert panel [17].
Clinical Pulmonary Index Score was used in four studies [19–22]. All these studies used BAL with or without CDC
VAP criteria as the gold standard for VAP diagnosis and compared Clinical Pulmonary Index Score with CDC
VAP or BAL. A score of ≥8 had 80% sensitivity and specificity [19], and when this cutoff in another study was ≥6
then the sensitivity was high (100%) but specificity dropped to 60% [21]. Similar results were found when the gold
standard for VAP diagnosis included both clinical and BAL findings; the sensitivity of a Clinical Pulmonary Index
Score score of ≥6 was 91–94% and specificity ranged between 50 and 83% [20,22].
Biomarkers were studied in four pediatric studies [21–24] and mainly CDC VAP was used as a gold standard. Soluble
Triggering Receptor Expressed on Myeloid cells (S-TREM-1) concentration in BAL showed good sensitivity and

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Systematic Review Iosifidis, Pitsava & Roilides

CDC GOSH CPIS

Ventilated children Ventilated children Ventilated children

Chest X-rays Variables 0 1 2

Radiologic Radiologic T (°C) 36.5-38.4 38.5-39.0

< 36.0 or
> 39.0
criteria criteria

Yes Yes
< 4.0 or > 11.0 > 11.0 +
and absence band
of band forms or
WBC
Clinical At least 3 clinical/ 4.0–11.0 forms or > 17.0
× 109 per L
> 11.0 to with no
criteria laboratory ≤ 17.0 and no differe-
criteria differentiation ntiation

-New/worsening purulent bronchial

< 1 yr secretions
Worsening -Core temperature ≥ 38.5°C or < 36°C (no
gas exchange other recognised cause) Pulmonary Present and Present &
-Leucopenia or leucocytosis (by age) Absent
and secretions non-purulent purulent
0 day–1 week > 34 × 109L
3/7 criteria 1week–1 month > 19.5 or < 5 × 109L
1 month–1 year > 17.5 or < 5 × 109L
Yes Yes 2–5 years > 15.5 or < 6 × 109L No
Diffue or
Localized
> 1 yr Chest X ray patchy
6–12 years > 13.5 or < 4.5 × 109L infiltrate infiltrate
3/6 criteria infiltrate
13 to < 18 years > 11 or < 4.5 × 109L
-Significant (+) culture from respiratory
secretions
-Relevant culture from alternative site of Oxygenation > 240 or < 240 and
infection (Pa02/FiO2) ARDS no ARDS

Microbiology Negative Positive

VAP VAP

Figure 2. Centers for Disease Control and Prevention score, GOSH criteria and Clinical Pulmonary Infection Score for diagnosing
Ventilator-Associated Pneumonia. Centers for Disease Control and Prevention: Radiologic Criteria: Patient with underlying disease (≥2
imaging test results) or healthy patient (≥1 imaging test results) with one of the following: New & Persistent or Progressive & persistent:
infiltrate or consolidation or cavitation or pneumatoceles (≤1 year old) Clinical Criteria: Age < 1 year: 1. Temperature instability 2.
Leukopenia (≤4000 WBC/mm3 ) or leukocytosis (≥15,000 WBC/mm3 ) and left shift (≥10% band forms) 3. New onset or change in
character of purulent sputum or increased respiratory secretions or increased suctioning requirements 4. Apnea, tachypnea, nasal flaring
with retraction of chest wall or grunting 5. Wheezing, rales or rhonchi 6. Cough 7. Bradycardia (<100 bts/min) or tachycardia(>170
bts/min). Age > 1 years or ≤12 years: 1. Fever (>38.0◦ C) or hypothermia (<36.0◦ C) 2. Leukopenia (≤4000 WBC/mm3 ) or leukocytosis
(≥15,000 WBC/mm3 ) 3. New onset or change in character of purulent sputum or increased respiratory secretions or increased suctioning
requirements 4. New onset or worsening cough or dyspnea or tachypnea 5. Rales or bronchial breath sounds 6. Worsening gas exchange
GOSH: Radiologic Criteria: New or progressive pulmonary infiltrates, consolidation or cavitation, pneumatoceles (≤1 year old) on 2 or
more serial chest-X rays.
WBC: White blood cell.

specificity (96 and 92%, respectively) [22]; whereas, concentration in exhaled ventilator condensate (a noninvasive
measure) had lower sensitivity (75%) and specificity (86%) [23]. Surfactant protein D (SPD) concentration in BAL
was shown by Said et al. that is higher in patients with VAP [21]. However, in a cohort of 33 patients, Srinivasan et al.
found that none of the biomarkers, Soluble Triggering Receptor Expressed on Myeloid cells, Surfactant protein
D, or the receptor for advanced glycation end products were associated to VAP, which was diagnosed according to
CDC VAP and expert opinion [24].
One study assessed VAP diagnosis using VAP signals in gene expression profiles. According to this study, which
used CDC VAP as a gold standard, there were 48 genes that discriminated patients with and without VAP [10].

VAP prevention
Overall, 16 original articles studied the implementation of interventions for preventing VAP in pediatric patients
(Table 2). Five of them were randomized clinical trials, three used interrupted time series and eight the methodology
of “before and after”. In term of preventive measures, most of these studies included implementation of a bundle
of actions; the characteristics of each are presented separately in Table 3. In randomized clinical trials, single
preventive measures were studied. Two of them [25,26] examined oral care with chlorexidine. Other studies compared:

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 Ventilator-associated pneumonia in neonates & children Systematic Review

Table 1. Original studies comparing at least two different approaches for ventilator-associated pneumonia diagnosis in
neonatal and pediatric patients.
Study (Year) Number Study Gold standard Comparison Evaluation of diagnostic approaches Ref.
of patient
Cocoros (2016) 9025 Surveillance No CDC VAP vs CDC (Ped) VAE (NEW Poor agreement between CDC VAP and new CDC [12]
VAE algorithm for children) PED VAE. CDC PED VAE associated to higher
hospital mortality
Iosifidis (2015) 119 Surveillance No CDC VAP vs CDC VAE Moderate agreement: K = 0.43. CDC VAE diagnosis [13]
associated to higher mortality than CDC VAP
Beardsley (2016) 271 Surveillance No CDC VAP vs CDC VAE Poor agreement: K = 0.16, CDC VAE diagnosis not [14]
associated to higher mortality than CDC VAP
Taylor (2014) 285 Surveillance No CDC VAP vs CDC VAE Poor agreement: K = 0.24. Fraction of inspired [51]
oxygen and not PEEP identifies VAP in children
Mariki (2014) 102 Surveillance No CDC VAP vs Microbiology (culture Poor agreement: K = 0.33. ET aspirate and culture [52]
and PMNs ++/+++) seems useful for the diagnosis of VAP
Cirulis (2016) 119 Surveillance CDC VAP 1. CDC VAP vs CDC VAE, 1. CDC VAE: SE 18%, SP 100% [11]
2. CDC VAP vs CDC mVAE (NEW 2. CDC mVAE: SE 33% SP 100%
algorithm for children)
Labenne (1999) 103 Surveillance Expert opinion PSB vs BAL PSB (culture 10ˆ5 CFUs): SE 26%, SP 97% [18]
BAL (culture 10ˆ5 CFUs): SE 48%, SP 89%
Gauvin (2003) 30 Targeted Expert opinion 1. Expert opinion vs CDC VAP 1. CDC VAP vs Expert opinion, poor agreement, [17]
surveillance 2. Expert opinion vs BAL K = 0.11, concordance 43%
3. Expert opinion vs ET 2. BAL Culture (10ˆ3 CFU): SE 60%, SP 75%, poor
agreement (K = 0.34), BAL BI (⬎5) SE 78%, SP
86%, good agreement (K = 0.61), BAL Intracellular
bacteria: SE 30%, SP 95%, poor agreement,
(K = 0.29), BAL GS:SE 50%, SP 81%, poor
agreement (K = 0.31)
3. ET: poor agreement, K = 0.24
Sachdev (2013) 34 Targeted Expert opinion Reproducibility of two BBS with • GS: PMNs vs culture, good agreement K = 0.65 [15]
surveillance 2-h interval: GS vs culture • GS: Presence of bacteria vs culture, good
agreement K = 0.68
Sachdev (2010) 30 Targeted Clinical +BAL† 1. TA vs BBS 1. TA culture (10ˆ5 CFUs): SE 84%, SP 77%, good [16]
surveillance 2. TA vs Blind BAL agreement (K = 0.63), 2) Blind BAL culture (10ˆ 3)
3. TA vs Bronchoscopic BAL CFUs): SE 96%, SP 80%, excellent agreement
(K = 0.78), 3) BBS 10ˆ4: SE 88%, SP 82%, good
agreement (K = 0.68)
Sachdev (2011) 30 Targeted BAL† BAL (≥10ˆ4 CFUs) vs mCPIS ≥ 6 mCPIS ( = 8): SEN 80%, SP 80% [19]
surveillance
Da Silva (2014) 70 Targeted CDC VAP +BAL† CDC VAP&BAL vs mCPIS≥6 mCPIS (≥6): SE 94%, SP 50% [20]
surveillance
Said (2012) 39 Targeted BAL† 1. BAL vs mCPIS≥6 1. mCPIS (≥6): SE 100% SP 60% [21]
surveillance 2. CDC VAP vs mCPIS 2. mCPIS vs CDC VAP, good agreement (K = 0.54)
3. BAL culture vs BAL SPD 3. BAL SPD levels signficantly higher in VAP
patients
Isguder (2017) 116 Case control CDC VAP +BAL† 1. CDC VAP vs CPIS 1. CPIS (cut off = 6): SE 91.3%, SP 83.3% [22]
2. CDC VAP vs s-TREM 2. s-TREM (cut off value 281pg/ml): SE 95.7%, SP
3. CDC VAP vs PCT 91.7%
3. PCT (cut off 1.9ng/ml): SE 93.5%, SP 91.7%
Matsuno (2013) 30 Cohort study‡ CDC VAP CDC VAP vs s-TREM-1 EVC s-TREM-1 EVC: SE 75%, SP 86% [23]
Srinivasan (2011) 33 Cohort study CDC CDC VAP/Experts vs Biomarkers • BAL PAI ≥ 2.8ng/ml: SE 81.3%, SP 76.5% [24]
VAP + expert in BAL • BAL levels of s-TREM, R.A.G.E.P., SPD not
opinion correlated to CDC VAP/expert opinion diagnosis
Werner (2012) 7 Case control CDC VAP CDC VAP vs circulating leukocyte Detectable VAP signal in gene expression profiles: [10]
gene expression signal 48 genes discriminated based on the presence of
(riboleukogram) VAP
† BAL: Culture ≥10ˆ5 CFUs, or otherwise specified
‡ Cohort study: cohort of children with congenital heart disease admitted to PICU after surgery
BAL: Bronchoalveolar lavage; BBS: Blind bronchial sampling; BI: Bacterial Index; CDC: Center for Disease Control and Prevention; CFU: Colony forming unit; CPIS: Clinical Pulmonary
Infection Score; ET: Endotracheal tube; EVC: Exhaled Ventilator Condensate; GS: Gram stain; mCPIS: Modified Clinical Pulmonary Infection score; mVAE: Modified ventilator associated
event; PAI: Platelet Activating Inhibitor; PCT: Procalcitonin; PEEP: Positive Expiratory End Pressure; PMN: Polymorphonuclear neutrophil; PSB: Protected Specimen Brush; R.A.G.E.P.:
receptor for advanced glycation end-products; SPD: Surfactant Protein D; S-TREM: Soluble Triggering receptor expressed on myeloid cells; TA: Tracheal aspirate; VAE: Ventilator associated
event; VAP: Ventilator associated pneumonia.

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Table 2. Interventions for preventing ventilator-associated pneumonia and main outcomes.

Study (year) Location Number of VAP diagnosis Study type Type of intervention Main outcome for VAP Ref.
PICU/NICUpatients reduction
Jácomo (2011) Brazil PICU 160 CDC RCT, Oral care with 0.12% Nonsignificant [25]
double-blind, chlorhexidine gluconate in
placebo- children undergoing cardiac
controlled surgery versus placebo
Kusahara (2012) Brazil PICU 96 CPIS, confirmed RCT, Oral care with 0.12% Nonsignificant [26]
by CDC double-blind chlorhexidine versus placebo
Sönmez Turkey PICU 40 CPIS, CDC Randomised, Comparison of intermittent No statistically significant [28]
Düzkaya (2016) controlled study feeding through a nasogastric difference
catheter vs continuous
feeding through a
nasoduodenal catheter
Banupriya India PICU 150 Criteria¶ RCT, open label Prophylactic administration of Significant reduction (17.1 vs [27]
(2015) probiotics 48.6% in probiotic vs control
group, p ⬍ 0.001. VAP
incidence decreased by 77 %)
Samransa- Thailand PICU 176 CDC RCT Frequency of ventilator circuit No statistically significant [29]
mruajkit changes (3 vs 7 days) on the
(2010) rate of VAP
Bigham (2009) US PICU 2846 CDC Interrupted time Bundle implementation‡ Significant reduction (VAP [30]
series (3 years) rate reduction from 5.6 to 0.3
infections per 1000 ventilator
days after bundle
implementation (p ⬍ 0.0001)
Peña-López Spain PICU 312 CDC Interrupted time Bundle implementation‡ Significant reduction (8.16, [31]
(2016) series 3.27 and 0.65 per 1000
tracheostomy ventilation-days
before intervention, after
general bundle
implementation and after
tracheostomy intervention,
respectively
Esteban (2013) Spain PICU 2.613 CDC Interrupted time Bundle implementation‡ Reduction (from 28.3 to [32]
series 10.6/1000 ventilation days;
p = 0.005)
Brierley (2012) United PICU 448 GOSH diagnostic Before-after Bundle implementation‡ Reduction (after the [36]
Kingdom criteria study institution of the bundle, no
pediatric case of VAP was
recorded over a 12-month
period)
Gupta (2014) India PICU 187 CDC Before and after Educational intervention for Reduction by 28% (20.2 vs [35]
study resident doctors and nurses§ 14.6 per 1000 ventilator-days;
p = 0.21)
Hill (2016) United PICU NR Before-after Bundle implementation‡ Significant reduction (19.5 [37]
Kingdom study vs 8.9 vs 7.6 per 1000
ventilator days at baseline,
1 and 2 years after,
respectively. VAP rate has
reduced by 61%)
Rosenthal (2012) Colombia, PICU 4339 CDC Before-after Bundle implementation‡ Significant reduction 11.7 [33]
Turkey, El study vs 8.1 (31% reduction,
Salvador, p = 0.028)
India,
Philippines
Gurskis (2009) Lithuania PICU 755 CDC Before and after Bundle implementation Significant reduction (5.6 [38]
study vs 1.9 per 100 patients,
p = 0.016)
† These units provide 19 intensive care (IC) cots and 21 high dependency cots.
‡ Different bundle implementations are shown in Table 3.
§ Education on HAIs, hand hygiene, standard precautions, medical and surgical asepsis, sterilization and disinfection, isolation precautions and site-specific HAIs (emphasis on DAIs).

Specific education on VAP, sterilization and disinfection of respiratory therapy equipment, aseptic procedures for suctioning of ventilated patients and proper collection of samples for
VAP diagnosis.
¶ Banupriya- criteria for diagnosing VAP: New (developing more than 48 h after the start of mechanical ventilation or within 48 h of extubation) or persisting radiographic infiltrate (for

at least 72 h) and one of the following: 1. Radiographic evidence of pulmonar abscess formation. 2. Two of the following: fever (increase in the core temperature of at least 1◦ C and
a core temperature of above 38.3◦ C), leukocytosis (25 % increase in circulating leukocytes from baseline/a leukocyte count ≥ 10,000/mm3 ) and purulent tracheal aspirate. 3. Positive
blood or pleural fluid culture with the microorganisms recovered from blood or pleural fluid cultures being identical to the organisms recovered from cultures of respiratory secretions
(tracheal aspirates). Blood and pleural fluid cultures had to be obtained within a period of 48 h before or after the clinical suspicion of VAP.
HAI: hospital-acquired infection; NICU: neonatal intensive care unit; NR: Not reported, VAP: Ventilator-associated pneumonia; PICU: pediatric intensive care unit; RCT: Randomized clinical
trial.

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 Ventilator-associated pneumonia in neonates & children Systematic Review

Table 2. Interventions for preventing ventilator-associated pneumonia and main outcomes (cont.).
Study (year) Location Number of VAP diagnosis Study type Type of intervention Main outcome for VAP Ref.
PICU/NICUpatients reduction
Azab (2015) Egypt NICU 143 CDC Before and after Bundle implementation‡ Reduction (67.8% [40]
corresponding to 36.4 VAP
episodes/1000 mechanical
ventilation days in Phase-I to
38.2% corresponding to 23
VAP/1000 MV days p =
0.0006) after VAP prevention
bundle implementation
(Phase-II)
Rogers (2010) Ireland NICU 5 NICUs† CDC Before and after Hand hygiene in very low Not statistically significant [39]
birth weight infants
Rosenthal (2012) Argentina, NICU 15 NICUs CDC Before and after Bundle implementation‡ Significant reduction 17.8 [34]
Colombia, (6,829 vs 12.0 (33% reduction,
India, neonate) p = 0.0009)
Mexico,
Morocco,
Peru,
Philippines,
El Salvador,
Tunisia,
Turkey
† These units provide 19 intensive care (IC) cots and 21 high dependency cots.
‡ Different bundle implementations are shown in Table 3.
§ Education on HAIs, hand hygiene, standard precautions, medical and surgical asepsis, sterilization and disinfection, isolation precautions and site-specific HAIs (emphasis on DAIs).
Specific education on VAP, sterilization and disinfection of respiratory therapy equipment, aseptic procedures for suctioning of ventilated patients and proper collection of samples for
VAP diagnosis.
¶ Banupriya- criteria for diagnosing VAP: New (developing more than 48 h after the start of mechanical ventilation or within 48 h of extubation) or persisting radiographic infiltrate (for

at least 72 h) and one of the following: 1. Radiographic evidence of pulmonar abscess formation. 2. Two of the following: fever (increase in the core temperature of at least 1◦ C and
a core temperature of above 38.3◦ C), leukocytosis (25 % increase in circulating leukocytes from baseline/a leukocyte count ≥ 10,000/mm3 ) and purulent tracheal aspirate. 3. Positive
blood or pleural fluid culture with the microorganisms recovered from blood or pleural fluid cultures being identical to the organisms recovered from cultures of respiratory secretions
(tracheal aspirates). Blood and pleural fluid cultures had to be obtained within a period of 48 h before or after the clinical suspicion of VAP.
HAI: hospital-acquired infection; NICU: neonatal intensive care unit; NR: Not reported, VAP: Ventilator-associated pneumonia; PICU: pediatric intensive care unit; RCT: Randomized clinical
trial.

intermittent feeding through a nasogastric catheter with continuous feeding through nasoduodenal catheter, the
frequency of ventilator circuit changes (3 vs 7 days) and the effect of prophylactic administration of probiotics for
preventing VAP [27–29].
With regard to outcome, the only randomized clinical trial that found a significant reduction in VAP rates was
the prophylactic administration of probiotics [27]. This study showed that prophylactic administration of probiotics
reduced VAP by 77% in a pediatric ICU setting with high VAP rate [27]. Baseline incidence of VAP was 39
episodes per 1000 ventilator days, which was decreased to 22 episodes per 1000 ventilator days. Both pediatric
ICU and hospital lengths of stay were reduced by 2.1 and 3.3 days, respectively. There was no documentation of
any complications by using probiotics in critically ill pediatric patients.
Two other randomized clinical trials examined the effect of oral hygiene with the use of chlorhexidine solution.
The first study included pediatric patients undergoing cardiac surgery and being hospitalized in a pediatric ICU
in Brazil [25]. Patients were allocated into two groups: chlorhexidine (0.12%) oral care group and control group
in which oral care was done with placebo. VAP diagnosis was based on CDC VAP criteria and the main result of
this study was that there was no difference in VAP rates between chlorhexidine and placebo group (18.3 vs 15%,
p = 0.57). In addition, no significant difference was found for intubation time as well as 28-day mortality (5.7 vs
6.8%; p = 0.77) [25]. The second study was also conducted in critically ill children in Brazil [26]. This study also
failed to decrease VAP rates in ventilated children using oral care with chlorhexidine 0.12%, performed twice daily
(32.6 vs 32.0%, p = 0.949). Pediatric ICU and hospital lengths of stay were similar for chlorhexidine and placebo
group (15.8 vs 10.8 days and 41.1 vs 30.3 days, respectively). Similarly, mortality did not differ between the two
groups (17.4% in chlorhexidine group and 24% in placebo group, p = 0.425) [26].
Differences in feeding practices for reducing VAP rates were evaluated in another randomized clinical trial
in critically ill children [28]. This study compared continuous feeding through a nasoduodenal catheter with
intermittent feeding through a nasogastric catheter and found no significant difference in VAP rates. In this study,
VAP was defined using both CPIS and CDC criteria. The frequency of ventilator circuit changes was addressed in

future science group www.futuremedicine.com 1437

1438
Table 3. Characteristic of different ventilator care bundles in pediatric patients.
Author HOB Oral care Hand Cuffed endotracheal Ventilator circuit Sterile suction and Other interventions Ref.
(Year) hygiene tube handling of respiratory
equipment
√ √ √ √
Peña-López [31]
(2016) Chlorhexidine Cuff pressure 20–30 (Circuit changes only if
(0.12%, q6h) and mmHg) the circuit becomes
Systematic Review

tooth brushing soiled or damaged)

(q12h)
√ √ √ √ √ √
Azab (2015) [40]
Normal saline and (Circuit changes only if 1. Intubation, re-intubation and endotracheal tube
suction of the circuit becomes (ETT) suction as strictly indicated by unit protocol
oro-pharyngeal soiled or damaged) 2. Daily evaluation for readiness for extubation to
secretions nasal continuous airway pressure (NCPAP)
√ √ √ √
Brierley [36]
(2012) Chlorhexidine or 1. Patients not on full feeds commenced on ranitidine
tooth brushing 2.Documentation of actions

Future Microbiol. (2018) 13(12)

√ √ √ √ √
Esteban [32]
Iosifidis, Pitsava & Roilides

(2013) Chlorhexidine Closed suction catheter

systems for patients
ventilated more than 24
h
√ √ √ √ √ √
Gurskis 1. Education of healthcare workers about [38]
(2009) Antiseptic and Before deflating the cuff (Circuit changes only if Drain and discard any epidemiology and infection control procedures
tooth brushing of endotracheal tube in the circuit becomes condensate that collects 2. Wear gloves to perform the previous procedure
preparation for tube soiled or damaged) in the tubing of a and/or handling the fluid
removal, or before (circuit changes only if mechanical ventilator, 3. Remove devices such as endotracheal,
moving tube ensure that the circuit becomes take precautions, do not tracheostomy and/or enteral tubes from the patients
secretions are cleared soiled or damaged) allow condensate to when no longer indicated
from above the tube cuff drain toward the patient 4. Routinely verify appropriate placement of the
feeding tube
5. Do not use antacids routinely for mechanically
ventilated patients
6. Avoid repeat endotracheal intubation in patients
who have received mechanical ventilation
√ √ √ √
Bigham 1. Checklists [30]
(2009) (Circuit changes only if
the circuit becomes
soiled)
√ √ √ √ √ √
Rosenthal [33]
(2012) Antiseptic Adherence At least 20 cm H2 O 40 Changing of the 1. Active surveillance
solution to guidelines ventilator circuit only 2. Daily assessment of readiness to wean and use of
when visibly soiled or weaning protocols
malfunctioning 3. Preference for orotracheal intubation over
Removal of condensate nasotracheal intubation
from ventilator circuits 4.Avoidance of gastric overdistention
keeping the ventilator 5. Avoidance of histamine receptor 2 blocking agents
circuit closed during and PPIs
condensate removal 6. Use of sterile water to rinse reusable respiratory
equipment
7.Use of noninvasive ventilation whenever possible,
minimizing the duration of ventilation

future science group

HOB: Head of bed, PPI: Protein pump inhibitor.
future science group
Table 3. Characteristic of different ventilator care bundles in pediatric patients (cont.).
Author HOB Oral care Hand Cuffed endotracheal Ventilator circuit Sterile suction and Other interventions Ref.
(Year) hygiene tube handling of respiratory
equipment
√ √ √
Rosenthal 1. Active surveillance [34]
(2012) Regular oral care Adherence Changing of the 2. Performance of daily assessments of readiness to
with an antiseptic to hand ventilator circuit only wean and use of weaning protocols
solution hygiene when visibly soiled or 3. Use of noninvasive ventilation whenever possible
guidelines malfunctioning and minimization of the duration of ventilation
Removal of condensate 4. Preferable use of orotracheal instead of
from ventilator circuits nasotracheal intubation
keeping the ventilator 5. Avoidance of gastric overdistention
circuit closed during 6. Avoidance of histamine receptor 2–blocking agents
condensate removal and proton pump inhibitors
7. Use of sterile water to rinse reusable respiratory
equipment
HOB: Head of bed, PPI: Protein pump inhibitor.
Ventilator-associated pneumonia in neonates & children

www.futuremedicine.com
1439
Systematic Review
Systematic Review Iosifidis, Pitsava & Roilides

Baseline period (≥ 2d) of stability or improvement and worsening oxygenation

Adult VAE, Mod. pediatric Pediatric VAE,

CDC VAE, cirulis cocoros

Daily min: Daily min: Daily min:

No No No No
FiO2 ≥ 20%, or FiO2 ≥ 20%, or FiO2 ≥ 25%, or
×2d No VAE ×1d ×2d VAE
PEEP ≥ 2cm H2O MAP ≥ 4 cm H2O
PEEP ≥ 3 cm H2O

Yes Yes Yes

Abn. †WBC or T No No Abn. ‡WBC or T New ABC starts No Ped

±2d VAC Mod. ±2d ±2d VAC
& & New ABC starts and
PED VAC
New ABC starts ≥ 4days cont. ≥ 4 days

Yes Yes Yes

1 out of 3 No No 1 out of 3 1 out of 3 No Ped

±2d microbiological IVAC Mod. AVAC
microbiological ±2d ±2d microbiological
criteria† PED IVAC
criteria† criteria†

Yes Yes Yes

PVAP Mod. Ped PVAP Ped-PVAP

Figure 3. New Centers for Disease Control and Prevention definition for Ventilator-associated Event. Simplified from CDC/2015.
† Microbiological criteria: 1) Positive culture via endotracheal aspirate, bronchoalveolar lavage, lung tissue or protected specimen brush,

with (semi) quantitative thresholds, 2) Purulent respiratory secretions and positive culture via specimens in criterion 1, but not meeting
those thresholds for growth, 3) one of the following: organism identified via pleural fluid, lung histopathology, legionella diagnostic test,
or respiratory secretion positive for viral organism.
ABC: Antimicrobial; ‡ Abn: Abnormal; FiO2 : Fraction of inspired oxygen; PEEP: Positive end-expiratory pressure; WBC: White blood cell.

a randomized clinical trial conducted by Samransamruajkit et al. and found no difference in VAP rates (3 vs 7 days
for changing the ventilator circuit) [29].
Beyond clinical trials, three studies used the methodology of interrupted time series in order to study implemen-
tation of bundle of actions for VAP reduction. This means that in these studies there were at least three time points
before and three time points after the implementation of the intervention. The first study conducted by Bigham
et al. [30] found that establishing a pediatric VAP prevention bundle (Table 3) produced a sustained reduction of
VAP rates in a Pediatric ICU setting in USA. In this study, VAP occurrence was significantly correlated not only
with Pediatric ICU length of stay but for the first time also with mortality. The mean rate of VAP was 5.6 and 8.8
episodes per 1000 ventilator days during baseline and implementation period, respectively, and dropped to a mean
rate of 0.3 episodes per 1000 ventilator days (p < 0.001) [30]. Compliance with bundle elements reached 100% at
the end of the implementation period using a multidisciplinary leadership team as well as compliance checklists
and real time data to drive change.
Similarly, in Europe Pena-Lopez et al. [31] recently found that implementing a ventilator care bundle (Table 3) had
a significant impact on preventing VAP in children. In this study overall VAP rates decreased by 74.7% (from 4.14
to 1.05 episodes per 1000 ventilator days, non-statistically significant). In ventilated children with tracheostomy
VAP incidence decreased from 8 to 0.65 episodes per 1000 ventilator days and this difference was statistically
significant [31]. Compliance to bundle elements was not assessed in this study.
A similar approach followed by Esteban et al. in Spain [32] found that using a quality improvement practice
focused on hand hygiene and specific bundles for the predominant nosocomial infections (VAP, central line

1440 Future Microbiol. (2018) 13(12) future science group

 Ventilator-associated pneumonia in neonates & children Systematic Review

associated bloodstream infections-CLABSIs and complicated urinary tract infections) in a Pediatric ICU found
significant and sustained decrease of all nosocomial infections including VAP. VAP rates initially decreased from 28.3
to 10.6 episodes per 1000 ventilator days and during the long-term period to 9.1 episodes per 1000 ventilator days
(p < 0.001). Hospital length of stay and mortality also tended to decrease (p = 0.048 and 0.058, respectively) [32].
Rosenthal et al. studied the implementation of a bundle of actions for VAP reduction in a large number of
hospitalized pediatric patients in eight Pediatric ICUs [33] and in 15 Neonatal ICUs [34]. The first study was
conducted in five developing countries, members of the International Nosocomial Infection Control Consortium
(INICC), and used a modified bundle with 13 elements (Table 3) for the reduction of VAP rates [33]. Intervention
period included education, outcome and process surveillance as well as feedback of VAP rates and performance
and the final result was a significant drop of VAP rates from 11.7 to 8.1 episodes per 1000 ventilator days (31%
reduction, p = 0.028). Using a similar INICC infection control program at 15 NICUs in ten developing countries
Rosenthal et al., found a 33% reduction in VAP rates [34]. Similarly, Gupta et al. conducting an interventional study
in India found a nonsignificant trend on VAP rates (20.2 to 14.6 episodes per 1000 bed-days, p > 0.05), whereas
a significant decrease in mortality (49.3–31.4%) [35].
In UK, Brierley et al. implemented a bundle of care for reducing VAP rates [36]. This bundle included simple and
costless interventions (Table 3) focusing on nurse education and frequent documentation of each bundle element.
In this study because of the high number of immunocompromised children a modified CDC diagnostic algorithm
was used for VAP diagnosis (UK VAP surveillance program, Figure 2). After 1 year of bundle implementation, no
new pediatric VAP were diagnosed in this Pediatric ICU setting, which had a baseline of 5.6 episodes per 1000
ventilator days [36]. Another study in UK [37] implemented a nurse-led ventilator bundle in a Pediatric ICU setting
because of high baseline VAP rates (19.5 infections per 1000 ventilator days) [37]. Using evidence-based elements for
the VAP bundle, behavior change techniques (engage, educate, execute and evaluate) and documenting compliance,
this intervention reduced VAP by 61%, which was sustained at least for 2 years [37]. Overall compliance was high
and only two elements, mouth care (65%) and sedation wean (58%) had the lowest compliance (7/11 bundle
elements had more than 90% compliance) [37].
Gurskis et al. applied a multimodal intervention including staff education and evidence-based bundles for
reducing nosocomial infections in three Pediatric ICUs in Lithuania. Three bundles were implemented targeting
the 3 most frequent nosocomial infections: VAP (Table 3), bacteremia and urinary tract infection. This study,
which used the ‘before and after’ methodology found a significant reduction of all nosocomial infections including
VAP (the most frequent). Incidence of VAP showed a tendency for reduction from 21.8 to 8.8 episodes per 1000
ventilator days (p = NS) [38].
There were two interventional studies conducted in Neonatal ICU patients. The first was conducted by Rogers
et al. in 5 NICU in UK [39]. This study used CDC definition for VAP and a before and after methodology. The
authors found that using a quality-improvement initiative for hand hygiene resulted in a statistically significant
increase in adherence to hand hygiene practices as well as a nonsignificant decrease (38%) of VAP rates in Very
Low Birth Weight neonates. The second study was conducted by Azab et al. [40], who used a specific bundle of
actions (Table 3) in order to reduce VAP rates in a Neonatal ICU setting of a developing country with relatively
high VAP rates. By using a ‘before and after’ methodology, they dropped incidence of VAP from 36.4 episodes
during baseline period to 23 episodes per 1000 ventilator days (p = 0.0006).

Discussion
In the absence of a gold standard, different diagnostic approaches have been studied for VAP diagnosis in critically ill
children for both clinical management and surveillance purposes. All of these approaches were adopted from adults
and then some of them were adapted to pediatric and neonatal patients. Traditional CDC VAP criteria, no longer
used for surveillance in adults in USA, predominate for clinical management, surveillance and prevention of VAP
in children despite significant limitations (mainly subjectivity). Newer diagnostic algorithms include ventilator-
associated events, adapted to pediatric population, are objective and have a significant impact on morbidity and
mortality. However, this definition is used only for surveillance and currently there are no data on prevention in
children. Administration of probiotics was the only measure, which was proved to be protective for VAP in children
according to data from a very limited number of clinical trials conducted in this age population. Ventilator bundle
interventions do have an impact on VAP rates in children, measured at least by traditional definitions but more
data are needed for the exact elements as well as how all or some of this work and therefore should be included for
prevention of VAP/VAE in pediatric patients.

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Systematic Review Iosifidis, Pitsava & Roilides

Traditionally microbiologic methods have been used for VAP diagnosis both in children and adults and the major
question is if invasive sampling is better than noninvasive. As previously discussed, Gauvin et al. found that CDC
VAP criteria, BAL culture and endotracheal aspirates in critically ill children failed to have a good agreement with the
gold standard, which was defined by an expert panel [17]. Direct comparison of invasive versus noninvasive methods
in critically ill children showed that tracheal aspirates had good agreement, whereas BAL cultures had excellent
agreement with a predefined ‘gold standard’ [19]. In children, the use of invasive (i.e., bronchoscopy, BBS) versus
noninvasive methods (i.e. tracheal aspirates) for VAP diagnosis remains controversial in terms of cost–benefit [41].
However, 2016 IDSA guidelines recommend the use of noninvasive rather than invasive sampling for initiation of
antimicrobials in adults with suspected VAP [42].
The use of biomarkers and Clinical Pulmonary Infection Score for diagnosing VAP has been examined in several
studies in children. Procalcitonin and Clinical Pulmonary Infection Score have shown controversial results for VAP
diagnosis in children. In clinical practice and according to IDSA guidelines, initiation of antibiotics for VAP is
based on clinical criteria alone and not in conjunction with biomarkers or Clinical Pulmonary Infection Score [42].
Procalcitonin and clinical criteria are encouraged to be used for discontinuing treatment for VAP in adults [42];
whereas, in children more data are needed including cut off values and ‘gold standard’ diagnosis [22].
Recently, surveillance of VAP in USA has been changed and VAE/VAP definition algorithm has been introduced
in adult ICUs [43]. The main reason for this change has been that CDC VAP definition included subjective elements
and poor sensitivity and specificity. Currently, no consensus for the pediatric VAE/VAP algorithm exists. However,
the few pediatric studies that have implemented VAE/VAP algorithm in critically ill children using criteria either
same as in adults or adapted to pediatric population [11–13] have shown poor agreement with current CDC VAP
criteria but a good correlation with morbidity and mortality in ventilated children. These data suggest that there is
a need for fine-tuning available data and validate a new pediatric VAE/VAP algorithm.
The use of probiotics for VAP prevention [27] has been assessed in the past in another RCT in critically ill
children for the reduction of nosocomial infections but the results were unexpected [44]. In detail, this study had
been terminated because there was a nonsignificant trend of increased infections in the patients receiving probiotics.
Furthermore, in adults a recent meta-analysis for the use of probiotics in ICU patients concluded that current data
are inconclusive for reduction of VAP rates, length of stay in ICU or mortality [45]. The role of probiotics for
reducing VAP or newer VAE definitions needs further investigation.
Very recently, Klompas et al. found that oral chlorhexidine, at least for adults may be correlated with harm [46].
Although this signal of increased mortality has not been proven in ventilated children treated with oral chlorhexidine,
oral care with or without chlorhexidine should be evaluated in bundle’ practices for reducing VAP/VAE in children.
Nebulized hypertonic saline, a totally new element for neonatal ventilator bundle care, was recently assessed in
a pilot clinical trial conducted in premature neonates in Egypt [47]. In this open-label trial, nebulized hypertonic
saline given twice per day for 10 days or until extubation, significantly reduced the incidence of VAP (30 episodes
per 1000 ventilator days in control group and 16/1000 ventilator days in intervention group). This study used
CDC criteria for VAP diagnosis and was published in July of 2017 [47].
Another issue in implementing bundles is the balance between cost of an intervention and the benefit. Two
studies have evaluated the cost–benefit of a quality improvement intervention to decrease VAP rates in children.
The first was conducted in USA and the second in a low-income country (Nicaragua). The first study showed a
reduction in hospital costs of US $2,353,222 for one financial year (2006) [48]. The second economic analysis found
that in a Pediatric ICU setting with high VAP prevalence (22.7%) a very small (0.5%) reduction of VAP would be at
least cost neutral for the money spent in the intervention [49]. According to this model, if the quality improvement
investigation reduced VAP rates more than 0.5%, which was shown to be feasible, then the intervention would
produce significant cost savings [49]. Similar results have been found in adult studies [50].
The present study summarizes all existing data on the diagnosis and prevention of VAP in neonates and children.
Only original studies were included and especially for diagnosis only those with comparison of at least two different
diagnostic approaches/procedures. These criteria may have reduced the number of studies evaluating single VAP
diagnostic approaches.

Conclusion
It should be emphasized that available data are not enough to reach a definitive conclusion regarding a gold standard
in both diagnosis and prevention of VAP in children. Beyond any reduction of VAP rates, defined by current or

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 Ventilator-associated pneumonia in neonates & children Systematic Review

newer metrics, prevention strategies should also target for prudent use of antibiotics, shortening length of stay and
mortality in pediatric ventilated patients.

Future perspective
In the absence of a gold standard for VAP diagnosis, a single definition may not be adequate for both clinical
and surveillance purposes. The newer diagnostic modalities of pediatric VAE will be more frequently used for
surveillance in the near future. However, there is a need to fine-tune existing neonatal/pediatric VAE definitions,
correlate them with clinical practice and implement them as a standard of VAP surveillance in neonatal and pediatric
intensive care units.
For clinical management, and especially for the initial diagnostic approach, a combination of symptoms and
signs in conjunction with specific laboratory findings should guide physicians for prompt initiation of antimicrobial
agents for VAP. Biomarkers should be further evaluated in VAP assessment in neonatal and pediatric patients. A
better evaluation is needed for the role of all these biomarkers, clinical scores including Clinical Pulmonary Infection
Score and VAE definitions in reducing prolonged courses of antimicrobials in intubated critical care patients.
Prevention strategies should not focus only in reducing VAP rates, defined by any new or old criteria, but
target also other outcome indicators such as length of invasive mechanical ventilation, antimicrobial use, length
of Pediatric ICU hospitalization and mortality. The role of probiotics should be further evaluated including new
insights from current or future studies evaluating microbiome of critically ill children. Ventilator care bundles are
important and should be part of clinical standard practices in Neonatal and Pediatric ICU. However, the appropriate
elements that should be included in these bundles must be further evaluated for efficacy, safety and cost benefit.

Executive summary
• Ventilator associated pneumonia (VAP) remains one of the commonest healthcare associated infections in
Pediatric ICU and is associated to increased antimicrobial usage and length of stay. Currently, in the absence of a
gold standard for VAP diagnosis, both old and new diagnostic methods and prevention strategies have been used
in neonatal and pediatric critical care patients.
Methods
• This systematic review focuses in original articles that have compared different diagnostic approaches and
prevention strategies for VAP in neonatal and pediatric critical care patients.
Results
• Among 17 original articles comparing different approaches for VAP diagnosis, the traditional CDC criteria for
VAP were most frequently used (13/17 articles). Other approaches included the newer Centers for Disease
Control and Prevention (CDC) criteria for VAE, the Clinical Pulmonary Infection Score and newer biomarkers.
• Agreement between different approaches varied significantly. In surveillance studies, agreement between two
different CDC criteria (CDC VAP and CDC ventilator-associated event) was poor to moderate. Assessment of
Clinical Pulmonary Infection Score in children was conducted in studies using bronchoalveolar lavage with or
without CDC VAP criteria and found to have high sensitivity and specificity.
• Newer biomarkers such as Soluble Triggering Receptor Expressed on Myeloid cells (sTREM-1) and Surfactant
protein D (SPD) concentrations in bronchoalveolar lavage have been used in pediatric critical care patients but
with inconclusive results.
• Prevention strategies for reducing VAP rates in children have been assessed as single element interventions in
clinical trials or as ventilator care bundles in quasi-experimental studies.
• In a very limited number of clinical trials conducted in children, the use of probiotics reduced VAP rates. Using
interrupted time series methodology the ventilator care bundle has been found to significantly reduce VAP rates.
Discussion-conclusion
• Most of VAP diagnostic approaches in pediatric and neonatal patients have been adapted from adults. For
surveillance, traditional CDC VAP criteria predominate but have major limitations and no correlation to mortality.
In contrast, VAE are more objective and have a significant impact on morbidity and mortality.
• Probiotics were protective for developing VAP in children but these data should be further evaluated in large
clinical trials. Ventilator care bundles reduce VAP rates according to traditional CDC definition but data are
needed for including the appropriate elements and further evaluation by newer VAP definitions.
• While current clinical practice and surveillance for VAP in children is challenged by the absence of a gold
standard, there is urgent need for preventing VAE/VAP, defined by current or newer definition, in order to
optimize antimicrobial use and reduce morbidity and mortality in pediatric ventilated patients.

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Systematic Review Iosifidis, Pitsava & Roilides

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or finan-
cial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria,
stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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