Journal Pre-proof

Identification of Streptococcus pneumoniae in Hospital-acquired Pneumonia in Adults:

A Systematic Review

Jose A. Suaya, Mark A. Fletcher, Leonidas Georgalis, Adriano Arguedas, John M.

McLaughlin, Germano Ferreira, Christian Theilacker, Bradford D. Gessner, Thomas
Verstraeten
PII: S0195-6701(20)30511-9
DOI: https://doi.org/10.1016/j.jhin.2020.09.036
Reference: YJHIN 6217

To appear in: Journal of Hospital Infection

Received Date: 1 August 2020

Revised Date: 16 September 2020
Accepted Date: 17 September 2020

Please cite this article as: Suaya JA, Fletcher MA, Georgalis L, Arguedas A, McLaughlin JM,
Ferreira G, Theilacker C, Gessner BD, Verstraeten T, Identification of Streptococcus pneumoniae in
Hospital-acquired Pneumonia in Adults: A Systematic Review, Journal of Hospital Infection, https://
doi.org/10.1016/j.jhin.2020.09.036.

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© 2020 Published by Elsevier Ltd on behalf of The Healthcare Infection Society.

Identification of Streptococcus pneumoniae in Hospital-acquired Pneumonia in Adults: A

Systematic Review

Jose A. Suaya1,*, Mark A. Fletcher2, Leonidas Georgalis3, Adriano Arguedas1, John M.

McLaughlin1, Germano Ferreira3, Christian Theilacker1, Bradford D. Gessner1, Thomas

Verstraeten3
1
Vaccines Medical Development & Scientific/Clinical Affairs, Pfizer Inc., New York, NY

10017, USA

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2
Emerging Markets Medical Affairs, Vaccines, Pfizer Inc., 75668 Paris, France

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3
P95 Epidemiology and Pharmacovigilance, Leuven, Belgium
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*
Corresponding author: Jose A. Suaya, +1 (212) 573-2323, Jose.suaya@pfizer.com
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Running title: S. pneumoniae in adult hospital-acquired pneumonia

Key words: nosocomial; pneumococcal pneumonia; ventilator-associated pneumonia;

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intensive care unit

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Summary (241 words, max. 250 words)

Background: Hospital-acquired pneumonia (HAP) is often more severe and life-threatening

than community-acquired pneumonia (CAP). The role of Streptococcus pneumoniae in CAP

is well-understood, but its role in HAP is unclear.

Aim: The objective of this study was to summarize the available literature on the prevalence

of S. pneumoniae in HAP episodes.

Methods: We searched MEDLINE for peer-reviewed articles on the microbiology of HAP in

individuals aged ≥18 years, published between 2008-2018. We calculated pooled estimates of

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the prevalence of S. pneumoniae in episodes of HAP using a random-effects, inverse-

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variance-weighted meta-analysis.
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Findings: 47/1908 articles met the inclusion criteria. Bacterial specimen isolation techniques
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for microbiologically-defined HAP episodes included bronchoalveolar lavage, protective
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specimen brush, tracheobronchial aspirate and sputum, as well as blood culture. Culture was
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performed in all studies; five studies also used urine antigen detection (5/47; 10.6%). S.

pneumoniae was identified in 5.1% (95%CI: 3.8-6.6%) of microbiologically-defined HAP

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episodes (n=20), with 5.4% (95%CI: 4.3-6.7%, n=29) in ventilator-associated HAP and 6.0%
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(95%CI: 4.1-8.8%, n=6) in non-ventilator-associated HAP. S. pneumoniae was identified in

5.3% (95%CI: 4.5-6.3%) of HAP occurring in the intensive care unit (ICU, n=41) and in

5.6% (95%CI: 3.3-9.5%, n=5) outside the ICU. A higher proportion of early-onset HAP

(10.3%; 95%CI: 8.3-12.8%, n=16) identified S. pneumoniae as compared to late-onset HAP

(3.3%; 95%CI: 2.5-4.4%, n=16).

Conclusion: S. pneumoniae was identified by culture in 5.1% of microbiologically-defined

HAP episodes. The importance of HAP as part of the disease burden caused by S.

pneumoniae merits further research.

2
Background

Hospital-acquired pneumonia (HAP, also commonly referred to as nosocomial pneumonia) is

defined as a lower respiratory tract infection that was not present at the time of hospital
1, 2
admission and that begins ≥2 days after hospitalization . HAP carries an important public

health burden related to its frequency, its association to intensive care and its impact on the

length of hospitalization. First, it is not uncommon, occurring at a rate of 5 to 10 cases per

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1,000 hospital admissions, with the incidence increasing from 6- to 20-fold in mechanically-

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3, 4
ventilated patients . In the US, HAP is estimated to represent 24.3% of hospital-acquired

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infections, or 157,000 hospitalizations annually 5. Second, the burden of HAP is particularly
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high in ICUs. In a study across 27 intensive care units from nine European countries, 75.9%
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of the pneumonias treated in those settings were HAP, including 72.9% of those requiring

mechanical ventilation 6. Lastly, HAP also adds significantly to the length of hospital stay: in
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one study, length of stay was 13 days in patients with HAP versus 5 days in patients with
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pneumonia as primary diagnosis 7.

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Within HAP, two subcategories are defined: ventilator-associated pneumonia (VAP) that
1, 2, 8
presents >48 hours after endotracheal intubation ; and non-ventilator-associated

pneumonia (nVAP) that is not associated with endotracheal intubation. As with VAP, nVAP

is also emerging as a major patient-safety concern, with a severity that is comparable to VAP

in both health and economic burden terms 9-11. For those HAP cases in which ventilator status

is not explicitly specified, they are labeled overall as HAP, without description of its type.

Early-onset HAP, defined as occurring within the first 4 days of hospitalization, or early-

onset VAP, occurring within the first 4 days of intubation, are more likely to be caused by

antibiotic-sensitive bacteria, and these usually carry a better prognosis as compared to late-

3
onset HAP or VAP. Late-onset HAP or VAP is more likely to be caused by multidrug-

resistant pathogens and is associated with increased patient mortality and morbidity 2, 12, 13.

While Streptococcus pneumoniae is the most frequent bacterial cause of community-acquired

pneumonia (CAP), its role in HAP is less clear 14. The most frequently identified organisms

in HAP or VAP are Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella species,

Escherichia coli, Acinetobacter species, and Enterobacter species, together causing

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approximately 80% of episodes . Early-onset VAP is more often caused by antibiotic

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sensitive, community-associated bacteria such as Haemophilus spp, and meticillin-sensitive

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S. aureus (MSSA), while late-onset VAP is more commonly caused by multidrug resistant

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pathogens associated with exposure to the healthcare environment, including P. aeruginosa,

Acinetobacter species, and meticillin-resistant S. aureus (MRSA) 15, 16.

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As the role of S. pneumoniae in the microbiology of hospital-acquired infections is being

17-19
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increasingly recognized , the overall goal of this study was to review the literature on

HAP and VAP among developed countries of North America and Europe, as well as Japan,
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Australia and New Zealand, to assess the potential contribution of S. pneumoniae in these two
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entities.

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Methods

The primary objective of this study was to assess the extent to which S. pneumoniae is an

identified pathogen for HAP, and to estimate the prevalence of S. pneumoniae in

microbiologically-confirmed episodes of HAP as well as in the sub-categories of VAP and

nVAP. The secondary objective was to compare S. pneumoniae prevalence according to

parameters such as the sample collection method, the health care setting (i.e., those occurring

within or outside the ICU) and the time of onset (i.e., between early- and late-onset HAP

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episodes). To accomplish these study objectives, we performed a systematic literature review

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and a meta-analysis using the Preferred Reporting Items for Systematic Reviews and Meta-

analyses (PRISMA) guidelines 20. -p

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Identification of studies
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We searched MEDLINE (PubMed) to identify peer-reviewed articles published between May

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2008 and May 7th, 2018 (date of search). Expecting most data to come from these areas, we
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focused on publications from North America, Europe, Japan, New Zealand and Australia that
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were written in English, French, Spanish, Portuguese, Dutch, German or Italian. We searched

for studies on HAP combined with terms for S. pneumoniae (see S1 File for details). To avoid

bias associated with studies that focused on or preferentially identified S. pneumoniae, we

also searched for studies on HAP combined with S. aureus, MRSA, P. aeruginosa, K.

pneumoniae, or Acinetobacter spp. (see S1 File for details). In addition, the reference lists of

identified review articles, published guidelines and meta-analyses were screened for

additional original studies that fulfilled the inclusion criteria.

Inclusion and exclusion criteria

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We included peer-reviewed publications about HAP that reported the microbiological

aetiology (in particular, explicitly the presence or absence of S. pneumoniae) and that were

conducted in adults (18 years or older), irrespective of the study design. We excluded

manuscripts reporting non-human data (e.g. in-vitro, in-silico, or animal models), economic

evaluation studies, or transmission modelling studies, as well as case reports, management

guidelines, and conference abstracts. Review papers were included only to search the

reference lists for potential additional papers.

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Selection process

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Articles were selected in three steps. First, titles and abstracts identified through the search
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strategy were screened independently by two reviewers (LG, GF) to classify potentially
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relevant articles. Any disagreements were either resolved between the two reviewers or, in
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cases where adjudication between the two reviewers was warranted, two additional reviewers
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made the final selection (JS, TV). Next, a full-text review of the articles retrieved in the first

screening step was performed to create a final list of relevant articles by a single reviewer
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(LG), consulting the same additional reviewers (JS, TV) in case of any doubt. The reference
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lists of relevant papers retrieved from the search were also reviewed to ensure that no

additional studies were missed. Finally, selected articles were screened to ensure that data

duplicated from the same study were not included. In instances of duplication, only the article

that presented the most complete data (e.g., longer follow-up) was included.

Data extraction

Relevant data from the final list of articles were extracted into an MS Access database by one

reviewer (LG) and quality checked by a second reviewer (TV). Only studies that explicitly

reported the presence or absence of S. pneumoniae were included in this review. The

following information was captured for each study: the number of HAP, VAP, or nVAP

6
episodes; the number of HAP, VAP, or nVAP episodes tested and microbiologically

confirmed; and the timing of HAP, whether early- or late-onset HAP (or late-onset VAP).

Late-onset HAP (or late-onset VAP) was defined as onset ≥5 days after hospitalization (or

ventilation) in all studies included in this review, except for a single VAP study where the
21
definition applied was occurrence after the first 7 days of intubation . Further information

captured included: the number of laboratory results positive for S. pneumoniae; whether

pneumonia diagnosis occurred in the ICU or outside of the ICU; and type of specimen

collected (i.e., respiratory tract, blood, or urine). For respiratory tract specimens, the

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following collection methods were distinguished: bronchoalveolar lavage (BAL),

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tracheobronchial aspiration, use of protective specimen brush (PSB), and sputum; and where
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possible, the same information was stratified by early- and late-onset cases.
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We assessed potential sources of bias based on domains in the Robins-I tools . As we did

not identify any specific confounders, or any selection, measurement, or classification biases
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that would apply to the studies included in this review, which were all descriptive in nature,
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we did not perform a systematic bias assessment.

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Statistical analyses

The prevalence of S. pneumoniae in microbiologically-confirmed episodes of HAP, VAP,

and nVAP was based on results from respiratory samples. The episode-specific prevalence

was estimated by dividing the number of pneumonia episodes (in which S. pneumoniae was

microbiologically identified) by the total number of microbiologically-confirmed episodes.

An additional separate analysis was based on identification of S. pneumoniae results from

blood culture or urine antigen detection. For those studies only reporting the total number of

pathogens detected (but not the number of episodes), the pathogen-specific prevalence was

derived by dividing the number of S. pneumoniae pathogens detected by the total number of

7
pathogens detected. To assess the impact of this alternative approach, we also performed a

sensitivity anlaysis that excluded those studies that did not report the number of episodes

from which the organisms were identified. Results were pooled using a random-effects,
23
inverse-variance-weighted meta-analysis , leading to a pooled estimate. All proportions

were logit transformed before doing the meta-analysis. The Cochrane Q statistic was

determined, with P values < 0.05 indicating a significant amount of heterogeneity, as well as

the I2 statistic, which is to be interpreted as the proportion of total variation in the estimates of

treatment effect that is due to heterogeneity between studies. Low, moderate and high levels

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of heterogeneity correspond to I2 values of 25%, 50% and 75% respectively.

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Most studies relied upon a combination of four different sample collection methods but did
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not report results stratified by these sample collection methods. Therefore, we could not
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perform analyses pooled for each individual sample method. As an alternative method of

analysis, and to indirectly assess the potential impact of a sampling method, we estimated the
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average prevalence of S. pneumoniae across studies relying upon the same combination of
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sample collection methods, weighted by the number of samples in each study. As we found
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BAL to be the most commonly included sample collection method, we compared the

prevalence of S. pneumoniae in studies that included BAL to those without BAL.

We also assessed potential differences in the role of S. pneumoniae between North America

and Europe, where most publications originated. All analyses were performed in R version

3.2.0 using the ‘metafor’ package for meta-analyses 24, 25.

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Results

We identified 1908 articles during the selection process (Figure 1). Of the 1908 articles, 47 6,
21, 26-70
provided sufficient detail to be included for the analysis of the primary objective (i.e.,

to assess the extent to which S. pneumoniae had been identified as a pathogen for HAP); 41

studies were included for the secondary objective (i.e., to compare S. pneumoniae prevalence

by sample collection method, by health care setting, or between early- and late-onset HAP).

One study provided two estimates, among patients with and without COPD 61. Both of these

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estimates were treated as a unique estimate in the meta-analysis, resulting in a total of 48

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unique estimates of S. pneumoniae prevalence among patients with HAP.

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Most studies relied upon several respiratory specimen collection methods (Table 1). The 48
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studies represented a total of 19,190 repiratory specimens obtained using various collection
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methods; only 12% (6/48) of the studies did not specify the collection method used for the
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respiratory specimens, but these studies accounted for 56.4% (10,829/19,190) of the

respiratory specimens (Table I). The methods included at least one of the following
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respiratory specimen collection methods: BAL in 70.8% (34/48), tracheobronchial aspiration

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in 62.5% (30/48), sputum in 27.1% (13/48), and PSB in 18.9% (9/48) of the studies.

Culture was performed and reported in all studies, either on respiratory samples only (35/48;

72.9%), or on both respiratory samples and blood or pleural fluid (13/48; 27.1%). Eight

studies (8/48; 16.7%) reported only the total number of pathogens detected without

specifying the number of episodes from which these pathogens were obtained. A few studies

reported separate results for blood culture (4/48; 8.3%) or urine antigen testing (2/48; 4.2%),

in addition to the respiratory cultures. The rate of identification of any pathogen tended to be
30, 46 52,
lower in nVAP episodes (range 18-42% ) compared to VAP episodes (range 47-98%
66
).

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 Objective 1: S. pneumoniae identification as a potential pathogen involved in HAP

We identified 20 studies that reported the proportion of S. pneumoniae identified in any HAP
6, 26-44
, with 4 of these also reporting separate results for VAP and nVAP. The remaining 27

studies focussed specifically on nVAP (n=2; 45, 46) or VAP (n=25; 21, 47-70) (Figure 2).

S. pneumoniae in HAP

The prevalence of S. pneumoniae ranged from 0.0% to 14.3% in any microbiologically-

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confirmed HAP episode, and the pooled estimate was 5.1% (95% confidence interval

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[95%CI]: 3.8-6.6%). Three of these studies reported 0% prevalence of S. pneumoniae in HAP
34 41
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episodes: one in solid organ transplant recipients , another in lung transplant recipients

and the third in patients across multiple wards 43. The highest prevalence of S. pneumoniae in
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HAP episodes was seen in two studies that included non-ICU patients, where S. pneumoniae
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was identified for 3 of 21 (14.3%) microbiologically confirmed episodes from an internal

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medicine department and for 6 of 42 (14.3%) microbiologically confirmed episodes from

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various departments (26 ICU and 16 non-ICU) 39, 71.

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S. pneumoniae in nVAP

Six studies reported S. pneumoniae detection in microbiologically confirmed nVAP episodes,

with the prevalence ranging from 0.0% to 20.0% and a pooled estimate of 6.0% (95%CI: 4.1-

8.8%, Figure 2). The study in which no S. pneumoniae was detected was carried out among

inpatients on acute internal medicine and general surgical wards 46. The highest prevalence of

S. pneumoniae was found among 2 of 10 elderly adults (>65 years of age) with a lower limb

fracture 45.

S. pneumoniae in VAP

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Reports of the presence of S. pneumoniae in HAP, patients with VAP represented the largest

number of studies (n=29). The prevalence of S. pneumoniae in microbiologically-confirmed

VAP episodes ranged from 1/215 (0.5%), found in a study among critically ill patients

receiving mechanical ventilation 64, to 16/94 positives (17%) among ventilated patients with
21
severe subarachnoid hemorrhage . The overall pooled estimate was 5.2% (95%CI: 4.3-

6.7%, Figure 2).

Objective 2: Importance of S. pneumoniae in HAP by specimen collection method,

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healthcare setting and onset

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When the collection method for respiratory specimens was specified, it was noted that a
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range of specimen collection method combinations had been used, with nine of the 16
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possible permutations of the four collection methods being reported. The average prevalence
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of S. pneumoniae ranged from 4.9% to 12.7% across these groups of studies (Table 1). The
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estimates were comparable between studies that relied exclusively on BAL (5.7%) compared

to those studies that relied exclusively on sputum (5.0%). The average prevalence of S.
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pneumoniae across studies was 7.3% when including BAL and 6.5% when not including
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BAL.

By healthcare setting, the pooled estimate of S. pneumoniae prevalence in microbiologically-

confirmed HAP episodes occurring in the ICU was estimated as 5.3% (95%CI: 4.5-6.3%),

with a range from 0.5% to 17.0%. This compared to 5.6% (95%CI: 3.3-9.5), with a range of

0.0% to 14.3%, outside of the ICU (Figure 3).

Considering the time of onset, the pooled estimates for the prevalence of S. pneumoniae in

HAP episodes was 10.3% (95%CI: 8.3-12.8%) for early-onset episodes and 3.3% (95%CI:

2.5-4.4%) for late-onset episodes (Figure 4). Similar trends of lower S. pneumoniae detection

11
levels in late-onset pneumonias, as compared to early-onset, were observed when analyzing

by HAP, nVAP, or VAP (data not shown).

Non-respiratory samples and sensitivity analysis

Among the four studies that reported the prevalence of S. pneumoniae among bacteraemic

HAP patients, the S. pneumoniae positivity rate of bacteremic HAP episodes in blood

cultures ranged widely, from 0.0% (0/26 patients 62) to 25.0% (1/4 patients, 46), with a pooled
40, 46, 47, 62
estimate of 3.0% among 132 episodes . Finally, two studies reported results of

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pneumococcal urine antigen detection test separately, and S. pneumoniae was identified in

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1.4% (1/69 patients 30) and 15.6% (12/77 patients 72) of HAP episodes. The pooled estimate
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of S. pneumoniae antigen detection in urine for these two studies was 8.9%.
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Episode-specific prevalence could be compared with the pathogen-specific prevalence. In this
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sub-analysis, the pooled prevalence estimate of S. pneumoniae among microbiologically-

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confirmed HAP was 5.4%. Exclusion of the studies that only reported the total number of
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pathogens, but not the number of episodes from which these were detected, did not result in
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significantly different results.

Importance of S. pneumoniae in HAP by regions

Fifteen and 31 of 47 studies were from North America and Europe, respectively. The

prevalence of S. pneumoniae estimates in North America and Europe were as follows: in

HAP, 6.9% vs. 4.9%; in VAP 5.5% vs. 6.3%; in NV-HAP, 5.7% vs 4.9%.

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Discussion

To the best of our knowledge, this is the first systematic review of studies describing S.

pneumoniae as a potential pathogen among microbiologically-confirmed HAP patients. We

found that S. pneumoniae detection rates ranged from 0 to 17.0%, with pooled estimates of

5.1% for HAP, 6.0% for nVAP and 5.4% for VAP.

It is projected that at least 530,000 episodes of pneumococcal pneumonia occur annually in

the context of CAP in adults aged ≥50 years in the United States, causing nearly 25,000

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73, 74
deaths , but this estimate does not take into account hospital-acquired episodes

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potentially caused by S. pneumoniae. While we calculated that S. pneumoniae is present in
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5.0% of microbiologically-confirmed HAP episodes, for CAP, S. pneumoniae has been
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estimated to be involved in 13.5% of microbiologically-confirmed cases in the United States
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75
(when S. pneumoniae was identified, in approximately 69% of the cases was the single
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organism identified and in 31% of the cases it was part of a coinfection) and 12-68% in

Europe 76. Although the documented contribution of S. pneumoniae is lower for HAP than for
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CAP, this difference may partly result from a difference in thoroughness in testing for the
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pneumococcus; almost all HAP studies in this review relied on culture. By contrast, recent

CAP studies have often employed molecular methods such as PCR or urine antigen detection.

For instance, in a recent study of CAP by Jain et al. 75, 67% of all S. pneumoniae CAP cases

were detected uniquely by using a commercially available urinary antigen detection test.

HAP comes with a higher mortality, a higher propensity to be caused by bacteria resistant to

empiric antibiotic therapy, longer length of stay, and higher utilization of intensive and

expensive health care services, as compared to CAP 77; consequently, even though there are

fewer HAP than CAP cases, the average HAP patient represents a greater burden to the health

care system. For example, in New York City alone, there were 283,927 hospitalizations with

13
pneumonia between 2010 and 2014, representing 6.2% of all hospitalizations; during that

period, HAP accounted for 15.6% of hospitalized patients with pneumonia and represented

25% of all pneumonia associated deaths 78. Similarly in Italy, during two 1-week surveillance

periods in 55 hospitals, HAP represented 13.5% of pneumonia episodes among hospitalized

patients 79. A meta-analysis of VAP prevention among 6284 patients from 24 trials estimated
80
the VAP attributable mortality at 13% , compared to CAP attributable mortality during
81
hospitalization of 6.5% . A review of 14 case-control studies between 1990 and 2007

estimated that having HAP prolonged the duration of stay by 11.5 days in the hospital and by

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8.7 days in the ICU 82.

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The intensity of resource utilization among patients with HAP is also substantial. For
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example, a 2011 multistate point-prevalence survey using the National Healthcare Safety
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Network criteria for hospital-acquired infections estimated that HAP cases represented 24.3%

of hospital-acquired infections (157,500, range: 50,800-281,400) and S. pneumoniae was

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identified in 6.4% of the HAP cases 5. Among European intensive care unit patients with
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pneumonia requiring mechanical ventilation, 75.9% had HAP; the others were diagnosed as
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CAP 6. Consequently, pneumococcal HAP adds substantially to the potentially preventable

public health burden of pneumococcal pneumonia. HAP also represents a substantial

economic burden. A US database analysis of 88,689 hospitalizations in 2009, where 2.5%

were identified as HAP, estimated that having HAP increased the hospitalization cost by

$39,828 (not adjusted into 2019 dollars) 83.

Although the specimen collection method can affect diagnosis of the respiratory etiology, our

analysis suggests that S. pneumoniae infection diagnosis in HAP is not related to

contamination from the throat or upper airways. For example, we did not find a difference in

the prevalence of S. pneumoniae when analysing studies with and without BAL as one of the

14
sample collection method. A similar observation was made by Gastmeier and colleagues who

found an identical proportion (6.0%) of S. pneumoniae among 11,285 samples collected from
59
various respiratory specimens and a subset of 1,609 samples collected via BAL .

Furthermore, studies relying upon different combination of collection methods could not

differentiate prevalence of S. pneumoniae by specific specimen collection method (Table 1).

7
Based on the 2012 US National Inpatient Sample dataset, Giuliano et al. concluded that

nVAP is an underappreciated and serious patient safety issue, resulting in statistically

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significant increases in cost, length of stay, and mortality. VAP can be diagnosed by any one

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84
of several standard criteria , and many hospitals have achieved significant reductions in

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VAP rates in their ICUs by implementing multifaceted infection-control measures aimed to
85, 86
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reduce the risk for VAP . In contrast, nVAP is more difficult to detect because of the
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difficulties to obtain respiratory specimens in non-intubated patients, which might be

compounded by the dispersion of cases across different hospital clinical service units.
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Nonetheless, we found a similar frequency in nVAP (6.0%, 95%CI:4.1-8.8%) and VAP

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(5.2%, 95%CI:4.3-6.7%). A study by Davis et al. showed that there were no statistically
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significant differences between VAP and nVAP case-mortality rates, and suggested that

cumulative medical costs will grow if prevention efforts continue to overlook nVAP by only

focusing largely on VAP.

With respect to the presence of S. pneumoniae by whether the HAP occurred within or

outside of the ICU, we found a slightly lower prevalence of S. pneumoniae in the ICU setting

compared to the non-ICU setting, while S. pneumoniae seems to play a particularly important

role in early hospitalization or ventilation (as indicated by the prevalence of S. pneumoniae in

early-onset HAP). The lower prevalence rates of S, pneumoniae in late-onset HAP may result

from a cumulative exposure to antibiotics, which greatly reduces the detection rate of S.

15
pneumoniae by culture methods. Likewise, exposure to the hospital environment, including

antibiotics, might lead to changes in the endogenous microbiome towards to a preponderance

of hospital-associated pathogens like S. aureus (including MRSA), P. aeruginosa, K.

pneumoniae or Acinetobacter spp. Furthermore, frailty and immunosuppression among ICU

patients may lead to greater susceptibility to hospital-associated pathogens.

Our study was subject to some limitations that may have affected the estimation of the

importance of S. pneumoniae as an identified pathogen in HAP. First, the findings are limited

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by geography, (i.e., countries in North America and Europe plus Japan, New Zealand and

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Australia). While we cannot generalize our findings to other geographic regions, it is worth

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noting that in a 1-day, prospective, point prevalence study in ICUs from 75 countries across
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all continents S. pneumoniae was identified in 4.1% of all culture-positive infected patients
87
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(though slightly lower in Asia and Oceania) . This estimated value is comparable to the

findings in our study.

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Second, most studies used microbiologically confirmed episodes of HAP to report the
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prevalence of S. pneumoniae, which can lack sensitivity. The success rate (where these rates
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were reported or could be derived from the available information) for identifying any

microbiological pathogen ranged from 18% to 98% across the studies. Not surprisingly, we

found higher detection rates in VAP episodes, where specimens can be collected more

straightforwardly. As we saw no clear correlation between the detection rates of S.

pneumoniae and overall microbiological detection (data not shown), we cannot infer whether

higher overall detection rates for microbiological pathogens would lead to greater or smaller

prevalence estimates for S. pneumoniae among HAP episodes. It is probable, however, that

many studies underestimated the presence of S. pneumoniae because they relied on culture

rather than on more sensitive molecular methods such as PCR or urine antigen detection.

16
Finally, the liberal use of antibiotics in the hospital setting may have also prevented etiologic

determination.

Third, some studies reported pathogen-specific prevalence (i.e., the pathogen distribution by

overall number of pathogens detected) without specifying the number of episodes. For

polymicrobial infections, the number of pathogens would exceed the number of episodes, so

including polymicrobial infections may have resulted in an underestimate of the prevalence

of any individual pathogen, such as S. pneumoniae. In a sensitivity analysis that excluded

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studies with polymicrobial infections, however, we arrived at a comparable estimate of the S.

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pneumoniae prevalence (5.4% compared to 5.1% for all studies), suggesting that

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polymicrobial infections may have been relatively rare.
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Fourth, we only included studies that explicitly mentioned the presence or absence of S.
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pneumoniae in their publications. It is possible that some investigators did not report the
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absence of S. pneumoniae in their specimens. If this is the case, we may have overestimated

the importance of S. pneumoniae.

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Fifth, due to an insufficient number of studies we did not stratify our findings on other factors

that may have influenced the microbiologic identification of HAP and VAP, such as

underlying risk factors, diagnostic sampling sources and frequency, microbiological

techniques used for detection, and differences in empiric treatment policies as well as

infection control measures in place. This may have resulted in the varying levels of

heterogeneity observed in the pooled estimates, with I2 values ranging from 15% to 82%.

With respect to diagnostic sampling sources and frequency, while 88% of the studies

specified the collection method of the respiratory specimens, the remaining 12% of studies

involved about half of the total respiratory specimens, where the potential impact of the

collection method could not be assessed. Nevertheless, BAL was used in 73% of studies as a

17
common sampling source in HAP episodes from which S. pneumoniae was identified.

Although the microbiological identification of S. pneumoniae or any other pathogen from a

non-invasive source does not confirm causality, this suggested that our results could not be

explained by nasopharyngeal carriage alone. In contrast, heterogeneity in our global estimates

may be related to differences between studies in the onset time of the episodes, as suggested

by the reduction in heterogeneity when stratifying the analyses by onset time. Other factors

potentially accounting for heterogeneity, but not tested, are geographical differences, the

impact of vaccination policies, as well as differences in microbiological testing practices. For

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example, in a post-hoc analysis, we found small differences in the prevalence of S.

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pneumoniae in HAP and VAP between North America and Europe, where most studies were

conducted.
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Finally, although we did not include other regions in the world for this systematic literature

review because it was beyond the scope of the study, considering the relatively high
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importance of S. pneumoniae in CAP and the lack of robust pneumococcal vaccination

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programs in other regions, it is likely that we would have found S. pneumoniae to play an
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substantial role in HAP.

Conclusions

While previous reports suggest that S. pneumoniae may not play an important role in HAP,

our meta-analysis identified S. pneumoniae in 5.1% of HAP episodes with an established

microbiological etiology. Previous reports have shown that HAP has substantially worse

outcomes and greater health service utilization than CAP. Future clinical studies could

elaborate the contribution of S. pneumoniae to HAP by more sensitive detection methods

(i.e., incorporating molecular detection methodologies in addition to culture) and by broader

patient inclusion (i.e., enrolling nVAP patients as well as VAP patients). Taken together, this

18
could help to establish that HAP, in addition to CAP, may need to be considered when

evaluating the total public health benefit of interventions to prevent pneumococcal

pneumonia.

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19
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Table I. Specimen collection methods used for Streptococcus pneumoniae detection.

Number % Spn
BAL Tracheobronchial PSB Sputum Specimens*
of studies positive
Yes 2 398 4.8%
Yes
No 4 1284 7.8%
Yes
Yes 8 1379 4.4%
No
No 10 2104 6.0%
Yes
Yes 0
Yes
No 2 388 11.6%
No
Yes 0
No
No 8 1289 5.2%
Yes 0
Yes

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No 1 57 1,8%
Yes
Yes 1 575 4.9%

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No
No 4 904 4.8%
No
Yes 0

No
Yes
No
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Yes 2 40 5.0%
No
No 0
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Unknown Unknown Unknown Unknown 6 10829 6.5%

Note.* with microbiological confirmation. Abbreviations: BAL – bronchoalveolar lavage;

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PSB – protective specimen brush; Spn – Streptococcus pneumoniae

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Figure 1. Hospital-acquired pneumonia SLR PRISMA flow diagram

Identification
Records identified through PubMed Additional records identified
(n = 1,907) through hand search
(n = 10)

Records after duplicates removed

(n = 1,908)
Screening

Records excluded because

Inclusion criteria applied of country of origin and

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language
(n = 1,019)

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Eligibility

Full-text articles assessed Full-text articles excluded,

for eligibility
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because of outcome
(n = 889) (n = 842)
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Studies included in qualitative &

quantitative synthesis (meta-analysis)
(n = 47)
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Included

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Studies contributing to Studies contributing to

primary objective both review objectives
(n = 47, one study (n = 41)
provided two datasets)

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Figure 2. Forest plot of the proportion of pneumonia episodes with identification of

Streptococcus pneumoniae.

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Figure 3. Forest plot of the proportion of hospital-acquired pneumonias with identification of

Streptococcus pneumoniae by ward type.

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Figure 4. Forest plot of the proportion of hospital-acquired pneumonias with identification of

Streptococcus pneumoniae by time of onset.

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Legends to the figures

Figure 1. Hospital-acquired pneumonia SLR PRISMA flow diagram.

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Figure 2. Forest plot of the proportion of pneumonia episodes with identification of

Streptococcus pneumoniae.

For each study the first author, publication year, country of study conduct and, if applicable,

the special patient population is given.

95%CI - 95% confidence interval; HAP - Hospital-acquired Pneumonia; nVAP - Non-

Ventilator Associated Hospital-acquired Pneumonia; RE – random effects; VAP - Ventilator

Associated Pneumonia.

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Figure 3. Forest plot of the proportion of hospital-acquired pneumonias with identification of

Streptococcus pneumoniae by ward type.

For each study the first author, publication year, country of study conduct, type of pneumonia

and, if applicable, the special patient population is given.

95%CI - 95% confidence interval; HAP - Hospital-acquired Pneumonia; ICU - Intensive

Care Unit; nVAP - Non-Ventilator Associated Hospital-acquired Pneumonia; RE – random

effects; VAP - Ventilator Associated Pneumonia.

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Figure 4. Forest plot of the proportion of hospital-acquired pneumonias with identification of

Streptococcus pneumoniae by time of onset.

For each study the first author, publication year, country of study conduct, type of pneumonia

and, if applicable, the special patient population is given.

95%CI - 95% confidence interval; HAP - Hospital-acquired Pneumonia; nVAP - Non-

Ventilator Associated Hospital-acquired Pneumonia; RE – random effects; VAP - Ventilator

Associated Pneumonia.

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Acknowledgement: The authors are grateful to Kaatje Bollaerts for statistical support and

Marc Baay for editorial support, both from P95 Epidemiology and Pharmacovigilance,

Leuven, Belgium.

Conflict of interest: Coauthors from Pfizer Inc may hold stock or stock options. Coauthors

from P95 received contracted research fees from Pfizer for the conduct of the study.

Funding: This is a Pfizer sponsored study, a collaboration with P95 Epidemiology and

Pharmacovigilance, Leuven, Belgium, as reflected by authorship.

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