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  • Research article
  • Open Access
  • Open Peer Review

Prevalence and serotype distribution of nasopharyngeal carriage of Streptococcus pneumoniae in China: a meta-analysis

  • 1,
  • 2,
  • 3 and
  • 4Email author
Contributed equally
BMC Infectious DiseasesBMC series – open, inclusive and trusted201717:765

https://doi.org/10.1186/s12879-017-2816-8

  • Received: 25 April 2017
  • Accepted: 2 November 2017
  • Published:
Open Peer Review reports

Abstract

Background

To explore the overall prevalence and serotype distribution of nasopharyngeal carriage of Streptococcus pneumoniae(S. pneumoniae) among healthy children.

Methods

A search for pneumococcal nasopharyngeal carriage studies including children published up to July 31th, 2016 was conducted to describe carriage in China. The review also describes antibiotic resistance in and serotypes of S. pneumoniae and assesses the impact of vaccination on carriage in this region. Summary measures for overall prevalence, antibiotic resistance, and serotype distributions extracted from the analyzed data were determined with 95% confidence intervals (CIs) using random-effects models. Heterogeneity was assessed using I 2 test statistics.

Results

Thirty-seven studies were included in this review, and the majority of studies (64.9%) were located in the pre-introduction period of 7-valent pneumococcal conjugate vaccine (PCV7) in China. The pooled prevalence of S. pneumoniae nasopharyngeal carriage was 21.4% (95% CI: 18.3–24.4%). Carriage was highest in children attending kindergartens [24.5%, (19.7–29.3%)] and decreased with increasing age. Before the introduction of PCV7 into China, the prevalence of S. pneumoniae nasopharyngeal carriage was 25.8% (20.7–30.9%), the pooled carriage of S. pneumoniae sharply dropped into the 14.1% (11.3–16.9%) by PCV7 vaccination period (P < 0.001). Before the pneumococcal conjugate vaccine (PCV) was introduced in China, the penicillin resistance rate in S. pneumoniae isolated from healthy children was 31.9% (21.2–42.6%); however, this rate sharply decreased after the introduction of PCV7 in China [21.6%, (7.4–35.9%)], and the difference between the rates during these two time periods was statistically significant (P value <0.05). Serotypes 19F, 6A and 23F were the most commonly isolated. Meta-analysis of data from young children showed a pooled rate estimate of 46.6% (38.8–54.4%) for PCV7 vaccine coverage and 66.2% (58.6–73.8%) for PCV13 vaccine coverage.

Conclusions

The prevalence of nasopharyngeal carriage among children was high in China. PCV7 immunization was found to be associated with reduction of nasopharyngeal colonization of S. pneumoniae. Conjugate vaccination coverage was slightly affected by the introduction of PCV7 into China because of low vaccination rate. The government should implement timely adjusted conjugate vaccination strategies based on our findings.

Keywords

  • Streptococcus Pneumoniae
  • Healthy children
  • Serotype distribution
  • Meta-analysis

Background

Streptococcus pneumoniae (S. pneumoniae) is a major pathogen that can cause invasive pneumococcal disease (IPD) and respiratory tract infections and result in high morbidity and mortality. The World Health Organization has reported that nearly 500,000 children under 5 years of age are infected by S. pneumoniae annually, and the vast majority of these infections occur in developing countries [1]. Asymptomatic nasopharyngeal carriage of S. pneumoniae is an essential element of the transmission of pneumococcal disease [2], a prerequisite for the occurrence of invasive pneumococcal disease, and a known risk factor for subsequent acute and recurrent otitis media [3, 4].

The prevalence of nasopharyngeal pneumococcal carriage has been found to vary in different countries and regions [5]. Because S. pneumoniae carriage is more common than the S. pneumoniae disease, it is important to investigate carriage status to evaluate the effect of new pneumococcal vaccines [6]. When the 7-valent pneumococcal vaccine was introduced in mainland China, the invasive pneumococcal disease burden decreased sharply, especially disease caused by the vaccine type (VT) serotypes; this decrease was accompanied by an increase in non-vaccine type (NVT) serotype, particularly serotype 19A, as previously seen in Europe [7, 8].

This systematic review was conducted to describe the nasopharyngeal carriage status of S. pneumoniae in healthy children, describe the major serotypes of S. pneumoniae, and evaluate the impact of pneumococcal vaccination on the coverage of PCV7.

Methods

Literature search

The following databases were searched for relevant articles through July 31, 2016 without language limitations: PubMed, Web of Science, EMBASE, CNKI, and WANFANG database. Keywords used for this search were: (“China” OR “Chinese”), (“nasal” OR “nasopharyngeal” OR “oropharyngeal”), (“children” OR “pediatric” OR “paediatric”), (“carriage” OR “colonization” OR “colonisation”) “Streptococcus pneumoniae”, “serotypes”, “pneumococcal vaccine”.

Inclusion and exclusion criteria

Studies were required to meet the following criteria for inclusion in this meta-analysis: (1) subjects were healthy children, (2) samples were collected from nasopharyngeal or oropharyngeal swabs, (3) studies focused on non-vaccination group and (4) sufficient information was provided to compute positive carriage rates and their 95% confidence intervals (CIs). Exclusion criteria were as follows: (1) if a study included both adults and children, only children data were enrolled, (2) studies reporting clinical infectious diseases caused by S. pneumoniae, (3) if studies included both vaccinated and non-vaccinated children, only non-vaccinated data were enrolled, (4)studies with a lack of sufficient baseline information to compute carriage rates and their 95CIs, (5) review studies, or conference studies or newspaper articles, (6) studies determining antibiotic resistance rates without carriage data, or studies were referred to infections rather than colonization, and (7) duplicate reports.

Data extraction

Two reviewers (LW and JF) independently identified and extracted the following data: first authors, sample year, study location, study population, number of participants, number of participants with pneumococcal carriage, pre/post vaccination period, vaccination history, type of swabs, immediately incubated into plates or not, transportation period, culture plates, culture into the 5% CO2 or not, identification methods, serotyping methods, storage medium, rates of antibiotic resistance, and prevalence of S. pneumoniae serotypes and their corresponding 95% CIs.

Quality assessment

The quality of included studies was assessed in accordance with the STROBE statement [9], studies with scores <8 were excluded from the systematic review.

Statistical analysis

STATA version 10.0 was used to perform the statistical analyses. DerSimonian and Laird random-effects models (REM) were used to pool the data. Funnel plots were used to examine publication bias, which was further assessed using Egger’s test, with P < 0.10 indicating potential bias [10]. Stratified analyses were carried out to assess the heterogeneity across subgroup defined by age and PCV7 vaccination period.

Results

Characteristic of included studies

The flow chart in Fig. 1 depicts the selection process for the included studies. Overall, 614 studies were written in Chinese, and 21 studies were written in English. By reviewing the titles and abstracts, 487 articles were excluded; by using the inclusion/exclusion criteria, 37 articles were selected for further investigation that included a total of 18,881 children. They were all cross-sectional studies. The main characteristics of the studies are listed in Table 1. The first study of nasopharyngeal carriage of S. pneumoniae in healthy children was conducted in two kindergartens in Beijing in 1999. All samples were from nasopharyngeal and nasal swabs. The ages of the healthy children included in the studies ranged from 0 to 14 years.
Fig. 1
Fig. 1

Flow chart of the study selection process

Table 1

The characteristic of the included studies

Author

Sample year

Location

Population

Pre/post vaccination period

Vaccination history

Number of participants

Number of participants with pneumococcal carriage

Quality scores

Guoling Ping [11]

2009

Beijing

12–18 months

Post

No

600

47

17

Yakun Liu [12]

2005

Hubei

kindergarten

Pre

No

297

78

12

Yan Kang [13]

2010

Heilongjiang

kindergarten

Post

N/A

100

23

13

Liping Zhang [14]

2011

Donguan

12–18 months

Post

No

600

115

14

Hongmei Yang [15]

2011

Hubei

kindergarten & > 5 years

Post

N/A

301

66

14

Fan Yang [16]

1997–1998

Shanghai

kindergarten

Pre

No

791

222

14

Yali Liu [17]

2009

National

12–18 months

Post

No

3635

451

15

Hao Li [18]

2000

Heinan

kindergarten

Pre

No

571

151

12

Xiyuan Zhao [19]

2005

Zhongshan

>5 years

Pre

No

327

25

11

Ancun Hou [20]

1995–2000

Beijing

All age groups

Pre

No

307

57

16

Jun Liu [21]

2005

Shenyang

kindergarten

Pre

No

110

14

11

Fuqin Li [22]

2005

Hebei

kindergarten

Pre

No

100

24

12

Jianping Liang [23]

2003

Guangdong

kindergarten

Pre

No

186

61

12

Mingzhi Di [24]

2010

Beijing

All age groups

Post

1.8%vaccinated

221

45

17

Yongming He [25]

2005

Guangdong

kindergarten

Pre

No

350

121

12

Chunzhen Hua [26]

2004

Zhejiang

kindergarten

Pre

No

1220

67

14

Sangjie Yu [27]

2000

Beijing

kindergarten

Pre

No

502

190

19

Ziyong Sun [28]

2007

Wuhan

kindergarten

Pre

No

605

135

16

Hong Zhou [29]

2002

Guangdong

kindergarten

Pre

No

150

35

15

Lihua Zhang [30]

2005

Guangdong

kindergarten

Pre

No

344

132

13

Hui Wang [31]

1999

Beijing

kindergarten

Pre

No

985

244

16

Hui Chen [32]

2010

Guangdong

kindergarten

Post

N/A

120

16

15

Jing Zhang [33]

2004

Wuhan

kindergarten

Pre

No

469

116

14

Aiying Bai [34]

2010

Shandong

12–18 months

Post

No

611

57

16

Zhipeng Gao [35]

2012

Beijing

kindergarten

Post

Half vaccinated

472

103

18

Benquan Wu [36]

2000

Guangdong

kindergarten

Pre

No

220

53

17

Lihua Jiang [37]

2014

Guangxi

kindergarten & > 5 years

Post

N/A

1475

148

18

Zhigang Lai [38]

2006

Guangdong

kindergarten

Pre

No

344

132

15

Defeng Zhao [39]

2009

Wuhan

12–18 months

Post

No

596

75

18

Youqun Zeng [40]

2003

Chongqing

All age groups

Pre

No

400

76

12

NY Lee [41]

1998–1999

Beijing

kindergarten

Pre

No

267

100

17

Jiayu Hu [42]

2009

Shanghai

12–18 months

Post

No

614

102

18

Xiaoming Luo [43]

2002

Guangdong

All age groups

Pre

No

199

60

12

Yanhui Liu [44]

2006

Guangdong

kindergarten

Pre

No

400

138

11

Yanjie Liu [45]

2007

Liaoning

kindergarten

Pre

No

130

17

10

Xinghua Cao [46]

2012

Heilongjiang

kindergarten

Post

N/A

345

9

12

Dongke Chen [47]

1999

Beijing

kindergarten

Pre

No

156

56

12

Nasopharyngeal carriage rates of S. pneumoniae in healthy children

A total of 37 studies including 19,120 healthy children reported nasopharyngeal carriage of S. pneumoniae. Among them, 4 children from Di [24] and 235 children from Gao [35] reported a vaccination history, were all excluded. Finally, only 3511 colonization were reported among 18881non-vaccination children, The lowest prevalence was reported by XH Cao [46], which was 2.6% (0.9–4.3%); the highest prevalence was reported by ZG Lai [38], which was 38.4% (33.2–43.5%). The pooled prevalence of nasopharyngeal carriage of S. pneumoniae in healthy children was 21.4% (18.3–24.4%) (Fig. 2).
Fig. 2
Fig. 2

The pooled rate of nasopharyngeal carriage of Streptococcus pneumoniae

Identification and confirmation of S. pneumoniae with different methods

Table 2 summarizes the methods used to identify and confirm the S. pneumoniae strains. Three different methods, including PCR, optochin disk with bile solubility and latex agglutination were used. There was no impact on the prevalence of S. pneumoniae when using three different identification methods, see Fig. 3.
Table 2

Characteristics of sampling, culture and serotyping techniques

Author

Type of swabs

Immediately incubated into plates or not

Transportation period

Culture plates

Culture into the 5% CO2

Identification methods

Serotyping methods

Storage medium

Guoling Ping [11]

NP

Yes

4 h

5% sheep blood agar

Yes

Latex agglutination

N/A

Skim milk powder

Yakun Liu [12]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Yan Kang [13]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Liping Zhang [14]

NP

Yes

4 h

5% sheep blood agar

Yes

Latex agglutination

N/A

N/A

Hongmei Yang [15]

NP

Yes

4 h

5% sheep blood agar

Yes

PCR

N/A

Skim milk powder

Fan Yang [16]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

Quellung

Sheep and broth

Yali Liu [17]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

Quellung

Skim milk powder

Hao Li [18]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Latex agglutination

N/A

Glycerol broth

Xiyuan Zhao [19]

NP

Yes

0.5 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Ancun Hou [20]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Jun Liu [21]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Fuqin Li [22]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Jianping Liang [23]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Mingzhi Di [24]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Latex agglutination

N/A

N/A

Yongming He [25]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Latex agglutination

N/A

Skim milk powder

Chunzhen Hua [26]

NP

Nutrition broth then subculture

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Latex agglutination

N/A

N/A

Sangjie Yu [27]

NP

Nutrition broth then subculture

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

Quellung

N/A

Ziyong Sun [28]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

Quellung

N/A

Hong Zhou [29]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

Skim milk powder

Lihua Zhang [30]

NP

Yes

4 h

5% sheep blood agar

Yes

Latex agglutination

N/A

N/A

Hui Wang [31]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

Quellung

Skim milk powder

Hui Chen [32]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Jing Zhang [33]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

Quellung

N/A

Aiying Bai [34]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Zhipeng Gao [35]

NP

Yes

N/A

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Benquan Wu [36]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Lihua Jiang [37]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Zhigang Lai [38]

NP

Yes

4 h

5% sheep blood agar

Yes

Latex agglutination

N/A

N/A

Defeng Zhao [39]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

Quellung

N/A

Youqun Zeng [40]

NP

Yes

N/A

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

NY Lee [41]

nasal

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

Quellung

N/A

Jiayu Hu [42]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

Quellung

N/A

Xiaoming Luo [43]

NP

Yes

N/A

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Yanhui Liu [44]

NP

Yes

4 h

5% sheep blood agar

Yes

Latex agglutination

N/A

Skim milk powder

Yanjie Liu [45]

NP

Yes

4 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

Xinghua Cao [46]

NP

Yes

4 h

5% sheep blood agar

Yes

Optochin disk +bile solubility

N/A

N/A

Dongke Chen [47]

NP

Yes

0.5 h

TSA + 5% sheep blood + 5 μg/ml gentamicin

Yes

Optochin disk +bile solubility

N/A

N/A

NP nasopharyngel swab, TSA Trypticase soy agar, N/A not mentioned or not acquired

Fig. 3
Fig. 3

Identification and confirmation of S. pneumoniae with different methods

Nasopharyngeal carriage of S. pneumoniae by age

Figure 4 summarizes the prevalence of nasopharyngeal carriage of S. pneumoniae in healthy children in different age groups. Six studies [11, 14, 17, 34, 39, 42] reported the prevalence of nasopharyngeal carriage of S. pneumoniae among children younger than 2 years of age. Among the 6656 healthy children in this age group, a total of 847 were identified to be positive for nasopharyngeal carriage of Streptococcus pneumoniae; thus, the pooled prevalence was 11.7% (9.1–14.2%). Twenty-seven studies [1216, 18, 2133, 3638, 41, 4447] including 10,480 kindergarten children (2–5 years of age) investigated the prevalence of nasopharyngeal carriage of S. pneumoniae. Within these studies, a total of 2437 children were identified to be positive for S. pneumoniae carriage, and the pooled prevalence was 24.5% (19.7–29.3%). Among the 1122 healthy children who were older than 5 years of age [15, 19, 37], 104 were identified as S. pneumoniae carriers; therefore, the prevalence of nasopharyngeal carriage was 8.8% (6.0–11.5%) in this age group. The prevalence of nasopharyngeal carriage of S. pneumoniae varied between the three age groups, with the highest rate reported in kindergarten children (P = 0.002).
Fig. 4
Fig. 4

The pooled prevalence of nasopharyngeal carriage of S. pneumoniae distributed by age

PCV7 and S. pneumoniae nasopharyngeal carriage

The 7-valent pneumococcal conjugate vaccine was introduced to China in October 2008, but it has not yet been included in the Chinese Expanded Program on Immunizations (EPI) [48]. Unlike the vaccination in Chinsed EPI schedule, the PCV7 vaccine was not free to the public and the coverage was estimated as 9.91% [49].

Before the PCV7 was introduced in mainland China, 24 studies [12, 16, 1823, 2531, 33, 36, 40, 41, 4345, 47] had reported the prevalence of nasopharyngeal carriage of S. pneumoniae; within these studies, the pooled prevalence was 25.8% (20.7–30.9%), Fig. 5. The prevalence of nasopharyngeal carriage sharply declined following the introduction of PCV7, with a pooled prevalence of 14.1% (11.3–16.9%) identified in studies conducted post-PCV7 introduction [11, 1315, 17, 24, 32, 34, 35, 37, 39, 42, 46]. There was a highly significance differences in the prevalence between these two time periods (P < 0.001). In kindergarten children, before the pcv7 vaccination period, the pooled prevalence was 27.2% (21.3, 33.2%) and 16.6% (9.5, 23.7%) in the post vaccination period (P < 0.001).
Fig. 5
Fig. 5

The pooled prevalence of nasopharyngeal carriage of S. pneumoniae stratified by vaccination period

Overall heterogeneity and publication bias

Stratified analyses were carried out to assess the heterogeneity across subgroups defined by age, PCV7 introduction period and PCV7 introduction period within kindergarten children groups. The sensitivity analysis indicated that the pooled prevalence of S. pneumoniae carriage had only slight variations by stratified studies into pre/post vaccination period when individual studies were omitted one by one. The prevalence estimates ranged from 13.4% (10.6, 16.1%) to 14.8% (12.5, 17.1%) in post vaccination period and from 25.2% (20.7, 31.1%) to 26.3% (21.1, 31.6%) in pre-vaccination period, suggesting that the results were stable.

Slight publication bias was noted from the statistical tests (Egger’s test, P = 0.011; Begg’s test, P = 0.01). After stratified the pooled prevalence of S. pneumoniae by PCV7 vaccination period, the potential publication bias was adjusted as no significant (Egger’s test, P = 0.134; Begg’s test, P = 0.602) in pre-vaccination period and (Egger’s test, P = 0.353; Begg’s test, P = 0.125) in post vaccination period.

Antibiotic resistance profiles of the isolates

A total of 20 studies [11, 12, 15, 16, 18, 20, 21, 23, 2528, 31, 33, 34, 36, 37, 4042] were identified that reported antibiotic resistance in S. pneumoniae. The rate of pneumococcal resistant to levofloxacin was 2.5% (0.3–4.6%), which was the lowest rate of antibiotic resistance identified. The highest resistant rate was reported against tetracycline antibiotics; for this class of antibiotics, a pooled resistance rate of 67.1% (33.8–96.4%) was identified. The pneumococcal resistance rate to penicillin was 28.9% (20.4–37.4%). Before the introduction of PCV7 [12, 16, 18, 20, 23, 2528, 31, 33, 36, 40, 41], the pooled resistant rate to penicillin was 31.9% (21.2–42.6%). This rate decreased by 21.6% (7.4–35.9%) following the introduction of PCV7 [11, 15, 21, 34, 37, 42]. The penicillin resistant rate varied significantly between the pre- and post-PCV7 time periods (P < 0.001) (Table 3). The results of subgroup analysis indicated that the heterogeneity of resistant to penicillin may came from pre/post vaccination period, while the rest of them may came from different age groups. A slightly publication bias was found in Chloromycetin resistant rate, no publication bias was found in the rest of the antibiotics.
Table 3

The resistance of antibiotic among all the S. pneumoniae

Antibiotic

No. of studies

Total no. of included strains

No. of included strains with antibiotic resistant

Resistant rate(%) (95%CI)

I 2

P

P value of Egger’s test

P value of Egger’s test

Penicillin

20

2105

541

28.9(20.4, 37.4)

69.9

0.000

0.147

0.298

Cefaclor

6

499

463

65.8(51.2, 80.4)

91.6

0.000

0.434

0.462

Ceftriaxone

8

771

90

19.4(9.2, 29.5)

96.9

0.000

0.175

0.266

Levofloxacin

13

1175

159

2.5(0.3, 4.6)

70.2

0.009

0.226

0.602

Erythromycin

14

1635

1185

65.9(57.0, 74.9)

93.6

0.000

0.131

0.108

Clindamycin

9

878

675

64.0(45.5, 82.5)

96.2

0.000

0.247

0.221

Tetracycline

12

1334

967

67.1(33.8,96.4)

99.7

0.000

0.249

0.548

Cotrimoxazole

13

1524

1103

64.5(51.2, 77.8)

96.7

0.000

1.000

0.704

Chloromycetin

13

1524

360

24.1(16.7, 31.5)

91.8

0.000

0.039

0.019

Serotypes and S. pneumoniae nasopharyngeal carriage

Nine studies [17, 18, 29, 30, 33, 35, 41, 43, 44] reported the serotypes of Streptococcus pneumoniae. In the 1626 isolates evaluated, 11 different serotypes were identified, and the predominant serotype was 19F. The pooled prevalence of serotype 19F was 19.1% (12.2–26.0%). The least prevalent serotype was 18C, which was identified in 3.2% (0.1–6.3%) of isolates (Fig. 6, Table 4). Of the 1626 isolates, 755 were identified as serotypes included in the coverage of PCV7, and 1059 were identified as serotypes included in the coverage of PCV13. The serotype coverage rates were 46.6% (38.8–54.4%) for PCV7 and 66.2% (58.6–73.8%) for PCV13. >Before PCV7 was introduced in mainland China [16, 27, 28, 31, 38, 41], the serotype coverage rates of PCV7 and PCV13 were 43.9% (34.1–53.6%) and 66.8% (56.1–76.0%), respectively. These rates changed to 52.1% (37.3–66.9%) and 66.3% (50.6–81.9%) for PCV7 and PCV13, respectively, following the introduction of PCV7 [17, 39, 42].
Fig. 6
Fig. 6

The pooled prevalence of major serotypes of S. pneumoniaedistributed among healthy children in China

Table 4

Analysis of major serotypes of Streptococcus pneumoniae

Serotype

No. of studies

Total no. of included strains

No. of included strains with identical serotypes

Prevalence(%)(95%CI)

I 2

P

P value of Egger’s test

P value of Egger’s test

23F

9

1175

187

14.0(8.4–19.7)

89.4

0.000

0.266

0.193

6A

9

1175

174

11.9(6.3–17.5)

90.2

0.000

0.032

0.063

19F

9

1626

322

19.1(12.2–26.0)

93.3

0.000

0.754

0.602

6B

6

1175

86

6.8(4.7, 8.9)

0.0

0.474

0.739

0.902

14

8

1382

85

5.5(4.0, 6.9)

31.3

0.187

0.910

0.754

18C

3

397

16

3.2(0.1, 6.3)

68.6

0.041

0.631

0.620

15

7

1332

86

5.7(3.6, 7.8)

63.6

0.011

0.502

0.548

19A

4

1192

99

8.7(5.9–11.6)

65.6

0.008

0.142

0.764

PCV7

 

1626

755

 

90.2

0.000

0.953

0.917

PCV13

 

1626

1059

 

90.0

0.000

0.644

0.602

Heterogeneity was detected in the serotype distributions of 23F, 6A, 19F, 18C, 15, 19A and PCV7, PCV13 vaccine coverage rate (all P values were <0.05), although after sequential exclusion of each study, the conclusion was not affected by the exclusion of any specific study.

Discussion

This systematic review analyzed the prevalence and serotype distributions of nasopharyngeal carriage of S. pneumoniae, antibiotic resistant rates in S. pneumoniae, and the rates corresponding the serotype coverage provided by PCV7 and PCV13.

Since the serotypes distribution of and antibiotic resistance in S. pneumoniae isolates have been found to vary from region to region, the prevalence of S. pneumoniae has also been found to vary in different populations. The prevalence of nasopharyngeal carriage of S. pneumoniae was found to be 60% in infants under 2 years of age in Greenland [49], while the prevalence of nasal carriage was only identified as 9.8% in elderly populations in Italy [50]. In Hong Kong, the prevalence of nasopharyngeal carriage S. pneumoniae was identified as 13.5% in children younger than 5 years of age who had never received any pneumococcal vaccines, 14.1% in children who received at least one dose of PCV13, and 15.3% in children who received at least 3 doses of the PCV13 vaccine [51]. In Taiwan, the prevalence of nasopharyngeal carriage of S. pneumoniae identified in children younger than 5 years of age was 14.1%, similar to that identified Hong Kong [52]. However, data collected in mainland China have differed from data collected in Taiwan and Hong Kong. The pooled prevalence of nasopharyngeal carriage of S. pneumoniae was determined to be 21.4% (18.3–24.4%) among children in China.

A variety of studies have confirmed that colonization by S. pneumoniae begins in infanthood and early childhood. It has been reported that carriage of this pathogen is acquired within the first 6 months of life and, the prevalence of the epidemic appeared to peak in children of pre-school age [53]. A study conducted by Ueno M [53] showed that prevalence of nasopharyngeal carriage of S. pneumoniae increased with age within pediatric age groups, with rates of 19 and 23% identified in infants younger than 1 years-old and children 2 to 3 years old, respectively. The highest prevalence has been identified during the pre-school period. Our data were consistent with the findings of Ueno M [53], suggesting that carriage trends differed with age. The prevalence was 12.8% (10.0–15.6%) in children younger than 2 years old; the prevalence increased with age and reached a peak at 24.7% (19.7–29.7%) in children aged 2 to 5 years and then decreased to 8.8% (6.0–11.5%) in children aged 5 years and older. It is well known that attending kindergarten has been identified as a risk factor [52, 53] for colonization by opportunistic pathogens, such as S. pneumoniae, due to poor hygiene, confined physical environmental conditions and frequent interaction with other children. Nasopharyngeal carriage of S. pneumoniae in kindergarten children results in this population serving as an asymptomatic reservoir that spreads this pathogen into community. Since the PCV7 was introduced into China in October 2008, the studies conducted between 2009 to 2012 in age 2 to 5 years-old children were the coverage and the active population of getting shot by PCV7 vaccine, which leads to a reduction of prevalence of nasopharyngeal carriage of S. pneumoniae.

Unlike the GAVI Alliance [54] in the world and EPI in China, the PCV7 is available at immunization clinics for a fee during 2008–2015, these clinics designated as “point of vaccination” centers, children at 2, 4, 6 months will get shot of one dose of PCV7 and at 1 years old will get the fourth shot of does to enhance the immunity after purchase the vaccine [54]. Because of the high price of PCV7, the PCV7 coverage level was not as many other countries [8, 9]. According to a survey of children age 1 to 2 years selected from 31 provinces throughout China conducted in 2012, 9.9% of children had received one dose of PCV7 [49]. Another study from Shanghai reported a similar PCV7 coverage level at 11.4% [55]. We observed a slightly change of PCV7 coverage level from 43.9% (34.1, 53.6%) to 52.1% (37.3, 66.9%) between pre/post vaccination period because of the limited herd immunity from low vaccine rate of pneumococcal conjugate vaccination.

High antibiotic resistance rates in S. pneumoniae may facilitate transmission of this pathogen among young children. Crowding and barriers to maintaining quality hygiene facilities could accelerate the transmission of highly antibiotic resistant S. pneumoniae in the kindergarten environment [56]. Our pooled data indicated that the rates of erythromycin, clindamycin, trimethoprim- sulfamethoxazole and tetracycline resistance among isolates were all more than 60%. High-level resistance to the aforementioned antibiotics has also been identified in previous studies [57]. Macrolides and lincosamides have been reported to be the first-line empirical antibiotic therapy for pneumococcal infections in China, and the use of these agents has led to a high rate of antibiotic resistance in S. pneumoniae [42, 57]. Previous studies have demonstrated that the penicillin-non-susceptible pneumococci (PNSP) rate varied in different regions. The prevalence of nasopharyngeal carriage of S. pneumoniae in Brazilian and Korean children who attended day care centers were identified as 26.0 and 31.3%, respectively [58, 59]. A marked modification in pneumococcal antibiotic susceptibility rates was observed after the introduction of pneumococcal conjugate vaccines. The PNSP rate was 47.1% before the introduction of PCV13 in France, and this rate rapidly decreased to 39% 3 years after PCV13 was introduced [60]. The pooled data in this study were consistent with results identified in France. The proportion of pneumococcal isolates resistant to penicillin identified in this study decreased from 31.9% (21.2–42.6%) to 21.6% (7.4–35.9%) after the introduction of PCV7.

A remarkable decrease in the incidence and mortality of invasive pneumococcal disease has been observed following the introduction of pneumococcal conjugate vaccines into pediatric immunization programs [61]. With the introduction of these PCVs and further reductions in the prevalence of nasopharyngeal carriage of S. pneumoniae in pediatric groups. Our data demonstrated that the prevalence of nasopharyngeal carriage of S. pneumoniae was 25.8% (20.7–30.9%) among healthy children before the introduction of PCV7. The prevalence dropped sharply to 14.1% (11.3–16.9%) following the introduction of PCV7 in China, indicating that the impact of PCV7 introduction on disease prevalence can be determined by assessing the nasopharyngeal carriage of S. pneumoniae in healthy children.

Conclusions

Pneumococcal carriage was identified to occur at generally high prevalence among children in China. PCV7 immunization was associated with a reduction in the rate of penicillin resistance among nasopharyngeal carriage isolates of S. pneumoniae. The distribution of serotypes identified in the nasopharynx was only slightly modified following the introduction of the PCV7 vaccination because of the low PCV7 immunization rates. The Centers for Disease Control and Prevention should timely adjust PCV vaccination strategies based on these findings to reduce the incidence and morbidity of pneumococcal invasive disease in pediatric populations.

Abbreviations

CIs: 

Confidence intervals

IPD: 

Invasive pneumococcal disease

NVT: 

Non-vaccine type

PCV: 

Pneumococcal conjugate vaccine

PNSP: 

Penicillin-non-susceptible pneumococci

REM: 

Random-effects model

S. pneumonia

Streptococcus pneumonia

VT: 

Vaccine type

Declarations

Acknowledgements

Not applicable.

Funding

This manuscript was funded by Guangxi Medical and Health Self-funding Project (No Z2014379) and Liuzhou Science and Technology Bureau Project (No 2014 J030422). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Availability of data and materials

We declare that the data supporting the conclusions of this article are fully described within the article, and provided as Additional file 1.

Authors’ contributions

LW and ZL designed the study and drafted an outline. LW and JF participated in data analysis, JF draft of initial manuscript, JC revised the manuscript and all of authors approved the final content off this manuscript.

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of Liuzhou Maternity and Child Healthcare Hospital.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Science and Education, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China
(2)
Department of Laboratory, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China
(3)
Department of Pediatrics, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China
(4)
Department of Neonatology, Liuzhou Municipal Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, China

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