High Prevalence of Vaccine-Type Infections Among Children with Pneumococcal Pneumonia and Effusion After 13-Valent Pneumococcal Conjugate Vaccine Introduction in the Dominican Republic

Abstract

Background

In 2013, the Dominican Republic introduced 13-valent pneumococcal conjugate vaccine (PCV13) using a 3-dose schedule (at 2, 4 and 12 months of age). We evaluated the impact of PCV13 on serotypes causing pneumococcal pneumonia with pleural effusion.

Methods

Surveillance data after PCV13 introduction (July 2014 to June 2016) were compared with data before PCV13 introduction (July 2009 to June 2011). Cases were defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years. Pneumococcus was detected in pleural fluid by either culture or polymerase chain reaction, and serotyping was performed. The Ministry of Health’s PCV13 uptake data for 2014–2016 were obtained.

Results

The prevalence of pneumococcus among cases was similar before and after PCV13 introduction (56.4% and 52.8%, respectively). The proportion of pneumococcal cases caused by vaccine serotypes was 86% for children <2 years old both before and PCV13 introduction. Compared with before PCV13, serotype 14 accounted for a smaller (28% vs 13%, respectively; P = .02) and serotype 1 for a larger (23% vs 37%; P = .09) proportion of pneumococcal cases after PCV13 introduction. National uptake for the first, second, and third PCV13 doses was 94%, 81%, and 28%, respectively, in 2014 and 75%, 61%, and 26% in 2015.

Discussion

While the decrease in pneumococcal pneumonia with pleural effusion caused by serotype 14 may reflect an early effect of PCV13 implementation, other vaccine serotypes, including serotype 1, are not well controlled. Better PCV13 coverage for all 3 doses is needed.

Two years after PCV13 introduction in the Dominican Republic, vaccine serotypes, including serotype 1, caused most pneumococcal pneumonia with pleural effusion, possibly due to low coverage of PCV13 booster dose. Vaccination of more birth cohorts and improved PCV13 coverage is needed.

Streptococcus pneumoniae (pneumococcus) is the leading cause of childhood pneumonia in resource-limited countries [1]. Before the introduction of pneumococcal conjugate vaccine (PCV), pneumococcus was estimated to cause 1.4 million clinic visits, 182 000 hospitalizations, and 12 000–28 000 deaths annually among children <5 years of age in Latin America and the Caribbean [2, 3]. The World Health Organization recommends the inclusion of PCV into the childhood immunization programs [4]. There are currently 2 formulations of PCV used in Latin America and the Caribbean, 10-valent PCV (PCV10), which includes serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, and 13-valent PCV (PCV13), which includes all serotypes found in PCV10 plus serotypes 3, 6A, and 19A. PCV10 and PCV13 cover ≥70% of all pneumococcal disease in Latin American children <5 years of age [5]. In the Dominican Republic (DR), acute respiratory infections are the leading cause of death in children <5 years of age [6].

Complicated parapneumonic effusions, a common sequela of pneumonia, affect nearly 40% of children hospitalized with pneumonia and are associated with longer hospital stays and admissions to the intensive care unit [7–9]. A study evaluating radiographic characteristics of severe pneumonia conducted in Latin American countries, including the DR, found that pneumococci were often isolated from pleural effusions [10]. In the DR’s largest tertiary care pediatric hospital, Robert Reid Cabral Children’s Hospital (RRCCH), 38% of children admitted to the infectious diseases (ID) ward with pneumonia had pleural effusions [11]. From 2009 through 2011, more than half of the admissions to RRCCH for pneumonia with pleural effusion were for cases caused by pneumococcus, 95% due to serotypes included in PCV13; serotypes 1, 3, and 14 were the most prevalent serotypes causing pneumococcal pneumonia with pleural effusions [11]. Of these, serotype 1 is most prone to causing outbreaks [12, 13].

Significant declines in pneumococcal disease among vaccinated and unvaccinated children have been documented in countries with good immunization coverage for their pediatric pneumococcal vaccine programs [14–18]. Some middle-income countries, such as Brazil and Uruguay, with coverage >80% for 3 PCV doses, observed a 56%–83% reduction in invasive pneumococcal disease (IPD) hospitalizations among children <5 years old [19]. However, active surveillance data that evaluates the impact of PCV13 on vaccine types causing pneumococcal pneumonia from low- and middle-income Latin America and Caribbean countries are still limited.

In August 2013, the DR’s Ministry of Health introduced PCV13 into the national childhood immunization program. The primary series is given at 2 and 4 months of age, with a booster dose at 12 months (2 + 1 schedule). No catch-up campaign was conducted, and neither 7-valent PCV nor PCV10 had been used previously. The first PCV13 dose was administered to children who were ≤2 months of age at the time of the introduction. We evaluated the impact of PCV13 on pneumococcal pneumonia with pleural effusions in the 2 years after the use of PCV13.

METHODS

RRCCH has a 34-bed ID ward, and its personnel have been conducting surveillance for pneumonia with pleural effusion in children <15 years of age intermittently since 2009. Children admitted with pneumonia and pleural effusion not requiring intensive care are sent to the ID ward for thoracentesis and treatment. In 2014, after PCV13 introduction, surveillance efforts were enhanced to encourage thoracentesis, if clinically indicated, in all children with pleural effusions, and surveillance personnel gathered additional clinical information for children hospitalized in the ID ward with pneumonia.

We compared data from 2 years of surveillance after PCV13 introduction (from 1 July 2014 to 30 June 2016) with data from the 2 years before PCV13 introduction (1 July 2009 to 30 June 2011). Data from 2012 were not available for inclusion, and data for 2013 were excluded because PCV13 was introduced that year.

A case was defined as radiologic evidence of pneumonia with pleural effusion in a child aged <15 years admitted to the ID ward with a history fever or measured temperature ≥38°C at admission and tachypnea (ie, respiratory rate >30/min in children <8 years old or >25/min in those 8–14 years old). For each hospitalized case, surveillance staff used a standardized case report form to collect demographic and clinical information, including patient sex, history of PCV13 receipt (documented in writing or self-reported), presence of underlying conditions, use of antibiotics (within 7 days of hospital admission), and clinical outcome.

Pleural fluid samples collected via thoracentesis were cultured at the hospital laboratory in accordance with the Manual of Clinical Microbiology [20] and underwent immunochromatographic testing (BinaxNOW) for rapid identification of S. pneumoniae. Any pleural fluid remaining after complete laboratory analyses was frozen at −70°C and sent to the Centers for Disease Control and Prevention (CDC) Streptococcus Laboratory for real-time polymerase chain reaction (PCR) to detect the lytA gene for S. pneumoniae, the hpd gene for Haemophilus influenzae, and the spy gene for Streptococcus pyogenes [21–23].

Pneumococcal isolates were serotyped by Quellung reaction, while lytA-positive specimens that were culture negative were serotyped using a quantitative multiplex PCR targeting 37 serotypes (including PCV13 serotypes). For lytA-positive specimens that were negative for all serotypes tested by real-time PCR and had a cycle threshold <25.0, conventional PCR targeting 70 serotypes was performed [24, 25]. Serotyping by PCR does not distinguish between the serotypes within the following serogroups: 6A/6B, 7F/7A, 9A/V, and 15B/C; thus, we classified according to their serogroup in the analysis. Cases were classified as pneumococcal pneumonia with pleural effusion if pneumococcus was isolated by culture or detected by either immunochromatographic testing or PCR in a pleural fluid specimen. Among the pneumococcal cases that were serotyped, those with any of the PCV13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, or 23F) detected were defined as vaccine type, and those with any other serotype detected or that were negative for all the serotypes detectable by PCR were defined as nonvaccine type.

We compared patient demographic and clinical characteristics of pre- and post-PCV13 cases, using χ ² and Wilcoxon rank sum tests for categorical and continuous variables, respectively. The distribution of cases by pathogen and the distribution of pneumococcal cases by serotype and patient age were also compared between periods. We used SAS (version 9.3) software for all analyses.

The total number of admissions to the ID ward at RRCCH was obtained through review of admission log books. We calculated the prevalence of pneumonia and vaccine-type pneumococcal cases per 1000 admissions to the ID ward in the pre- and post-PCV13 periods. The 2014–2016 national coverage for 3 doses of the PCV13 was obtained from the DR’s Ministry of Health.

The surveillance protocol was evaluated and approved by the Ethics Committee of the Fundación Dominicana de Infectología (reference no. DEI002-14). The CDC Human Subject Research Protection Office determined the activity to be nonresearch, public health surveillance activities, and review by the CDC Institutional Review Board was not required.

RESULTS

A total of 248 cases of pneumonia with pleural effusion were identified after PCV13 introduction, compared with 94 cases in the pre-PCV13 period (Figure 1). Of the 248 cases identified in the post-PCV13 period, 218 (87.9%) had laboratory and clinical data available and were included in the comparison of clinical and demographic characteristics with the pre-PCV13 cases. Median patient age, the proportion of cases in male patients, and the proportion of cases with antibiotic exposure before admission were similar before and after PCV13 introduction (Table 1). Most cases were in otherwise healthy children, but this proportion decreased from the pre- to the post-PCV13 period. Higher case-fatality ratios were seen in the post-PCV13 period than in the pre-PCV13 period (9.1% [19 of 210] vs 0% [0 of 94]; P < .01). Among 162 children with pneumococcal vaccination information available in the post-PCV13 period, 17 (10.5%) received 1 dose, 17 (10.5%) received 2, and only 3 (1.9%) received 3 doses of PCV13. Immunization data obtained from the Ministry of Health indicated that national PCV13 uptake in 2014 for first, second, and third doses was 94%, 81%, and 28%, respectively; in 2015, it was 75%, 61%, and 26%; and, in 2016, it was 73%, 68%, and 24%.

Figure 1.

Pneumonia with pleural effusion cases captured by the surveillance system during the pre–13-valent pneumococcal conjugate vaccine (PCV13) period (1 July 2009 to 30 June 2011) (A) and the post-PCV13 period (1 July 2014 to 30 June 2016) (B) in Santo Domingo, Dominican Republic.

Table 1.

Clinical and Demographic Characteristics of Children with Pneumonia and Pleural Effusion Before and After the Introduction of 13-Valent Pneumococcal Conjugate Vaccine, Santo Domingo, Dominican Republic

Characteristic	Children, % (No./Total Sample No.)a		P Value
	Pre-PCV13 (n = 94)	Post-PCV13 (n = 218)
Age, median (range), y	2.6 (0.03–14.7)	3.0 (0.11–14.9)	.60
Male sex	68.8 (64/94)	61.0 (133/218)	.19
History of ≥1 PCV13 dose received before admission	0	23 (37/162)	…
Underlying illnessb
None	86.0 (80/93)	76.2 (166/218)	.05
>1 Underlying illness	0	3.2 (7/218)	.11
Asthma	5.4 (5/93)	4.3 (15/218)	.77
Sickle cell disease	2.2 (2/93)	3.2 (7/218)	.73
Tuberculosis	1.1 (1/93)	0.9 (2/218)	>.99
HIV	0	0.5 (1/218)	>.99
Antibiotic use within 7 d before admission	59.5 (50/84)	62.4 (126/202)	.65
Death	0	9.1 (19/210)	<.01

Abbreviations: HIV, human immunodeficiency virus; PCV13, 13-valent pneumococcal conjugate vaccine.

^aData represent % (no./total sample no.) of children, unless otherwise identified.

^bCategories for underlying illness were not mutually exclusive.

Pneumococcus was detected in similar proportion of cases before and after PCV13 introduction (56.4% vs 52.8%; P = .51) (Table 2). Staphylococcus aureus and S. pyogenes were detected in the pleural fluid for 16% and 1% of cases, respectively, across both periods. Gram-negative bacteria (eg, Serratia marcenses, Pseudomonas aeruginosa, Enterobacter cloacae, Klebsiella pneumoniae, Escherichia coli, and Acinetobacter spp.) accounted for a higher proportion of cases in the post-PCV13 period. H. influenzae was found in 13 cases (5.2%) in the post-PCV13 period, compared with 10 (11%) in the pre-PCV13 period (P = .05). Among the 13 H. influenzae pneumonia cases with pleural effusion in the post-PCV13 period, 9 (69.2%) were nontypable and the remaining 4 (30.8%) were serotype b. Of the 10 H. influenzae pneumonia with pleural effusion cases in the pre-PCV13 period, all were nontypable except for 1 serotype b case. In nearly a quarter of the cases, no bacterial pathogen was detected by PCR or culture across both periods.

Table 2.

Etiology of Pneumonia and Pleural Effusion Based on Culture and/or Polymerase Chain Reaction Among Children <15 Years Old in Santo Domingo, Dominican Republic

Pathogens Detected by Culture and/or PCRa	Cases, % (No.)b		P Value
	Pre-PCV13 (n = 94)	Post-PCV13 (n = 248)c
Streptococcus pneumoniae	56.4 (53)	52.8 (131)	.55
Staphylococcus aureus	16.0 (15)	16.5 (41)	.90
Haemophilus influenzae	11 (10)d	5.2 (13)	.05
Streptococcus pyogenes	1.1 (1)	1.21 (3)	1.0
Other	0	7.3 (18)e	<.01
No cause determined	27.7 (26)	24.6 (61)	.56

Abbreviations: PCR, polymerase chain reaction; PCV13, 13-valent pneumococcal conjugate vaccine.

^aPathogens were not mutually exclusive.

^bData represent % (no.) of cases, unless otherwise identified.

^cIncludes 30 cases captured in surveillance with only laboratory information available.

^dFive cases were unavailable for H. influenzae testing (n = 89).

^eIncluding 3 cases of Serratia marcenses, 3 of Pseudomonas aeruginosa, 2 of Acinetobacter spp., 2 of Enterobacter cloacae, 2 of Klebsiella pneumoniae, 2 of Escherichia coli, and 4 Streptococcus spp.

There was an 18% increase in pediatric admissions to the ID ward in the post-PCV13 compared with the pre-PCV13 period (1349 vs 1136 admissions, respectively). Of the admissions to the ID ward, twice as many were due to pneumonia in the post-PCV13 compared with the pre-PCV13 period (463 vs 235 cases). The proportion of pneumonia admissions with pleural effusion detected increased from 40% (94 of 235) in the pre-PCV13 to 53.6% (248 of 463) in the post-PCV13 period (P < .01).

Compared with the pre-PCV13 period, the proportion of pneumococcal cases caused by PCV13-serotypes in the post-PCV13 period remained stable among children <2 years old (86% before and 88% after PCV13 introduction; P = >.99) (Figure 2). Serotype 1 pneumococcal cases were more common (37% vs 23%; P = .09), although not significantly so, during the post-PCV13 period (Figure 3A). In the post-PCV13 period, serotype 1 pneumococcal cases occurred rarely among children <2 years old; no serotype 1 pneumococcal cases were identified among children <2 years in the pre-PCV13 period (Figure 3B). Approximately the same number of serotype 1 pneumococcal cases were noted among children 2–14 years old over the 2 years after PCV13 introduction, suggesting that they were not part of an outbreak. More serotype 1 disease was seen across age groups in the post-PCV13 than in the pre-PCV13 period, although the difference was not statistically significant (Figure 3B). Compared with the pre-PCV13 period, serotype 14 accounted for a decreased proportion of pneumococcal cases in the post-PCV13 period (13% vs 28%; P = .02) (Figure 3A). Specifically, there was a decrease in the proportion of pneumococcal pneumonia with pleural effusion cases among children <2 years old that were serotype 14 (33% for pre-PCV13 vs 9% for post-PCV13 period; P = .05) (Figure 3C). No differences were seen between periods in the proportions of pneumococcal cases caused by the remaining vaccine serotypes (Figure 3A).

Figure 2.

Prevalence of 13-valent pneumococcal conjugate vaccine (PCV13)–type infections among children with pneumococcal pneumonia with pleural effusion before and after PCV13 introduction by age group, Santo Domingo, Dominican Republic.

Figure 3.

Prevalence of serotypes among children with pneumococcal pneumonia with pleural effusions, before and after introduction of 13-valent pneumococcal conjugate vaccine (PCV13). A, Serotype distribution. B, Serotype 1 by age group. C, Serotype 14 by age group. Abbreviation: PCR, polymerase chain reaction.

Discussion

While our analysis noted some shifts in serotypes causing pneumococcal pneumonia with pleural effusion in children in the Dominican Republic (DR), we did not observe overall declines in vaccine-type infections. Disease caused by serotype 14, the most common serotype causing pneumococcal pneumonia in the DR before PCV13 introduction [11], declined, but the increase observed in serotype 1 pneumococcal pneumonia offset this decline. Previous studies in developed countries (eg, the United States, Canada, and England) of pneumococcal vaccine programs, which are notable for high vaccine uptake (>90%) with some having catch-up vaccination for older children, demonstrated dramatic declines in IPD among children [14–18]. The impact against IPD was also high among children <5 years old in Brazil and Uruguay, where PCV coverage of the 3 primary doses is >85% [26–28].

The lack of PCV13 effect noted in our analysis is likely due to several reasons: data were obtained from the early years of the pediatric PCV13 program, coverage for each of the 3 PCV13 doses declined over time instead of increasing with extremely low coverage for the booster dose, PCV13 was introduced without a catch-up program for older children, and, finally, a higher proportion of children in the post-PCV period had underlying conditions compared with the pre-PCV period (25% vs 14%), which may have increased their risk of IPD. A recent case-control study from the DR did show that PCV13 was effective against IPD [29]. However, the vaccine effectiveness of ≥1 PCV dose against IPD (67.2%) was lower than that measured in Brazil (81.9%) [30]. In Brazil, 72% of the control children enrolled in the vaccine effectiveness study received ≤2 PCV doses, compared with 90% of the control children in the DR [29, 30]. In addition, only 44% of the control children in the DR’s case-control study were up to date with PCV based on their age, confirming the low PCV13 coverage data reported by the Ministry of Health.

Low coverage of the third dose (<30%) of PCV13 in the DR may have led to lack of reduction in the prevalence of vaccine-type pneumococcal pneumonia with pleural effusion and potentially the relative increases in the proportion of pneumococcal pneumonia with pleural effusion caused by serotypes that are less responsive to just 1 or 2 infant doses of PCV13, such as serotype 1 [31]. Serotype 1 pneumococci are more prone to cause outbreaks and are significantly more resistant to opsonization and complement deposition compared with some other serotypes, which could explain the high degree of invasiveness of this serotype [12, 13, 32]. Data from Ghana and Burkina Faso also suggest lack of herd effect for serotype 1 with the 3-dose primary series of PCV13 in the absence of a booster dose [12, 33]. Poor coverage of the PCV13 booster dose may have resulted in continued transmission of serotype 1 in the DR, and the high proportion of disease caused by serotype 1, especially for children >2 years old, is not surprising. Our finding underscores the importance of adequate coverage of the booster dose in the pneumococcal immunization program.

Toddlers and older children, rather than infants (<1 year old), are more involved in pneumococcal transmission as described in an US study among the Navajo Nation and the White Mountain Apache American Indian tribes [34]; the study showed that decreasing carriage among this age group through optimal PCV13 coverage of the booster dose may help control transmission of vaccine serotypes. Whether serotype 1 will be better controlled with vaccination of more birth cohorts is unclear, especially if coverage with a booster dose does not improve in the DR. A study in South Africa showed promising results; after the introduction of a PCV schedule consisting of 2 primary series doses at 6 and 14 weeks of age with a booster dose at 9 months and in a setting of high vaccination coverage for all 3 doses, dramatic reductions in serotype 1 disease were observed in both children and adults [35].

The current study highlights the struggle to maintain PCV coverage in middle-income countries, such as the DR, that are not eligible to receive funding for vaccine purchase from Gavi, The Vaccine Alliance. The DR relies on the Pan American Health Organization Revolving Fund, which bulk-purchases vaccines for 41 countries and territories to decrease vaccine costs. Even though the cost of a PCV dose is lower than what’s paid by many countries (because of Revolving Fund support), purchase of PCV still accounts for a substantial fraction of the total immunization budget. PCV is the most expensive vaccine in the immunization program; a single PCV dose costs US $12.85–$14.50, compared with US $6.50 for rotavirus vaccine or US $1.06 for pentavalent vaccine (diphtheria-tetanus-pertussis, hepatitis B, and H. influenzae type b) [36]. Therefore, coverage may be higher for the lower-cost vaccines. For example, in 2015, coverage for 3 doses of pentavalent vaccine was 85%, compared with 26% for 3 doses of PCV13 in the DR (Ministry of Health Expanded Program on Immunizations, personal communication).

Despite high coverage of pentavalent vaccine in 2015, Pan American Health Organization data for immunization coverage in the DR has shown a decline in coverage for multiple vaccines from 2014 to 2016, including rotavirus vaccine and even the pentavalent vaccine, for which coverage in 2014 was 91%, suggesting that the country may be struggling in maintaining high coverage for multiple vaccines [37]. The reasons for this decline in coverage are unclear, and it may be related to a vaccine procurement issue or missed opportunities for vaccination [38]. As shown by our data, poor coverage of PCV13 doses may have resulted in little overall benefit for vaccine-type pneumococcal pneumonia. In addition, the drop in H. influenzae type b vaccine coverage may explain the relative increase in the proportion of H. influenzae pneumonia caused by serotype b in the post-PCV13 period.

There were several limitations to our analysis. First, clinical information was not available for 30 (12%) of the post-PCV13 cases; therefore, comparison of case characteristics may have been biased. Regardless, demographic characteristics were similar between cases before and after PCV13 introduction, but most importantly, laboratory data for these 30 cases contributed to the analysis of PCV13 impact on the prevalence of vaccine serotypes.

Second, it is possible that not all cases were captured in the pre-PCV13 period (2009–2011), and it is unclear how many pneumococcal cases were missed. Because of a country-wide dengue outbreak in the pre-PCV13 period, some patients with pneumonia were admitted to other wards in the hospital and were likely missed during surveillance. It is also possible that the clinical personnel in the ID department did not perform the procedure on all children admitted with pleural effusion in the pre-PCV13 period, because guidance to attempt thoracentesis on all non–intensive care unit admissions of pleural effusion was implemented in 2014. Thus, we cannot use our data to describe overall vaccine impact on disease burden, and changes in the number of cases should be interpreted with caution.

Third, we observed no serotype 1 pneumococcal pneumonia with pleural effusion in children <2 years old in the pre-PCV13 period, making it difficult to evaluate PCV13 vaccine impact. Finally, individual-level vaccination data were unavailable for almost a third of the children, and surveillance staff did not consistently check vaccination cards. It is possible that some children may have been misclassified as unvaccinated. Therefore, we could not perform an analysis comparing vaccinated with unvaccinated children. However, given the low coverage of the 3 PCV doses reported by the Ministry of Health and the low coverage found in a case-control study conducted during the same time of the surveillance, we estimate that >70% of age-eligible children did not receive 3 doses of the vaccine [29].

A decrease in serotype 14 pneumococcal pneumonia suggests an early effect of the PCV13 vaccine. However, our analysis provided no evidence that serotype 1 is controlled, and other vaccine serotypes continued to cause pneumonia with effusion in the early post-PCV13 era. Higher vaccine uptake of 3 doses of PCV13 may be needed to reduce the pneumococcal disease burden in the DR. Analysis of surveillance data from more years will help to determine whether coverage of more birth cohorts or improvements in the national immunization program are translating to health benefits.

Notes

Acknowledgments. We thank the infectious diseases fellows and surveillance personnel at the Robert Reid Cabral Children’s Hospital (RRCCH) for identifying cases, collecting demographic and clinical data, and obtaining pleural effusion specimens. We thank Melída Perez for entering all case report forms into the electronic database, and medical epidemiologist Jennifer Verani for providing the pre–13-valent pneumococcal conjugate vaccine surveillance data. We also thank the RRCCH and the Centers for Disease Control and Prevention Streptococcus Laboratory for processing pleural fluid specimens and characterizing Streptococcus pneumoniae and other bacterial isolates.

Disclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the official positions of the Centers for Disease Control and Prevention.

Supplement sponsorship. This supplement is sponsored by the World Health Organization and the U. S. Centers for Disease Control and Prevention.

Financial support. US federal funds were used for the laboratory work and epidemiology. No external funds were provided for routine surveillance at RRCCH.

Potential conflicts of interest.All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.