Published online August 7, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e801-e809 (doi:10.1542/peds.2005-3195)
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ARTICLE

Epidemiologic Features of Invasive Pneumococcal Disease in Belgian Children: Passive Surveillance Is Not Enough

Anne Vergison, MDa, David Tuerlinckx, MD, PhDb, Jan Verhaegen, MD, PhDc, Anne Malfroot, MD, PhDd for the Belgian Invasive Pneumococcal Disease Study Group

a Department of Pediatric Infectious Diseases, Infection Control and Hospital Epidemiology Unit, Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium
b Department of Pediatrics, Université Catholique de Louvain, Cliniques Universitaires Mont Godinne, Mont Godinne, Belgium
c Department of Microbiology, National Reference Laboratory for Pneumococci, Katholieke Universiteit van Leuven, Leuven, Belgium
d Department of Pediatrics, Pediatric Respiratory Medicine, Infectious Diseases and Cystic Fibrosis Clinic, Academisch Ziekenhuis-Vrije Universiteit, Brussels, Belgium


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. Reliable epidemiologic surveillance of infectious diseases is important for making rational choices for public health issues such as vaccination strategies. In Belgium, as in most European countries, surveillance relies on voluntary passive reporting from microbiology laboratories; therefore, reported incidence rates are probably inaccurate.

METHODS. We conducted national, active, laboratory-based and clinically based surveillance of invasive pneumococcal disease in young children.

RESULTS. During the study period, the incidences of invasive pneumococcal disease in children <2 years of age (104.4 cases per 105 person-years and 16.1 cases per 105 person-years for invasive pneumococcal disease and meningitis, respectively) and in children 0 to 59 months of age (59.5 cases per 105 person-years for invasive pneumococcal disease and 7.7 cases per 105 person-years for meningitis) were twice those reported previously through the passive surveillance system. Overall, 67% of the Streptococcus pneumoniae strains isolated from children <5 years of age belonged to 7-valent pneumococcal conjugate vaccine serotypes and 18% to vaccine-related serotypes (mainly serotype 19A). Erythromycin resistance was frequent, especially among children <2 years of age (59%).

CONCLUSIONS. Under-reporting can explain the reported low incidence of invasive pneumococcal disease in countries (such as Belgium) that depend on a passive epidemiologic surveillance system, which could lead to erroneous choices in vaccination policies. There is a need for an active system of epidemiologic surveillance for vaccine-preventable diseases such as invasive pneumococcal disease, at the national or European level.

Key Words: epidemiology • Streptococcus pneumoniae • surveillance

Abbreviations: IPD—invasive pneumococcal disease • PCV-7—7-valent pneumococcal conjugate vaccine • MIC—minimal inhibitory concentration

Knowledge of the Belgian epidemiologic features of invasive pneumococcal disease (IPD) relies on voluntary reporting and the sending of Streptococcus pneumoniae strains to the national reference laboratory by local microbiology laboratories. The incidence of IPD reported from 1996 to 2000 (30 cases per 105 child-years among children <5 years of age)1 was far below the US incidence (96.7 cases per 105 child-years in 1998 and 1999).2 Under-reporting is assumed to explain the lower incidence of IPD in European countries, together with a higher threshold for blood culture drawing.3,4 Local epidemiologic data on age, serotype distribution, and antibiotic resistance are important for guidance of vaccination strategies and for analysis of the impact of immunization programs. Universal immunization of all children <2 years of age with 7-valent pneumococcal conjugate vaccine (PCV-7) has been implemented in the United States, whereas vaccination has been targeted to children with risk factors in most European countries.

In Belgium, data regarding serotype distribution were not available. Recent data suggested an association of a specific serotype with either nasopharyngeal colonization or IPD, with some serotypes being more likely to cause specific pediatric infections such as pneumonia.5 Moreover, determination of serotype distribution is important for estimation of the fraction of IPD cases that could be prevented with PCV-7. We wanted to assess the real burden of IPD in children <5 years of age in Belgium, compared with the existing national laboratory-based surveillance data, to calculate the theoretical coverage of PCV-7 according to our local serotype distribution, and to establish the antibiotic susceptibility profiles of the S pneumoniae strains recovered from these pediatric IPD cases.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design
Active surveillance was established in 128 Belgian hospitals with pediatric wards (covering 98.5% of all pediatric wards) for 1 year, from March 18, 2002, to March 17, 2003. Eligible cases needed to meet the following inclusion criteria: (1) age from birth to 59 months, (2) isolation of S pneumoniae from a normally sterile body site (eg, blood or cerebrospinal fluid) by the hospital microbiology laboratory, and (3) signing of written informed consent forms by the child's parents or guardians. The local ethics committees approved the study. Case identification was based on 2 independent, active surveillance approaches, one clinical (hospital based) and one microbiologic (laboratory based).

Clinical Data
Case report forms were completed by local pediatricians and were recorded on a Web site directly by the physician or by the data manager. The data manager was aware of all strains of pneumococci sent to the reference laboratory and eventually could confirm that clinical data had been sent for all strains; she could also check that the local laboratories had sent all strains to the national reference laboratory. Recall messages were sent monthly to all participating pediatricians and microbiologists, to ensure good participation in the study. We defined the following clinical entities: (1) meningitis confirmed by positive cerebrospinal fluid culture, (2) septicemia with septic shock, (3) bacteremia without a major focus of infection, (4) pneumonia with pleural effusion with a positive blood culture and/or positive pleural fluid culture, (5) pneumonia (confirmed by chest radiograph) with a positive blood culture, and (6) other (eg, arthritis or peritonitis).

Strain Collection
All pneumococcal isolates from the local laboratories were sent to the National Reference Laboratory for Pneumococci. Identification was confirmed with standard methods, capsular serogroups were determined with the quellung reaction with 46 group sera from the Staten Serum Institute (Copenhagen, Denmark), and some isolates were sent to the Staten Serum Institute for serotyping. Antimicrobial susceptibility tests for penicillin, erythromycin, tetracycline, and ofloxacin were performed with the disk diffusion method. For strains with reduced susceptibility to penicillin, minimal inhibitory concentrations (MICs) were determined with the E-test (AB Biodisk, Stockholm, Sweden) for penicillin and cefotaxime, according to National Committee for Clinical Laboratory Standards methods.6

Statistical Analyses
In Belgium, birth rates are fairly stable (ranging from 111225 to 114883 births per year for 2000–2003). Age-specific incidences were calculated by using a birth cohort of 115000 children per year. Incidences are presented with 95% confidence intervals (calculated from counts in the Poisson distribution). Statistical analyses were performed with SPSS software (version 12.0; SPSS, Chicago, IL) (Pearson test and Fisher's exact test for expected counts of <5; median comparisons with the Mann-Whitney test, for non-Gaussian distributions). The {chi}-score test was used to compare annual incidences, with the assumption of Poisson distribution.

Role of the Funding Source
The data manager was employed by Wyeth Pharmaceuticals and financial incentive was provided (by Wyeth) for sending the S pneumoniae strains and collecting the clinical data. The Belgian Society of Pediatrics also supported the study, with advertising at an annual meeting before the start of the study.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Clinical and Epidemiologic Data
A total of 342 patients with IPD (57% male) were reported during the study period, of whom 330 (96.5%) were admitted to a hospital. No cases were registered in 38 hospitals, 1 or 2 cases in 49 hospitals, 3 to 8 cases in 32 hospitals, and ≥9 cases in 9 centers. The median age was 13.8 months (age range: 0–59 months). Thirteen children (4%) were <3 months of age, 227 (67%) were 3 to 23 months of age, and 102 (30%) were 24 to 59 months of age.

The incidence of IPD in children <5 years of age was 59.5 cases per 105 child-years (95% confidence interval: 52.6–66.7 cases per 105 child-years), and the cumulative risk of IPD in these children was 296.5 cases per 105 child-years (95% confidence interval: 260.5–332.6 cases per 105 child-years). The annual incidence was greater for children 0 to 23 months of age (IPD: 104.4 cases per 105 child-years; 95% confidence interval: 91.2–117.6 cases per 105 child-years; meningitis: 16.1 cases per 105 child-years; 95% confidence interval: 11.3–22.2 cases per 105 child-years) than for children 24 to 59 months of age (IPD: 29.6 cases per 105 child-years; 95% confidence interval: 24.1–35.9 cases per 105 child-years; meningitis: 2.0 cases per 105 child-years; 95% confidence interval: 0.8–4.2 cases per 105 child-years; P < .001 for both comparisons).

The distribution of the clinical entities of IPD cases for the different age groups is shown in Table 1. Pneumonia, with or without pleural effusion, was significantly more frequent in the 24- to 59-month-old group than in the <2-year-old group (P < .0001). There was a trend toward older age for children presenting with pneumonia and pleural effusion (median age of 36.5 months, compared with 19.5 months for pneumonia without pleural effusion; P = .12).


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  		TABLE 1 Distribution of Clinical IPD Cases According to Clinical Presentation in Different Age Groups

 
Data on previous antibiotic use were available for 291 patients (85%). A total of 157 patients (54%) had received systemic antibiotic therapy in the previous 6 months, and 35 (12%) had taken antibiotics within 48 hours before the IPD diagnosis. Of the 35 children who were receiving antibiotics at the time of IPD diagnosis, 15 (43%) received a macrolide, 9 (26%) amoxicillin, with or without clavulanate, and 5 (14%) cefaclor.

One or more underlying medical conditions was present in 7% of the cases (24 patients). Only 3 patients (0.9%) had hemoglobinopathy (sickle cell anemia), and only 2 (0.6%) had HIV infection. Five patients (1.5%) had congenital heart defects, 5 (1.5%) had congenital immunodeficiency, 5 (1.5%) had malignant hematologic disease, and 4 had miscellaneous conditions (2 had chronic pulmonary disease, 1 had renal insufficiency, and 1 had a cerebrospinal fluid leak).

The case fatality proportion for IPD, at 0 to 59 months of age, was 2.3%. Of the 8 children who died, 5 had meningitis, 2 septicemia, and 1 initial peritonitis with secondary meningitis and septicemia. Six of the 8 children were <2 years of age, and 3 had an underlying medical condition. Of all reported IPD cases, 11 patients (3.2%), all <2 years of age and with meningitis, had sequelae at the time of hospital discharge (deafness and/or neurologic deficits). Two of these children had underlying medical conditions.

Serotypes of S pneumoniae Recovered From IPD
Serotypes were determined for 280 of 342 strains of S pneumoniae (Table 2). The remaining 62 strains either were not sent by the hospital laboratory (41 strains, 12%) or could not be cultured after transport (21 strains). Overall, 67% of S pneumoniae strains (188 of 280 strains) belonged to PCV-7 serotypes (14, 23F, 6B, 18C, 19F, 4, and 9V), and 18% of strains (49 of 280 strains) belonged to vaccine-related serotypes (19A, 6A, 19C, 23A, and 9N). Serotype 19A was the third most frequent serotype (10%). However, serotypes were unevenly distributed in the different age groups (Fig 1); 25%, 75%, and 57% of strains belonged to a vaccine serotype for children <3 months, 3 to 23 months, and 24 to 59 months of age, respectively. Strains belonging to a vaccine-related serotype were recovered from 17%, 16%, and 21% of children in the same respective age groups. Children infected with serotype 1 were significantly older (median age: 48 months) than children with IPD with another serotype (median age: 13 months; P < .0001). Serotype distribution also varied according to the infection localization (Table 3). For pneumonia, there were noticeable differences in serotypes between the age groups. For children <2 years of age with pneumonia without pleural effusion, serotype 14 was the most frequent (17 of 40 strains, 43%, compared with 5 of 30 strains, 17%, for the 2-5-year-old group; P = .02). For 24- to 59-month-old children with pneumonia, strains from serotype 1 were the most commonly isolated (12 of 39 strains, 31%), whereas only 1 child <2 years of age had pneumonia with pleural effusion attributable to serotype 1 S pneumoniae (P < .001).


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  		TABLE 2 Serotype Distributions and Incidences of S pneumoniae Strains in Different Age Groups

 

Figure 1
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  		FIGURE 1 Incidence of IPD according to serotypes in 3 groups of children <5 years of age. VST indicates vaccine serotypes; VRST, vaccine-related serotypes; NVST, nonvaccine serotypes.

 

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  		TABLE 3 Distribution of Serotypes for the Main Clinical Entities

 
Antibiotic Susceptibility of the Pneumococci Isolated From IPDs
The 280 serotyped S pneumoniae strains were tested for antibiotic susceptibility (Table 4). No strains were resistant to penicillin (MIC: >2 mg/L), cefotaxime (MIC: >2 mg/L), or ofloxacin (MIC: >8 mg/L). Penicillin-intermediate strains were distributed equally among the age groups (15% and 14% for <2 years and 2–5 years, respectively). Erythromycin-resistant strains were much more prevalent in the <2-year-old group (59%) than in the 2- to 5-year-old group (35%; P < .001). Similarly, tetracycline resistance was higher in the youngest age group, with 45% resistance in strains isolated from children <2 years of age and 35% resistance in strains from the 24- to 59-month-old group (P = .02). A total of 164 (59%) of 280 pneumococcal strains were intermediate or resistant to at least penicillin, erythromycin, or tetracycline. Twenty-four strains (9%) were intermediate or resistant to all 3 antibiotics and 91 (33%) were resistant to 2 antibiotics, mostly with combined erythromycin and tetracycline resistance (90%). Most of the nonsusceptible strains belonged to a vaccine serotype (91%, 81%, and 74% for penicillin, erythromycin, and tetracycline, respectively). Resistance also was distributed unequally among the serotypes. "Multiresistant" strains (resistant to penicillin, erythromycin, and tetracycline) were more likely from serotype 14 (17 of 24 strains, 71%), whereas 13 (68%) of 19 serotype 23F strains were fully susceptible.


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  		TABLE 4 Distribution of Penicillin-, Erythromycin-, and Tetracycline-Nonsusceptible Strains Among Vaccine, Vaccine-Related, and Nonvaccine Serotypes

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Variations in IPD Incidences
This study stresses the impact of the quality of epidemiologic surveillance on IPD incidence. By conducting active surveillance for 1 year, we found that the estimated incidence rate of IPD for children <5 years of age doubled, compared with the previous estimated incidence rate calculated from data collected passively by the reference laboratory (30 cases per 105 child-years for IPD and 4 cases per 105 child-years for meningitis).1 Our findings confirm the importance of under-reporting as a cause of underestimation of disease incidence for IPD in Belgium. Disparities in reported rates of IPD were hypothesized to explain the variations in IPD incidence between Europe and the United States,3 but such disparities had never been demonstrated. IPD incidence rates usually reported for Europe vary from <10 cases per 105 person-years to 24 cases per 105 person-years for children <5 or <6 years of age7,8 (Table 5). A few countries (Spain, Israel, and Greece) have reported higher rates of 42 to 56 cases per 105 person-years.9–12 Most European countries have reported rates from national or regional passive laboratory surveillance. With passive surveillance, changes in IPD incidence must be interpreted with caution, because the number of reporting laboratories varies13 (J.V., unpublished data). However, 1 German study and 1 Austrian study found equally low incidences (9–14 cases per 105 person-years and 4–6 cases per 105 person-years for IPD and meningitis, respectively, in the <5-year-old group) despite active prospective surveillance based on both laboratory and clinical reports.14,15 The meningitis incidence rate for infants <2 years of age (16.1 cases per 105 person-years) was comparable to rates in various European countries (Spain, Denmark, or Great Britain), but it was more than twice the incidence in the United States (7.5 cases per 105 person-years) before licensure.16 In contrast, the incidence rate for IPD for children <5 years of age observed in this study was still much lower than the incidence reported for the United States before PCV-7 use (96.7 cases of IPD per 105 person-years).2 Along with the variation in reported rates, differences in blood culture practice and underdiagnosis of mild IPD have also been proposed to explain the lower IPD incidences in Europe, compared with the United States.3 When meningitis incidences are compared between different countries and are compared with IPD incidences (Table 5), differences in blood culture practice probably also occur among different European countries. Some countries with relatively high meningitis incidences, compared with overall IPD incidences (such as Netherlands, Denmark, and England), may draw fewer blood cultures than Belgium or Spain, for example. Under-diagnosis of mild IPD cases probably occurs in Belgium, because blood cultures are not performed in outpatient settings. Consequently, the incidence rate found in this study is probably underestimated.


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  		TABLE 5 Incidence of IPD and Meningitis in Reported European and Israeli Studies

 
Furthermore, the incidence of S pneumoniae infections varies over time; it has been increasing in past decades in several Northern European countries,17–19 and changes in dominant serotypes throughout the world have been described.5 Another explanation for a lower IPD incidence, compared with the United States, was the relatively low rate of underlying comorbidities we found in the study (7%). In the 6-year surveillance of IPD reported by Kaplan et al,20 25.5% of children <5 years of age had underlying medical conditions. In Belgium, at-risk patients such as children with hemoglobinopathies or HIV infection undergo close follow-up monitoring; in selected centers, they were vaccinated with PCV-7, although it was not recommended for general use.

Important Vaccine-Related or Nonvaccine Serotypes
Serotype 19A was the third most prevalent in this study, isolated equally from infants and from older children. It was isolated much more frequently from IPD than was serotype 19F, as described for children from several countries (Israel,11 Italy,21 and France22). With vaccination implementation in these countries, we fear replacement of the vaccine serotypes by serotype 19A, because antibodies against serotype 19F have been suspected of providing poor cross-immunity against serotype 19A.23 The estimated vaccine effectiveness against serotype 19A was 41% in the analysis published in 2003 (3 years after the licensure of PCV-7 in the United States),24 but recent US surveillance data raised concerns about both protection against serotype 19F and cross-protection against serotype 19A, with increased relative proportions of IPD caused by these serotypes.25 Moreover, penicillin-resistant or multiresistant clones of serotype 19A are circulating both in Europe (Switzerland)26 and in the United States.25,27

Serotype 1 is also worthy of attention; it has been reported commonly for many European countries, including Sweden,28 Israel,10,11 England and Wales,29 and Norway.17 In our study, it was recovered from 29% of blood cultures from children 24 to 59 months of age with pneumonia. Serotype 1 was associated with pneumonia but not specifically with pleural effusion. Serotype 1 was recovered from 22% of pleural effusion cases, compared with 50% in a recent study.30 For the pneumonia group, however, we were not able to look at complications other than pleural effusion that might be associated with serotype 1.31

There were important effects of age. Children <6 months of age with meningitis were more likely to be infected with a less-prevalent serotype, which suggests that there could be partial protection by maternal antibodies against the more-common serotypes (such as serotype 14 or 6B), at least for severe infection. Infants <3 months of age had a different serotype pattern distribution than did the 3- to 23-month-old group; however, we did not find the serotype 1 prevalence evident for neonates in England and Wales.32

Antibiotic Susceptibility
The trend toward an increase in antibiotic resistance in "Belgian" S pneumoniae was not confirmed for penicillin, compared with previous data from the 1994 to 2000 period.33 In that study, the authors found a 17.6% proportion of penicillin-nonsusceptible isolates (with 11% of strains with high-level resistance) among IPD isolates from all age groups. In our study of children <5 years of age, the penicillin resistance rate was slightly lower, with no strains with high-level resistance. However, erythromycin resistance was higher in the present study (52%) than in 2000 among children with bacteremia (47.6%).33 Erythromycin and tetracycline resistance rates were significantly different between children 0 to 23 months of age and those 24 to 59 months of age. These resistant pneumococci belonged mostly to the 3 most frequently isolated IPD serotypes (serotypes 14, 19A, and 6B) recovered from children <2 years of age, which could suggest clonal dissemination of these strains.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
National active surveillance allowed us to demonstrate the importance of under-reporting as a cause of an apparently low incidence of IPD in Belgium. Establishing an active epidemiologic surveillance program led to a twofold increase in the incidence rate of IPD. Active epidemiologic surveillance should go on to evaluate the impact of vaccination on the incidence of IPD and on serotype distribution. For instance, serotype 19A, which was one of the most prevalent serotypes in this study, is likely to increase in proportion in the future, and this should be documented. There might also be a need to adapt the vaccine serotype composition to any changing epidemiologic features over time. This work stresses the importance of standardized, reproducible, national (or European), laboratory-based and clinically based, epidemiologic surveillance.


   ACKNOWLEDGMENTS
 
This work was supported by Wyeth Pharmaceuticals and the Belgian Society of Pediatrics.

The Belgian Invasive Pneumococcal Disease Study Group includes Jean-Paul Buts (Université Catholique de Louvain), Samy Cadranel (Université Libre de Bruxelles), Frans De Baets (Universitair Ziekenhuis Ghent), Philippe Lepage (Université de Liège), Jack Levy (Université Libre de Bruxelles), Anne Malfroot (Vrije Universiteit Brussel), Marc Raes (Hasselt), José Ramet (Universitair Ziekenhuis Antwerpen), Marijke Proesmans (Katholieke Universiteit van Leuven), Etienne Sokal (Université Catholique de Louvain), David Tuerlinckx (Université Catholique de Louvain), Jan Verhaegen (Katholieke Universiteit van Leuven), and Anne Vergison (Université Libre de Bruxelles).

We thank Sophie Leyman and Patricia Slachmuylders from Wyeth Pharmaceuticals for their support, and we thank Wyeth Pharmaceuticals for financial support. We thank all Belgian pediatricians and microbiologists who participated in the study and the Belgian Society and Academy of Pediatrics for scientific support of this study. We also thank Jean Vanderpas for his help in the statistical analysis and Mark Fletcher for critical proofreading of the manuscript.


   FOOTNOTES
 
Accepted Mar 27, 2006.

Address correspondence to Anne Vergison, MD, Department of Pediatric Infectious Diseases, Infection Control and Hospital Epidemiology Unit, Université Libre de Bruxelles, Hôpital Universitaire des Enfants Reine Fabiola, 15, Avenue JJ Crocq, 1020 Brussels, Belgium. E-mail: anne.vergison{at}ulb.ac.be

The authors have indicated they have no financial relationships relevant to this article to disclose.


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 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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