Immunology Laboratory and Departments of
Pediatrics and Internal Medicine, Hospital Regional de Temuco, and
the Departments of Basic Sciences, Pediatrics and Internal Medicine,
Universidad de la Frontera, Temuco, Chile1;
Laboratory Section, Childhood and Respiratory Disease Branch,
Division of Bacterial and Mycotic Diseases, National Center for
Infectious Diseases, Centers for Disease Control and Prevention,
Atlanta, Georgia2; and Department of
Pediatrics, Louisiana State University Health Sciences Center, New
Orleans, Louisiana3
Received 23 June 2000/Returned for modification 8 August
2000/Accepted 15 February 2001
 |
INTRODUCTION |
Capsular serotypes of
Streptococcus pneumoniae causing invasive infections vary
according to geographic location and socioeconomic status of the study
population (2, 3, 11, 30, 31). Information about these
serotypes in different areas of the world is essential for the
formulation of conjugate vaccines (24).
Bacterial factors are likely to influence the selection of serotypes
causing invasive infections. When both nasopharyngeal carriage and
invasive infections have been studied in the same individual, a high
degree of correlation in serotypes has been found (9). On
the other hand, some pneumococcal serotypes found colonizing the
nasopharynx have little tendency to cause invasive disease (11,
16, 27). These observations suggest that certain pneumococcal
serotypes have characteristics that represent an advantage for
invasiveness. In addition, differences in infection-causing pneumococcal serotypes have been attributed to the emerging, worldwide antibiotic resistance of some serotypes (2, 3, 7, 13, 31).
The characteristics of the host may also contribute to serotype
selection. Underlying central nervous system and heart diseases, as
well as malignancies, are frequently identified in patients developing
invasive infections (13). Recently, human immunodeficiency virus (HIV) infections have become a major risk factor for the development of invasive pneumococcal infections (19). The
extent to which these factors select for infections with specific
serotypes is presently unknown.
Age has a clear influence on the overall incidence of invasive
infections most frequent in the first years of life (14) and also in persons older than 65 years (1). Some studies
suggest that different serotypes cause infections in different age
groups (20). We had an opportunity to explore this
possibility further in a relatively homogenous patient population
without HIV infection, where pneumococcal antibiotic resistance was not
a factor during the 5-year study period. Our results document
interesting differences in serotypes causing invasive disease at
different ages.
| |
MATERIALS AND METHODS |
Study population.
The study population consisted of patients
of all ages seeking medical care and being admitted to any of the
in-patient services of the Hospital Regional in Temuco, a city of
300,000 inhabitants in southern Chile. The low- and middle-income
populations of this city generally seek medical care from the Chilean
National Health Service at this hospital, where patients are admitted
to the internal medicine, surgery, obstetric, and pediatric services.
All samples were sent to the Central Laboratory of the hospital. Both
HIV type 1 (HIV-1) and HIV-2 serology was performed by enzyme-linked immunosorbent assay (Abbott Laboratories, Chicago, Ill.) on all patients in this study. No HIV-seropositive patients with pneumococcal infections were identified.
Sample definition and collection.
All S. pneumoniae strains from invasive infections or infections in
normally sterile sites were included in this study. Strains isolated
from blood, spinal fluid, pleural fluid, or ascitic fluid were defined
as invasive, and strains isolated from the conjunctiva, middle ear, or
sinus cavities were classified as coming from sterile sites. Clinical
isolates were collected and serotyped between February 1994 and
September 1999.
Pneumococcal serotyping.
Serotyping of S. pneumoniae strains was performed by one of us (J.I.) in the
pneumococcal serotyping laboratory at the Centers for Disease Control
and Prevention (Atlanta, Ga.). Before serotyping, cultures were
transferred to 5% sheep red cell agar plates (Difco Laboratories,
Detroit, Mich.) overnight. All serotyping results were confirmed by
Quellung test.
Antibiotic sensitivities of all strains were determined by the E-test
for penicillin, cefotaxime, and vancomycin.
| |
RESULTS |
Epidemiology.
For analysis, the study population was divided
into three age groups: under 5 years of age, 5 to 64 years old, and
over 64 years old. The total population cared for at the Temuco
Regional Hospital during the 5-year study period in each of these age
groups was as follows: <5 years, 34,631; 5 to 64 years, 248,305;
>64 years, 19,180. The yearly incidence of pneumococcal
infections per 100,000 individuals during the same period was as
follows: <5 years, 193/100,000; 5 to 64 years, 54/100,000; >64 years,
234/100,000. A separate analysis of children under 2 years of age
revealed 53 infections with a yearly incidence of 348/100,000 and 16 infections in children 2 to 4 years old with an incidence of
76/100,000. A breakdown of the data for each age group in each of the 5 study years revealed that the yearly incidence of invasive pneumococcal infections in each age group remained constant (data not shown).
Serotypes and age.
Two hundred and forty-seven S. pneumoniae strains with a total of 50 serotypes were isolated
during the entire study period (Table
1). Sixty-nine, 129, and 49 strains
causing infections in children under 5 years of age, patients 5 to 64 years old, and patients over 64 years old, respectively, were found.
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TABLE 1.
Distribution of S. pneumoniae serotypes
isolated from invasive and sterile-site infections according to
agea
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There was no difference in the serotypes causing infection in each of
the 5 years of the survey. A separate analysis also revealed that there
were no differences in serotypes causing infection between the 5- to
15- and the 16- to 64-year-old patients (data not shown).
In the study population as a whole, the five most frequent serotypes
were 1 with 35 isolates, 5 with 22, 3 with 19, 19F with 15, and 23F
with 13. However, the distribution was markedly different in young
children and older patients. In children under 5 years of age, there
were nine strains of serotype 1, eight of 5, seven each of 6B and 23F,
six of 19F, and five of 6A, while in patients 65 years and older
serotypes 3 with seven strains, 7F with five, and 1, 19F, and 38 with
three strains each were found most frequently.
Only 11 serotypes were isolated in all age groups, namely, 1, 5, 6A,
6B, 7F, 12F, 15B, 15C, 19A, 19F, and 23F. All other serotypes were
found exclusively in one or two age groups, e.g., patients over 4 or
under 64 years only.
Children under 5 years of age differed from patients 5 years and older.
Notably, 20 serotypes present in the other age groups were not isolated
from the youngest group, i.e., 3, 7A, 8, 9N, 10A, 10B, 11A, 11F, 13, 16, 17F, 18F, 20, 22F, 24F, 29, 35A, 35B, 36, and 38. Of these,
serotype 3 caused of 19 infections in patients 5 years and older
(15%). Five serotypes were isolated exclusively in the youngest age
group, i.e., 9A, 21, 28F, 31, and 34, each causing one infection.
Twenty-two serotypes present in the other age groups were not isolated
in patients over 64 years of age: 4, 7A, 8, 9A, 9V, 10A, 11A, 11F, 13, 14, 16, 17F, 18A, 20, 21, 23B, 23C, 24F, 28F, 31, 33F, and 34. Particularly notable was the absence of infections with serotype 14 in
patients 64 years and older, since this serotype was isolated from nine
infections in younger patients.
Three serotypes were isolated exclusively from patients older than 64 years, namely, 10B, 22F, and 27, each causing one infection.
Serotype 4 was isolated only twice, once in a child under 5 years and
once in the 5- to 64-year-old group.
Antibiotic resistance was identified in only one clinical isolate, from
a child younger than 5 years. This was a serotype 23F strain highly
resistant to penicillin and cefotaxime but not to vancomycin
(8).
The estimated coverage offered by various vaccines to patients of
different age groups in this study is shown in Table
2. Table 1 shows the serotypes included
in the 23-valent polysaccharide vaccine and also those included in the
proposed 11-valent conjugate vaccine. Including protection offered by
serogroup cross-reactivity, the estimated coverage of the three
conjugate vaccines for infections in children younger than 5 years
ranged from 72 to 78%, denoting only a small increase in coverage
going from the heptavalent to the 11-valent vaccine. In patients over
64 years, the coverage from conjugate vaccine ranged from 31 to 78%.
This estimated coverage for the 11-valent conjugate vaccine is the same
for this age group as that estimated for the 23-valent polysaccharide
vaccine.
| |
DISCUSSION |
Epidemiology.
Our results confirm the high incidence of
pneumococcal infections in young children observed in other studies
(6, 29). A recent study of invasive infections in children
under 5 years of age in west Africa estimated that the incidence of
invasive infection was 240/100,000/year in children younger than 5 years and 554/100,000/year in children younger than 1 year
(18). Our data confirm a very sharp drop in the incidence
of invasive pneumococcal infections after 2 years of age, with an
incidence in children 2 to 4 years old only slightly higher than that
in individuals 5 to 64 years old. This may reflect the absence of
high-risk groups, i.e., children with sickle cell disease and/or HIV
infections, in our study population.
An analysis of serotypes causing infections in these different age
groups suggests that there are risk factors in young children and in
elderly populations that may be serotype specific. Two serotypes stand
out as representative of age differences in susceptibility because of
their relatively high frequencies in the general population: serotype
3, absent in young children, and serotype 14, absent in the elderly.
Several studies have shown that serotype 3 is a frequent isolate from
the respiratory tract (10, 12) but an infrequent cause of
invasive S. pneumoniae infections in children (17, 20,
23). In a recent study of invasive infections in children under
5 years of age in Santiago, Chile, serotype 3 caused only 3.3% of
infections (three-pneumonias) (15).
The absence of serotype 14 in isolates from elderly patients in our
study is surprising, since this was a common serotype isolated from
patients over 60 years old in the United States and New Zealand
(4, 17).
A study in Israel also found differences in the serotypes isolated in
children under 13 years and in adults (20) but a
distribution of serotypes different from that found in Chile. For
example, while serotype 6B was isolated almost exclusively in adults in Israel, it caused 11.3% of infections in children under 2 years of age
in Temuco.
The relatively high frequency of infections with high-numbered
serotypes (28F to 38) in children under 5 years and in adults over 64 years in Temuco is interesting. Serotypes 28F, 31, 33F, 34, 35F caused
11% of invasive and sterile-site infections in children under 5 years
in Temuco. Yet none of these serotypes is included in the conjugate
vaccines, and only serotype 33F is included in the polysaccharide
vaccine. Nor were any of these serotypes identified in young children
with invasive infections in Santiago, Chile, further documenting the
importance of local variations in serotype predominance
(15).
Taken together, our data and those reported by others support the
notion that age plays a role in the serotypes causing infection. Socioeconomic and geographical differences do not explain our results
for a homogeneous patient population living in the same geographical
area (11). Year-to-year variation in serotype distribution was not a factor in our study or in other studies of infections over
time (20, 30). Furthermore, antibiotic resistance due to
preventive-antibiotic use in special-risk populations (26) and underlying immune system abnormalities such as those due to HIV
infection (19) were also ruled out as an explanation for our results for different age groups. Lastly, our population was not
immunized with any form of pneumococcal vaccine that could have altered
the immune response and therefore the incidence of infections with some serotypes.
Whether or not differences in the immune response may account for some
of these observations is questionable. Transplacental transmission of
immunoglobulin G (IgG) antibodies is very efficient for serotypes 3 and
14 (5), so that this is an unlikely explanation for the
absence of serotype 3 infections and the high incidence of serotype 14 infections in young children. Furthermore, transplacentally transmitted
antibodies decrease rapidly during the first 6 months of life
(22). In patients with recurrent infections, serotype 3 is
clearly more immunogenic in children than serotype 14, while in adults
serotype 14 induces a very high concentration of IgG antibodies
(25). For serotype 14 antibodies detected by enzyme-linked immunosorbent assay also correlate well with antibody avidity and
opsonophagocytic activity in the elderly (21). Since
antibodies to other serotypes have low opsonophagocytic activity in the
elderly, our observations may be explained by the functional properties of antibodies against pneumococcal serotypes in this age group. However, this would not explain the high incidence of serotype 14 infection in adults in New Zealand (17). We conclude that age differences are probably due to multiple factors, defying a clear
interpretation at this point.
Our findings are relevant for prevention strategies, antibiotic usage,
and vaccine design. Current recommendations for vaccine formulation are
based on serotypes and serogroup distribution for invasive and
sterile-site pneumococcal infections (24). Conjugated
vaccines are recommended for children under 5 years of age
(28). If our results are confirmed in other studies, the
age of the patient population to be immunized in different regions of
the world will have to be considered. One important observation is that
serotype 3, included in all conjugate vaccines, and serotype 7F,
included in the 11-valent conjugate vaccine, are very infrequent causes
of infections in children under 5 years of age in Temuco, Chile.
Continued surveillance of pneumococcal infections at different ages is
necessary to design the most-effective vaccines to be used at the
most-appropriate ages.
We thank Terry Thompson for his advice and support in the
serotyping of streptococcal strains at the CDC and Patricia A. Giangrosso for assistance in the preparation of the manuscript.
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Abstract
Introduction
