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Group A Streptococci Among School-Aged Children: Clinical Characteristics and the Carrier State

November 25, 2004

ABSTRACT. Objective. A 4-year longitudinal study of school-aged children was conducted to describe the clinical characteristics and epidemiologic features of infections with group A streptococci (GAS).

Methods. Between 1998 and 2002, surveillance throat cultures were performed twice per month (October to May) for a cohort of elementary school children in Pittsburgh, Pennsylvania. In addition, throat cultures were obtained during any respiratory illness. Erythromycin and clindamycin susceptibility testing was performed for all isolates. Molecular typing was performed with field- inversion gel electrophoresis. Representative isolates from each field-inversion gel electrophoresis group were emm typed. Strict definitions were used to characterize each GAS infection. Children were classified into 4 categories each year, ie, single episode, recurrent episodes, carriers of GAS, and no infections.

Results. A total of 48 to 100 children per year were studied for 4 years; 61 (49%) were male. The mean age was 9.6 years (range: 5- 15 years). A total of 5658 throat cultures were performed; 878 (15.5%) were positive for GAS. Antimicrobial agents were used to treat 209 episodes of infection. Thirteen emm types were observed during the 4-year period. GAS were isolated most often from children who were carriers; isolates from single episodes were next most common. Children carried a single emm type for a mean of 10.8 weeks (range: 3-34 weeks). Carriers were likely to be classified again as carriers in subsequent years and frequently switched emm types. Sixty-two percent of the children had ≥1 year with no infections.

Conclusions. GAS infections are common among school-aged children. The majority of positive throat cultures observed in this longitudinal study were obtained from children who were carriers of GAS. Carriers switched emm types but tended to become carriers repeatedly during the study. Practitioners should consider treating children known to be GAS carriers when they develop a new illness that is consistent with streptococcal pharyngitis, because they may acquire new emm types and be at risk for rheumatic heart disease. Pediatrics 2004;114:1212-1219; group A streptococcus, surveillance, epidemiology, pharyngitis, carrier.

ABBREVIATIONS. GAS, group A streptococci; FIGE, field-inversion gel electrophoresis; CFU, colony-forming units.

Group A streptococci (GAS) (Streptococcus pyogenes) are the most common cause of bacterial pharyngitis among children and adults.1 They are the leading cause of acquired heart disease among children throughout the world, and increasingly they are a major cause of deaths attributable to bacterial sepsis among both children and adults.2-4

Children are the major reservoir of GAS and are the target population for pharyngitis, as well as the suppurative and nonsuppurative complications caused by GAS.2 They represent the pool from which adults with severe invasive disease acquire their infections.4 The peak age incidence for infections caused by GAS is between 5 and 15 years. The frequency of GAS infections decreases markedly after 15 years of age unless large numbers of young adults from diverse locations are assembled in close quarters, as in military settings.5

GAS were previously grouped into >100 different serotypes with a typing system based on the M-protein in the cell wall. A recent alternative to serotyping is the designation of emm type by sequencing the 5′-terminal end of the emm gene.6 It is not known whether children develop repeated infections with the same or different emm types of GAS. There is limited understanding of why and how children become immune to infection with GAS. Previous studies of large cohorts of children were performed before the availability of emm typing, when the majority of isolates could not be serotyped for the M-proteins.7-10 The purpose of this longitudinal study was to describe the epidemiologic features of GAS infections in a group of school-aged children, with the use of modern molecular methods.

METHODS

Setting and Participants

A longitudinal study of the epidemiologic features of GAS infections in a private, tuition-supported, elementary school was initiated in 1998. This school serves 285 children and is located in Pittsburgh, Pennsylvania. Forty percent of the children who attend have parents who are faculty members of the University of Pittsburgh. Children attend kindergarten through grade 8. They are divided into 3 major cohorts according to age, ie, 5-7 years, 8-10 years, and 11-15 years. Within each group, there are 4 homerooms. Placement for each instructional setting (eg, math and reading) is based on readiness rather than age or grade level. Therefore, there is significant mixing between groups of students. Class size is limited to 24 students, and most classes have 12 to 15 students. All classrooms were represented in the study.

All students attending the school were invited to join the study, but participation was voluntary. All students who were willing to participate were enrolled. The protocol was approved by the institutional review board of Children’s Hospital of Pittsburgh, as well as by the school. Informed consent was obtained from ≥1 of the parents of the children who participated. The children provided assent.

Processing of Throat Cultures

Throat cultures were performed for each child approximately every 2 weeks during each school year, from October through May. Each child underwent a minimum of 17 cultures per school year. A throat culture was also performed each time a child developed a new respiratory illness, to ensure the identification of all new acquisitions of GAS. Study personnel were “on call,” and an ill child was examined within 1 day after the identification of a new respiratory illness. If a child saw his or her personal physician because of an illness, then a throat culture was performed by the practitioner and retrieved by study personnel. Follow-up cultures were performed 2 to 4 days after completion of antimicrobial therapy for all new acquisitions of GAS that were treated. Follow-up cultures were performed 1 week after the initial culture when new positive cultures for GAS were not treated.

Throat culture specimens were obtained with a rayon-tipped swab (BBL Becton Dickinson, Sparks, MD), transported to the laboratory within 2 hours, and processed the same day with standard techniques, as described previously.11 Beginning in October 2000, the relative numbers of GAS colonies were indicated on a scale of 1 to 4 (1+, 10 CFU but 50 CFU but streptococci not predominant; 4+, streptococci predominant). More than 90% of the throat swabs were obtained by the principal investigator (J.M.M.); the processing of throat cultures was overseen by 1 senior laboratory technician (K.A.B.).

Typing of the GAS Isolates

The genetic relatedness of the GAS strains was investigated with field-inversion gel electrophoresis (FIGE), a type of pulsed-field gel electrophoresis, with previously described methods.12,13 A 4-mm slice of each GAS plug was initially digested with 24 units of SmaI in 1 restriction buffer (New England Biolabs, Beverly, MA). Similar digestions were conducted with ApaI and/or EagI, in their respective restriction buffers, for isolates that could not be digested with SmaI.11

The migration of DNA bands was compared with that of the λ ladder standard. Bands within the 50- to 250-kilobase range were used for analysis. Comparison of banding patterns was performed with visual inspection, and interpretation of clonal relatedness was based on guidelines proposed by Tenover et al.14 One or more representative isolates from each FIGE type from each year and 4 erythromycin-resistant strains from the third year were selected and sent to the Centers for Disease Control and Prevention for emm typing.6

Susceptibility Testing

GAS isolates were screened initially for their susceptibility to erythromycin and clindamycin with the Kirby-Bauer disk diffusion test (BBL Becton Dickinson), on Mueller-Hinton agar with 5% sheep’s blood, according to published guidelines and as described previously.11,15 The minimal inhibitory concentration was then determined with the E-test (AB Biodisk, Piscataway, NJ) for isolates that were either intermediate or resistant in susceptibility to erythromycin or clindamycin. To screen for the mechanism of resistance, double-disk diffusion tests were performed.16 Resistance to erythromycin was classified as an inducible MLS^sub B^ phenotype, a constitutive MLS^sub B^ phenotype, or an M phenotype. All GAS isolates were stored at -70C for later use.

Definitions

Physical examination of the pharynx was performed for each throat culture specimen obtained. At the time of culture sample collection, the child was questioned regarding his or her symptoms, with a standard data sheet. In addition to the symptoms reported by the child, information regarding symptoms was solicited from a parent for each illness visit. The physical examination results, as well as the symptoms, were documented in a database. When any throat culture was positive for GAS, the principal investigator (J.M.M.) called a par\ent within 48 hours after obtaining the positive result. A standard instrument was used to assess symptoms and duration.

Each child was classified into 1 of 4 categories for each school year. The following definitions were used for each subject from whom an isolate of GAS was recovered. A child was classified as a carrier if GAS were recovered from ≥2 sequential surveillance cultures obtained ≥1 week apart in the absence of symptoms. Children were assigned to this category if they were ever GAS carriers during a school year. This included children who cleared their carriage and later had a single throat culture positive for GAS, with or without symptoms. A child was categorized as having recurrent episodes if either clinical or subclinical acquisitions of GAS were documented and separated by a minimum of 1 negative culture (and a 3-week interval) while the child was not receiving antimicrobial therapy. This designation was independent of GAS typing results. A child was designated as having had a single episode if a single positive throat culture was preceded and followed by negative throat cultures during a single school year. Children whose throat cultures were negative for GAS throughout a single school year were designated as having no infections.

All episodes of GAS-positive throat cultures were classified as being either clinical or subclinical. Clinical episodes were those associated with any respiratory symptoms. Typical episodes were those in which sore throat was a prominent complaint. Atypical episodes were those in which the child reported the new onset of rhinorrhea and/or cough, without sore throat. Subclinical episodes occurred when a child with a single positive throat culture had no symptoms.

The outcome of each episode of classic GAS pharyngitis (in which sore throat was the prominent complaint) was classified both clinically and bacteriologically in follow-up evaluations, on the basis of the result of the throat culture and the presence of clinical symptoms. An episode was defined as a clinical cure if the child no longer had symptoms of pharyngitis, as a clinical failure if the child had persistent symptoms of pharyngitis, as a bacteriologic cure if the child had a negative follow-up throat culture for GAS, and as a bacteriologic failure if the child had a positive follow-up throat culture for GAS of the same FIGE type as the initial infection. Each episode in which a child experienced a second positive culture after a bacteriologic cure was classified as a new acquisition if the child had a throat culture that was positive for GAS with a different FIGE pattern or emm type, compared with the child’s previous GAS isolate, or as a reacquisition if the child had a throat culture that was positive for GAS with the same FIGE pattern or emm type as the child’s previous GAS isolate. Duration of carriage was defined as the length of time between the first positive culture of one emm type and the first negative culture or the first positive culture with a new emm type during the school year.

Treatment

Patients with new respiratory complaints of sore throat or rhinorrhea (with or without sore throat) and a new positive throat culture for GAS were treated with orally administered penicillin V or amoxicillin by a single study physician (J.M.M.). Children with rhinorrhea without sore throat were treated only if the child’s previous 2 throat cultures were known to have been negative for GAS. This decision was made because western Pennsylvania is known to have a high incidence of acute rheumatic fever and many children diagnosed as having rheumatic fever do not recall an antecedent sore throat.17-19 Unlike clinical practice, the circumstances of the study afforded the opportunity to identify readily episodes of new acquisition of GAS.

The dose of penicillin V or amoxicillin used for all children was 500 mg twice per day for 10 days. At the beginning of the longitudinal study, erythromycin or azithromycin was prescribed only for children who were allergic to penicillin. Beginning in February 2001, either cephalexin or clindamycin was used for patients who were allergic to penicillin or amoxicillin. These medications were dosed on a milligrams per kilogram basis for a 10-day course, with the exception of azithromycin, which was used for 5 days. Treatment was not prescribed when a surveillance culture was positive for an asymptomatic child. No attempts were made to eradicate the carrier state.

Statistical Methods

Data were entered into a Microsoft Access (Microsoft, Redmond, WA) database. All of the data from the laboratory and a random sample of 10% of the entries were double-checked for accuracy. Calculations were made with STATA 7 (Stata Corp, College Station, TX). χ^sup 2^ analysis was used for comparisons of dichotomous variables, and the t test was used for comparisons of continuous variables.

RESULTS

Demographic Characteristics of the Study Population

A total of 125 children participated in this longitudinal study at some time between October 1998 and May 2002. Figure 1 summarizes the subjects’ entry into and departure from the study. Of the 125 children, 33 (26%) were monitored for 4 years, 50 (40%) were monitored for 3 years, 22 (18%) were monitored for 2 years, and 20 (16%) were monitored for only 1 year.

Forty-nine percent of the students were male; 73% were white, 13% Asian, 7% Hispanic, and 7% black. The demographic features of the children in each study year were similar to those of the school as a whole. The mean age of subjects for the entire study was 9.6 years (range: 5-15 years).

Laboratory Results

Table 1 shows the number of cultures that were performed in each year of the study and the number and percentage that were positive for GAS. The modest increase in the proportion of positive cultures was significantly different when year 3 was compared with years 1 and 4. No isolate of GAS was determined to be resistant to clindamycin. In the first 2 years of the study (1998-2000), there were no isolates that were resistant to erythromycin. However, as previously reported, 156 of 318 GAS isolates (49%) and 126 of 238 GAS isolates (53%) in years 3 and 4 of the study, respectively, were found to be resistant to erythromycin.11 Table 2 shows the distribution of emm types of the GAS isolates for the 4 years. Thirteen different emm types circulated during the 4-year study period, with an average of 9 emm types per year. The predominant emm type was different each year for the first 3 years. The most prominent emm type in year 2 was not observed among the cohort in the previous year. In January of year 3, an erythromycin-resistant strain was isolated for the first time (emm 6, M phenotype, and mef(A) positive).11 This became the predominant strain during years 3 and 4 of the study. There were 22 emm 6 isolates in years 1 and 2 of the study; however, they were not resistant to erythromycin and they had different FIGE patterns, compared with the epidemic strain.

Fig 1. Entry and departure of participants during the 4-year study.

TABLE 1. Comparison of the Percentages of GAS-Positive Throat Cultures According to Study Year

TABLE 2. Distribution of emm Types of the GAS Isolates Recovered in the 4 Years of the Study

The density of GAS was recorded for each throat culture after October 2000. Density did not correlate with clinical category. For children with typical symptoms, 33% of the throat cultures were 1+ positive and 45% were 4+ positive; for children with no symptoms, 39% of the cultures were 1+ positive and 24% were 4+ positive; for children with atypical symptoms, 54% of the cultures were 1+ positive and 21% were 4+ positive.

Classification of Isolates According to Symptoms

Each child with a positive culture for GAS was classified according to symptoms, with strict definitions. No symptoms were present (carriers plus transient subclinical infections) at the time of recovery for the majority of isolates (75%; range: 74-80% for each year). For the remaining positive cultures, 18% (range: 10-20% for each year) were associated with typical symptoms and 7% (range: 6-10% for each year) were associated with atypical symptoms. Overall, 8% of all episodes of illnesses associated with nasal congestion and/or cough but without sore throat were positive for GAS. This number excludes illnesses among children who were already known to be GAS carriers. There were no significant differences in the mean ages of children with no symptoms, typical symptoms, and atypical symptoms.

Children experienced episodes of acute GAS pharyngitis throughout the school year. The number of episodes of positive throat cultures associated with typical symptoms was examined according to the month of the year for each year of the study. In years 2, 3, and 4, there was a bimodal distribution of cases; the month in which episodes associated with typical symptoms peaked was variable (December, February, or April). The seasonal occurrence of episodes of GAS- positive throat cultures associated with typical symptoms and a new emm type was not different between children who were classified as GAS carriers and children who were not classified as carriers (P = .49).

Clinical Characteristics of Streptococcal Infections

Every child was classified into 1 of 4 groups for each year, ie, single episode, recurrent episodes, carrier, and no infections. The relative frequencies of each of the 4 categories were constant for the 4 years of the study. Little variation in the frequency of a given category was observed from year to year (Table 3). The most common classification was children with no infections (38-46%), whereas the least common category was recurrent infections (6-14%).

Fifty-six children were classified as experiencing a single episode in ≥1 school year. For the children with single episodes, 56% were associated with typical symptoms, 21% with atypical symptoms, and 23% with no \symptoms. Forty of these children were monitored for ≥1 year after their single episode. Only 3 (8%) experienced a single episode in the following school year; in each case, the second episode involved a different emm type. Ten of the 40 children (25%) became carriers in the subsequent year, whereas 25 children (63%) had no infections in the subsequent year.

Recurrent episodes were very uncommon. They were observed for only 22 children during the 4-year period; most had only 2 episodes in 1 study year (Table 4). No more than 7 children had recurrent episodes in any given year. Twenty of the 22 children with recurrent episodes were monitored for ≥2 years, and only 2 of those children had recurrent episodes in subsequent years. Children were treated with an antibiotic in 19 of the episodes because they were associated with clinical symptoms. Fifty percent of recurrent episodes were with different emm types. The mean time between infections was 9.33 weeks (SD: 7.59 weeks), with a range of 3 to 29 weeks. Recurrent episodes with the same emm type versus a different emm type were equally likely to occur independently of 1) the interval between episodes (30 days apart) (P = .71), 2) the symptoms with the first episode (P = .73), and 3) whether the child received an antibiotic for the first episode (P = .5). For children who experienced recurrences with the same emm type, the 2 isolates had identical FIGE types. All children with recurrences with different emm types also had different FIGE types. All of the children who had recurrent episodes experienced a clinical and bacteriologic cure before the second episode of infection. There were only 3 children with a single negative throat culture between episodes of GAS with the same emm type. For all of these children, both episodes had typical symptoms and were treated promptly with an antibiotic. The mean time between episodes of the same emm type for all children was 10.68 weeks, and the mean time between episodes of different emm types was 8.84 weeks; these values were not significantly different.

TABLE 3. Comparison of the Clinical Characteristics of the Children in the 4 Years of the Study

TABLE 4. Characteristics of Children With Recurrent Episodes of Infection With GAS in a Single Study Year

Seventy-seven children completed ≥1 study year with no infections. Twenty-eight of the 50 children (56%) monitored for ≥1 year continued to have no infections in subsequent study years. Twenty-two of these 50 children (44%) were monitored for 4 years. Three had no infections during the entire 4-year period. Three had no infections in 3 years, and 12 had no infections in 2 years.

Carriers of GAS accounted for 27 to 32% of the cohort in each year of the study. The mean prevalence of carriers calculated according to month was 15.9% (SD: 4.99%; range: 4.2-26%). Eleven of the 13 children who were carriers in year 1 of the study were monitored for all 4 years. Ten of the 11 (91%) were carriers in subsequent years of the study. Seven were carriers for all 4 years, 1 for 3 years, and 2 for 2 years. If children were carriers in their first year of the study, then they were significantly more likely to continue to be carriers, compared with children who were not carriers in their first year (P

Fifty-three children were classified as GAS carriers at least once. Of these 53 children, 24 (45%) had a positive throat culture when their first culture was performed; they were identified as carriers at study entry. The remaining 29 children began with negative throat cultures for GAS. Thirteen of these 29 children (45%) had typical symptoms at the time of their first positive throat culture. The remaining 16 (55%) had atypical symptoms or were asymptomatic when their first carrier culture was positive. Children who were classified as carriers had variable numbers of throat cultures that were positive during that school year; 29% had 75% of all throat cultures positive for GAS.

Thirty-one of the 53 children who were carriers during ≥1 school year switched emm types at some point. There were 107 episodes in which these 31 children switched from carrying one emm type to carrying a different emm type during a single school year. Sixteen of the 107 episodes (15%) were associated with typical clinical symptoms at the time of type switching. Most episodes of switching (85%) were not associated with any clinical symptoms. Occasionally, a child who was a carrier of one emm type had a clinical infection with a second emm type and then resumed carriage with the first emm type. Three children switched emm types 7 times in the 4 years of the study.

The mean duration of carriage of one emm type was 10.8 weeks (SD: 9.1 weeks; range: 2-34 weeks). By definition, the duration of carriage could not be longer than 1 school year (34 weeks), because throat cultures were not performed during the summer break. However, there were 21 occurrences in which a child was noted to carry the same emm type in the last throat culture of one school year and the first throat culture of the following school year. If we presume that these children remained carriers of that emm type throughout the summer (June to September), then the maximal duration of carriage of one emm type was 127 weeks. For those 21 episodes, the range was 24 to 127 weeks, with a mean duration of 49 weeks.

Treatment

There were 209 episodes that were treated with an antibiotic. Of these, 78% involved typical symptoms of classic streptococcal pharyngitis. Eighty-six percent of these were treated with amoxicillin or penicillin, 7% were treated with azithromycin (before February 2001), 5% were treated with clindamycin, and 2% were treated with cephalexin. No clinical treatment failures were observed.

DISCUSSION

In clinical practice, the assignment of GAS as the cause of an episode of pharyngitis is based on temporal association. A child is considered to have streptococcal pharyngitis if he or she has a sore throat and a positive rapid diagnostic test or culture for GAS. Although microbiologie confirmation is essential, the recovery of GAS does not establish causality. The tests do not distinguish carriage of GAS in a child with pharyngitis attributable to another cause from an acute infection caused by GAS. To establish causality, it is theoretically necessary to demonstrate the host’s response to the infection in the form of antibody production. However, this antibody response (serologic evidence of infection) does not occur for 2 to 3 weeks. Furthermore, the antibody response is frequently aborted with appropriate early antibiotic therapy.20 The unique contribution of this study is the acquisition of systematic longitudinal data for school children, which overcomes the problems of interpretation of sporadic data obtained in clinical situations. All children in this cohort were accurately classified, during each year of the study, into 4 categories, ie, single episodes, recurrent episodes, carriers, and no infections.

Longitudinal studies that described the epidemiologic features of GAS infections among school children and in families were conducted previously.7-10 However, the lack of available antisera and molecular typing systems when those studies were performed prevented precise tracking of infections. In 1 study, as many as 90% of the GAS isolates were nontypeable.10 The inability to type the GAS isolates prevented the accurate categorization of episodes in which GAS were recovered. In contrast, the use of FIGE techniques and emm typing in our study, in conjunction with careful physical examinations and determination of clinical symptoms, allowed precise classification of each episode of infection/colonization with GAS.

One of the original goals of this investigation was to study how immunity to GAS is acquired. We hypothesized that a single infection with a given emm type would provide partial or complete immunity to reinfection with the same emm type. Recurrent infections were relatively uncommon among the subjects in this study. Approximately one-half of the recurrent episodes were caused by a GAS isolate of the same emm type as the first infection, independent of both the time between episodes and previous antibiotic treatment. This suggests that a single infection with a specific emm type may not be sufficient to induce type-specific immunity or that early treatment may abort the development of type-specific immunity. However, because recurrent episodes proved to be the least common of the clinical manifestations of infection with GAS, we are limited in our ability to speculate about the induction of immunity. A larger study of children presenting with symptomatic GAS pharyngitis will be necessary for determination of the epidemiologic features of recurrent episodes.

Although recurrent episodes were least common, single episodes were frequent. When a child had a single episode in 2 subsequent school years, the episodes always involved different emm types. These children might have acquired some type-specific protection. Many single episodes were typical in clinical presentation; however, 21% were atypical and 23% were completely asymptomatic. Some children had a single positive throat culture temporally associated with a clinical constellation that resembled a viral upper respiratory tract infection. The association of the clinical syndrome of rhinorrhea and GAS warrants additional study, to determine whether a causal relationship exists and to assess the potential implications of this relationship.

An intriguing observation in this study was that almost 40% of children remained uninfected each school year, despite the fact that they resided within this reservoir of GAS infection. The mean age of children wit\h no infections was similar to that of the group as a whole. More than one-half of those who were uninfected in 1 year remained free of infection in a subsequent year. The local and systemic mechanisms that provide protection under these circumstances remain unknown. Protection may be based on mucosal immunity to the specific portion of the M-protein, local or systemic immunity to the conserved portion of the M-protein, or local production of peptides with antibacterial properties.21,22

The traditional definition of a GAS carrier is an asymptomatic individual with a positive throat culture and no serologic response. A second accepted definition is an asymptomatic child with a GAS- positive throat culture after completion of an appropriate course of antimicrobial treatment. In an effort to maintain participation in this study, serologic data were not sought from enrolled subjects. Instead, meticulous tracking of throat culture results, GAS typing, and correlation with the presence of clinical symptoms permitted accurate classification of each positive throat culture and each child. Demonstration of the persistence of identical GAS isolates with time, in the absence of any symptoms, provides strong evidence that a child is a GAS carrier.23 This is independent of the relative number of GAS colonies found on the culture plate or serologic information.

Carriers of GAS constituted the largest group of children with positive throat cultures in our study. The prevalence of carriage varies dramatically according to the setting in which it is studied. In previous longitudinal studies like our own, carriage rates were reported to be extremely high (up to 25%).7-10 In contrast, carriage rates evaluated in clinical practice or as part of a therapeutic trial were reported to be 2.5% to 11.5%.24-27 Our study showed the prevalence of carriage to be 27% to 32% over the course of a school year, with an average point prevalence of 15.9% for any given month of the study (range: 4.2-26%). When the point prevalence is compared with the results of clinical practice studies, the results appear to be similar. Longitudinal studies may enhance the identification of carriers because asymptomatic children undergo repeated cultures. Furthermore, symptomatic children in our study were treated primarily with penicillin and amoxicillin. Some authors think that treatment with these antimicrobial agents may result in higher carrier rates after episodes of symptomatic infection, compared with other antimicrobial drugs.27

There are few studies that describe the natural history of pharyngeal carriage with GAS. Our data show that carriage is both common and persistent. The duration of carriage of a single emm type persisted between 3 and 123 weeks. Children who cleared the carrier state spontaneously demonstrated that they were likely to become carriers again. Ten of 11 children who were GAS carriers in the first year and were monitored over time remained carriers. This phenomenon has not been noted previously and may suggest a GAS carrier phenotype. Furthermore, the use of molecular markers in our study permitted recognition of the frequent changes in emm types among children who were carriers. Occasionally, the acquisition of a new emm type by a GAS carrier was associated with clinical symptoms. Usually, the children continued to carry the new strain; rarely, they reverted to carriage of their original emm type.

The observation that children who are carriers of GAS often acquire infection with new emm types has implications for the clinical approach for children who are known to be carriers. Although the conventional teaching has been that children who are carriers of GAS are not at risk to develop acute rheumatic fever,28 children may be at risk when they acquire new emm types. It was recognized previously that 5% of children who are thought to be carriers have a serologic response to infection with GAS.29 We hypothesize that this may be explained by the acquisition of a new emm type. On the basis of these observations and because we practice in an area of the country with a high rate of acute rheumatic fever,17-19 we now routinely treat all infections associated with a GAS-positive throat culture among children with typical symptoms (sore throat and absence of cough and nasal congestion), even if the child is known to be a carrier of GAS. Practitioners in other areas of the country with similarly high rates of acute rheumatic fever should consider this approach.

Thirteen different emm types were identified among pharyngeal isolates of GAS during this 4-year study period. There are relatively few data on the distribution and frequency of various emm types among children with pharyngitis. Data from North Carolina showed that 6 M types caused most disease in that community between October 1993 and May 1994.30 Haukness et al31 found 12 emm types in 63 GAS isolates from 3 clinical offices in the Chicago area, during a 3-week period. Data from a study of GAS isolates obtained between September 2001 and May 2002 in the Pittsburgh community showed 7 different emm types among the erythromycin-resistant isolates.32 Information that is available regarding invasive strains suggests that there is substantial overlap in the predominant emm types causing disease in different locations.33 Because invasive strains generally reflect the predominant pharyngeal strains, it is anticipated that there will be substantial overlap in the emm types causing pharyngeal infections in different geographic areas. A comparison of the emm types of pharyngeal strains recovered in different geographic areas would provide important insights into the epidemiologic features of GAS infections at a national level.

The study population in this private school might be different from populations found in neighborhood, public, or religious schools in the United States, which might limit the generalizability of these data. There is substantial mixing of students at different grade levels, because instructional settings are based on readiness rather than age. In addition, these children are from many different school districts and >20 different zip codes. They have contact with children in their neighborhoods who do not attend the same school. On one hand, this may allow exposure to a greater number of emm types, compared with children in more traditional public school settings; on the other hand, because all children did not participate in the study, it is possible that the number of emm types circulating in the school has been understated. The fact that a single individual obtained 90% of the throat swabs and that all of the cultures were processed in the laboratory by a single senior technician minimizes the variability in collection and interpretation of throat cultures.

GAS-positive throat cultures are very common among school-aged children. The majority of positive throat cultures in this longitudinal study were obtained from children who proved to be carriers of GAS. Their cultures were not associated with the symptoms of GAS pharyngitis or with acute infection. This supports the recommendation of both the American Academy of Pediatrics and the Infectious Disease Society of America that only children who present with typical symptoms should have a rapid streptococcal test or throat culture performed to detect the presence of GAS.23,34 Although children with GAS infections may present with atypical respiratory symptoms, until there is the capability of rapidly distinguishing acutely infected patients from carriers, testing for GAS should be performed selectively in clinical settings.

This study has allowed us to describe the various clinical and subclinical manifestations of infection with GAS among school-aged children. The factors that govern the clinical expression of streptococcal infection are unknown. How and why some children regularly incorporate GAS as part of their normal flora is also unknown. Neither local nor systemic mechanisms that protect against acquisition of streptococcal infection have been delineated. Despite our long familiarity with this resurgent pathogen, many questions remain to be answered.

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grant 5K23 AI01713-02, General Clinical Research Center of the Children’s Hospital of Pittsburgh grant MOIRR000084, the Competitive Medical Research Fund of the University of Pittsburgh, the American Heart Association Pennsylvania-Delaware Affiliate, and the Research Advisory Committee of the Children’s Hospital of Pittsburgh.

We acknowledge Bernard Beall, PhD, and the Centers for Disease Control and Prevention for providing the emm typing results.

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10. Quinn RW, Federspiel CF. The occurrence of hemolytic streptococci in school children in Nashville, Tennessee, 1961-1967. Am J Epidemiol. 1973;97:22-33

11. Martin JM, Green M, Barbadora KA, Wald ER. Erythromycin- resistant group A streptococci in schoolchildren in Pittsburgh. N Engl J Med. 2002;346:1200-1206

12. Shah R, Green M, Barbadora K, et al. Comparison of M- and T- type antigen testing to field inversion gel electrophoresis in the differentiation of strains of group A streptococcus. Pediatr Res. 1995;38:988-992

13. Martin JM, Wald ER, Green M. Field inversion gel electrophoresis as a typing system for group A streptococcus. J Infect Dis. 1998;177:504-507

14. Tenover FC, Arbeit RD, Goering RV, et al. Interpreting chromosomal DNA restriction patterns produced by pulsed-field gel electrophoresis: criteria for bacterial strain typing. J Clin Microbiol. 1995;33:1020-1027

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17. Wald ER, Dashefsky B, Feidt C, et al. Acute rheumatic fever in western Pennsylvania and the tristate area. Pediatrics. 1987;80:371-374

18. Loeffler AM, Neches WH, Ortenzo M, et al. Identification of cases of acute rheumatic fever managed on an outpatient basis. Pediatr Infect Dis J. 1995;11:975-978

19. Zangwill KM, Wald ER, Londino A. Acute rheumatic fever in western Pennsylvania: a persistent problem into the 1990′s. J Pediatr. 1991;118: 561-563

20. Kaplan EL. The group A streptococcal upper respiratory tract carrier state: an enigma. J Pediatr. 1980;97:337-345

21. Nizet V, Ohtake T, Lauth X, et al. Innate antimicrobial peptide protects the skin from invasive bacterial infection. Nature. 2001;22:454-457

22. Dessen D, Fischetti VA. Passive acquired mucosal immunity to group A streptococci by secretory immunoglobulin A. J Exp Med. 1988;167: 1945-1950

23. American Academy of Pediatrics, Committee on Infectious Diseases. Red Book: Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:573-584

24. Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Green JL, Sorrento A. Incidence of streptococcal carriers in private pediatric practice. Arch Pediatr Adolesc Med. 1999;153:624-628

25. Breese BB, Disney FA, Talpey W. The incidence of β- hemolytic streptococcal illness in a private pediatric practice. Pediatrics. 1966;38:277-285

26. Hofkosh D, Wald ER, Chiponis DM. Prevalance of non-group-A β-hemolytic streptococci in childhood pharyngitis. South Med J. 1988;81: 329-331

27. Pichichero ME, Casey JR. Defining and dealing with carriers of group A streptococci. Contemp Pediatr. 2003;20:46-56

28. Shulman ST, Gerber MA, Tanz RR, Markowitz M. Streptococcal pharyngitis: the case for penicillin therapy. Pediatr Infect Dis J. 1994;13: 1-7

29. Kaplan EL, Gastanaduy AS, Huwe BB. The role of the carrier in treatment failures after antibiotic for group A streptococci in the upper respiratory tract. J Lab Clin Med. 1981;98:326-335

30. Kiska DL, Thiede B, Caracciolo J, et al. Invasive group A streptococcal infections in North Carolina: epidemiology, clinical features, and genetic and serotype analysis of causative organisms. J Infect Dis. 1997; 176:992-1000

31. Haukness HA, Tanz RR, Thomson RB Jr, et al. The heterogeneity of endemic community pediatric group A streptococcal pharyngeal isolates and their relationship to invasive isolates. J Infect Dis. 2002;185: 915-920

32. Green M, Martin JM, Barbadora KA, Beall B, Wald ER. Reemergence of macrolide resistance in pharyngeal isolates of group A streptococci in southwestern Pennsylvania. Antimicrob Agents Chemother. 2004;48: 473-476

33. Active Bacterial Core Surveillance (ABCs) Report Emerging Infections Program Network. Group A streptococcus, 2001. Available at: www.cdc.gov/ncidod/dbmd/abcs/survreports/gas01-provis.pdf. Accessed March 22, 2004

34. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH, Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of group A streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125

Judith M. Martin, MD; Michael Green, MD, MPH; Karen A. Barbadora, MT(ASCP); and Ellen R. Wald, MD

From the Department of Pediatrics, Division of Allergy, Immunology, and Infectious Diseases, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.

Accepted for publication May 10, 2004.

doi:10.1542/peds.2004-0133

Address correspondence to Judith M. Martin, MD, Department of Pediatrics, Division of Allergy, Immunology, and Infectious Diseases, Children’s Hospital of Pittsburgh, 3705 Fifth Ave, Pittsburgh, PA 15213. E-mail: judy.martin@chp.edu

PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Academy of Pediatrics.

Copyright American Academy of Pediatrics Nov 2004