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Seven-Year Surveillance of North American Pediatric Group A Streptococcal Pharyngitis Isolates

  1. Stanford T. Shulman1,2,
  2. Robert R Tanz2,3,
  3. James B. Dale4,5,
  4. Bernard Beall6,
  5. William Kabat1,
  6. Kathleen Kabat1,
  7. Emily Cederlund1,
  8. Devendra Patel1,
  9. Jason Rippe1,
  10. Zhongya Li6,
  11. Varja Sakota6, and
  12. North American Streptococcal Pharyngitis Surveillance Groupa
  1. 1Division of Infectious Diseases, Children's Memorial Hospital, Chicago, Illinois
  2. 2Division of General Academic Pediatrics, Children's Memorial Hospital, Chicago, Illinois
  3. 3Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
  4. 4Department of Medicine, University of Tennessee Health Science Center and VA Medical Center, Memphis
  5. 5Department of Molecular Sciences, University of Tennessee Health Science Center and VA Medical Center, Memphis
  6. 6Centers for Disease Control and Prevention, Respiratory Diseases Branch, Atlanta, Georgia
  1. Reprints or correspondence: Dr. Stanford T. Shulman, Div. of Infectious Diseases, 2300 Children's Plaza, Box 20, Chicago, IL 60614 (sshulman{at}northwestern.edu).

  • ↵a Members of the North American Streptococcal Pharyngitis Surveillance Group are listed at the end of the text

 
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Abstract

Background. Pharyngeal group A streptococcal (GAS) emm type surveillance enhances understanding of the epidemiology of pharyngitis and invasive GAS disease and formulation of multivalent type-specific vaccines. In addition, such surveillance provides pre-GAS vaccine baseline data. We assessed geographic and temporal trends in GAS emm -type distribution among pediatric pharyngeal isolates collected systematically in the United States and Canada from 2000 to 2007.

Methods. We collected ∼100 acute GAS pharyngitis isolates from each of 13 widely scattered sites (10 in the United States and 3 in Canada) annually for 7 seasons (2000–2007) from 3- to 18-year-old children. We assessed emm type and subtype by DNA sequencing and analyzed temporal and geographic trends.

Results. A total of 7040 US and 1434 Canadian GAS isolates were studied. The 6 most prevalent emm types (in descending order) were 1, 12, 28, 4, 3, and 2 in the United States and 12, 1, 28, 4, 3, 2, and 77 in Canada, constituting 70%-71% of isolates in each country; 10 emm types constituted 87%-89% total. Fifty-six emm types were identified in the United States, including 8 new types, and 33 types in Canada. Although a few types predominated nationally, marked variability among individual sites and at individual sites from year to year was observed. US-Canadian differences in type distribution were apparent. Twenty percent of isolates represented emm subtypes that differed slightly from reference types; 110 new subtypes were identified. An experimental 26-valent M protein vaccine covers 85% of pharyngitis isolates.

Conclusions. Although overall US and Canadian emm type distribution was consistent and relatively few types dominated nationally, striking intersite and temporal variations within individual sites in prevalent emm types of GAS occurred. These results have important implications for the development and formulation of type-specific GAS vaccines.

We established a North American surveillance system in 2000 to collect acute pharyngeal group A streptococcal (GAS) isolates recovered from children in a systematic fashion for the primary purpose of assessing the emm type and subtype distribution of organisms responsible for pediatric pharyngitis [1]. The emm gene encodes M protein, which is largely responsible for type-specific immunity to GAS. We previously reported emm data from 9 US sites for December 2000-May 2001 (year 1) and from 1 Canadian and 10 US sites for December 2001-May 2002 (year 2) [1]. The most predominant GAS emm types were similar in the 2 study years, and intersite and intrasite variations occurred in emm -type distribution. We report 7 years of surveillance data (years 1–7) from 10 widely geographically scattered US and 3 diverse Canadian sites to characterize temporal and geographic trends more completely and to contrast the emm type and subtype distributions at US and Canadian sites.

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Methods

Subjects and specimens. We collected pharyngeal GAS specimens from children 3–18 years old who presented with acute pharyngitis at 10 geographically widely scattered US sites (9 primary care offices and 1 laboratory in California that serves several linked offices) and at 3 Canadian sites in Vancouver, British Columbia, Montreal, Quebec, and Halifax, Nova Scotia, each at a children's hospital. Each site had 3–4 collection periods within each December to May GAS pharyngitis season, and each site provided ∼100 specimens per season. Throat swabs or culture plates were shipped to the Infectious Diseases Laboratory at Children's Memorial Hospital, where isolates were confirmed as GAS by standard techniques with confirmation by agglutination with PathoDx (Remel). Crude GAS DNA templates were prepared and shipped to the Streptococcal Research Laboratory at the Centers for Disease Control and Prevention (CDC), where they were emm typed by sequencing polymerase chain reaction products generated by standard techniques [2], and subtypes were assigned as previously described [1] using the CDC emm sequence database ( http://www.cdc.gov/ncidod/biotech/strep/strepblast.htm). Specimens were identified only by age and sex and by date and location of acquisition. The study was approved as an exempt study by the Children's Memorial Hospital Institutional Review Board.

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Results

Cumulative data by country. The numbers of organisms collected by site in each of the 7 US and 6 Canadian surveillance years are given in table 1. A total of 7040 US isolates and 1434 Canadian isolates were included in this study. Table 1gives the proportions of the 13 most prevalent emm types in the United States and Canada for each of the 7 study years and for the entire study period. A total of 56 different emm types were isolated in the United States and 33 in Canada during the study. Eight new (provisional) types were found among the US isolates, representing 11 individual isolates. Figures 1and 2 show the cumulative proportions of isolates for each country during the entire study period.

Figure 1
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Figure 1

US pharyngeal group A streptococcal emm types for study years 1–7, 2000–2007 (n=7040). “+Others” indicates 35 emm types with <10 isolates each.

Figure 2
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Figure 2

Canadian pharyngeal group A streptococcal emm types for study years 2–7, 2000–2007 (n=1434). “+Others” indicates 14 emm types with <4 isolates each.

It is apparent that the distributions of the 6 most prevalent pharyngeal GAS types were similar in the United States and Canada, with emm types 12, 1, 28, 4, 3, 2, and 77 (emm types 2 and 77 were equal in number) predominating in Canada overall and emm types 1, 12, 28, 4, 3, and 2 in the United States, accounting for 70%-71% of isolates in each country (table 1 and figures 1 and 2). The 10 most prevalent emm types in each country accounted for 87%-89% of the total. Almost one-half of cases of pharyngitis are caused by emm types 1, 12, and 28 each year in each country. However, substantial year-to-year differences in the national distribution of emm types were observed, which are apparent in table 1. For example, the proportions of Canadian emm type 1 isolates ranged from a low of 9.8% to a high of 27.2% in different study years, US emm type 1 from 14.6% to 22.0%, US emm type 3 isolates from 6.2% to 14.7%, and Canadian emm type 28 from 6.5% to 15.9% (table 1).

Table 1
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Table 1

Geographic distribution of group A streptococci.

Table 2
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Table 2

Pharyngeal emm type distribution in the United States and Canada, by year.

Table 3
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Table 3

National differences in pharyngeal emm type prevalence for 2002–2007 (years 3–7).

US-Canadian differences. Despite the overall similarity in national data for the most common emm types, it is apparent that the distribution of a number of emm types differed significantly between the 2 countries (table 1). Data from years 3–7 are given in this table because they are years in which we collected the most complete data in Canada. emm Types 3, 2, 75, 44, and 118 were significantly more common among US isolates, whereas emm types 28 and 77 were more prevalent in Canada. The US-Canadian differences in proportions of emm type 118 and emm type 44 isolates are particularly striking.

Geographic variability. Despite the high degree of similarity of the emm type distributions in the 2 countries taken as a whole, marked intersite variability was observed within each season. For example, during 2006–2007 (year 7), emm type 4 was highly prevalent at some sites (33% in South Dakota, 26% in Connecticut, and 17% in Florida), less prevalent at others (13% in Quebec, 11% in Pennsylvania, 10% in Washington, and 7% in California), and uncommon at the other sites (4% in Utah, 4% in Nova Scotia, and 3.5% in Illinois) during that season. Similar variability was apparent for emm type 3, which was most prevalent in Pennsylvania (30%) and Utah (19%) but not among the top 6 or 7 types in Connecticut (1%), South Dakota (1%), Quebec (0.7%), or Washington (0.7%) during the same season. Other emm types (e.g., 6, 2, 1, and 28) also showed marked intersite variation. Similar variability in prevalence of specific emm types was observed during each of the 7 study years. Extremes of prevalence of the 6 most common types overall at any site during 1 of the 7 study years (such as 1% in Nova Scotia and 42% in Florida for emm type 1, 3% in Utah and 44% in Connecticut for emm type 12, and 1% in South Dakota and 33% in South Dakota for emm type 4 in a different year) highlight the great degree of variability of even the most prevalent types overall during our study period.

Temporal variability. In addition to striking intersite variability of emm type distribution within a given season, we observed marked year-year variability in emm type distribution at individual sites, as reflected by analysis of the most prevalent emm types at a given site in each of the 7 study years. At the Illinois site, for example, emm 12 was highly prevalent in each year, but there was impressive variability of emm types 1, 2, 3, 4, 75, and 89 from year to year during the study period. Similar temporal variability was also observed at virtually all other study sites.

Subtype (or allelic) diversity. During this study, 110 new subtypes, or allelic variants, were identified. We observed considerable variability among the 10 most prevalent emm types in the United States and Canada with respect to diversity of emm subtypes. Within emm type 1, 3, 6, and 12 strains, there were a large number of variants, with 23–33 subtypes each, accounting for 3.5%-81% of all isolates of a given emm type. Other common types (28, 4, 2, 75, 89, and 77) showed little or no such diversity, with only 1–3 subtypes each.

Rheumatogenic types. The classic rheumatogenic GAS types 3, 5, 6, 14, 18, 19, and 29 comprised 16.0% of US pharyngeal isolates and 14.1% of Canadian isolates in this data set. This finding is consistent with our previous report that these rheumatogenic types comprised 49.7% of throat isolates in Chicago during 1961–1968, when rheumatic fever was common, but were found in a significantly (P<.001) lower proportion in recent years, when rheumatic fever has become unusual in North America [3].

Vaccine types. We assessed the proportion of US and Canadian pharyngeal isolates that were included in the candidate 26-valent M protein vaccine [4-6]. Approximately 85% of pharyngeal isolates in both countries were encompassed by the emm types included in this candidate vaccine. The most notable emm type not included in the vaccine was emm 4, which accounted for 9.6% (annual range, 7.8%-13.2%) of US and 11.1% (annual range, 6.9%-13.6%) of Canadian streptococcal pharyngitis types.

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Discussion

Our systematically acquired collection of 8474 pediatric pharyngeal GAS isolates from 13 widely scattered geographic sites in North America from 2000 to 2007 provides a unique opportunity to assess the characteristics of GAS-causing acute pharyngitis and to extend our earlier experience [1]. We observed considerable diversity in emm types but dominance by relatively few types. Three emm types (12, 1, and 28) accounted for ∼50% of isolates in the United States and Canada, the 6 most prevalent types (12, 1, and 28 plus 4, 3, and 2) accounted for ∼70% of isolates, and the 10 most prevalent for 87%-89% of isolates. These data are fairly similar to most reports from western Europe. For example, Darenberg et al. [7] reported that among 389 pharyngeal isolates in Sweden (median patient age, 18 years) from 2002 to 2004 emm types 12 (20.1%), 28 (16.7%), 4 (10.0%), 1 (9.3%), and 89 (7.5%) predominated.

The emm distribution and degree of diversity of pharyngeal GAS from other geographic regions are often different from those of North America and Europe. Recent pediatric data from Fiji included 99 throat isolates that represented 43 different emm types; no emm type 1 was found, and there was no dominant type [8]. Predominant pharyngeal types in Northern India were recently reported to be emm types 81, 112, 15, 11, and 49, which were completely different from those found in North America [9]. Erdem et al. [10] reported that pediatric pharyngeal isolates from Oahu, Hawaii, and American Samoa represent some common emm types similar to those we found in the continental United States and Canada, with approximately one-third in Hawaii being emm types 12, 1, and 28, but there were also a number of types that are uncommon or unknown in North America. The small sample of 14 Samoan isolates included only a single emm type 1 and none of the other 14 most prevalent North American types (which comprise 98% of North American isolates). In addition, virtually all of this small sample of Samoan isolates were types not identified at all in North America.

Most studies of GAS emm type distribution have focused on invasive isolates. Our data confirm that pharyngeal emm types and invasive isolates have similarities but that significant differences exist. O'Loughlin et al. [11] from the CDC recently reported emm types associated with invasive GAS infection from 2000 to 2004 in the US Active Bacterial Core surveillance program [11]. Prominent emm types were 1, 3, and 28, accounting for 40% of invasive isolates, whereas these 3 plus emm types 12, 89, and 82 made up 58%, with the 30 most prevalent types encompassing 95% of isolates. When comparing our pharyngeal isolates to the CDC's report of invasive GAS, selected emm types, such as emm types 12, 4, 2, 6, and 118, appear overrepresented in the pharyngeal group, whereas emm types 3, 89, 1, and 82 are overrepresented among 2000–2004 invasive US isolates [11]. These observations are similar to those reported by us in our 2-year data set [1]. Invasive pediatric isolates of GAS from Europe in 2003–2004 (with 62% of isolates coming from the United Kingdom) were similar to the US invasive infection data, with emm types 1 (26%), 12 (11%), 3 (10%), 4 (10%), and 28 (7%) most prevalent [12]. A recent report of 278 invasive GAS isolates from adults and children from Denmark in 2003–2004 found emm types 28 (26%), 1 (24%), 3 (11%), and 89 (7%) to predominate [13]. Doloy et al. [14] presented data on pediatric invasive GAS from France in 2007 and found emm types 1 (40%), 12 (12%), 89 (9%), 4 (9%), 3 (5%), and 28 (4%) to predominate.

We found that 85% of pharyngeal isolates are of emm types that are included in the experimental 26-valent M-protein vaccine [4]. This exceeds the reported 79% of invasive US GAS strains in the recent CDC study [11]. Among pharyngeal emm types not included in this vaccine, emm 4 is the most prominent because it is the fourth most prevalent emm type, representing 9.6% of US and 11.1% of Canadian isolates. The possibility that utilization of an M protein-based vaccine might lead to serotype replacement, as observed with widespread use of conjugate pneumococcal vaccine [15], must be considered, further supporting the need for ongoing serotype surveillance. However, pneumococcal replacement disease is still modest, with an overall incidence of invasive infection in children during 2006 markedly reduced compared with preconjugate vaccine years [16].

Our data clearly demonstrate striking geotemporal variation in pharyngeal emm types among our 13 sites in the United States and Canada. Although the cumulative US and Canadian distributions of types were similar, there was striking intersite variation within any given season and intrasite variation from season to season. It is possible that increased levels of immunity to certain predominant types contributed to this variation, thus resulting in decreased prevalence of some of those types in subsequent years. We have also reported that several of the more common emm types account for a progressively lower proportion of pharyngeal isolates among older children and teenagers than in younger children, suggesting a role for type-specific immunity [17]. In support of this concept, recently Jaggi et al. [18] reported that serum antibody levels to several common M proteins were higher in older than in younger children.

The North American emm type data from 2000 to 2007 clearly confirm and extend our previous observation that the classic rheumatogenic types (3, 5, 6, 14, 18, 19, and 29) have markedly decreased in prevalence, and in some instances completely disappeared, compared with their prevalence among pharyngeal types circulating in the 1960s when acute rheumatic fever was a common pediatric illness [3]. Of 8474 pharyngeal isolates in this study, only 1 emm type 14, 18 emm type 18, no emm type 19, and 15 emm type 29 isolates were recovered. In addition, emm types 3, 5, and 6 made up only 8.4%, 1.6%, and 5.3%, respectively, of our modern throat isolates compared with 15.4%, 7.1%, and 12.6% in the 1960s (P<.001for each) [3]. The decrease in prevalence of these classic rheumatogenic types and the near disappearance of some types from North America directly parallel the marked decrease in incidence of rheumatic fever in North America.

In general, we observed much more subtype variation among strains known not to express the opacity factor (OF)-positive phenotype. This finding is consistent with the numbers of known subtypes in the CDC global emm database associated with either “OF+ emm types” or “OF− emm types” (see ftp://ftp.cdc.gov/pub/infectious_diseases/biotech/tsemm/for a total compilation of subtypes) [19, 20]. The emm types with limited diversity all express OF, the product of the sof gene, whereas the highly diverse types are OF negative [21]. Traditionally, rheumatogenic types are sof negative, whereas the sof -positive types are considered capable of causing both skin and pharyngeal infection rather than either skin or pharyngeal infection and are nonrheumatogenic [22]. For example, the OF-negative emm types 1, 12, 3, and 6 (in order of decreasing prevalence among US pharyngitis isolates, table 1) are associated with 41, 47, 50, and 62 known subtypes, respectively. Note that emm type 12 is phenotypically OF negative but sof positive, containing a full-length sof gene, which is defective because of a single base detection [19, 23] In contrast, the common OF-positive types emm type 28, emm type 4, emm type 75, and emm type 89 account for only 8, 10, 3, and 12 known subtypes, respectively [19, 20]. The reasons why OF-negative emm types are associated with more subtypes is not fully understood; it is conceivable that these observations reflect greater immunologic pressure exerted on them. However, in the case of emm type 6, it is apparent that adjacent tandem repeats overlap with the 150-base subtype-determining region, and the resultant intragenic mispairings lead to a relatively large number of subtypes (B. Beall, unpublished data). Most subtypes represent only a few amino acid substitutions, and we showed that, for several OF-negative types with many subtypes, those tested were still opsonized by type-specific antisera [24]. This suggests that a multivalent M protein vaccine is not likely to permit variant subtypes to escape in a highly immunized population. In addition, subtype assessment provides a strain marker that may be useful for assessing epidemiologic associations among clinical isolates of GAS.

The data obtained during our 7-year, multisite US and Canadian GAS pediatric pharyngitis surveillance study demonstrate that emm type distribution was rather consistent when viewed nationally, with the 6 most prevalent types encompassing ∼70% of isolates. Often striking intersite differences in prevalent emm types and temporal differences within individual sites during the surveillance were apparent. An experimental 26-valent M protein vaccine covered ∼85% of pharyngeal isolates in each country, with emm type 4 the most prevalent type not included in the vaccine.

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North American Streptococcal Pharyngitis Surveillance Group

Richard Nachman and Teresa Rhim, Chicago, Illinois; Edward Rothstein, Sellersville, Pennsylvania; Thomas Zavelson and John Hellrung, Gainesville, Florida; Andrew Gellady, New Port Richey, Florida; Roopal Patel, Tampa, Florida; Cathy Hofer, Chris Tiongson, Rich Kooima, and Michael Elliott, Sioux Falls, South Dakota; Heather Christianson, Mitchell, South Dakota; Marcene Bloom, Rapid City, South Dakota; S. Michael Marcy and Emily Chang Wong, Panorama City, California; Susan Novak-Weekley and Anne Vannier, North Hollywood, California; Jon Almquist, Federal Way, Washington; Delbert Hodder, Bristol, Connecticut; John Ledbetter and Tracey Stewart, Little Rock, Arkansas; Paige Suffredini, Austin, Texas; Julie Gustin and Tiffany Glasgow, Sandy, Utah; Jane McDonald, Montreal, Quebec; Scott Halperin and Annette Morris, Halifax, Nova Scotia; and Annette Castell and Laura Book, Vancouver, British Columbia.

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Acknowledgments

Financial support. ID Biomedical Corporation, National Institutes of Health (3R37 AI 10085 to J.B.D.), and Children's Memorial Research Center.

Potential conflicts of interest. S.T.S. has received research support from ID Biomedical and lecture fees by Pfizer, Wyeth, Abbott, and Glaxo-Smith Kline. J.B.D. is the inventor of certain technologies related to the development of GAS vaccines, including the 26-valent vaccine that has been the subject of clinical trials; and has served as a consultant for ID Biomedical, which partially funded this study. All other authors: no conflicts.

  • Received December 5, 2008.
  • Accepted February 12, 2009.
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  1. Clin Infect Dis. (2009) 49 (1): 78-84. doi: 10.1086/599344
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