The group A streptococcus (GAS) is the main bacterial cause of pharyngitis and is responsible for around 15% to 30% of cases of acute pharyngitis in children.1,2 The incidence of GAS pharyngitis in children varies from region to region with estimates as high as 95 cases per 100 child-years in children in Northern India.3 The incidence of GAS pharyngitis is unknown in Pacific Island countries, including Fiji, despite some of the highest rates of rheumatic fever and rheumatic heart disease in the world occurring in the Pacific region.4–6
Identification of children with GAS pharyngitis is important in areas where rheumatic fever is common because appropriate antibiotic treatment can prevent rheumatic fever.7,8 The diagnosis of GAS pharyngitis is made by bacteriologic culture or rapid antigen assay from a throat swab in children with sore throat. In many countries, access to microbiologic diagnostic services is poor and clinicians must rely on their clinical acumen to separate GAS and non-GAS causes of sore throat. The symptoms and signs of pharyngitis caused by GAS and pharyngitis caused by other organisms overlap.1,9
The primary aim of this study was to determine the incidence of GAS culture-positive sore throat, and the prevalence of GAS carriage in asymptomatic children. The secondary aims of the study were the determination of the incidence of GCS/GGS culture-positive sore throat, determination of the prevalence of GCS/GGS carriage, the description of the clinical features of sore throat, and the description of the molecular epidemiology of GAS, GCS, and GGS by emm typing.
MATERIALS AND METHODS
We conducted a prospective cohort survey of school children aged 5 to 14 years over a period of 10 months from February 2006 through November 2006.
Fiji is a nation of approximately 330 islands located in the Western Pacific. It has a population of 827,900 people comprising of 2 major racial groups: Indigenous Fijians (57.3%) and Indo-Fijians (37.6%).10 Fiji is ranked 90 of 177 nations on the United Nations Development Programme Human Development Index. It has a GDP per capita of USD 6066 and an infant mortality rate of 16.8 per 1000.11,12 The overall crude mortality rate in Fiji is 6.1 per 1000, and life expectancy at birth is 63.8 years for men and 66.8 years for women.12,13 Approximately 49% of the population lives in rural areas.10
This study was conducted in 4 primary schools in the Central Division of Fiji. The Central Division has a total population of 340,843 people, of whom 75,462 are 5 to 14 years of age.10 Primary schools in Fiji extend from class 1 (5 years of age) to class 8 (14 years of age). School A and school B are located in a rural area while schools C and D are located in Fiji’s capital city, Suva.
To determine the rate of asymptomatic streptococcal carriage, carriage swabs were taken in the first month of the study (February 2006). Children with a sore throat on the day of carriage swabbing or on any of the preceding 7 days were excluded from this portion of the study. To determine the incidence of cases of culture-positive sore throat, we commenced surveillance for cases of sore throat on March 6, 2006 and continued until November 21, 2006. During the surveillance period we visited each classroom in each school where we asked the children, “Do you have a sore throat today or have you had a sore throat in the last 7 days?” We recognized that sore throat could lead to absenteeism from school. To ensure that children with a sore throat who may have been absent at the previous visit were included, visits were made twice per week; however, children who complained of a sore throat more than once within the same 7-day period had information collected only for the initial complaint. All children with a sore throat had a throat swab taken and a clinical examination performed by a trained research assistant under the supervision of a pediatrician. A history was also taken and if it was deemed that the child was unable to give a reasonable history a questionnaire was sent to the child’s home for the parent to complete.
The surveillance period was 37.4 weeks; however, because of interruptions (eg, school holidays and examination periods) the actual number of weeks of surveillance was fewer than this. We calculated the number of child-weeks of observation for each school by multiplying the number of children under surveillance at each school by the adjusted number of weeks each school was surveilled. The total number of child-weeks of observation for the study was the sum of the 4 figures from the 4 schools.
We based our case definitions on consensus definitions developed by a World Health Organization/US National Institutes of Health working group in 2005 that are currently being prepared for publication (personal communication, F Rubin, National Institutes of Health, Bethesda, MD). A case of sore throat was defined simply as any child who complained of a sore throat. A case of GAS culture-positive sore throat was defined as a child with a sore throat in whom GAS was isolated from a throat swab and who had not met the case definition within the previous 30 days. The exceptions to this 30-day rule were cases of GAS culture-positive sore throat that occurred within 30 days and from which a different emm type was identified. We also counted cumulative cases of GAS culture-positive sore throat, defined as the proportion of individuals who had at least 1 episode of GAS culture-positive sore throat during 1 year of child-observation, meaning that only the first case of GAS culture-positive sore throat during the study period for each child was counted. These case definitions were extended to GCS/GGS culture-positive sore throat as well.
Treatment of Positive Cases
Discussion between our investigator group, the Fiji Ministry of Health, the health clinics in the area of each school, and the ethics committee in Fiji led to an agreed protocol that children identified with GAS culture-positive sore throat be referred to their local health clinic for treatment with follow-up arranged by these clinics. The standard treatment regimen in Fiji for GAS pharyngitis is either 10 days of oral penicillin V or a single dose of intramuscular benzathine penicillin G.14
Throat swabs were transported in a sealed bag containing desiccant and inside a cold box as described previously.15 All swabs were plated onto sheep blood agar containing colistin and nalidixic acid within 6 hours. After incubation at 35°C in 5% CO2 for up to 24 hours, plates were checked for beta-hemolytic colonies and the predominant colony on each plate was subcultured onto sheep blood agar for Lancefield grouping (Oxoid, Cambridge, UK). All beta-hemolytic isolates were transported to the Queensland Institute of Medical Research for emm sequence typing, using the standard methods developed by the US Centers for Disease Control.16 Novel nucleotide sequences were submitted to the Streptococcal Reference Laboratory at the Centers for Disease Control where they were assigned a sequence type by the laboratory moderator. Beta-hemolytic isolates that had small colony morphology and failed to produce a PCR product for the emm gene underwent sequencing of 16s rRNA gene to identify their species.17 Isolates that were identified as Streptococcus anginosus using this method were classified as S. anginosus rather than by their carbohydrate group.
To calculate the prevalence of streptococcal carriage, the number of asymptomatic children with GAS, GCS, and GGS isolated from throat swab in the first month of the study was divided by the total number of asymptomatic children swabbed. To calculate the annual incidence of streptococcal culture-positive sore throat, the number of cases of GAS, GCS, and GGS culture-positive sore throat was divided by the total number of child-years observation. We also calculated the cumulative incidence of GAS and GCS/GGS culture-positive sore throat.
We employed a marginal logistic regression model using generalized estimating equations that accounted for school clustering to calculate odds ratios when analyzing demographic associations with pharyngeal carriage. Relative risks were calculated when comparing clinical features associated with GAS culture-positive sore throat and non-GAS sore throat. The statistical package STATA version 10.0 (Stata Corporation, College Station, Texas) was used to analyze the data.
Ethical approval was obtained from the Fiji National Research Ethics Review Committee, the Fiji National Health Research Committee, the University of Melbourne Human Research Ethics Committee, and the Queensland Institute of Medical Research Human Research Ethics Committee. Before commencing the study we conducted visits to the schools to explain the study to students, parents, and teachers in open forums. Information sheets in Fijian and English were provided to families. Children were enrolled only if written consent from a parent or guardian was obtained. We also obtained written assent from children 10 years of age or older.
Of the total eligible sample of 1045 children, 685 children were enrolled (65.6%). The most common reason for nonparticipation in the study was failure to complete the consent form, with actual refusal to consent occurring in fewer than one percent. Enrollment rates at the 4 schools (A, B, C, and D, respectively) were 91.6%, 80.2%, 49.1%, and 68.1%.
Denominator Figures for Carriage and Pharyngitis
Of the 685 children enrolled in the study, 665 were included in the analysis of beta-hemolytic streptococci (BHS) carriage (20 children were excluded: 7 children refused a swab on the day of the examination and 13 children complained of a sore throat on that day or in the preceding 7 days). We considered all original 685 children eligible for the sore throat surveillance portion of the study, regardless of whether they were excluded from the carriage portion of the study. Of these 685 eligible children, 667 were included in the analysis of BHS culture-positive sore throat (18 children were excluded as they withdrew from the surveillance portion of the study at varying times during the study, mostly due to emigration or a change of school). The adjusted period of surveillance was 416.2 child-years of observation (Table 1).
Table 2 summarizes the recovery of BHS from throat carriage swabs. In total, 199 of the 665 throat cultures (29.9%) yielded BHS, and of these there were 40 GAS (6.0%), 46 GCS (6.9%), and 80 GGS (12.0%). Of the remaining 33 BHS isolates there were 16 group B streptococci, 2 group F streptococci, 8 isolates identified as S. anginosus by sequencing of the 16s rRNA gene, and 7 isolates that were not able to be characterized by Lancefield carbohydrate grouping and that did not produce a PCR product for emm sequence typing.
Sore Throat Episodes
Table 3 summarizes episodes of sore throat during the study. Of the 678 complaints of sore throat, 114 occurred within 30 days of a previous sore throat. Three hundred twenty-six children complained of a sore throat at least once during the study period; therefore, 78.4% (95% CI, 74.1–82.2) of children had at least one episode of sore throat per year (cumulative incidence).
There were 24 episodes of pharyngitis in which children had received antibiotics before the swab being taken. In 2 of the cases GAS was isolated from throat swab. All of these children were included in the analysis.
BHS were isolated from throat swabs in 220 episodes of sore throat (32.4%). Group A streptococci were isolated in 62 episodes of sore throat, however, one of these children had 2 GAS culture-positive sore throats within 30 days that were of the same emm type. Therefore, there were 61 episodes of GAS culture-positive sore throat based on our case definition. The annual incidence of GAS culture-positive sore throat was 14.7 cases per 100 child-years observation (95% CI, 11.2–18.8), and 11.8% (95% CI, 8.7–15.6) of children had at least one episode of GAS culture-positive sore throat per year. If the case definition for GAS culture-positive sore throat was adjusted to include only cases where there were clinical findings of infection (pharyngeal erythema), then the incidence fell to 10.1 per 100 child-years (95% CI, 7.3–13.6).
Group C streptococci were isolated in 56 episodes of sore throat, however, 6 of these isolates were identified as S. anginosus, leaving 50 episodes which equates to an annual incidence of 12 cases per 100 child-years (95% CI, 8.9–15.8). Group G streptococci were isolated in 79 episodes of sore throat, however, 5 of these isolates were S. anginosus and there were 4 children who had 2 GGS culture-positive sore throats within 30 days that were of the same emm type, leaving 70 episodes and equating to an annual incidence of 16.8 per 100 child-years (95% CI, 13.1–21.3). Altogether there were 120 cases of GCS/GGS culture-positive sore throat, which is an annual incidence of 28.8 cases per 100 child-years (95% CI, 23.9–34.5), and 21.4% (95% CI, 17.2–26.3) of children had at least one episode of GCS/GGS culture-positive sore throat per year. None of the children in this study were diagnosed with acute rheumatic fever during the study period.
Comparison of Carriage and Sore Throat Recovery Rates
The proportion of swabs positive for GAS in the carriage portion of the study was 6.0%, and during the sore throat portion of the study it was 9.0% (odds ratio 1.5, 95% CI, 1.0–2.5, P = 0.055). In contrast, the proportion of swabs positive for GCS/GGS in the carriage and sore throat portions were 18.9% and 17.7%, respectively (odds ratio 0.9, 95% CI, 0.7–1.2).
Recurrent Episodes of Culture-Positive Sore Throat
There were 7 children who had more than one episode of GAS culture-positive sore throat, with 3 of these children having 3 episodes and 1 child having 4 episodes. Five of these children had the same emm type at each episode. One child had 3 episodes all with different emm types and another child had 4 episodes with 3 different emm types. There were 21 children who had more than one episode of GCS/GGS culture-positive sore throat.
Demographic Associations With Carriage and Culture-Positive Sore Throat
Carriage of GAS was higher in Indo-Fijian children (8.6%) when compared with Fijian children (4.5%) and children of other races (7.3%) and this difference reached statistical significance in our regression model (odds ratio 1.3, 95% CI, 1.2–1.4). The incidence of GAS culture-positive sore throat was higher in Indo-Fijian children (16.6 per 100 child-years) when compared with Indigenous Fijian children (14.8 per 100 child-years) and children of other races (3.7 per 100 child-years), but did not reach statistically significance (odds ratio 1.6, 95% CI, 0.7–4.0). Conversely, carriage of GCS/GGS was higher in Indigenous Fijian children (24.1%) when compared Indo-Fijian (8.6%) and children of other races (19.5%) with an odds ratio of 2.3 (95% CI, 1.4–3.9).
Although carriage of GAS was higher in children attending urban schools (7.7%) when compared with those attending rural schools (3.2%) with an odds ratio of 2.3 (95% CI, 1.1–4.7), the incidence of GAS culture-positive sore throat in the 2 groups was almost identical (14.7 per 100,000 and 14.6 per 100,000, respectively). The carriage of GCS/GGS was higher in children attending rural schools (25.5%) than those attending urban schools (15.1%), and the incidence of GCS/GGS culture-positive sore throat was also higher (odds ratio 1.9, 95% CI, 1.7–2.2).
Clinical Features of GAS Culture-Positive Sore Throat
When comparing the clinical features of children with GAS culture-positive sore throat cases to those of children with non-GAS culture-positive sore throat, children with GAS sore throat had higher point estimates of the classic features of streptococcal pharyngitis (fever on history or examination, tender and enlarged anterior cervical lymph nodes, pharyngeal erythema, tonsillar enlargement, and tonsillar exudates), and lower point estimates of some of the features usually associated with viral sore throat including hoarse voice and coryza (Table 4, Supplemental Digital Content 1, http://links.lww.com/A943).9 Only history of hoarse voice reached statistical significance (relative risk 0.5, 95% CI, 0.3–0.9). In contrast, children with GCS/GGS culture-positive sore throat had very similar point estimates of the classic features of streptococcal pharyngitis when compared with children with non-GAS/GCS/GGS sore throat.
emm Typing of Streptococcal Isolates
All 101 GAS isolates included in analysis underwent emm sequence typing. There were 45 emm types and 46 emm subtypes. There was a wide distribution of emm types with no dominant emm types; the most frequently detected emm types were st6030.1 and emm92 with 6 isolates each (6%). There were 14 emm types (30%) that were shared between carriage and sore throat isolates but none of these shared emm types were found in the same child; 8 children had GAS isolated both from a carriage swab and from a sore throat swab and none of these swabs was of the same emm type in individual children.
Of the 245 GCS/GGS isolates, 233 were emm typed. There were 37 emm types and 46 emm subtypes which were broadly distributed, and the most common types were stG480, stG653, and stC74a, which accounted for 13.3%, 11.2%, and 8.2%, respectively. There were 7 emm types shared between GCS and GGS isolates. There was 1 emm type that is normally associated with GAS in 9 isolates (emm 12.8). There were also 6 novel emm sequences discovered for the first time in Fiji (1 GAS and 5 GCS/GGS). There were 23 emm types (62%) that were shared between carriage and sore throat isolates. There were 28 children who had GCS or GGS isolated both from a carriage swab and from a sore throat swab; 7 of these children had the same emm sequence type of both carriage and sore throat swabs.
This is the first prospective cohort surveillance study of sore throat using a recently developed WHO consensus protocol, and provides a reliable estimate of the incidence of GAS culture-positive sore throat with a readily repeatable methodology. Our results suggest that the incidence of GAS culture-positive sore throat in Fiji (14.7 per 100 child-years) is similar to rates of GAS pharyngitis reported from temperate, industrialized settings such as urban Australia (12.8 per 100 child-years), and the United States (15 per 100 child-years).18,19
Although we have accurately estimated the incidence of GAS culture-positive sore throat, it is possible that our results are an overestimate of the rate of GAS pharyngitis by the inadvertent inclusion of cases of GAS carriage in the numerator. The clinical nature of cases of GAS culture-positive sore throat in our study appeared to be mild, which may have been a reflection of the school-based design of the study because we used direct enquiry about sore throat symptoms, or it may have been because the presentation of GAS pharyngitis is less severe in Fiji. When we included only cases with clinical signs of infection (pharyngeal erythema) the incidence in our study fell to 10.1 per 100 child-years. Only 4.9% of children with GAS culture-positive sore throat had fever, which compares to 50% in clinic-based studies.1
We found a high prevalence of carriage of GCS and GGS in this study at 6.9% and 12.0% respectively, higher than the prevalence of GAS carriage at 6.0%. The prevalence of GAS carriage in industrialized nations in cooler climates is generally between 15% to 30%, varying with season.20–24 Carriage of GCS and GGS in these settings is less common, although does occur, ranging from 0.7% to 9%.22,24–28 In tropical and subtropical countries, although available data are limited, the prevalence of GAS carriage is around 3% to 15% and carriage of GCS and GGS is often higher, ranging from 5% to 21%.29–32 We also found a very high incidence of GCS/GGS culture-positive sore throat at 28.8 cases per 100 child-years (GCS: 12 cases per 100 child-years; GGS: 16.8 per 100 child-years). Although it is known that GCS and GGS can cause epidemic outbreaks of pharyngitis, the role of GCS/GGS in endemic pharyngitis is controversial.33–35 Data from our study do not support a role for GCS/GGS in causing true pharyngitis, although the evidence is limited and should be interpreted with caution. First, the clinical nature of GCS/GGS culture-positive sore throat in our study was very mild, with point estimates for fever, tender anterior cervical nodes, and pharyngeal erythema being lower for GCS/GGS compared with GAS culture-positive sore throat and indeed non-GAS/GCS/GGS sore throat. Second, 62% of GCS/GGS emm sequence types were shared between carriage and sore throat isolates compared with only 32% of GAS emm sequence types. Third, the odds of a positive culture from sore throat swabs was higher than that from carriage swabs for GAS (odds ratio 1.5, 95% CI, 1.0–2.5) while lower for GCS/GGS (odds ratio 0.9, 95% CI, 0.7–1.2). Some investigators have found laboratory evidence to suggest that GCS and GGS could potentially cause acute rheumatic fever.36,37 However, because it is well established that rheumatic fever follows streptococcal infection but not carriage,38 the apparently low pathogenicity of GCS and GGS found in our study fail to support a role for GCS and GGS in causing rheumatic fever in Fiji.
Overall, the differences in GAS and GCS/GGS carriage and culture-positive sore throat between ethnic groups in this study are difficult to explain, particularly as Indigenous Fijian children have higher rates of GAS diseases including invasive disease, acute rheumatic fever, and rheumatic heart disease.35,39 The higher incidence of GAS culture-positive sore throat in Indo-Fijian children was unlikely to be due to a higher rate of sore throat complaints because the incidence of sore throat complaint was actually higher in Indigenous Fijian children; rather it was probably due to the inclusion of some cases of GAS carriage in sore throat calculations.
The molecular epidemiology of pharyngeal GAS in our study differed considerably to that in industrialized nations. There were no predominant types of GAS found in this study and the distribution of emm types was very different to that found in industrialized countries. In the United States emm1, emm2, emm3, emm4, emm12, and emm28 isolates account for more than 69% of pharyngitis isolates40,41; none of these types were found in our study among GAS isolates (although there were 4 isolates that were identified as emm subtype 1–2.3, the sequence of this emm type is considered sufficiently divergent from emm 1 to be considered as a separate type). The multivalent vaccine currently undergoing clinical trials would provide poor coverage for pharyngeal types of GAS as only 9 of the 26 emm types included in the vaccine were found in this study, and therefore only 28% of isolates (20% of emm types) would be covered by the vaccine.42 A different scientific design of vaccine construction using highly conserved antigens may be a more plausible approach for tropical developing countries like Fiji with highly diverse circulating emm types of GAS.
The findings of this study have implications for GAS vaccine research and implementation in Fiji and probably in other tropical and subtropical developing countries. GAS culture-positive sore throat was as common in Fijian school-children as in children in temperate wealthy countries. GCS and GGS carriage is common and further investigation is required to determine the contributory role of these organisms in pharyngitis. The finding of a wide variety of emm types without dominant types combined with the lack of emm types included in the 26-valent GAS vaccine currently in clinical trials mean that a multivalent vaccine may not be a viable approach. The reproducible nature of the design of our study means that GAS culture-positive sore throat could be an appropriate clinical end point for phase III clinical trials of GAS vaccines in Fiji. Because of our suspicion that not all cases of GAS culture-positive sore throat were cases of true GAS pharyngitis, and given the uncertainty of the effect of GAS vaccines on carriage, vaccine clinical trials would need to be powered on the basis of a relatively small reduction in GAS culture-positive sore throat cases.
The authors thank the children, their parents, their schools, and their communities for participating in this study, and the Fiji Ministry of Health for their close collaboration in the project, particularly Dr Lepani Waqatakirewa. The authors thank the able assistance of the Fiji Group A Streptococcal Project research team including Loraine Kelpie, Laisiana Matatolu, Frances Matanatabu, Jyotishna Mani, and Maureen Ah-Kee and also Jon Hartas for his assistance with the emm sequence typing at the Queensland Institute of Medical Research. The authors also thank Dr Sophie LaVincente from the University of Melbourne for her assistance with the statistical analysis.
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