Signs and symptoms of Group A versus Non-Group A strep throat: A meta-analysis

Signs and symptoms of Group A versus Non-Group A strep throat: A meta-analysis Abstract Introduction Both non-Group A streptococcal (non-GAS) pharyngitis and Group A streptococcal (GAS) pharyngitis are commonly found in patients with sore throat. It is not known whether or not they present with similar signs and symptoms compared to patients with non-streptococcal pharyngitis. Methods MEDLINE was searched for prospective studies that reported throat culture for both GAS and non-GAS as a reference standard, and reported at least one sign, symptom, or the Centor score. Summary estimates of sensitivity, specificity, likelihood ratios (LR+ and LR−), and diagnostic odds ratios (DOR) were calculated using a bivariate random effects model. Summary receiver operating characteristic (ROC) curves were created for key signs and symptoms. Results Eight studies met our inclusion criteria. Tonsillar exudate had the highest LR+ for both GAS and non-GAS pharyngitis (1.53 versus 1.71). The confidence intervals of sensitivity, LR+, LR−, and DOR for all signs, symptoms, and the Centor score between two groups overlapped, with the relative difference between sensitivities within 15% for arthralgia or myalgia, fever, injected throat, tonsillar enlargement, and tonsillar exudate. Larger differences in sensitivities were observed for sore throat, cervical adenopathy, and lack of a cough, although the difference for lack of a cough largely due to a single outlier. Discussion Signs and symptoms of patients with GAS and non-GAS pharyngitis are generally similar. No signs or symptoms clearly distinguish GAS from non-GAS infection. Further work is needed to determine whether Group C streptococcus is a pathogen that should be treated. Group A, non-Group A, pharyngitis, signs, streptococcus, symptoms Introduction Sore throat is the second most common acute infection seen by family physicians, and Group A β-hemolytic streptococcus (GAS) is the most common bacterial pathogen causing acute pharyngitis (1). In 2010–2011, pharyngitis was one of the three most common diagnoses leading to an antibiotic prescription, with 56% of children and 72% of adults receiving one (2). However, the prevalence of GAS in this study was only 37% in children and 18% in adults (2). Non-group A streptococcal pharyngitis (non-GAS), most commonly Group C streptococcus (GCS) or Group G streptococcus (GGS), is also observed in patients with sore throat. According to a recent meta-analysis, the prevalence of GCS was 6.6% in laboratory-based studies of throat cultures and 6.1% in outpatients with sore throat (3). Nevertheless, whether GCS and GGS are pathogenic for pharyngitis is controversial. Many virulence properties found in GCS and GGS are similar to those of GAS (4). GCS and GGS infections have been associated with severe or recurrent pharyngitis, reactive arthritis, and other adverse outcomes such as acute glomerulonephritis, streptococcal toxic shock-like syndrome, and subdural empyema in case reports (5–12). Antibiotics have been recommended by some authors for non-GAS pharyngitis, in particular for Group C strep (13,14). However, the potential benefits of treatment for non-GAS pharyngitis have not been well studied. A double blind randomized controlled trial showed that in patients with high colony counts of non-GAS infection, penicillin resolved symptoms 1.3 days earlier as compared with the placebo (14). Currently, there is insufficient evidence to support antibiotic treatment for patients with GCS or GGS infections (15–17). Rapid antigen detection tests (RADTs) are not available for non-GAS (18), so initial diagnosis of non-GAS pharyngitis is mainly based on clinical signs and symptoms and then confirmed by culture. One unanswered question in the literature is whether GAS and non-GAS infections present similarly. Some researchers have found that GAS and non-GAS pharyngitis present with similarly (18,19), while another found six clinical distinctions between GAS and GCS infection (20). The current study will be the first meta-analysis comparing the accuracy of signs and symptoms for distinguishing GAS and non-GAS pharyngitis from non-streptococcal pharyngitis. Put another way, do GAS and non-GAS present similarly or differently? Methods Inclusion and exclusion criteria We included studies that reported at least one sign, symptom, or the Centor score for diagnosis of both GAS and non-GAS (Group B, C, D, F, or G) streptococcus in the same population. The Centor score assigns one point for each of the following clinical criteria: tonsillar exudates, swollen tender anterior cervical nodes, lack of a cough, and fever, with higher scores associated with a higher likelihood of GAS (21). Our target population was children or adults presenting with pharyngitis or sore throat as the chief complaint. The reference standard had to be throat culture reporting the number with both GAS and non-GAS infection. Only studies that had a cohort design with prospective data collection of signs and symptoms were included in our review. We excluded studies that included a specialized population (e.g. HIV positive, immunosuppressed, undergoing surgery), case-control studies, retrospective studies (‘chart reviews’) or studies without adequate data to calculate test accuracy. There were no language limits in our study. Search strategy and data abstraction We searched MEDLINE using two search strategies shown in Supplementary Search Strategy. First, we searched for previous published systematic reviews of the diagnosis of GAS or any non-GAS infection from 01 January 2000 to the current time (26 March 2016). We then compiled a list of all studies that had been included in at least one of the systematic reviews. These articles were all reviewed in full. Second, a bridge search was performed to find more recent studies of GAS and any non-GAS clinical diagnosis that were published since the year of the most recent systematic review in the first search strategy (from 01 January 2010 to 26 March 2016). Two investigators reviewed those abstracts in the bridge search in parallel, and the full articles of any abstract identified by either investigator as potentially relevant were pulled to review in full. Every full article from both search strategies was carefully reviewed by two investigators to evaluate for the inclusion and exclusion criteria. At least two investigators abstracted data about study design, study quality, and accuracy of signs, symptoms, and the Centor score. Any conflict in the review process was resolved by consensus discussion, generally involving all three researchers. Once data were abstracted, we combined similar variables. Notably, adenitis, adenopathy, cervical adenitis, tender cervical lymph nodes, and cervical adenopathy were combined as ‘cervical adenopathy’; enlarged tonsils or tonsillar hypertrophy as ‘tonsillar enlargement’; and tonsillar exudate, follicular tonsils, and purulent tonsils as ‘tonsillar exudate’. Quality assessment The QUADAS-2 framework was adapted for the purpose of this study (22) and is shown in Supplementary QUADAS-2 Instrument. Each study was assessed for patient selection, index test, reference standard test, and flow and timing with total 16 criteria. If a study met a criteria, then yes (Y) was assigned, if it did not meet a criteria no (N) was assigned, and if it was not possible to evaluate a criteria based on the study’s information, uncertain (U) was assigned. Overall risk of bias was low if all domains were at low risk of bias; moderate if one domain was at high risk of bias; and high if two or more domains were at high risk of bias. Based on these criteria, the quality of the included studies was assessed independently by two investigators. A consensus discussion resolved any disagreements between them. Analytic strategy R version 3.2.4 and the mada (Meta-Analysis of Diagnostic Accuracy) package was used to perform a bivariate random effects meta-analysis for each test using the Reitsma procedure (23,24). For signs, symptoms and the Centor score for low and high risk groups, summary statistics for accuracy including sensitivity, specificity, likelihood ratios (LR+, LR−), area under receiver operating characteristic curves (AUROCC), and the diagnostic odds ratio (DOR) were calculated. The calibrate package was used to plot the calibration curve of sensitivities of signs, symptoms, and the Centor score (25). For individual studies with sensitivities of 0 or 1, we added 0.5 to each cell of the 2 × 2 table to calculate LR+ or LR- (26).We assessed heterogeneity using visual inspection of the summary ROC curves and by calculating 95% confidence intervals. Where possible, we evaluated accuracy separately for studies of children only. We also performed a statistical test to compare sensitivity of each sign, symptom, and the Centor score between GAS and non-GAS pharyngitis. Specificities were the same for GAS and non-GAS pharyngitis, since in each case these groups were compared within a study to the same group of patients with non-streptococcal pharyngitis. We did a search for studies reporting the prevalence of GAS and non-GAS infections in both symptomatic patients and controls. Pooled estimates of prevalences were calculated by using metaprop procedure of meta package (27). Results Study characteristics The result of the two search strategies is presented in the PRISMA diagram in Supplementary Prisma Flow S1. One study was excluded from our review because of the small number of non-GAS infections identified (1 case of GCS, 1 case of GGS) (28). A total of eight studies met our inclusion criteria; their characteristics are summarized in Table 1. Four studies enrolled only children (19,29–31), one enrolled only adults (32) and three enrolled both children and adults (18,33,34). Settings included a hospital emergency department (30), an outpatient department (19,31), a general practice (18,33), or a healthcare centre (29,32,34). All eight studies used a prospective cohort design with throat culture as the reference standard. Four studies reported signs or symptoms (18,29–31), one study reported only the Centor score (34), and three studies reporting both signs, symptoms, and the Centor score (19,32,33). One study was an extreme outlier with regards to absence of cough (reportedly present in all 589 patients with non-streptococcal pharyngitis) and cervical adenopathy (present in only 6% with GAS pharyngitis, as opposed to 58% to 100% in the other studies) (31). Table 1. Characteristics of included studies of children and children or adults, with data collected between 1964 and 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 aAcute otitis media; bLower respiratory tract infection; cUpper respiratory tract infection. View Large Table 1. Characteristics of included studies of children and children or adults, with data collected between 1964 and 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 aAcute otitis media; bLower respiratory tract infection; cUpper respiratory tract infection. View Large Quality of included studies The results of the quality assessment are summarized in Supplementary Table S1, including our adaptation of the QUADAS-2 framework for the current study. Because the individual domains were at low risk of bias for all eight studies, the overall risk of bias of all eight studies was assessed to be low. Accuracy of signs and symptoms For each sign or symptom, we evaluated its accuracy as a test for distinguishing GAS from non-streptococcal infection, and for distinguishing non-GAS infection (i.e. Group B, C, D, F or G streptococcal infection) from non-streptococcal infection. We selected common signs and symptoms among the included studies for our pooled analysis: arthralgia or myalgia (2 studies), cervical adenopathy (6 studies), lack of a cough (5 studies), fever (6 studies), injected throat (3 studies), sore throat (4 studies), tonsillar enlargement (2 studies), tonsillar exudate (4 studies), Centor score of 2 or higher (3 studies), Centor sore of 3 or higher (4 studies). The accuracy of signs and symptoms for both GAS and non-GAS infections is summarized in Table 2. A detailed table that shows data for individual studies is shown in Supplementary Table S2. Table 2. Accuracy of signs, symptoms, and Centor score for the diagnosis of Group A strep versus non-streptococcal pharyngitis in all included studies Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) aExcluding Principi’s study as an outlier due to its very low sensitivity in cervical adenopathy in Group A strep (6%) and its very low specificity in lack of cough (0%). bIncluding Principi’s study. View Large Table 2. Accuracy of signs, symptoms, and Centor score for the diagnosis of Group A strep versus non-streptococcal pharyngitis in all included studies Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) aExcluding Principi’s study as an outlier due to its very low sensitivity in cervical adenopathy in Group A strep (6%) and its very low specificity in lack of cough (0%). bIncluding Principi’s study. View Large Summary sensitivities of signs and symptoms for GAS pharyngitis and non-GAS pharyngitis are presented in Figure 1. In both GAS and non-GAS infections, the two most sensitive signs and symptoms were injected throat (0.86 versus 0.84) and cervical adenopathy (0.82 versus 0.70). The sensitivities of injected throat (0.86 versus 0.84) and tonsillar enlargement (0.62 versus 0.61) were nearly identical. All but three signs and symptoms had point estimates for sensitivity within 15% of each other, and the 95% confidence intervals for all signs and symptoms overlapped between GAS and non-GAS pharyngitis vs non-streptococcal pharyngitis. A larger difference was seen for lack of cough, but this was largely due to a single outlier study (31). When the outlier was excluded, the relative difference in sensitivities was 15%. Figure 1. View largeDownload slide Summary ROC curve sensitivities of signs, symptoms, the Centor score 2 or higher (CS 2+), and Centor score 3 or higher (CS 3+) in Group A strep and non-Group A strep (two boundary lines show the limit of 15% difference among two groups). Figure 1. View largeDownload slide Summary ROC curve sensitivities of signs, symptoms, the Centor score 2 or higher (CS 2+), and Centor score 3 or higher (CS 3+) in Group A strep and non-Group A strep (two boundary lines show the limit of 15% difference among two groups). Because we compared signs and symptoms of GAS and non-GAS pharyngitis in the same population against non-streptococcal infections, the specificities were the same for both GAS and non-GAS pharyngitis. The sign or symptom having the highest specificity was arthralgia or myalgia (0.87), while the one with lowest specificity was injected throat (0.19). No individual sign or symptom for either GAS or non-GAS pharyngitis had a LR+ greater than 2.0. Tonsillar exudate had the highest LR+ in both GAS pharyngitis (1.5) and in non-GAS pharyngitis (1.7). Only cervical adenopathy, sore throat, and tonsillar enlargement had more than a 15% difference in LR+. Five out eight signs and symptoms had small differences in LR− between GAS and non-GAS pharyngitis; larger relative differences were seen for cervical adenopathy, fever, and lack of cough with the percentage of difference −39%, +33%, and −29%, respectively. However, the confidence intervals of LR+ and LR- for all signs and symptoms between GAS and non-GAS infections largely overlapped. Cervical adenopathy was fairly good at discriminating GAS infection from non-streptococcal infection (AUROCC 0.72), but it was much less accurate in predicting non-GAS infection (AUROCC 0.57). Injected throat had the highest AUROCC (0.66) in non-GAS infection, but its AUROCC was the second lowest (0.55) in GAS infection. Beside cervical adenopathy, AUROCC of other signs and symptoms between GAS and non-GAS infection had limited differences. Summary ROC curves for selected signs and symptoms are shown in Figure 2 and in Supplementary Figures S2–S6. The sensitivities were similar for arthralgia or myalgia, while the sensitivities of cervical adenopathy, lack of a cough, and sore throat for GAS infection were consistently higher than for non-GAS infection. Sensitivities of arthralgia or myalgia, cervical adenopathy, and lack of cough in children were generally lower than those observed in studies of both children and adult patients. Figure 2. View largeDownload slide Summary ROC curve for cervical adenopathy without outlier (a), fever (b), lack of a cough with outlier (c), and tonsillar exudate (d) in Group A strep and non-Group A strep. Figure 2. View largeDownload slide Summary ROC curve for cervical adenopathy without outlier (a), fever (b), lack of a cough with outlier (c), and tonsillar exudate (d) in Group A strep and non-Group A strep. Accuracy of Centor score The accuracy of the Centor score for both GAS and non-GAS infections is shown in Table 2 (a detailed table with data of individual studies is shown in Supplementary Table S3). For a Centor score of 2 or higher versus score less than 2, sensitivity and LR+ were similar between GAS and non-GAS infections, while LR− and DOR had some small differences. For a Centor score of 3 or higher versus less than 3, there were larger differences between GAS and non-GAS regarding sensitivity, LR+, LR−, and DOR. Again, though, the confidence intervals for these parameters for GAS pharyngitis largely overlapped those for non-GAS infections. The area under the ROC curve was greater for GAS pharyngitis than for non-GAS pharyngitis for both the Centor score of 2 or higher and the Centor score of 3 or higher. Summary ROC curves for the Centor score 2 or higher and Centor score 3 or higher are shown in Supplementary Figures S7 and S8. In each individual study, the sensitivity of the Centor score was higher for GAS infection than for non-GAS infection. Discussion In general, individual signs and symptoms have limited accuracy for the diagnosis of both GAS and non-GAS pharyngitis. As seen most clearly in Figure 1, the sensitivity of each sign and symptoms was generally similar for patients with GAS and non-GAS pharyngitis, with the largest differences in sensitivity seen for cervical adenopathy, lack of cough, and fever. The sensitivity of signs and symptoms was higher for the diagnosis of GAS pharyngitis than for non-GAS pharyngitis. The general similarity in clinical presentation between GAS and non-GAS pharyngitis provides some support for the idea that non-GAS may be a pathogen in patients with pharyngitis. As shown in Table 3, GAS is significantly more common in symptomatic persons than in asymptomatic controls (35–39). While non-GAS was also present more often in symptomatic patients than in asymptomatic controls in four of five studies, this difference was statistically significant in only one of these studies (35–39). Pooling the data from the five studies shown in Table 3, non-GAS had a prevalence of 5% in symptomatic patients and 2% in asymptomatic controls (P = 0.38). However, these results were dominated by a very large study that found no difference in prevalence, but that only enrolled patients retrospectively who had at least four of the following: sore throat, erythema of tonsils, exudate on tonsils, painful cervical lymph nodes, and fever, creating an important selection bias (37). Table 3. Prevalence of Group A strep and non-Group A strep in symptomatic and asymptomatic groups Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 aNot reported by the original study View Large Table 3. Prevalence of Group A strep and non-Group A strep in symptomatic and asymptomatic groups Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 aNot reported by the original study View Large Antibiotic treatment for non-GAS pharyngitis is currently not recommended (15,40). However, some have argued that because the symptoms are similar, that patients with non-GAS pharyngitis (in particular group C strep) would benefit from antibiotic treatment (3,13,14,18). In fact, a clinical decision rule was recently developed that identifies patients with both Group A and Group C streptococcal pharyngitis to guide antibiotic treatment (41). At a minimum, clinicians should be aware of the possibility that a patient with a negative rapid strep test may have non-GAS pharyngitis and may benefit from treatment, especially if symptoms otherwise resemble GAS pharyngitis. Limitations There are several limitations in this review. Only high quality studies reporting signs, symptoms, or the Centor score for both GAS and non-GAS pharyngitis were selected, which improved validity but limited the number of studies included in our review. The comparison of signs, symptoms, and Centor score between GAS and non-GAS infections were not fully stratified and evaluated by age group, confidence intervals were relatively broad, and the summary ROC curves each had a relatively small number of studies. In addition, the definitions of signs and symptoms likely varied somewhat between the included studies. For example, a patient with temperature from 37.3 °C was considered as fever in one study (29), while another study used a cutoff of 38°C (19). There was significant heterogeneity for most of the signs, symptoms, and the Centor score, notably cervical adenopathy, fever, or the Centor score 3 or 4. Suggestions for future research First, the number of studies comparing signs and symptoms of GAS and non-GAS infections in the same population is very limited. More research should be conducted that compares clinical characteristics among GAS, GCS, GGS, and non-GAS infections. Second, there are many clinical decision rules for GAS pharyngitis or viral sore throat (21,42–46). Most of these rules were also validated in alternative studies (47–49). However, the development and validation of clinical decision rules for GCS is still limited (18,33), so further work is needed to prospectively validate them. Lastly, there is no clear evidence that treatment of non-GAS pharyngitis provides a net clinical benefit in terms of reduction in the duration of symptoms, decreased transmission, or fewer complications. Randomized controlled trials are needed to determine whether or not GCS pharyngitis should be treated. Supplementary Material Supplementary data are available at Family Practice online. Declaration Ethical approval: not necessary. Funding: departmental resources Conflict of interest: none. Reference 1. Worrall GJ . Acute sore throat . Can Fam Physician 2007 ; 53 : 1961 – 2 . Google Scholar PubMed 2. Fleming-Dutra KE , Hersh AL , Shapiro DJ et al. 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Mada (R package): Meta-analysis of Diagnostic Accuracy, version 0.5.7. 2015. https://www.r-project.org/ (accessed on 15 June 2017) . 25. Graffelman J . Calibrate (R package): Calibration of Scatterplot and Biplot Axes, version 1.7.2. 2013. https://www.r-project.org/ (accessed on 15 June 2017) . 26. Irwig L , Macaskill P , Glasziou P , Fahey M . Meta-analytic methods for diagnostic test accuracy . J Clin Epidemiol 1995 ; 48 : 119 – 30; discussion 131 –2. Google Scholar CrossRef Search ADS PubMed 27. Schwarzer G . Meta (R package): General Package for Meta-Analysis, version 4.5-0. 2016. https://www.r-project.org/ (accessed on 15 June 2017) . 28. Atlas SJ , McDermott SM , Mannone C , Barry MJ . BRIEF REPORT: The role of point of care testing for patients with acute pharyngitis . J Gen Intern Med 2005 ; 20 : 759 – 61 . Google Scholar CrossRef Search ADS PubMed 29. Bassili A , Barakat S , Sawaf GE , Zaher S , Zaki A , Din Saleh EE . 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Clinical symptoms and signs in sore throat patients with large colony variant β-haemolytic streptococci groups C or G versus group A . The British Journal of General Practice 2005 ; 55 : 615 – 19 . Google Scholar PubMed 34. Llor C , Hernández Anadón S , Gómez Bertomeu FF , Santamaria Puig JM , Calviño Domínguez O , Fernández Pagés Y . [Validation of a rapid antigenic test in the diagnosis of pharyngitis caused by group a beta-haemolytic Streptococcus] . Aten Primaria 2008 ; 40 : 489 – 94 . Google Scholar CrossRef Search ADS PubMed 35. Hedin K , Bieber L , Lindh M , Sundqvist M . The aetiology of pharyngotonsillitis in adolescents and adults - Fusobacterium necrophorum is commonly found . Clin Microbiol Infect 2015 ; 21 : 263.e1 – 7 . Google Scholar CrossRef Search ADS 36. Centor RM , Atkinson TP , Ratliff AE et al. The clinical presentation of Fusobacterium-positive and streptococcal-positive pharyngitis in a university health clinic: a cross-sectional study . Ann Intern Med 2015 ; 162 : 241 – 7 . Google Scholar CrossRef Search ADS PubMed 37. Begovac J , Bobinac E , Benic B et al. Asymptomatic pharyngeal carriage of beta-haemolytic streptococci and streptococcal pharyngitis among patients at an urban hospital in Croatia . Eur J Epidemiol 1993 ; 9 : 405 – 10 . Google Scholar CrossRef Search ADS PubMed 38. Hayden GF , Murphy TF , Hendley JO . Non-group A streptococci in the pharynx. Pathogens or innocent bystanders ? Am J Dis Child 1989 ; 143 : 794 – 7 . Google Scholar CrossRef Search ADS PubMed 39. Hofkosh D , Wald ER , Chiponis DM . Prevalence of non-group-A beta-hemolytic streptococci in childhood pharyngitis . South Med J 1988 ; 81 : 329 – 31 . Google Scholar CrossRef Search ADS PubMed 40. National Institute for Health and Care Excellence . NICE guidelines: respiratory tract infections (self-limiting): prescribing antibiotics . 2008 [cited 2017 May 31]; Available from: https://www.nice.org.uk/guidance/cg69. 41. Little P , Hobbs FD , Mant D , McNulty CA , Mullee M ; PRISM investigators . Incidence and clinical variables associated with streptococcal throat infections: a prospective diagnostic cohort study . Br J Gen Pract 2012 ; 62 : e787 – 94 . Google Scholar CrossRef Search ADS PubMed 42. Breese BB . A simple scorecard for the tentative diagnosis of streptococcal pharyngitis . Am J Dis Child 1977 ; 131 : 514 – 7 . Google Scholar PubMed 43. McIsaac WJ , White D , Tannenbaum D , Low DE . A clinical score to reduce unnecessary antibiotic use in patients with sore throat . CMAJ 1998 ; 158 : 75 – 83 . Google Scholar PubMed 44. Attia MW , Zaoutis T , Klein JD , Meier FA . Performance of a predictive model for streptococcal pharyngitis in children . Arch Pediatr Adolesc Med 2001 ; 155 : 687 – 91 . Google Scholar CrossRef Search ADS PubMed 45. Joachim L , Campos D Jr , Smeesters PR . Pragmatic scoring system for pharyngitis in low-resource settings . Pediatrics 2010 ; 126 : e608 – 14 . 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Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Family Practice Oxford University Press

Signs and symptoms of Group A versus Non-Group A strep throat: A meta-analysis

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Abstract

Abstract Introduction Both non-Group A streptococcal (non-GAS) pharyngitis and Group A streptococcal (GAS) pharyngitis are commonly found in patients with sore throat. It is not known whether or not they present with similar signs and symptoms compared to patients with non-streptococcal pharyngitis. Methods MEDLINE was searched for prospective studies that reported throat culture for both GAS and non-GAS as a reference standard, and reported at least one sign, symptom, or the Centor score. Summary estimates of sensitivity, specificity, likelihood ratios (LR+ and LR−), and diagnostic odds ratios (DOR) were calculated using a bivariate random effects model. Summary receiver operating characteristic (ROC) curves were created for key signs and symptoms. Results Eight studies met our inclusion criteria. Tonsillar exudate had the highest LR+ for both GAS and non-GAS pharyngitis (1.53 versus 1.71). The confidence intervals of sensitivity, LR+, LR−, and DOR for all signs, symptoms, and the Centor score between two groups overlapped, with the relative difference between sensitivities within 15% for arthralgia or myalgia, fever, injected throat, tonsillar enlargement, and tonsillar exudate. Larger differences in sensitivities were observed for sore throat, cervical adenopathy, and lack of a cough, although the difference for lack of a cough largely due to a single outlier. Discussion Signs and symptoms of patients with GAS and non-GAS pharyngitis are generally similar. No signs or symptoms clearly distinguish GAS from non-GAS infection. Further work is needed to determine whether Group C streptococcus is a pathogen that should be treated. Group A, non-Group A, pharyngitis, signs, streptococcus, symptoms Introduction Sore throat is the second most common acute infection seen by family physicians, and Group A β-hemolytic streptococcus (GAS) is the most common bacterial pathogen causing acute pharyngitis (1). In 2010–2011, pharyngitis was one of the three most common diagnoses leading to an antibiotic prescription, with 56% of children and 72% of adults receiving one (2). However, the prevalence of GAS in this study was only 37% in children and 18% in adults (2). Non-group A streptococcal pharyngitis (non-GAS), most commonly Group C streptococcus (GCS) or Group G streptococcus (GGS), is also observed in patients with sore throat. According to a recent meta-analysis, the prevalence of GCS was 6.6% in laboratory-based studies of throat cultures and 6.1% in outpatients with sore throat (3). Nevertheless, whether GCS and GGS are pathogenic for pharyngitis is controversial. Many virulence properties found in GCS and GGS are similar to those of GAS (4). GCS and GGS infections have been associated with severe or recurrent pharyngitis, reactive arthritis, and other adverse outcomes such as acute glomerulonephritis, streptococcal toxic shock-like syndrome, and subdural empyema in case reports (5–12). Antibiotics have been recommended by some authors for non-GAS pharyngitis, in particular for Group C strep (13,14). However, the potential benefits of treatment for non-GAS pharyngitis have not been well studied. A double blind randomized controlled trial showed that in patients with high colony counts of non-GAS infection, penicillin resolved symptoms 1.3 days earlier as compared with the placebo (14). Currently, there is insufficient evidence to support antibiotic treatment for patients with GCS or GGS infections (15–17). Rapid antigen detection tests (RADTs) are not available for non-GAS (18), so initial diagnosis of non-GAS pharyngitis is mainly based on clinical signs and symptoms and then confirmed by culture. One unanswered question in the literature is whether GAS and non-GAS infections present similarly. Some researchers have found that GAS and non-GAS pharyngitis present with similarly (18,19), while another found six clinical distinctions between GAS and GCS infection (20). The current study will be the first meta-analysis comparing the accuracy of signs and symptoms for distinguishing GAS and non-GAS pharyngitis from non-streptococcal pharyngitis. Put another way, do GAS and non-GAS present similarly or differently? Methods Inclusion and exclusion criteria We included studies that reported at least one sign, symptom, or the Centor score for diagnosis of both GAS and non-GAS (Group B, C, D, F, or G) streptococcus in the same population. The Centor score assigns one point for each of the following clinical criteria: tonsillar exudates, swollen tender anterior cervical nodes, lack of a cough, and fever, with higher scores associated with a higher likelihood of GAS (21). Our target population was children or adults presenting with pharyngitis or sore throat as the chief complaint. The reference standard had to be throat culture reporting the number with both GAS and non-GAS infection. Only studies that had a cohort design with prospective data collection of signs and symptoms were included in our review. We excluded studies that included a specialized population (e.g. HIV positive, immunosuppressed, undergoing surgery), case-control studies, retrospective studies (‘chart reviews’) or studies without adequate data to calculate test accuracy. There were no language limits in our study. Search strategy and data abstraction We searched MEDLINE using two search strategies shown in Supplementary Search Strategy. First, we searched for previous published systematic reviews of the diagnosis of GAS or any non-GAS infection from 01 January 2000 to the current time (26 March 2016). We then compiled a list of all studies that had been included in at least one of the systematic reviews. These articles were all reviewed in full. Second, a bridge search was performed to find more recent studies of GAS and any non-GAS clinical diagnosis that were published since the year of the most recent systematic review in the first search strategy (from 01 January 2010 to 26 March 2016). Two investigators reviewed those abstracts in the bridge search in parallel, and the full articles of any abstract identified by either investigator as potentially relevant were pulled to review in full. Every full article from both search strategies was carefully reviewed by two investigators to evaluate for the inclusion and exclusion criteria. At least two investigators abstracted data about study design, study quality, and accuracy of signs, symptoms, and the Centor score. Any conflict in the review process was resolved by consensus discussion, generally involving all three researchers. Once data were abstracted, we combined similar variables. Notably, adenitis, adenopathy, cervical adenitis, tender cervical lymph nodes, and cervical adenopathy were combined as ‘cervical adenopathy’; enlarged tonsils or tonsillar hypertrophy as ‘tonsillar enlargement’; and tonsillar exudate, follicular tonsils, and purulent tonsils as ‘tonsillar exudate’. Quality assessment The QUADAS-2 framework was adapted for the purpose of this study (22) and is shown in Supplementary QUADAS-2 Instrument. Each study was assessed for patient selection, index test, reference standard test, and flow and timing with total 16 criteria. If a study met a criteria, then yes (Y) was assigned, if it did not meet a criteria no (N) was assigned, and if it was not possible to evaluate a criteria based on the study’s information, uncertain (U) was assigned. Overall risk of bias was low if all domains were at low risk of bias; moderate if one domain was at high risk of bias; and high if two or more domains were at high risk of bias. Based on these criteria, the quality of the included studies was assessed independently by two investigators. A consensus discussion resolved any disagreements between them. Analytic strategy R version 3.2.4 and the mada (Meta-Analysis of Diagnostic Accuracy) package was used to perform a bivariate random effects meta-analysis for each test using the Reitsma procedure (23,24). For signs, symptoms and the Centor score for low and high risk groups, summary statistics for accuracy including sensitivity, specificity, likelihood ratios (LR+, LR−), area under receiver operating characteristic curves (AUROCC), and the diagnostic odds ratio (DOR) were calculated. The calibrate package was used to plot the calibration curve of sensitivities of signs, symptoms, and the Centor score (25). For individual studies with sensitivities of 0 or 1, we added 0.5 to each cell of the 2 × 2 table to calculate LR+ or LR- (26).We assessed heterogeneity using visual inspection of the summary ROC curves and by calculating 95% confidence intervals. Where possible, we evaluated accuracy separately for studies of children only. We also performed a statistical test to compare sensitivity of each sign, symptom, and the Centor score between GAS and non-GAS pharyngitis. Specificities were the same for GAS and non-GAS pharyngitis, since in each case these groups were compared within a study to the same group of patients with non-streptococcal pharyngitis. We did a search for studies reporting the prevalence of GAS and non-GAS infections in both symptomatic patients and controls. Pooled estimates of prevalences were calculated by using metaprop procedure of meta package (27). Results Study characteristics The result of the two search strategies is presented in the PRISMA diagram in Supplementary Prisma Flow S1. One study was excluded from our review because of the small number of non-GAS infections identified (1 case of GCS, 1 case of GGS) (28). A total of eight studies met our inclusion criteria; their characteristics are summarized in Table 1. Four studies enrolled only children (19,29–31), one enrolled only adults (32) and three enrolled both children and adults (18,33,34). Settings included a hospital emergency department (30), an outpatient department (19,31), a general practice (18,33), or a healthcare centre (29,32,34). All eight studies used a prospective cohort design with throat culture as the reference standard. Four studies reported signs or symptoms (18,29–31), one study reported only the Centor score (34), and three studies reporting both signs, symptoms, and the Centor score (19,32,33). One study was an extreme outlier with regards to absence of cough (reportedly present in all 589 patients with non-streptococcal pharyngitis) and cervical adenopathy (present in only 6% with GAS pharyngitis, as opposed to 58% to 100% in the other studies) (31). Table 1. Characteristics of included studies of children and children or adults, with data collected between 1964 and 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 aAcute otitis media; bLower respiratory tract infection; cUpper respiratory tract infection. View Large Table 1. Characteristics of included studies of children and children or adults, with data collected between 1964 and 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 Study Patient population Setting Sample size Sign/ symptom included Sample size of GAS Sample size of non-GAS Sample size of non streptococcus Mean age and/or age range Country Year(s) of data collection Children  Kaplan, 1971 Children under 15 years with symptoms of uncomplicated pharyngitis. Excluded if AOMa or LRTIb. Hospital emergency room 624 Adenitis, adenopathy, coryza, lack of a cough, exudate, fever, injected throat, previous URTIc, sick siblings, sore throat 218 38 368 Mean 6.8 years USA 1964 to 1967  Principi, 1990 Consecutive children with symptomatic pharyngitis and at least one of the following: hyperemia, fever, sore throat, exudate, or palatine petechiae. Excluded if recent antibiotic or peritonsillar abscess. Outpatient Department 865 Adenitis, lack of a cough, exudate, fever, headache, hyperemia, petechiae, sore throat 230 46 589 Range 5 months to 14 years; 394/852 were 3 to 5 years. Italy 1988 to 1989  Bassili, 2002 Children 1 to 15 years with uncomplicated tonsillopharyngitis and either pharyngeal erythema or exudate, or tonsillar enlargement and redness. Excluded if recent antibiotics, AOMa, or other infections. Private health services and public facilities 578 Abdominal pain, arthralgia or myalgia, lack of cough, dysphagia, fever, hoarseness, injected throat, petechiae, pharyngeal exudate, scarlatiniform rash, sore throat, throat congestion, tonsillar enlargement, tonsillar exudate, vomiting, watery eyes 98 69 411 Mean age 6.3 years, range 1 to 15 years Egypt 2000  Fretzayas, 2009 Children age 4 to 14 years with pharyngitis. Excluded if recent antibiotics. Outpatient department 144 Adenitis, exudate, sore throat, tonsillar enlargement, Centor score of 0 to 4 57 13 74 Mean 6.5 years Greece 2006 Children and adults  Seppala, 1993 Adults with sore throat. Excluded if received antibiotics last month Private health centre 106 Centor score of 3 to 4, adenitis, fever, rhinorrhea and/or cough, tonsillar exudate 5 19 82 Mean 30.1 years, range 15 to 62 years Finland 1986  Lindbaek, 2005 Adults and children presenting with sore throat. Excluded if recent antibiotics. General practices 306 Centor score of 0 to 4, adenitis, lack of a cough, dysphagia, fever, injected throat, tonsillar exudate 127 33 146 Mean 23.9 years Norway 2000 to 2002  Llor, 2008 Consecutive patients 14 years and older with sore throat and at least Centor score 2. Excluded if recent antibiotics. Primary care centre 182 Centor score of 2 to 4 40 42 100 Mean 30.6 years Spain 2007 to 2008  Little, 2012 Adults and children at least 5 years of age with chief complaint of sore throat of less than 2 week duration or physician diagnosed pharyngitis as the primary symptom. Excluded if judged to have non-infectious cause of sore throat. General practice 592 Adenopathy, age less than 10 years, arthralgia or myalgia, absence of coryza, lack of a cough, fever, headache, prior duration ≤3 days, sore throat, tonsillar exudate 136 45 410 Range 5 years and older; 67 of 605 were age < 10 years. England 2007 to 2008 aAcute otitis media; bLower respiratory tract infection; cUpper respiratory tract infection. View Large Quality of included studies The results of the quality assessment are summarized in Supplementary Table S1, including our adaptation of the QUADAS-2 framework for the current study. Because the individual domains were at low risk of bias for all eight studies, the overall risk of bias of all eight studies was assessed to be low. Accuracy of signs and symptoms For each sign or symptom, we evaluated its accuracy as a test for distinguishing GAS from non-streptococcal infection, and for distinguishing non-GAS infection (i.e. Group B, C, D, F or G streptococcal infection) from non-streptococcal infection. We selected common signs and symptoms among the included studies for our pooled analysis: arthralgia or myalgia (2 studies), cervical adenopathy (6 studies), lack of a cough (5 studies), fever (6 studies), injected throat (3 studies), sore throat (4 studies), tonsillar enlargement (2 studies), tonsillar exudate (4 studies), Centor score of 2 or higher (3 studies), Centor sore of 3 or higher (4 studies). The accuracy of signs and symptoms for both GAS and non-GAS infections is summarized in Table 2. A detailed table that shows data for individual studies is shown in Supplementary Table S2. Table 2. Accuracy of signs, symptoms, and Centor score for the diagnosis of Group A strep versus non-streptococcal pharyngitis in all included studies Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) aExcluding Principi’s study as an outlier due to its very low sensitivity in cervical adenopathy in Group A strep (6%) and its very low specificity in lack of cough (0%). bIncluding Principi’s study. View Large Table 2. Accuracy of signs, symptoms, and Centor score for the diagnosis of Group A strep versus non-streptococcal pharyngitis in all included studies Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) Sign/ Symptom/ Centor Score GAS or Non-GAS Sensitivity (95% CI) % Diff GAS versus Non-GAS Specificity (95% CI) LR+ (95% CI) % Diff GAS versus Non-GAS LR- (95% CI) % Diff GAS versus Non-GAS AUROCC DOR (95% CI) % Diff GAS versus Non-GAS Signs and symptoms  Arthralgia or myalgia GAS 0.18 (0.06–0.44) −10% p = .885 0.87 (0.70–0.95) 1.42 (1.00–1.91) −13% 0.93 (0.78–1.00) +2% 0.60 1.55 (1.01–2.27) −15% Non-GAS 0.20 (0.08–0.42) 1.64 (1.10–2.38) 0.91 (0.78–0.98) 0.57 1.83 (1.13–2.81)  Cervical adenopathya GAS 0.82 (0.71–0.89) +17% p = .192 0.40 (0.23–0.61) 1.40 (1.12–1.89) +18% 0.46 (0.32–0.66) −39% 0.72 3.17 (1.74–5.32) +85% Non-GAS 0.70 (0.48–0.86) 1.19 (0.91–1.57) 0.76 (0.45–1.15) 0.57 1.71 (0.79–3.22)  Cervical adenopathyb GAS 0.72 (0.40–0.91) +7% p = .835 0.41 (0.26–0.58) 1.20 (0.74–1.64) +3% 0.72 (0.25–1.38) −9% 0.52 2.16 (0.56–5.94) +39% Non-GAS 0.67 (0.48–0.82) 1.16 (0.93–1.45) 0.79 (0.52–1.11) 0.56 1.55 (0.83–2.67)  Fever GAS 0.58 (0.42–0.73) −15% p = 0.433 0.46 (0.30–0.63) 1.09 (0.84–1.40) −13% 0.93 (0.67–1.26) +33% 0.53 1.22 (0.68–2.05) −35% Non-GAS 0.68 (0.44–0.85) 1.25 (1.06–1.44) 0.70 (0.46–0.94) 0.57 1.87 (1.16–2.91)  Injected throat GAS 0.86 (0.63–0.95) +2% p = .995 0.19 (0.06–0.43) 1.1 (0.93–1.26) +4% 0.80 (0.43–1.35) −8% 0.55 1.47 (0.69–2.74) +10% Non-GAS 0.84 (0.70–0.93) 1.06 (0.95–1.32) 0.87 (0.51–1.48) 0.66 1.34 (0.64–2.49)  Lack of cougha GAS 0.77 (0.63–0.87) +15% p = .266 0.40 (0.30–0.51) 1.28 (1.02–1.61) +13% 0.60 (0.33–0.97) −29% 0.58 2.35 (1.04–4.60) +68% Non-GAS 0.67 (0.60–0.74) 1.13 (0.93–1.38) 0.84 (0.61–1.15) 0.65 1.40 (0.82–2.25)  Lack of coughb GAS 0.75 (0.64–0.84) +27% p = 0.109 0.19 (0.03–0.67) 1.08 (0.70–2.53) +24% 2.39 (0.29–10.90) −54% 0.67 1.47 (0.06–7.51) +53% Non-GAS 0.59 (0.41–0.75) 0.87 (0.42–2.27) 5.25 (0.39–27.3) 0.47 0.96 (0.02–5.73)  Sore throat GAS 0.64 (0.46–0.79) +19% p = 0.522 0.45 (0.29–0.62) 1.17 (1.05–1.32) +18% 0.80 (0.65–0.94) −18% 0.55 1.47 (1.13–1.89) +41% Non-GAS 0.54 (0.29–0.78) 0.99 (0.74–1.17) 0.98 (0.70–1.20) 0.49 1.04 (0.62–1.63)  Tonsillar enlargement GAS 0.62 (0.49–0.74) +2% p = 0.823 0.52 (0.20–0.83) 1.47 (0.87–3.07) +18% 0.80 (0.52–1.50) +8% 0.62 2.08 (0.58–5.35) +14% Non-GAS 0.61 (0.20–0.91) 1.25 (0.94–1.65) 0.74 (0.39–1.03) 0.58 1.82 (0.91–3.28)  Tonsillar exudate GAS 0.38 (0.27–0.51) −12% p = 0.578 0.74 (0.64–0.83) 1.53 (1.00–2.24) −11% 0.83 (0.67–1.00) +8% 0.59 1.89 (0.99–3.27) −17% Non-GAS 0.43 (0.33–0.53) 1.71 (1.13–2.51) 0.77 (0.63–0.94) 0.57 2.27 (1.22–3.86) Centor score  Centor score 2 or higher GAS 0.93 (0.72–0.99) +3% p = 0.652 0.11 (0.01–0.63) 1.15 (0.99–1.93) +10% 0.70 (0.33–1.60) −36% 0.74 2.05 (0.62–5.06) +77% Non-GAS 0.90 (0.51–0.99) 1.05 (0.92–1.50) 1.09 (0.50–2.41) 0.59 1.16 (0.40–2.65)  Centor score 3 or higher GAS 0.65 (0.41–0.83) +44% p = 0.191 0.71 (0.48–0.86) 2.30 (1.35–4.05) +40% 0.51 (0.28–0.77) −35% 0.73 4.92 (1.87–10.60) +129% Non-GAS 0.45 (0.32–0.59) 1.64 (1.00–2.80) 0.79 (0.64–1.00) 0.54 2.15 (1.00–4.05) aExcluding Principi’s study as an outlier due to its very low sensitivity in cervical adenopathy in Group A strep (6%) and its very low specificity in lack of cough (0%). bIncluding Principi’s study. View Large Summary sensitivities of signs and symptoms for GAS pharyngitis and non-GAS pharyngitis are presented in Figure 1. In both GAS and non-GAS infections, the two most sensitive signs and symptoms were injected throat (0.86 versus 0.84) and cervical adenopathy (0.82 versus 0.70). The sensitivities of injected throat (0.86 versus 0.84) and tonsillar enlargement (0.62 versus 0.61) were nearly identical. All but three signs and symptoms had point estimates for sensitivity within 15% of each other, and the 95% confidence intervals for all signs and symptoms overlapped between GAS and non-GAS pharyngitis vs non-streptococcal pharyngitis. A larger difference was seen for lack of cough, but this was largely due to a single outlier study (31). When the outlier was excluded, the relative difference in sensitivities was 15%. Figure 1. View largeDownload slide Summary ROC curve sensitivities of signs, symptoms, the Centor score 2 or higher (CS 2+), and Centor score 3 or higher (CS 3+) in Group A strep and non-Group A strep (two boundary lines show the limit of 15% difference among two groups). Figure 1. View largeDownload slide Summary ROC curve sensitivities of signs, symptoms, the Centor score 2 or higher (CS 2+), and Centor score 3 or higher (CS 3+) in Group A strep and non-Group A strep (two boundary lines show the limit of 15% difference among two groups). Because we compared signs and symptoms of GAS and non-GAS pharyngitis in the same population against non-streptococcal infections, the specificities were the same for both GAS and non-GAS pharyngitis. The sign or symptom having the highest specificity was arthralgia or myalgia (0.87), while the one with lowest specificity was injected throat (0.19). No individual sign or symptom for either GAS or non-GAS pharyngitis had a LR+ greater than 2.0. Tonsillar exudate had the highest LR+ in both GAS pharyngitis (1.5) and in non-GAS pharyngitis (1.7). Only cervical adenopathy, sore throat, and tonsillar enlargement had more than a 15% difference in LR+. Five out eight signs and symptoms had small differences in LR− between GAS and non-GAS pharyngitis; larger relative differences were seen for cervical adenopathy, fever, and lack of cough with the percentage of difference −39%, +33%, and −29%, respectively. However, the confidence intervals of LR+ and LR- for all signs and symptoms between GAS and non-GAS infections largely overlapped. Cervical adenopathy was fairly good at discriminating GAS infection from non-streptococcal infection (AUROCC 0.72), but it was much less accurate in predicting non-GAS infection (AUROCC 0.57). Injected throat had the highest AUROCC (0.66) in non-GAS infection, but its AUROCC was the second lowest (0.55) in GAS infection. Beside cervical adenopathy, AUROCC of other signs and symptoms between GAS and non-GAS infection had limited differences. Summary ROC curves for selected signs and symptoms are shown in Figure 2 and in Supplementary Figures S2–S6. The sensitivities were similar for arthralgia or myalgia, while the sensitivities of cervical adenopathy, lack of a cough, and sore throat for GAS infection were consistently higher than for non-GAS infection. Sensitivities of arthralgia or myalgia, cervical adenopathy, and lack of cough in children were generally lower than those observed in studies of both children and adult patients. Figure 2. View largeDownload slide Summary ROC curve for cervical adenopathy without outlier (a), fever (b), lack of a cough with outlier (c), and tonsillar exudate (d) in Group A strep and non-Group A strep. Figure 2. View largeDownload slide Summary ROC curve for cervical adenopathy without outlier (a), fever (b), lack of a cough with outlier (c), and tonsillar exudate (d) in Group A strep and non-Group A strep. Accuracy of Centor score The accuracy of the Centor score for both GAS and non-GAS infections is shown in Table 2 (a detailed table with data of individual studies is shown in Supplementary Table S3). For a Centor score of 2 or higher versus score less than 2, sensitivity and LR+ were similar between GAS and non-GAS infections, while LR− and DOR had some small differences. For a Centor score of 3 or higher versus less than 3, there were larger differences between GAS and non-GAS regarding sensitivity, LR+, LR−, and DOR. Again, though, the confidence intervals for these parameters for GAS pharyngitis largely overlapped those for non-GAS infections. The area under the ROC curve was greater for GAS pharyngitis than for non-GAS pharyngitis for both the Centor score of 2 or higher and the Centor score of 3 or higher. Summary ROC curves for the Centor score 2 or higher and Centor score 3 or higher are shown in Supplementary Figures S7 and S8. In each individual study, the sensitivity of the Centor score was higher for GAS infection than for non-GAS infection. Discussion In general, individual signs and symptoms have limited accuracy for the diagnosis of both GAS and non-GAS pharyngitis. As seen most clearly in Figure 1, the sensitivity of each sign and symptoms was generally similar for patients with GAS and non-GAS pharyngitis, with the largest differences in sensitivity seen for cervical adenopathy, lack of cough, and fever. The sensitivity of signs and symptoms was higher for the diagnosis of GAS pharyngitis than for non-GAS pharyngitis. The general similarity in clinical presentation between GAS and non-GAS pharyngitis provides some support for the idea that non-GAS may be a pathogen in patients with pharyngitis. As shown in Table 3, GAS is significantly more common in symptomatic persons than in asymptomatic controls (35–39). While non-GAS was also present more often in symptomatic patients than in asymptomatic controls in four of five studies, this difference was statistically significant in only one of these studies (35–39). Pooling the data from the five studies shown in Table 3, non-GAS had a prevalence of 5% in symptomatic patients and 2% in asymptomatic controls (P = 0.38). However, these results were dominated by a very large study that found no difference in prevalence, but that only enrolled patients retrospectively who had at least four of the following: sore throat, erythema of tonsils, exudate on tonsils, painful cervical lymph nodes, and fever, creating an important selection bias (37). Table 3. Prevalence of Group A strep and non-Group A strep in symptomatic and asymptomatic groups Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 aNot reported by the original study View Large Table 3. Prevalence of Group A strep and non-Group A strep in symptomatic and asymptomatic groups Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 Study GAS Non-GAS Symptomatic group Asymptomatic group p value Symptomatic group Asymptomatic group p value Hedin, 2015 (35) 0.30 (66/220) 0.02 (3/128) <0.001 0.04 (8/220) 0.01 (1/128) 0.16 Centor, 2015 (36) 0.07 (21/312) 0.01 (2/180) 0.009a 0.06 (19/312) 0.03 (6/180) 0.26a Begovac, 1993 (37) 0.45 (281/629) 0.06 (107/1796) <0.001 0.01 (9/629) 0.01 (16/1796) 0.36a Hayden, 1989 (38) 0.39 (58/150) 0.16 (24/150) <0.001 0.17 (25/150) 0.21 (32/150) >0.05 Hofkosh, 1988 (39) 0.20 (189/929) 0.05 (19/414) <0.01 0.06 (60/929) 0.01 (4/414) <0.01 Pooled estimate (95% CI) 0.25 (0.15–0.40) 0.05 (0.03–0.10) <0.001 0.05 (0.03–0.10) 0.02 (0.00–0.13) 0.38 aNot reported by the original study View Large Antibiotic treatment for non-GAS pharyngitis is currently not recommended (15,40). However, some have argued that because the symptoms are similar, that patients with non-GAS pharyngitis (in particular group C strep) would benefit from antibiotic treatment (3,13,14,18). In fact, a clinical decision rule was recently developed that identifies patients with both Group A and Group C streptococcal pharyngitis to guide antibiotic treatment (41). At a minimum, clinicians should be aware of the possibility that a patient with a negative rapid strep test may have non-GAS pharyngitis and may benefit from treatment, especially if symptoms otherwise resemble GAS pharyngitis. Limitations There are several limitations in this review. Only high quality studies reporting signs, symptoms, or the Centor score for both GAS and non-GAS pharyngitis were selected, which improved validity but limited the number of studies included in our review. The comparison of signs, symptoms, and Centor score between GAS and non-GAS infections were not fully stratified and evaluated by age group, confidence intervals were relatively broad, and the summary ROC curves each had a relatively small number of studies. In addition, the definitions of signs and symptoms likely varied somewhat between the included studies. For example, a patient with temperature from 37.3 °C was considered as fever in one study (29), while another study used a cutoff of 38°C (19). There was significant heterogeneity for most of the signs, symptoms, and the Centor score, notably cervical adenopathy, fever, or the Centor score 3 or 4. Suggestions for future research First, the number of studies comparing signs and symptoms of GAS and non-GAS infections in the same population is very limited. More research should be conducted that compares clinical characteristics among GAS, GCS, GGS, and non-GAS infections. Second, there are many clinical decision rules for GAS pharyngitis or viral sore throat (21,42–46). Most of these rules were also validated in alternative studies (47–49). However, the development and validation of clinical decision rules for GCS is still limited (18,33), so further work is needed to prospectively validate them. Lastly, there is no clear evidence that treatment of non-GAS pharyngitis provides a net clinical benefit in terms of reduction in the duration of symptoms, decreased transmission, or fewer complications. Randomized controlled trials are needed to determine whether or not GCS pharyngitis should be treated. Supplementary Material Supplementary data are available at Family Practice online. Declaration Ethical approval: not necessary. Funding: departmental resources Conflict of interest: none. Reference 1. Worrall GJ . Acute sore throat . Can Fam Physician 2007 ; 53 : 1961 – 2 . Google Scholar PubMed 2. Fleming-Dutra KE , Hersh AL , Shapiro DJ et al. 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Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Family PracticeOxford University Press

Published: Oct 13, 2017

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