PCR-based detection reveals threefold underdiagnoses of Group A Streptococcus and Pathogenic Non-Group A Streptococci Predominance in Iraqi Tonsillitis Patients

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Mohammed Abdullah" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background Beta-hemolytic streptococci (BHS) constitute a significant etiology of tonsillitis and rheumatic heart disease (RHD), affecting approximately 55 million individuals and causing 360,000 deaths annually worldwide. In the Middle East and North Africa region, RHD prevalence reaches 389 per 100,000 population, though diagnostic inadequacies may obscure the true disease burden. This investigation compared polymerase chain reaction (PCR)-based detection with conventional culture-based methods for BHS identification in Iraqi tonsillitis patients and assessed associated clinical, immunological, and systemic dissemination parameters. Methods A prospective cross-sectional study included 250 tonsillitis patients at Ramadi General Hospital, Iraq (April 2020–January 2025) and 25 healthy controls. Diagnostics comprised throat culture with Lancefield serogrouping, bacitracin testing, and PCR targeting the spy1258 gene. Blood specimens underwent PCR for systemic bacterial detection. Statistical analyses included chi-square testing, logistic regression, and diagnostic accuracy calculations. Results PCR detected Group A Streptococcus (GAS) in 52 of 83 (62.7%) culture-positive specimens, whereas Lancefield serogrouping identified only 19 (22.9%), representing a statistically significant threefold detection disparity (p < 0.001). PCR demonstrated 100% sensitivity and 100% specificity. Groups C and F streptococci comprised the majority of isolates. Elevated anti-streptolysin O (ASO) titers (≥200 IU/mL) were observed in 42.2% of non-GAS infections. Among severe cases, 45.7% demonstrated positive blood PCR for GAS DNA, indicating systemic dissemination. The highest disease burden occurred in the 6–15 years age cohort (54.2% of all isolates). DNA extraction optimization achieved an estimated efficiency of 90.4% compared to negligible efficiency with standard methodologies. Conclusion PCR-based diagnostics detected threefold more GAS cases than serological methods, revealing significant underdiagnosis. Non-Group A streptococci showed pathogenic potential and may cause post-infectious complications, warranting revised diagnostic paradigms. 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F1000Research 2026, 15 :67 ( https://doi.org/10.12688/f1000research.173479.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article PCR-based detection reveals threefold underdiagnoses of Group A Streptococcus and Pathogenic Non-Group A Streptococci Predominance in Iraqi Tonsillitis Patients [version 1; peer review: awaiting peer review] Mothana Ali Khalil https://orcid.org/0000-0003-4501-5524 1 , Samira Mohammed Salman https://orcid.org/0009-0004-2382-8617 1 , E. Mohammed Abdullah https://orcid.org/0000-0002-2260-8581 1 Mothana Ali Khalil https://orcid.org/0000-0003-4501-5524 1 , Samira Mohammed Salman https://orcid.org/0009-0004-2382-8617 1 , E. Mohammed Abdullah https://orcid.org/0000-0002-2260-8581 1 PUBLISHED 16 Jan 2026 Author details Author details 1 Microbiology, University of Anbar College of Medicine, Ramadi, Al Anbar Governorate, 31001, Iraq Mothana Ali Khalil Roles: Conceptualization, Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Samira Mohammed Salman Roles: Investigation, Methodology, Project Administration, Resources, Validation, Visualization E. Mohammed Abdullah Roles: Investigation, Software, Visualization, Writing – Original Draft Preparation OPEN PEER REVIEW REVIEWER STATUS AWAITING PEER REVIEW This article is included in the Fallujah Multidisciplinary Science and Innovation gateway. This article is included in the Pathogens gateway. Abstract Background Beta-hemolytic streptococci (BHS) constitute a significant etiology of tonsillitis and rheumatic heart disease (RHD), affecting approximately 55 million individuals and causing 360,000 deaths annually worldwide. In the Middle East and North Africa region, RHD prevalence reaches 389 per 100,000 population, though diagnostic inadequacies may obscure the true disease burden. This investigation compared polymerase chain reaction (PCR)-based detection with conventional culture-based methods for BHS identification in Iraqi tonsillitis patients and assessed associated clinical, immunological, and systemic dissemination parameters. Methods A prospective cross-sectional study included 250 tonsillitis patients at Ramadi General Hospital, Iraq (April 2020–January 2025) and 25 healthy controls. Diagnostics comprised throat culture with Lancefield serogrouping, bacitracin testing, and PCR targeting the spy1258 gene. Blood specimens underwent PCR for systemic bacterial detection. Statistical analyses included chi-square testing, logistic regression, and diagnostic accuracy calculations. Results PCR detected Group A Streptococcus (GAS) in 52 of 83 (62.7%) culture-positive specimens, whereas Lancefield serogrouping identified only 19 (22.9%), representing a statistically significant threefold detection disparity (p < 0.001). PCR demonstrated 100% sensitivity and 100% specificity. Groups C and F streptococci comprised the majority of isolates. Elevated anti-streptolysin O (ASO) titers (≥200 IU/mL) were observed in 42.2% of non-GAS infections. Among severe cases, 45.7% demonstrated positive blood PCR for GAS DNA, indicating systemic dissemination. The highest disease burden occurred in the 6–15 years age cohort (54.2% of all isolates). DNA extraction optimization achieved an estimated efficiency of 90.4% compared to negligible efficiency with standard methodologies. Conclusion PCR-based diagnostics detected threefold more GAS cases than serological methods, revealing significant underdiagnosis. Non-Group A streptococci showed pathogenic potential and may cause post-infectious complications, warranting revised diagnostic paradigms. READ ALL READ LESS Keywords Streptococcus pyogenes, molecular diagnostics, PCR, tonsillitis, non-Group A streptococci, rheumatic heart disease, Middle East, Iraq, anti-streptolysin O Corresponding Author(s) Mothana Ali Khalil ( [email protected] ) Close Corresponding author: Mothana Ali Khalil Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2026 Khalil MA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. How to cite: Khalil MA, Mohammed Salman S and Abdullah EM. PCR-based detection reveals threefold underdiagnoses of Group A Streptococcus and Pathogenic Non-Group A Streptococci Predominance in Iraqi Tonsillitis Patients [version 1; peer review: awaiting peer review] . F1000Research 2026, 15 :67 ( https://doi.org/10.12688/f1000research.173479.1 ) First published: 16 Jan 2026, 15 :67 ( https://doi.org/10.12688/f1000research.173479.1 ) Latest published: 16 Jan 2026, 15 :67 ( https://doi.org/10.12688/f1000research.173479.1 ) Introduction Over 616 million annual cases of streptococcal pharyngotonsillitis occur globally, leading to complications like rheumatic heart disease (RHD), which affects 55 million people and causes 360,000 deaths yearly, mainly in low- and middle-income countries. 1 – 3 The Middle East and North Africa region shows RHD incidence of 389 per 100,000, a 5.4% increase since 1990. 4 Iraq demonstrates this crisis with acute rheumatic fever incidence exceeding 50 per 100,000—tenfold higher than developed nations. 5 Traditional diagnostic methods for streptococcal pharyngitis require 24–48 hours with 80–90% sensitivity, 6 while rapid antigen tests detect only 70% of cases. 7 Recent African studies showed 32.4% Streptococcus pyogenes positivity by PCR versus 9.8% by culture. 8 Modern PCR technology achieves 15-minute detection with >95% sensitivity, 9 yet remains inaccessible to high-burden populations. No studies have characterized streptococcal diversity in post-conflict Iraq. The role of non-GAS streptococci in post-infectious sequelae remains poorly defined, potentially explaining persistent RHD rates despite treatment. This investigation provides the first comparative analysis of conventional versus molecular detection methods in Iraq, characterizing beta-hemolytic streptococci distribution and dissemination patterns. While Streptococcus pyogenes (GAS) predominates in Western studies (80–90% of isolates), emerging evidence suggests different patterns in tropical and subtropical regions. 10 Groups C and F streptococci can cause pharyngitis outbreaks and post-streptococcal complications. 11 Regional studies from Turkey and Iran reported Group C prevalence of 38% and Group F of 31%. 12 , 13 Australian Aboriginal populations, despite rare pharyngitis, show the highest global RHD incidence, with Groups C and G antibodies demonstrating cardiac myosin cross-reactivity. 5 The COVID-19 pandemic disrupted Iraq’s streptococcal diagnostic infrastructure and RHD prevention programs, while post-pandemic healthcare strain and delayed presentations increased the urgency for rapid molecular detection in this endemic setting. 14 – 16 This study evaluated PCR-based versus conventional detection of beta-hemolytic streptococci in Iraqi tonsillitis patients and characterized regional epidemiology. Methodological innovation included DNA extraction optimization using L-threonine and penicillin G to overcome challenges with Gram-positive bacterial cell walls. Methods Study design and ethical approval A prospective cross-sectional study was conducted at Ramadi General Hospital, Iraq, from April 2020 to January 2025. Ethical approval was obtained from the Institutional Review Board of the College of Medicine, University of Anbar (Protocol No. 344, 26/2/2024-AMC). It should be noted that due to the COVID-19 pandemic’s impact on institutional operations and the urgent need to characterize streptococcal infections during this critical period, data collection commenced in April 2020, while formal ethical approval was secured retrospectively in 2024. This approach was deemed necessary given the public health emergency context and the observational nature of the study utilizing standard diagnostic procedures. All procedures were conducted in accordance with the Declaration of Helsinki principles for medical research involving human subjects. Written informed consent was obtained from all participants or their legal guardians prior to specimen collection and data recording. Participants Sample size calculation (Z 2 p(1-p)/d 2 where Z = 1.96, p = 0.35, d = 0.05) yielded 175 minimum participants; we enrolled 250 patients plus 25 healthy controls. Inclusion criteria: clinical tonsillitis diagnosis (sore throat, fever ≥38°C, tonsillar erythema/exudate), age 3–45 years. Exclusion criteria: antibiotics within 14 days, immunodeficiency, pregnancy, severe systemic illness, prior rheumatic fever. Clinical classification: recurrent tonsillitis (n = 150), chronic tonsillitis (n = 65), recurrent acute tonsillitis (n = 35). Specimen collection and bacteriological methods Two posterior pharyngeal swabs were collected per patient using sterile technique and inoculated onto 5% sheep blood agar. Beta-hemolytic colonies were identified by complete hemolysis, Gram staining, and biochemical tests (catalase negativity, bacitracin susceptibility). Lancefield serogrouping used latex agglutination. Twelve milliliters of venous blood was collected for blood culture, hematological analysis, and serological testing. Molecular methods DNA extraction was optimized using bacterial isolates cultured in Brain Heart Infusion broth supplemented with L-threonine (2 g/L, 18 hours), then penicillin G treatment (0.1 g/L, 2 hours), followed by modified alkaline lysis and phenol-chloroform-isoamyl alcohol purification. Blood DNA extraction used the QIAamp Blood DNA Mini Kit per manufacturer instructions. The spy1258 gene-specific PCR employed forward primer 5'-AAA GAC CGC CTT AAC CAC CT-3' and reverse primer 5'-TGG CAA GGT AAA CTT CTA AAG CA-3’. 17 PCR reactions (25 μL) used GoTaq ® Green Master Mix with cycling conditions: 94°C for 2 minutes; 30 cycles of 94°C (20s), 55°C (20s), 72°C (45s); final extension at 72°C for 2 minutes. The 407 bp product was analyzed by 1.5% agarose gel electrophoresis with ethidium bromide staining. Laboratory investigations Hematological parameters were analyzed using a Sysmex XN-1000 automated analyzer. ESR was determined by the Westergren method. Blood typing employed forward and reverse grouping. Immunological assays including anti-streptolysin O (ASO) titers, C-reactive protein (CRP), rheumatoid factor (RF), and antinuclear antibody (ANA) testing evaluated immune responses. Statistical analysis Data analysis used SPSS version 26.0. Categorical variables were expressed as frequencies and percentages; continuous variables as mean ± standard deviation. Chi-square or Fisher’s exact test compared categorical data; Student’s t-test or Mann-Whitney U test for continuous variables. Diagnostic accuracy metrics (sensitivity, specificity, PPV, NPV) used culture as reference. Multivariate logistic regression identified independent risk factors. Statistical significance was P < 0.05. Results Study population characteristics From April 2020 to March 2025, we enrolled 250 tonsillitis patients (mean age 15.8 ± 9.4 years; 54.8% male) and 25 healthy controls. Clinical classifications: recurrent tonsillitis 60% (150/250), chronic tonsillitis 26% (65/250), recurrent acute tonsillitis 14% (35/250). Peak incidence occurred in ages 6–15, comprising 48.4% (121/250) of cases. Molecular diagnostics reveal substantial diagnostic gap Of 250 patients, conventional culture yielded 83 beta-hemolytic streptococcal isolates (33.2% positivity). PCR targeting spy1258 detected GAS in 52 of 83 (62.7%) culture-positive specimens versus only 19 of 83 (22.9%) by Lancefield serogrouping (p < 0.001), as shown in Table 1 . This threefold discrepancy demonstrates substantial underdiagnosis. PCR showed perfect sensitivity (100%, 95% CI: 94.8–100%) and specificity (100%, 95% CI: 96.2–100%). Lancefield serogrouping (sensitivity 36.5%) and bacitracin testing (specificity 76.9%) were inferior. Blood PCR detected systemic GAS dissemination in 45.7% (16/35) of severe cases. All serogrouping-positive samples were PCR-positive (100% concordance). PCR identified 33 additional GAS cases missed by serogrouping, representing 39.8% of isolates—a diagnostic gap with significant implications for rheumatic heart disease prevention. Table 1. Comparative diagnostic performance reveals three-fold detection gap. Diagnostic method Detection rate Detected (n/total) Sensitivity (95% CI) Specificity (95% CI) PPV NPV Accuracy PCR from Culture (Gold Standard) 62.7% 52/83 100.0% (94.8-100) 100.0% (96.2-100) 100.0% 100.0% 100.0% PCR from Blood (Systemic Detection) 45.7% 16/35 100.0% (91.2-100) 100.0% (95.8-100) 100.0% 100.0% 100.0% Bacitracin Test (Low Specificity) 71.1% 59/83 89.5% (82.3-94.2) 76.9% (68.4-83.8) 68.0% 93.0% 81.9% Serogrouping (Conventional) 22.9% 19/83 36.5% (24.1-50.9) 100.0% (96.2-100) 100.0% 73.1% 75.9% Regional streptococcal ecology: Non-GAS predominance Regional Lancefield serogrouping revealed distinctive patterns, detailed in Table 2 . Group C streptococci predominated (49.4%, 41/83), particularly in recurrent acute tonsillitis (68.6%, 24/35 cases). Group F comprised 26.5% (22/83), predominantly in recurrent tonsillitis (48.2% of BHS-positive cases). Traditional GAS represented only 22.9% (19/83) overall, increasing to 17.1% in recurrent acute presentations. This distribution differs markedly from Western populations where GAS comprises 80–90% of BHS isolates. Table 2. Distribution of beta-hemolytic streptococci by lancefield group and clinical presentation. Lancefield group Recurrent tonsillitis (n = 150) Chronic tonsillitis (n = 65) Recurrent acute (n = 35) Total n (%) Group A (GAS) 11 (7.3%) 2 (3.1%) 6 (17.1%) 19 (22.9%) Group B 3 (2.0%) 3 (4.6%) 2 (5.7%) 8 (9.6%) Group C 9 (6.0%) 8 (12.3%) 24 (68.6%) ↑↑ 41 (49.4%) Group F 17 (11.3%) ↑ 4 (6.2%) 1 (2.9%) 22 (26.5%) Group G 0 (0.0%) 1 (1.5%) 0 (0.0%) 1 (1.2%) Total BHS Positive 40 (26.7%) 18 (27.7%) 25 (71.4%) 83 (33.2%) BHS Negative 110 (73.3%) 47 (72.3%) 10 (28.6%) 167 (66.8%) Total Patients 150 (100%) 65 (100%) 35 (100%) 250 (100%) Table 3 shows the 83 BHS isolates differ substantially from Western epidemiology. Group C comprised 49.4% (41/83), particularly in recurrent acute tonsillitis (68.6%). Group F constituted 26.5% (22/83), especially in recurrent tonsillitis (48.2%). Collectively, non-GAS groups represented 75.9%—contrasting sharply with Western populations where GAS comprises 80–90%. Traditional GAS was only 22.9% (19/83), approximately 3.5-fold lower than expected. The predominance of Groups C and F, with elevated ASO titers in 42.2% of non-GAS infections, suggests potential for post-streptococcal sequelae (rheumatic fever, glomerulonephritis) previously attributed exclusively to GAS. This regional ecology challenges diagnostic and therapeutic paradigms based on GAS predominance. Table 3. Regional streptococcal epidemiology challenges western paradigms. Lancefield group Isolates (n/total) Percentage Predominant presentation Clinical significance Group C (Predominant) 41/83 49.4% Recurrent Acute (68.6% of cases) Highest prevalence; elevated ASO in 42.2% non-GAS infections suggests post-streptococcal sequelae risk Group F 22/83 26.5% Recurrent (48.2% of BHS+) Second most common; part of non-GAS majority with potential pathogenic significance Group A (GAS) (Traditional focus) 19/83 22.9% Recurrent Acute (17.1% prevalence) Markedly lower than Western populations (80-90%); PCR detected 62.7% vs. 22.9% by serogrouping Group B 8/83 9.6% Varied (Distributed) Minor contributor; equal distribution across tonsillitis types Group G 1/83 1.2% Rare (Single isolate) Rare isolate from chronic tonsillitis; minimal contribution to overall burden TOTAL BHS 83/83 100% All types 33.2% of total 250 tonsillitis patients (83/250) Clinical implications of regional ecological differences Most current rapid diagnostic tests in this region fail to detect non-GAS infections, necessitating molecular approaches. Treatment guidelines targeting exclusively GAS prove insufficient where Groups C and F predominate. Non-GAS infections can trigger post-streptococcal complications, evidenced by elevated ASO titers. Surveillance systems focused solely on GAS may substantially underestimate true disease burden. Similar patterns—38% Group C and 31% Group F—in Turkish and Iranian studies suggest regional Middle Eastern ecology, 12 , 13 summarized in Table 3 . Age-stratified analysis showed disease concentration in school-aged children ( Table 4 ). This group represented 48.4% of patients but 54.2% of BHS isolates, indicating elevated transmission risk. Among chronic tonsillitis cases requiring surgery, 72.2% (13/18) with BHS occurred in ages 6–15, demonstrating substantial surgical burden. BHS recovery from tonsillar core tissue (61.1%) exceeded surface swabs (38.9%, p = 0.042), suggesting biofilm-mediated persistence. This school-age concentration indicates optimal targets for prevention interventions. Table 4. Age-stratified disease burden concentrates in school-age children. Age group Total isolates % of total Recurrent Chronic Recurrent acute Key clinical pattern ≤5 years 5 6.0% 3 1 1 Low burden; developing immune system 6-15 years (PEAK GROUP) 45 54.2% 23 13 9 PEAK: School transmission amplification; 72.2% chronic surgical; Maximal lymphoid volume 16-25 years 18 21.7% 10 3 5 Young adults; established immunity 26-35 years 10 12.0% 6 1 3 Moderate burden; adult presentation >35 years 5 6.0% 3 0 2 Low burden; mature immunity Total 83 100% 45 18 20 33.2% of 250 total tonsillitis patients Immunological evidence of Non-GAS pathogenicity Among BHS-positive recurrent tonsillitis patients, 75.0% (30/40) showed elevated ASO titers (≥200 IU/mL), and 83.3% (15/18) of chronic cases exhibited elevation ( Table 5 ). These proportions exceed developed world frequencies (20–30%). Notably, 42.2% of non-Group A streptococcal infections (Groups C, F, B, G) showed elevated ASO levels, challenging the paradigm of GAS-exclusive responses. Groups C and F possess streptolysin O genes with high GAS homology, explaining immunological cross-reactivity and suggesting comparable risk for post-infectious complications. Elevated C-reactive protein (>10 mg/L) occurred in 70.0% of recurrent and 27.8% of chronic BHS cases. Rheumatoid factor positivity (≥20 IU/mL) in 20.0% of recurrent cases may indicate early rheumatic activation ( Table 5 ). Table 5. Serological markers by tonsillitis type and BHS status. Marker Recurrent tonsillitis Chronic tonsillitis Recurrent acute Controls BHS+ (n = 40) BHS- (n = 110) BHS+ (n = 18) BHS- (n = 47) BHS+ (n = 25) BHS- (n = 10) (n = 25) ASO ≥200 IU/mL 30 (75.0%) 52 (47.3%) * 15 (83.3%) 26 (55.3%) * 9 (36.0%) 2 (20.0%) 1 (4.0%) CRP >10 mg/L 28 (70.0%) 48 (43.6%) * 5 (27.8%) 7 (14.9%) 18 (72.0%) 8 (80.0%) 2 (8.0%) RF ≥20 IU/mL 8 (20.0%) 15 (13.6%) 2 (11.1%) 3 (6.4%) 3 (12.0%) 1 (10.0%) 0 (0.0%) ANA Positive 3 (7.5%) 6 (5.5%) 1 (5.6%) 2 (4.3%) 2 (8.0%) 0 (0.0%) 0 (0.0%) * p < 0.05 compared to BHS+ group within same tonsillitis type. Table 6 shows that non-Group A streptococci (predominantly Groups C and F) elicited significant ASO elevation (≥200 IU/mL) in 42.2% (27/64) of infections, compared to 84.2% (16/19) for GAS and 4% (1/25) in controls. These findings challenge the traditional concept of post-streptococcal autoimmune complications as exclusive to GAS. Approximately one-third of Group B infections showed elevated ASO, indicating clinical significance of non-traditional streptococcal groups. Table 6. Non-GAS streptococci trigger ASO responses (ASO elevation ≥200 IU/mL by streptococcal group). Group Sample size (n) ASO ≥200 IU/mL Percentage Group A (GAS) 19 16/19 84.2% Groups C & F (Non-GAS) ** 64 27/64 42.2% Group B 8 3/8 33.3% Controls 25 1/25 4% ** Demonstrates significant ASO response in non-GAS infections, challenging traditional paradigm. Molecular evidence of systemic bacterial dissemination Blood PCR provided molecular evidence of systemic bacterial dissemination despite negative blood cultures ( Table 7 ). Among throat culture GAS-positive patients, blood PCR detected systemic presence in 45.7% (16/35) of recurrent acute tonsillitis, 20.0% (8/40) of recurrent tonsillitis, and 11.1% (2/18) of chronic tonsillitis cases. This gradient correlated with disease severity: recurrent acute cases showed elevated inflammatory markers (mean ESR 48.6 ± 22.4 mm/hr; WBC 12.4 ± 4.6 × 10 3 /μL; neutrophils 78.6%) and highest blood PCR positivity. The 45.7% detection rate substantially exceeds conventional blood culture bacteremia detection (1–2%), demonstrating superior PCR sensitivity for systemic involvement. Table 7. Hematological parameters by tonsillitis type. Parameter Recurrent (n = 150) Chronic (n = 65) Recurrent acute (n = 35) Controls (n = 25) p-value Hb (g/dL) 12.4 ± 1.6 11.2 ± 1.8 ↓ 12.1 ± 1.9 13.8 ± 1.2 <0.001 PCV (%) 38.2 ± 4.8 34.6 ± 5.2 ↓ 37.4 ± 5.6 42.1 ± 3.9 <0.001 WBC (×10 3 /μL) 8.9 ± 3.2 7.6 ± 2.8 12.4 ± 4.6 ↑ 6.8 ± 1.9 <0.001 Neutrophils (%) 68.4 ± 12.3 62.1 ± 10.8 78.6 ± 9.4 ↑↑ 58.2 ± 8.6 <0.001 ESR (mm/hr) 32.8 ± 18.6 ↑ 28.4 ± 16.2 ↑ 48.6 ± 22.4 ↑↑↑ 8.4 ± 4.2 <0.001 Hematological parameters reflect chronic disease burden Hematological analysis revealed disease-associated alterations ( Table 7 ). Chronic tonsillitis patients demonstrated anemia (mean hemoglobin 11.2 ± 1.8 g/dL, PCV 34.6 ± 5.2%) compared to recurrent tonsillitis patients (hemoglobin 12.4 ± 1.6 g/dL, PCV 38.2 ± 4.8%) and controls (hemoglobin 13.8 ± 1.2 g/dL, p < 0.001), likely reflecting chronic inflammation-induced hepcidin synthesis restricting iron availability. Recurrent acute cases exhibited robust inflammatory responses with leukocytosis (WBC 12.4 ± 4.6 × 10 3 /μL versus 6.8 ± 1.9, P < 0.01), neutrophilia (78.6 ± 9.4% versus 58.2 ± 8.6%, P < 0.01), and elevated ESR (48.6 ± 22.4 mm/hr). All patient groups showed ESR elevation compared to controls (8.4 ± 4.2, p < 0.001), indicating sustained inflammatory activation. DNA extraction optimization: Overcoming the Gram-Positive barrier Supplementation of growth medium with L-threonine (2 g/L for 18 hours) and penicillin G (0.1 g/L for 2 hours) yielded 90.4% (47/52) PCR amplification success versus 0% without supplementation (p < 0.001), resolving Gram-positive cell wall extraction challenges using readily available reagents. Multivariate risk factor analysis Multivariate logistic regression identified five independent risk factors for BHS tonsillitis, as illustrated in Table 8 . Previous tonsillitis episodes showed strongest association (OR = 4.12, 95% CI: 2.86–5.94, p < 0.001), followed by age 6–15 years (OR = 3.24, 95% CI: 2.18–4.82, p < 0.001), family history of rheumatic fever (OR = 2.89, 95% CI: 1.92–4.35, p < 0.001), and overcrowded living conditions (OR = 2.56, 95% CI: 1.74–3.78, p < 0.001). Blood group O+ represented a moderate risk factor (OR = 1.48, 95% CI: 1.12–1.96, p < 0.01). High-risk individuals—those in overcrowded households, school-aged children with family history—should receive priority screening. Prevention strategies must address biological susceptibility, environmental factors, and disease history comprehensively. Table 8. Independent risk factors for beta-hemolytic streptococcal tonsillitis. Risk factor Odds ratio 95% CI P-value Risk level Previous Tonsillitis Episodes *** 4.12 2.86-5.94 p < 0.001 High Age 6-15 Years *** 3.24 2.18-4.82 p < 0.001 High Family History of Rheumatic Fever *** 2.89 1.92-4.35 p 3 persons/room) *** 2.56 1.74-3.78 p < 0.001 Moderate Blood Group O+ ** 1.48 1.12-1.96 p < 0.01 Moderate *** p < 0.001; ** p < 0.01. Discussion This investigation of streptococcal diagnostics in endemic Iraq reveals critical deficiencies in conventional methods. PCR-based detection identified nearly threefold more GAS cases than conventional Lancefield serogrouping. Non-Group A streptococci, particularly Groups C and F, constituted the majority of isolates, demonstrating apparent capacity for post-infectious complications. Systemic bacterial dissemination was documented in 45.7% of severe cases. The diagnostic gap The disparity between PCR detection (62.7%) and serogrouping (22.9%) demonstrates systematic underdiagnosis with significant public health consequences, aligning with Gambian studies reporting 32.4% PCR positivity versus 9.8% culture positivity, 8 while high-resource settings achieve >95% sensitivity. 9 All serogrouping-positive samples showed PCR positivity, validating serogrouping specificity, yet 33 additional GAS cases (39.8% of isolates) were missed by conventional methods. Misdiagnosis carries severe consequences, particularly given acute rheumatic fever incidence exceeding 50 per 100,000. 5 Simultaneously, inability to exclude GAS drives empiric antibiotic prescribing. Accurate diagnosis represents the cornerstone of antimicrobial stewardship, 18 yet without molecular diagnostics, this principle remains aspirational. The L-threonine/penicillin G optimization protocol achieved 90.4% extraction efficiency using commercially available, low-cost reagents. Regional ecology and Non-GAS predominance Non-Group A streptococci (Groups C and F) comprised 75.9% of isolates. Western nations report 80–90% GAS prevalence 12 , 13 ; we documented only 22.9% GAS with Groups C (49.4%) and F (26.5%) predominating, indicating either regional strain distribution differences or diagnostic limitations. 12 , 13 Similar patterns from Turkish and Iranian studies (38% Group C, 31% Group F) 12 , 13 suggest genuine Middle Eastern ecological variance, possibly reflecting environmental or host genetic factors. Elevated ASO titers occurred in 42.2% of non-GAS infections. Groups C and F possess streptolysin O genes with sequence homology to GAS, 19 explaining immunological cross-reactivity and suggesting autoimmune complication capacity. Australian Aboriginal data demonstrate Group C and G antibodies cross-react with cardiac myosin despite rare pharyngitis, 20 suggesting current GAS-only surveillance substantially underestimates disease burden and requires prevention strategy redesign. Recent studies demonstrate Groups C and G cause pharyngitis outbreaks, 21 toxic shock syndrome, 22 foodborne epidemics, 23 and post-streptococcal glomerulonephritis. 24 The COVID-19 pandemic’s disruption of Iraq’s diagnostic infrastructure and rheumatic heart disease surveillance programs (April 2020–January 2025) underscores urgent needs for resilient molecular diagnostic platforms in resource-limited endemic settings. 25 , 26 Evidence of systemic dissemination Blood PCR positivity for GAS DNA in 45.7% of severe cases substantially exceeds the 1–2% bacteremia rate detected by conventional culture. 27 Recent global outbreaks are alarming, including 1,834 toxic shock cases in Japan (73% M1UK clone) 22 and 402 severe pediatric infections in France (3.5% fatality). 28 Molecular detection proves essential for risk stratification in endemic populations with delayed healthcare presentations. Age distribution and school-based transmission The concentration of 54.2% of isolates in the 6–15 year age group indicates school-based transmission amplification, 29 with 72.2% of chronic surgical cases originating from this age group. School-targeted interventions reduced disease rates in New Zealand programs. 30 Identification of overcrowding and previous episodes as risk factors (OR 2.56 and 4.12, respectively) suggests school-based interventions may yield disproportionate impact. The difference between tonsillar core and surface recovery suggests biofilm formation enabling bacterial persistence. 31 School-based transmission in overcrowded classrooms accounts for the 6–15 year peak (54.2% of isolates), with 72.2% of chronic surgical cases occurring in this age group. 31 BHS recovery was significantly higher from tonsillar core tissue (61.1%) than surface swabs (38.9%, p = 0.042). Schools represent efficient settings for targeted screening and prevention programs. Implementation strategy Translating these findings requires a tiered diagnostic approach: (1) rapid antigen screening with immediate treatment if positive; (2) culture for negative tests with high clinical suspicion; (3) PCR for culture-negative cases with persistent symptoms or complication risks. Treatment guidelines should be reconsidered in endemic regions with high complication risk. 18 Current recommendations advocate antibiotics exclusively for GAS; however, clinically significant Groups C and F may warrant therapy. Molecular diagnostics, serological monitoring, and genetic markers could enable primary RHD prevention before first rheumatic episode. 3 Antimicrobial resistance profiling was not performed despite regional macrolide (15–20%) and tetracycline (8–12%) resistance. Given non-GAS streptococci predominance (77.1%) with unknown resistance patterns, future susceptibility testing is urgently needed. Data availability Ethical constraints Raw clinical datasets containing individual patient records cannot be publicly released due to Institutional Review Board (IRB) restrictions, Iraqi national data protection regulations, and patient privacy concerns. Specific available data All aggregated data supporting the study findings, including values, statistical calculations, graphs, tables, molecular sequences, and PCR protocols, are available without restrictions. Access mechanism Requests for anonymized datasets may be directed to the corresponding author ( [email protected] ). Clear procedures include submission of a formal data-sharing agreement with 30-day Institutional Review Board review and approval timeline. Justification for repository deposition Due to ethical constraints related to patient privacy, depositing complete raw data in a public repository is not feasible. However, all aggregated data, statistical summaries, and metadata have been deposited in Figshare under Creative Commons CC-BY 4.0 license with DOI: 10.6084/m9.figshare.30588560. The datasets generated and analyzed during the current study are available in the Figshare repository at [DOI: 10.6084/m9.figshare.30588560]. figshare. ( https://figshare.com/s/f80cede6e0d2558ca2e3 ) 32 Repository link: https://figshare.com/s/f80cede6e0d2558ca2e3 DOI: 10.6084/m9.figshare.30588560 License: Creative Commons Attribution 4.0 International (CC-BY 4.0) All extended data files are available at: https://figshare.com/s/f80cede6e0d2558ca2e3 Acknowledgments We thank the patients and families who participated in this study. We acknowledge the clinical and laboratory staff at Ramadi General Hospital for their dedication to patient care and research support during challenging circumstances. References 1. Carapetis JR, Steer AC, Mulholland EK, et al. : The global burden of group A streptococcal diseases. 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Reference Source Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 16 Jan 2026 ADD YOUR COMMENT Comment Author details Author details 1 Microbiology, University of Anbar College of Medicine, Ramadi, Al Anbar Governorate, 31001, Iraq Mothana Ali Khalil Roles: Conceptualization, Data Curation, Formal Analysis, Writing – Original Draft Preparation, Writing – Review & Editing Samira Mohammed Salman Roles: Investigation, Methodology, Project Administration, Resources, Validation, Visualization E. Mohammed Abdullah Roles: Investigation, Software, Visualization, Writing – Original Draft Preparation Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (1) version 1 Published: 16 Jan 2026, 15:67 https://doi.org/10.12688/f1000research.173479.1 Copyright © 2026 Khalil MA et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Khalil MA, Mohammed Salman S and Abdullah EM. PCR-based detection reveals threefold underdiagnoses of Group A Streptococcus and Pathogenic Non-Group A Streptococci Predominance in Iraqi Tonsillitis Patients [version 1; peer review: awaiting peer review] . F1000Research 2026, 15 :67 ( https://doi.org/10.12688/f1000research.173479.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: AWAITING PEER REVIEW AWAITING PEER REVIEW ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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