Group A Streptococcus (GAS, also known as Streptococcus pyogenes), is an important pathogen that most commonly colonizes the upper respiratory tract and skin epithelium (Rouchon et al., 2017). Its pathogenicity corresponds to a broad spectrum of conditions, including pharyngitis, impetigo, scarlet fever, nephritis, rheumatic fever, rheumatic heart disease, and many other diseases (Chaudhary et al., 2018) and can also lead to severe invasive infections such as sepsis, necrotizing fasciitis, and toxic shock syndrome, which are associated with high morbidity, mortality, and disability rates (McMillan et al., 2007). The pathogenic bacteria most commonly found to be responsible for septic arthritis are Staphylococcus aureus (Jin et al., 2015), Haemophilus influenzae (Zhang et al., 2019), and Streptococcus agalactiae (Dhekane et al., 2020), and although less common, septic arthritis caused by S. pyogenes infection has been reported. In the present case series, we retrospectively analyzed the clinical data of children treated for septic arthritis due to S. pyogenes infection in our hospital to provide a basis for the diagnosis and treatment of septic arthritis cases due to S. pyogenes infection.

Septic arthritis is a rapidly progressive, highly destructive and life-threatening joint disease. A study in the UK found that the incidence of septic arthritis increased from 5.5/100,000 in 1998 to 7.8/100,000 in 2013 (Rutherford et al., 2016). According to the literature, the most predominant pathogen causing sepsis in joints is Staphylococcus, followed by Streptococcus pneumoniae and Klebsiella, but also Salmonella spp, Haemophilus influenzae type b, and group B streptococci (Wang et al., 2003; Frazee et al., 2009; Rutherford et al., 2016; Xu et al., 2016; Dernoncourt et al., 2019; van den Boom et al., 2021; Yagupsky, 2021). S. pyogenes can also cause septic arthritis and is easily overlooked. A case of septic arthritis caused by S. pyogenes infection was first reported in 1984, and in that case, a serious infection caused by S. pyogenes occurred in a nursing home patient and resulted in sepsis, necrotizing fasciitis, septic arthritis, and cellulitis (Ruben et al., 1984). Septic arthritis after toxic shock syndrome caused by S. pyogenes was reported in 1995 (González-Ruiz and Ridgway, 1995). S. pyogenes infection causing multifocal septic arthritis has also been reported (Marti and Anton, 2007). In contrast, a 10-year case summary in Hong Kong found that in 31 cases of septic arthritis in children, the predominant causative organism was S. aureus (42%), followed by S. pyogenes (23%) (Kuong et al., 2012). In another study in France, 1 of 26 cases of diffuse infection in infants younger than 3 months of age was septic arthritis due to S. pyogenes infection (Germont et al., 2020). Another study in France isolated bacteria from 377 children with suspected joint infections, of which S. pyogenes accounted for 15% (Brehin et al., 2020). Methicillin-resistant S. aureus infection and septic arthritis combined with osteomyelitis have been reported in the literature as risk factors for the development of sequelae (Wang et al., 2003). A study in Spain reported that the invasive diseases caused by S. pyogenes in the Spanish pediatric population include septic arthritis/osteomyelitis, and the common types of S. pyogenes are emm1/ST28, emm12/ST36-ST242, (Sanchez-Encinales et al., 2019). In the present pediatric case series, cases 1 and 2 were emm1/ST28 and case 3 was emm12/ST36, and these results were basically consistent with those of previous studies. Overall, our case serious combined with the literature reports show that S. pyogenes cannot be overlooked as a potential cause of septic arthritis.

Previous research has shown that S. pyogenes can invade the joint microenvironment, and step in the development of septic arthritis (Le Hello et al., 2009). Volzke et al (Volzke et al., 2020) inoculated mice intravenously with S. pyogenes and observed septic arthritis 3~20 days after infection with increased levels of interleukin (IL)-1β and IL-6 in the joints along with an increased amount of nuclear factor (NF)-κB receptor activator ligand (RANKL), which is a key cytokine for osteoclast formation. S. pyogenes infection can increase RANKL expression by increasing the production of activators to induce infectious arthritis.

Septic arthritis occurs in lower limb joints in 90% of cases, with the hip being the most commonly involved, followed by the knee (Wang et al., 2003; Xu et al., 2016). Sternoclavicular joint involvement has also been reported (Dhekane et al., 2020; Kwon et al., 2020). Joint pain (81%) is the most common presentation, followed by fever, swelling and limitation of movement, and 89% of patients show an increased ESR (≥20 mm/h) (Wang et al., 2003). The age at onset of septic arthritis due to S. pyogenes varies, with reports of onset in neonates and small infants less than 3 months of age (Umadevi et al., 2013; Germont et al., 2020). The age of onset in our pediatric case series ranged from 2–7 years. A study in Hong Kong reported that only 52% of 31 children with septic arthritis had a temperature below 38.5°C on admission; i.e., nearly half of their patients had a temperature above 38.5°C on admission. Additionally, 71% of their patients had a WBC count below 12×10⁹/L, and the rate of positive blood culture was not high (negative in 74% of cases) (Kuong et al., 2012). In the present case series, all three children presented with a significantly elevated WBC count (30×10⁹/L or more) and a significantly increased ESR. The CRP level was also significantly increased in two cases, while the procalcitonin level was mildly increased in only one case. Previous studies have suggested that procalcitonin is more sensitive than ESR and CRP level for the diagnosis of septic arthritis, and that the combination of these three indicators is beneficial for improving diagnostic sensitivity and specificity (Wang et al., 2014; Wei et al., 2015). In contrast, Chen (Chen et al., 2013) found that the CRP level is more sensitive than procalcitonin for the identification of local bacterial infection. The results in our pediatric case series are more consistent with the findings of Chen et al (Chen et al., 2013).

The standard treatment for septic arthritis in children is arthrocentesis combined with antibacterial drug therapy (Kwon et al., 2020). Studies have shown that adequate use of antimicrobial drugs and a single arthrocentesis is sufficient to treat septic arthritis in most pediatric cases, regardless of the infecting agent or site of infection, as long as the clinical response is good (Peltola et al., 2009). Additional research had indicated that early antibiotic treatment, incision and drainage, and combined non-pharmacological treatments such as drainage and early physiotherapy should be given (Couderc et al., 2020). More recent studies have suggested that targeted synovial cell therapy may be a promising treatment for septic arthritis (Volzke et al., 2020). Penicillin has been widely used worldwide for many years, and so far, no penicillin-resistant strains of S. pyogenes have been identified. The reasons for this are not yet known. In recent years, increased minimum inhibitory concentration (MIC) values of penicillin have been reported, and penicillin-nonsusceptible S. pyogenes strains have emerged. In 2006, Capoor et al. (Capoor et al., 2006) reported S. pyogenes with elevated MIC values to penicillin (0.19~0.25 µg/mL), and S. pyogenes with elevated MIC values to penicillin (0.25~0.75 µg/mL) were also found in Mexico (Ogawa et al., 2011). Additionally, several resistance surveillance networks in China have reported S. pyogenes “resistance” to β-lactam antimicrobials, but we confirmed that these strains are not truly resistant, and whether they carry a mutated gene for penicillin-binding protein 2X (pbp2x) needs to be confirmed by further studies (Vannice et al., 2020; Musser et al., 2020; Yu et al., 2020). In the present case series, S. pyogenes was cultured from the joint cavity pus of all three children, and they were considered sensitive to β-lactam antibiotics based on the outcomes in these cases. No antibiotic susceptibility testing was performed. However, in case 3, S. pyogenes was cultured from the blood, and antibiotic susceptibility testing suggested sensitive to β-lactam antibiotics such as penicillin and cephalosporin. For this case, amoxicillin sodium + sulbactam was selected and provided satisfactory treatment. Therefore, in clinical practice, once pus culture identifies S. pyogenes, the choice of β-lactam antibiotics is sufficient, and prompt step-down treatment should be given, as it is not advisable to continue advanced antibiotic therapy. In case 1 of our series, after the pus culture result was clear, vancomycin was promptly changed to amoxicillin sodium + sulbactam with good effect, while in case 2, vancomycin combined with β-lactams treatment was considered to be related to the doctor’s insufficient knowledge of S. pyogenes. In case 3, intravenous infusion of amoxicillin sodium + sulbactam was administered from the time of admission with good effect.

In conclusion, antimicrobial agents commonly used to treat S. pyogenes infections are highly active against clinical strains.S. pyogenes is an important pathogen causing septic arthritis, and WBC count, ESR, and CRP level are sensitive indicators for the diagnosis of septic arthritis. If S. pyogenes infection is confirmed upon culture of pus drained from an infection joint, β-lactam antibacterial therapy with antibiotics such as penicillin or cephalosporin can be selected for treatment.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Shenzhen Children’s Hospital. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

WW and YY contributed to conception, design, and administrative support. DY, QL, WG, DG,YC, and YZ provided study materials and patients. DY contributed to the collection and assembly of data, data analysis, interpretation and the manuscript writing. All authors contributed to the article and approved the submitted version.