iGAS infections have been responsible for 1.8 million cases around world, threatening young children and older people with over 20% mortality rate[13]. In Belgium, overall incidence of iGAS infections rose by 1.3 to 1.6-fold in 2022 and by 1.8 to 2-fold in 2023 compared to pre-COVID-19 years[14]. Incidence of GAS is higher during winter months[15]. In our study, 93.33% cases occurred in the fourth quarter of 2023 which was consistent with previous research[3, 16]. Social and travel gatherings, as well as decline of masking and social distance, return to school after the first year of SARS-CoV-2 pandemic, may be behind increased GAS infection[17]. In our previous study, we presented hundreds of GAS infection diseases from 2016–2021. Under SARS-CoV-2 pandemic, GAS infection was dramatically decline[18]. The prevalent of GAS infection in our research slightly higher among males (60%) than female (40%). Females are more frequently impacted by upper respiratory tract infections (URTIs), while males are more affected by lower-RTIs (respiratory tract infections). Nevertheless, most RTIs are more severe in males than in females, and these differing outcomes could be attributed to anatomical, lifestyle, behavioral, and socio-economic variations between gender differences[19].
Children between 5 and 15 were more vulnerable to streptococcal throat infections than younger children. Infants less than 12-month have been presented high-risk group for iGAS infection. Our generalized GAS infections were more likely to occur in children between 53-month and 126-month, which might be related to this age group having more clustered activities, including social and travel gatherings, as well as study in school.
Bacterial culture serves as standard for diagnosing GAS infection. Nevertheless, it necessitates up to 48 hours and standard facilities. In our study, 74.67% patients were RADT tested positive. Samples cultured from pharynx, skin lesions, urinary tract, or female genital tract of the same patient were identified the same emm type GAS strain.
In addition, many Chinese families have two or more children, which also have a certain impact on the outbreak of GAS clustering. Risk factors associated with pediatric iGAS infections have been identified, such as nonsteroidal anti-inflammatory drugs treatment, coinfection with varicella, and RSV[20],[16]. Influenza A and B virus were found in 2% iGAS patients, rhinovirus or rhinovirus/enterovirus was detected in 43% iGAS patients, human metapneumovirus was detected in 26% iGAS patients, meanwhile, adenovirus was detected in 22% iGAS patients[21]. In our research, certain patients experienced infections with influenza A virus, influenza B virus, and mycoplasma pneumoniae prior to contracting GAS infection. No patients were associated with preceding or coinciding RSV and varicella virus. Our findings did not align with prior studies[22]. 66.67% our patients had fever. 5 patients had mycoplasma pneumoniae, influenza A virus, and influenza B virus infections. Nevertheless, it couldn’t be discounted that patient refrained from seeking medical assistance when experiencing fever, or that the pathogen went undetected. Respiratory virus dynamics have contributed to the changes in iGAS epidemiology[23]. Multiple infections impact patient's immune function, thereby inducing or exacerbating iGAS infection.
In our study, pharyngitis, sore throat, accompanied with paronychia/blistering dactylitis/ hand and foot abscess are diagnostic clues for GAS, especially with patients having many cutaneous infections such as deep abscess. Blistering distal dactylitis usually caused by GAS, staphylococcus aureus or streptococcus agalactiae which predominantly impacted children aged 2–16 years[24]. Cohen included children under 15 with tonsillopharyngitis, perianal infections, paronychia/blistering dactylitis, and scarlet fever. Paronychia/blistering dactylitis with RADTs accounted for 0.1% of GAS infected children[7]. However, our patients had severe dactylitis/paronychia with hand and foot abscess which had not been reported before. Asymptomatic throat carriage GAS was responsible for high prevalence of endemic GAS-linked skin infection[25].
Generalized GAS infection may indicate that patients have latent infections or immune metabolic diseases, such as diabetes, as well as iGAS infection. Accurate clinical evaluation, timely identification of symptomatic/asymptomatic patients with persistent GAS infection, and immediate initiation of treatment for patients can decrease economic burden of treatments and save life.
GAS generates numerous surface-bound and extracellular virulence factors that contribute to pathogenesis of iGAS infection[26]. Certain types of emm have been strongly linked to invasive infections. However, there is a well-known geographical diversity in distribution of emm types[27]. Furthermore, spread of specific highly infectious emm types within the community could affect seriousness and clinical manifestations of iGAS infections. GAS pattern types may be deduced from emm type (via emm-clustering) and have been proposed as an indicator of tissue tropism, with pattern A-C linked to throat infections, pattern D to skin, and pattern E to either throat or skin[28].
GAS cases associated with emm1 were more prevalent in iGAS cases than in cases of tonsillopharyngitis, whereas emm4 and emm89 were more frequently found in tonsillopharyngitis than in iGAS infections[29]. In Netherlands, novel emm4 has been the emergence emm type however, emm1 was the predominant emm type in Belgium[14] as well as in France[23]. During 2007–2019, the most common emm types in iGAS in Spain were emm1, emm89, and emm3[30].
In Beijing, between 2011 and 2018, M12 S. pyogenes declined, while M1 started to increase and eventually surpassed M12 during 2013–2014[9]. Emm1.0 and emm12.0 were prevalent and resulted in different diseases among Chinese children from 2016 to 2018[31]. 36.2% pediatrics suffered blistering distal dactylitis or paronychia had GAS infection with emm89 as the most prevalent, followed by emm12 and emm1[32]. In Southern Taiwan, the most frequent types were emm12, emm4, emm1. A-C4 was the most prevalent cluster, followed by E1, and A-C3. Emm clusters A-C4 and E1 were linked to non-invasive presentations, while emm cluster E6 was linked to both invasive and non-invasive illnesses[33]. In our study, emm12.0 was the most prevalent emm type in GAS infection pediatrics, which was consistent with the main emm typing GAS strains in China[9], as well as our previous research results[33]. Both emm and emm cluster typing systems could offer additional assistance in monitoring and preventing GAS infections on a global scale.
Antimicrobial resistance poses a significant threat to public health. The combination of clindamycin and penicillin plays a crucial role in treating the most severe GAS infections. The high prevalence of emm4/ST39/mefA-msrD/M, emm12/ST36/mefA-msrD/M, and emm28/ST52/ermB/MLSBc clones accounts for the high rate of erythromycin resistance[34]. Lillie observed emm92 and emm11 accounted 86% of erythromycin-resistance iGAS/nGAS strains. Emm89 was the third most common emm type which was susceptible to erythromycin[35].
Antibiotic treatments continue to be a crucial aspect of care for managing both nGAS and iGAS infections[36]. GAS prevailing sensitive to β-lactam antibiotics. First-line adjunctive and penicillin-alternate treatment regimens, such as macrolide and lincosamide, could lead to recurrent infection, treatment failure, and poor outcomes. The preferred medication for treating bacterial pharyngitis is oral penicillin for a duration of 10 days or intramuscular benzathine penicillin. First-line treatment for Streptococcal throat infection in patients with penicillin allergy involves the use of macrolides and first-generation cephalosporins[37]. It's important to note that certain strains of GAS have developed resistance to macrolides, making them a third-line treatment option[38]. Severe iGAS infection can be effectively managed using vancomycin or clindamycin[39]. In cases of soft tissue skin infection, intravenous antibiotic therapy and surgical removal of necrotic tissue are recommended.
In Northwest Ethiopia, GAS isolates presented resistant to tetracycline, erythromycin, and azithromycin with the rate of 56.5%, 39.1%, and 30.4% respectively. Conversely, penicillin, vancomycin, chloramphenicol, clindamycin, and ceftriaxone demonstrated effectiveness against 100%, 95.7%, 95.7%, 91%, and 87% of GAS isolates[19]. However, in our study, 93.33% GAS strains were resistant to clindamycin, which was consistent with our research results between 2016 and 2021. Our GAS isolates were sensitive to penicillin, ceftriaxone, cefotaxime, cefepime, vancomycin, and levofloxacin, which was presented by other studies worldwide, as well[40]. Meanwhile, they were resistant to erythromycin, clindamycin, and tetracycline with the rate of 93.33%, 93.33%, and 86.67%. respectively. These findings corroborated our study of 2016–2021. Our patients treated with penicillin or ceftriaxone could control the progression of GAS infection.
Our study has several limitations. Firstly, our current research is conducted at a single center, and our GAS isolates are indicative of a particular geographical region. Our dataset is relatively small and the factors, clinical features in GAS pediatrics should not be overinterpreted. We can’t characterize the whole clinical spectrum of current pediatric GAS infections.
In conclusions, our study reported clinical features of generalized GAS infection in pediatrics, identifying prevalent emm-type during the year of 2023 from dermatological perspective. The notable clinical characteristics in skin including paronychia/blistering dactylitis/ hand and foot abscess, paronychia, subungual abscess, angular stomatitis, scarlatiniform rash and desquamation. Most of patients had premorbid conditions, such as virus infection, mycoplasma pneumoniae infection. Generalized skin infections suggest that patients may have systemic infections. Attention should be paid to the possibility of widespread bacterial infections in the later stage of multiple viral infections. Early detection and on-time initiation of treatments for children with iGAS infection could potentially save lives. In the future, long-term monitoring and investigation of the iGAS/nGAS prevalence are imperative.