General Warning Signs

For the emergency physician, the key challenge is General warning signs in pediatric patients with iGAS infections are usually vague and nonspecific. Therefore, a high index of suspicion is essential. Early detection is crucial to prevent progression of the disease and avoid high mortality, morbidity, and ICU admission rates, especially after COVID-19 [6]. Clinical decision-making should be triggered by warning signs, including rapid clinical deterioration, impaired mental status, and cardiovascular instability (e.g., tachycardia and hypotension), all of which increase the risk for pediatric intensive care unit (PICU) admission [15]. Additional clinical signs strongly associated with severe disease requiring PICU admission or leading to death include reduced consciousness (odds ratio (OR), 7.61; 95% CI, 1.84–34.41), dyspnea (OR, 9.98; 95% CI, 3.04–32.14), and abnormal auscultation findings (OR, 6.32; 95% CI, 2.18–18.32) [6]. Also, gastrointestinal (GI) symptoms such as abdominal pain, vomiting, and diarrhea are considered significant warning signs. Rivano et al., an Italian case series study, assessed iGAS patients aged < 16 years after COVID-19 and reprted GI manifestations in four patients (44.4%) with iGAS. These findings indicate the GI symptoms might occur as part of the early clinical presentation, but they should not be interpreted as independent predictors of poor outcomes based on this case series study [16]. Severe pain, swelling, blisters, or necrosis suggesting necrotizing fasciitis constitutes a surgical emergency [6]. Ultimately, these findings highlight the importance of early detection, as any delays are associated with high morbidity and mortality rates.

Red Flags for Streptococcal Toxic Shock Syndrome (STSS)

STSS in pediatric patients is infrequently developed; however, it could progress rapidly. STSS is a powerful independent predictor of poor outcome, associated with a markedly increased risk of severe disease (OR, 11.71; 95% CI, 4.39–31.18) [6]. Clinical red flags include Skin or soft-tissue infections and necrosis, which were present in 36% of STSS cases in one retrospective study [7]. Multiorgan failure developing over hours, manifesting as acute kidney injury (AKI), liver dysfunction, neurological dysfunction (e.g., lethargy, agitation, and confusion), or respiratory failure in iGAS patients should prompt immediate consideration of STSS [7].

Red Flags for Necrotizing Fasciitis

Early recognition of clinical key red flags of necrotizing fasciitis is important for rapid diagnosis and preventing progression to life-threatening complications. The earliest signs include severe pain out of proportion and local edema and erythema overlying firm skin, while Purple skin discoloration, ecchymoses, and bullae are late but ominous signs, indicating vascular compromise and underlying tissue necrosis [17]. Rapid progression of iGAS symptoms (e.g., < 24 h) is a hallmark characteristic, with the infection spreading along the fascial planes far beyond the clinical area of skin infection involvement [18]. Suspected necrotizing fasciitis mandates immediate surgical consultation. Do not wait for imaging confirmation.

High Risk Groups

The major high-risk group for iGAS infections is children under age 5. A Canadian case series study compared different age groups (e.g., 0–4, 5–9, 10–17) in iGAS patients. Of them, children younger than 5 years showed the highest proportion in iGAS patients (241/498; 48.39%). Among this age group, bacteremia without focus (79/241) and soft tissue infection (66/241) were the predominant presentations [3]. Age-specific patterns also show that children 5–9 years were more likely to present with bone or joint infections, while the emm1 type was more likely to be associated with pneumonia [3]. Notably, when surgical management was required, it occurred less commonly in children under 5 years compared to older children, suggesting age-related differences in disease presentation or progression [3].

Additional factors associated with increased risk of iGAS include: a prior pulmonary infection, post-COVID-19 diagnosis, and meningitis or encephalitis [6]. Varicella infection requires special attention as it has been consistently linked to increased iGAS risk, particularly for necrotizing fasciitis, due to skin barrier disruption. An Irish clinical case review of 180 iGAS cases post-covid found active varicella in 33 out of 49 patients with skin and soft tissue infections [15]. However, it is important to note that while varicella is a risk factor for acquiring iGAS, preceding varicella infection has not been independently associated with increased disease severity, suggesting that the post-pandemic surge in severe cases is likely driven by other factors such as emerging virulent strains [6, 19, 20]. Therefore, an effective and protective varicella vaccine is required to decrease the incidence of iGAS infection [15].

Other factors associated with increased risk of severe disease include pulmonary involvement (OR, 8.64; 95% CI, 5.50–13.55), and a post-COVID-19 pandemic diagnosis (OR, 3.49; 95% CI, 2.31–6.26) [6]. Nonsteroidal anti-inflammatory drug (NSAID) use has also been identified as a significant risk factor (OR, 10.64; 95% CI, 2.08–54.61). However, this association should be explained cautiously because NSAIDs may have been administered in response to early severe pain or inflammation rather than causing disease progression [20].

Clinical Phenotypes and Proposed Risk Stratification Framework

iGAS infection is now widely recognized as a heterogeneous syndrome comprising distinct clinical phenotypes, rather than a single uniform entity. Large contemporary pediatric cohorts demonstrate reproducible patterns of presentation that reflect underlying pathophysiology and predict disease severity and outcomes [3]. It is critical to note that the following tiered categorization represents an author-proposed clinical framework rather than a formally derived and externally validated risk tool. It has not been validated to dictate definitive patient disposition or treatment decisions and should serve only to support clinical judgment. For clinical decision-making, it is useful to group iGAS phenotypes into three primary categories:

1-A toxin-dominant shock phenotype is defined by STSS, characterized by abrupt hypotension, multiorgan failure, and severe systemic toxicity induced by superantigen-mediated immune activation [3, 21].

2-A rapidly invasive soft tissue phenotype includes necrotizing fasciitis, myositis, and severe deep cellulitis, marked by severe localized pain, rapid tissue destruction, early bacteremia, and frequent need for urgent surgical intervention [1, 3].

In contrast, 3- Primary bacteremic phenotype presents as bloodstream infection without an identifiable focal source, often with nonspecific fever or sepsis, particularly in younger children, and carries a variable but potentially severe clinical course [3, 14].

Collectively, these phenotypes are associated with markedly different risks of deterioration, intensive care admission, and mortality, supporting their use as the foundation for structured clinical risk assessment. These distinct clinical phenotypes translate into recognizable bedside warning signs that can be systematically organized to guide early diagnosis and risk stratification, as summarized in Table 1.

Table 1 Clinical red flags for iGAS (General vs STSS vs Necrotizing Fasciitis)

Based on this phenotypic framework, a tiered risk stratification can guide emergency management:

Low-risk disease in this framework is redefined to include children presenting with less fulminant forms of confirmed or suspected invasive disease, such as isolated bacteremia without an identifiable focus (occult bacteremia) or haemodynamically stable localised soft tissue infections in patients who do not exhibit symptoms of rapid clinical deterioration, exhibit no systemic toxicity, and preserve entirely stable vital signs [1, 3]. Recommended actions for this stable invasive tier include the initiation of appropriate intravenous or definitive antibiotic therapy, hospital admission for close clinical observation, and the provision of explicit safety-net instructions for parents upon discharge [1].

As a proposed clinical approach, intermediate-risk disease is characterized by fever with focal pain, evolving soft tissue findings, or borderline vital signs. Without noticeable shock, these patients warrant hospital admission, blood cultures, early combination antimicrobial therapy including clindamycin (tailored to syndrome severity, local resistance, and pediatric sepsis guidance), close clinical reassessment, and early infectious diseases or surgical consultation as indicated [3, 12].

Within this proposed framework, high-risk disease includes hypotension, altered mental status, rapidly progressive soft tissue infection, or features of toxin-mediated shock; this tier requires immediate escalation with intensive care admission, aggressive hemodynamic resuscitation, urgent source control, combination antimicrobial therapy aligned with pediatric sepsis guidelines, and consideration of adjunctive intravenous immunoglobulin in cases of STSS [14, 21].

This dynamic risk-based approach links clinical phenotype to management urgency and reduces delays in recognition and treatment of severe pediatric iGAS disease.

Laboratory markers for risk assessment: Inflammatory biomarkers, including elevated serum procalcitonin and C-reactive protein (CRP), have been identified as significantly associated with an increased risk of PICU admission, while a higher estimated glomerular filtration rate (eGFR) is associated with a reduced risk (OR, 0.64; 95% CI, 0.49–0.84) [6, 22]. However, rather than functioning as strict, standalone binary decision thresholds, these biomarkers reflect a continuous association with disease severity. Neither value should be used in isolation to trigger intensive care admission or the initiation of vasoactive treatment [6, 22].

Diagnostic Approach

For the emergency physician, the diagnostic approach to suspected iGAS must be multimodal and time sensitive. Although GAS infections are often localized, complications from systemic invasion (e.g., STSS and necrotizing fasciitis) are critical and require an urgent multi-modal strategy. The diagnosis of iGAS mandates a comprehensive approach, including clinical evaluation, laboratory investigation, and/or imaging (Fig. 1; Table 2). For all critically ill patients, the Surviving Sepsis Campaign (SSC) recommends systematic screening to achieve early recognition and timely management, improving outcomes. The SSC states that a tailored approach should be individualized based on the context of clinical presentation and availability of resources [23, 24].

Fig. 1

ED diagnostic & action algorithm for suspected pediatric iGAS (created by the authors based on Weiss et al. [24], Szilagyi et al. [29], and Di Pietro et al. [23]) [23, 24, 29]

Table 2 ED diagnostic & action algorithm for suspected pediatric iGASEssential Laboratory Investigations

iGAS complications, especially STSS, are associated with clinical hypotension (systolic blood pressure less than 5th percentile for age) and signs of impaired tissue perfusion and organ dysfunction. Abnormal laboratory findings reflect the associated systemic inflammatory response and microvascular thrombosis. These include leukocytosis, coagulopathy (thrombocytopenia or disseminated intravascular coagulation (DIC)), elevated creatinine, elevated levels of aspartate aminotransferase, alanine aminotransferase, or total bilirubin. Therefore, initial investigations for suspected cases should include a complete blood count (CBC) with differential, coagulation profile, and a comprehensive metabolic panel (CMP) [23, 24].

Inflammatory and prognostic markers, including serum lactate, procalcitonin level (PCT), and C-reactive protein (CRP), help in risk stratification of pediatric patients with suspected septic shock or sepsis-associated organ dysfunction. Serum lactate is an indirect marker of hypoperfusion associated with adverse outcomes. Although serum lactate is included in the Hour-1 Sepsis Bundle for adults, with a threshold of > 2 mmol/L defined as hyperlactatemia, the SSC could not issue a recommendation regarding a specific serum lactate threshold in pediatric patients, as the optimal threshold defining hyperlactatemia remains unclear. However, they recommend using serial measurements of serum lactate to guide resuscitation and hemodynamic stability [24]. Additionally, serum PCT (> 0.05 ng/mL) and CRP (≥ 15 mg/dL) have been identified as significantly associated markers of PICU admission, highlighting the importance of these markers in decision-making [22].

Microbiology and Cultures 1-

Blood cultures should be obtained before antibiotic administration whenever possible, provided this does not delay treatment [24]. Bacterial cultures from normally sterile sites (e.g., blood, pleural fluid, or CSF) remain the gold standard for iGAS diagnosis and pathogen identification [26]. Throat swaps or rapid antigen detection tests (RADTs) are useful for pharyngitis diagnosis, but a negative RADT does not rule out iGAS in a critically ill child [27]. The Infectious Diseases Society of America (IDSA), American Academy of Pediatrics (AAP), and American Heart Association (AHA) recommend using RADTs for GAS pharyngitis in patients without typical viral symptoms, with follow-up culture for negative results [26, 28]. On the other hand, probable iGAS is defined by severe clinical presentation and GAS isolation from non-sterile sites (e.g., throat, skin, or wound), with no other etiology of the invasive disease. Such cases should be considered for management benefits [25]. For NF, diagnosis is confirmed through intraoperative findings and specimens sent for Gram stain, culture, and pathology [29]. Anti-streptococcal antibody titers have no role in acute iGAS diagnosis [23].

Imaging

The role of imaging is most evident in suspected necrotizing fasciitis (NF). Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) have been used in the evaluation of NF. CT may demonstrate deep fascial thickening and fluid or gas within the soft tissue planes surrounding the superficial fascia. A pediatric NF review reported CT sensitivity of 88.5% and specificity of 93.3% for fascial gas [29]. Ultrasound may demonstrate thickening, distortion, and fluid collections along the deep fascia, while MRI may identify fluid within and around fascial planes [29]. However, these imaging accuracy estimates have not been established specifically in pediatric iGAS cohorts. Surgical exploration remains the definitive diagnostic approach, and imaging should not delay surgery when NF is clinically suspected [29].

POCUS may also be used to assess myocardial dysfunction in hemodynamically unstable patients and guide resuscitation [30, 31].

For respiratory presentations with suspected pleural involvement, chest radiography is used as an initial imaging study. Chest ultrasonography can further characterize pleural effusions as simple or complicated. Chest computed tomography is not routinely recommended and may be considered when the child fails to respond to treatment or when an alternative aetiology is suspected [22, 25, 32].

Diagnostic Pitfalls

The emergency physician must maintain a high index of suspicion despite normal initial findings. Clinical manifestations of iGAS, especially in children, are nonspecific and may overlap with viral illnesses. Many children present with fever and pain, with normal or mildly abnormal laboratories, before deteriorating rapidly [13, 26]. Necrotizing fasciitis is particularly challenging as it is rare in children, often misdiagnosed as cellulitis, and delayed diagnosis leads to rapid progression to septic shock and death. The classic "pain out of proportion" to physical findings should trigger urgent surgical consultation even with normal initial studies [29].

Emergency Department Management: Critical Interventions

Management follows a systematic approach: initial stabilization, antibiotic therapy, adjunctive treatment, and timely surgical consultation when indicated [25] (Fig. 2).

Fig. 2

Systems model of early recognition, stabilisation, and escalation. (created by the authors based on Moore et al. [25], Weiss et al. [24], and van Kempen et al. [6, 24, 25]

Initial Stabilization

Currently, no iGAS-specific guidelines exist. However, septic shock protocols are implemented since iGAS (STSS/NF) manifests as toxin-mediated septic shock. The main goal of initial stabilization is to provide hemodynamic support and maintain tissue perfusion. Intravenous (IV) fluids and vasoactive medications are cornerstone therapies. Although IV fluids, preferably balanced crystalloids, are the first line of management to correct hypovolemia, they have been linked to adverse effects due to their composition, rate, volume, and variations in response [33,