Abstract
Introduction
Streptococcus pyogenes (S. pyogenes) can cause streptococcal toxic shock syndrome (STSS), especially in immunocompromised individuals. Early diagnosis is the key to treat STSS effectively. This study presents a fatal case of STSS caused by the emerging M1(UK) S. pyogenes lineage in a patient with type 2 diabetes mellitus (T2DM), alongside a comprehensive literature review.
Case presentation
A 65-year-old man with T2DM presented with altered consciousness, necrotizing soft tissue injury and was diagnosed with STSS. Bacterial cultures were obtained from right lower limb exudate, right hand mass pus and scrotal pus. Antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS), phylogenomic analysis, and virulence profiling were performed. S. pyogenes isolates from all sites were identified as M1(UK) (emm1/ST28) lineage, closely related to UK strains. The strain was resistant to tetracycline, erythromycin, and clindamycin (ermB, tetM, lmrP) but remained susceptible to β-lactams. Key virulence genes included slo, speC/speG, hasABC and scpA. The slo-mediated endothelial lysis and speC/G-induced cytokine storm contributed to capillary leakage and rapid clinical deterioration. Increased hasABC-mediated capsule expression under hyperglycemia further impaired bacterial clearance.
Conclusion
This case highlights the threat of antimicrobial-resistant M1(UK) S. pyogenes in patient with T2DM. The pathogenicity of strain was driven by cytolytic toxins, superantigens, and immune evasion. Early STSS diagnosis is facilitated by microscopic examination and rapid antigen detection test (RADT) of group A streptococcus.
Clinical trial number
Not applicable.
Keywords: Streptococcal toxic shock syndrome, Streptococcus pyogenes, M1(UK) lineage, Type 2 diabetes mellitus, Early diagnosis
Background
Streptococcal toxic shock syndrome (STSS) is a life-threatening systemic condition driven by bacterial superantigens, characterized by fever, hypotension, and rapid multi-organ failure. Invasive group A streptococcal strains, particularly hypervirulent clones like Streptococcus pyogenes (S. pyogenes), account for rising mortality due to delayed recognition and antibiotic resistance [1–3]. The virulence of S. pyogenes hinges on a synergistic interplay between superantigens, cytolytic toxins and immune evasion mechanisms. These factors collectively trigger a cytokine storm, disrupt endothelial integrity, and impair neutrophil-mediated clearance [4–6]. This process exacerbated in patients with type 2 diabetes mellitus (T2DM). Chronic hyperglycemia in T2DM impairs neutrophil extracellular trap formation, promotes microvascular leakage via advanced glycation end-products (AGEs), and creates a nutrient-rich microenvironment that enhances bacterial proliferation [7, 8]. Therefore, it is essential to analyze the causes of STSS and the infectious bacteria comprehensively, and explore the methods of early diagnosis and treatment.
This integrated case analysis and literature review examines a fatal STSS complicating poorly controlled T2DM in a 65-year-old male, manifesting as necrotizing fasciitis and septic shock. Isolates from all sites were identified by whole genome sequencing (WGS) as S. pyogenes M1(UK) (emm1/ST28) lineage, which harbored slo, speC, speG, scpA and hasABC virulence determinants, resistant to macrolides but β-lactam susceptible. Our findings highlight the critical interplay between T2DM-associated immunometabolic dysfunction and hypervirulent group A Streptococcus (GAS) evolution, while underscoring the continued value of conventional microbiological methods, including rapid antigen detection tests (RADT) and microscopic examination, in facilitating early STSS diagnosis.
Methods
Case presentation
A 65-year-old male with poorly controlled T2DM and hypertension was admitted to the Emergency of Qingyuan People’s Hospital on November 3, presenting with altered consciousness and recurrent vomiting. Physical examination revealed hypotension, along with significant findings in the right extremities. These included marked swelling of the right lower limb with exudation of light red fluid, and extensive ecchymosis and swelling on the medial thigh and ankle area, where partial epidermal exfoliation revealed a pale, mottled wound base. Furthermore, the third and fourth fingers of the right hand exhibited swelling and black-purple discoloration (Fig. 1). Laboratory findings on admission (Table 1) were critical for the diagnosis: a profound leukocytosis, alongside markedly elevated C-reactive protein (CRP) and procalcitonin (PCT) levels, confirmed a severe systemic infection. This was accompanied by metabolic acidosis, evidenced by a low pH, decreased bicarbonate (HCO3−), and a compensatory low partial PCO2. coagulation function were markedly abnormal, with elevated PT, APTT, fibrinogen, and D-dimer, consistent with developing disseminated intravascular coagulation (DIC). Microscopic examination revealed the presence of Gram-positive cocci in the right lower limb exudate, suspected to be streptococcus species, and RADT of GAS was positive (Fig. 2). Symptomatic treatment, including imipenem-cilastatin and vancomycin, as well as drugs to correct electrolyte imbalances and protect vital organs was initiated.
Fig. 1.
Clinical manifestations of STSS in patient with T2DM. (A-B) Necrotizing fasciitis with gangrenous changes in the third and fourth digits of the right hand; (C-D) Purulent exudate at the right lower extremity infection site; (E-F) Scrotal mass formation
Table 1.
Laboratory parameters of the patient
| Parameter | Date | ||
|---|---|---|---|
| November 3rd, 2024 | November 4th, 2024 | ||
| Blood routine examination | WBC (×109/L) | 24.88 | 30.73 |
| Neutrophils (%) | 0.86 | 0.93 | |
| Hb (g/L) | 125 | 65 | |
| PLT (×109/L) | 292 | 102 | |
| Blood coagulation | PT (s) | 19 | 27.8 |
| APTT (s) | 41.8 | 58.2 | |
| Fbg (g/L) | 9.48 | 3.74 | |
| D-Di (mg/L) | 5.38 | - | |
| Blood gas | PH | 7.11 | 7.15 |
| PCO2 (mmHg) | 20 | 27 | |
| PO2 (mmHg) | 115 | 95 | |
| HCO3− (mmol/L) | 6.4 | 9.4 | |
| BEecf (mmol/L) | -23.1 | -19.5 | |
| Beb (mmol/L) | -21.3 | -17.9 | |
| Blood biochemistry | Glu (mmol/L) | 27 | > 27.8 |
| Lac (mmol/L) | > 15.0 | 11.9 | |
| Urea (mmol/L) | 15.29 | 20.38 | |
| Cr (µmol/L) | 264.8 | 280.3 | |
| ALT (U/L) | 41 | 872 | |
| AST (U/L) | 126 | 2915 | |
| K+ (mmol/L) | 5.28 | - | |
| Na+ (mmol/L) | 132.8 | - | |
| Cl− (mmol/L) | 94.6 | - | |
| CRP (mg/L) | 337.58 | 249.66 | |
| PCT (ng/mL) | 31.65 | - | |
| BNP (pg/mL) | - | 319.54 | |
| Pro-BNP (pg/mL) | - | 4238.00 | |
| cTnI (µg/L) | 0.009 | 16.576 | |
| CK (U/L) | - | 23,833 | |
| Mb (µg/L) | - | > 1200 | |
Fig. 2.
Rapid diagnostic evaluation of GAS infection. (A) Gram-stained smear of right lower limb exudate demonstrating Gram-positive cocci in chains (× 1,000 magnification, oil immersion); (B) Positive RADT for GAS antigen using immunochromatographic assay.
However, on November 4, progressive clinical deterioration was observed: fever (T: 37.8 °C), worsening right lower limb edema with hemorrhagic exudation. Critically, the infection had spread to the perineum, manifesting as significant scrotal swelling and erythema. Repeat laboratory tests showed escalating inflammatory markers and multi-organ dysfunction (SOFA score: 4). Contrast-enhanced CT demonstrated soft tissue swelling surrounding the left orbit. Scattered patchy and cord-like opacities were observed in both lung fields. A pericardial effusion was present. Abnormal densities were noted in the perinephric regions bilaterally, with stranding and blurring of the perirenal fat planes. Additionally, there was decreased calibre of the systemic veins. These findings indicate that the condition of the patient is extraordinary.
A multidisciplinary team (MDT) consultation prioritized bedside microbiological sampling. Microscopic examination of the right hand mass pus and scrotal pus confirmed Gram positive streptococcus, aligning with prior findings. Emergency debridement and negative-pressure wound therapy were performed immediately. Despite aggressive intervention, the patient remained unconscious post-surgery, succumbing to multi-organ failure on November 4. On November 6, Microbial identification via MALDI-TOF mass spectrometry (MS) confirmed S. pyogenes in right lower limb exudate, right hand mass pus, and scrotal pus (Fig. 3). Antimicrobial susceptibility testing (AST) revealed resistance to erythromycin, clindamycin, and tetracycline, with retained susceptibility to β-lactams, vancomycin and carbapenems.
Fig. 3.
Microbiological characterization of clinical isolates. (A-C) β-hemolytic colonies on sheep blood agar (5% CO₂, 37 °C, 24 h) from (A) right lower limb exudate, (B) right hand mass pus, (C) scrotal pus; (D-F) Gram-positive streptococcal chains observed by light microscopy (×1,000); (G) MALDI-TOF MS identification (Bruker Biotyper® system) showing characteristic protein spectra matching S. pyogenes reference database.
Microbiological testing
According to the manufacturer’s instructions, the right lower limb exudate sample was preliminarily identified using RADT kit for Group A/B Streptococcus antigen (Guangzhou Huaao Biotechnology Co., Ltd.). Right lower limb exudate, right hand mass pus, and scrotal pus were cultured on columbia blood agar plates (5% sheep blood) under aerobic conditions at 37 °C for 24 to 48 h. Bacterial identification was performed using MALDI-TOF MS (Bruker Biotyper® system) [9]. Bacterial suspension was adjusted to a 0.5 McFarland standard. Subsequently, 50 µL of colorimetric indicator was added to the susceptibility broth, and the mixture was inoculated into a Gram-negative panel for automated antimicrobial susceptibility testing (AST) using the Phoenix™ M50 system (BD Diagnostics), with results interpreted according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines (version 13.0, 2023; https://www.eucast.org).
Whole genome sequencing, phylogenetic analysis, and in silico prediction of antimicrobial resistance and virulence genes of S. pyogenes
WGS was performed on three S. pyogenes isolates from the right lower limb exudate, right hand mass pus and scrotal pus. The isolates were cultured in lysogeny broth (LB) medium and grown to the mid-logarithmic phase at 30 °C in a shaking incubator. DNA extraction was carried out using a genomic DNA isolation kit (Promega, Madison, WI). DNA quality and concentration were assessed using the Nanodrop 2000 (Thermo Fisher Scientific, Germany). WGS was performed on an Illumina platform (Eurofins Genomics, Germany GmbH). After sequence cleaning and normalization, high-quality reads were assembled using SPAdes. The emm type and sequence type were determined using standard online databases. For phylogenomic analysis, the assembled genome of the clinical isolate was compared against the NCBI nt database using BLAST + to identify homologous strains. Thirty representative reference strains with complete genome annotations were selected and retrieved for comparative analysis. To construct a high-resolution phylogenetic tree, single nucleotide polymorphisms (SNPs) were identified from the core-genome alignment of all strains using Snippy. A maximum-likelihood phylogenetic tree was then reconstructed based on these core-genome SNPs using MEGA version 11 [10, 11], with branch support assessed by bootstrap analysis. Additionally, a separate phylogenetic tree based on aligned 16 S rRNA gene sequences was constructed for broad taxonomic reference. For pangenome analysis, Roary was used to identify homologous gene clusters and generate a pangenome profile, which also served as the basis for constructing another phylogenetic tree reflecting gene content relatedness. Antimicrobial resistance and virulence genes were predicted using the Comprehensive Antibiotic Resistance Database (CARD: https://card.mcmaster.ca/analyse/rgi) and the Virulence Factor Database (VFDB: http://www.mgc.ac.cn/VFs/), respectively.
Results and discussion
This report presents a fulminant and fatal case of STSS in a patient with T2DM, which culminated in septic multi-organ failure despite maximal therapeutic efforts. The rapid clinical deterioration and lethal outcome highlight the formidable virulence of S. pyogenes and the persistent challenges in treating STSS. Secretion or pus samples were collected from three distinct anatomical sites of the patient, which including the right lower limb, the right-hand mass, and the scrotal mass. Bacterial culture from all three sites yielded β-hemolytic colonies (Fig. 3A-C). Following Gram staining of smears prepared from each colony type, microscopic examination confirmed the presence of Gram-positive cocci, with no notable morphological variations among the isolates from different sites (Fig. 3D-F). Subsequent identification by MALDI-TOF MS consistently produced characteristic spectral profiles matching S. pyogenes for all three isolates (Fig. 3G). To further investigate the fatal outcome of this patient, genomic DNA was extracted from the S. pyogenes isolates obtained from each site and subjected to WGS. Comparative analysis confirmed that the sequences from the three geographically distinct isolates were identical. The core-genome phylogenomic analysis demonstrated that all clinical S. pyogenes isolates from different sites formed a single cluster and were closely related to the M1(UK) reference strains MGAS1882 and MGAS15252. This genetically confirmed their clonal origin and their identity as emm1/ST28 (Fig. 4). In silico prediction of resistance genes revealed the presence of lmrP, ermB, and tet(M). The virulence gene repertoire included ssa, speC, speG, slo, mf2, mf/spd, speB, hasA/B/C, lmb, and scpA (Table 2).
Fig. 4.
(A-C) Phylogenomic analysis of M1(UK) S. pyogenes isolated from right lower limb exudate (A), right hand mass pus (B) and scrotum pus (C). The branch lengths represent genetic distance. Values at nodes indicate bootstrap support based on 1,000 replicates
Table 2.
Computer prediction of resistance and virulence genes of S. pyogenes isolated from right lower limb exudate, right hand mass pus and scrotal pus
| Antimicrobial resistance | ||
|---|---|---|
| Drug class | Antimicrobial resistance gene family | Related genes |
| Macrolides | Major facilitator superfamily (MFS) antibiotic efflux pump | lmrP |
| Macrolides | Erm erythromycin ribosome methyltransferase | ErmB |
| Tetracycline | Ribosomal protection protein | tet(M) |
| Virulence | ||
|---|---|---|
| Virulence factor class | Virulence factors | Related genes |
| Superantigens | Type III secretion system | ssa |
| Streptococcalpyrogenicexotoxin C | speC | |
| Streptococcalpyrogenicexotoxin G | speG | |
| Toxins | Streptolysin O | slo |
| Exoenzyme | Mitogenicfactor 2 | mf2 |
| Mitogenicfactor | mf/spd | |
| SpeB/cysteineproteinase | speB | |
| Adherence | Capsule | hasA |
| Capsule | hasB | |
| Capsule | hasC | |
| Laminin-binding protein | lmb | |
| Immune evasion | C5a peptidase | scpA |
WGS delineated a comprehensive virulence profile for the M1(UK) S. pyogenes isolate, identifying key genes implicated in distinct pathogenic stages which was showed in Table 2. These virulence genes collectively form a pathogenic network. Among them, ssa, mf2, and mf/spd may mediate bacterial adhesion and invasion [12]. slo, speC, and speG are associated with toxin release and cytokine storm induction [13, 14]. While the hasABC gene cluster likely contributes to immune evasion [15]. The patient in this case had T2DM, which is reported in the literature to be associated with impaired neutrophil function, microvascular damage, and a pro‑inflammatory microenvironment, this conditions that provide a favorable setting for pathogen proliferation and invasion [16]. Therefore, we conclude that the patient’s fatal outcome resulted from the synergistic interaction between the virulence genes of the M1(UK) S. pyogenes and the host microenvironment of T2DM. Specifically, ssa, mf2, and mf/spd first mediate bacterial adhesion and tissue penetration. Subsequently, streptolysin O encoded by slo triggers cell lysis and exacerbates inflammation, which together with the superantigens speC and speG drives a severe cytokine storm. This may be a key mechanism leading to septic shock. Meanwhile, capsule synthesis mediated by hasABC may assist the bacteria in evading immune clearance. The inherent immune dysfunction and imbalanced local microenvironment of the patient further amplify the damaging effects of bacterial toxins and hinder local infection control, ultimately leading to the full release of bacterial virulence and rapid progression to irreversible multi-organ failure.
Resistance gene analysis revealed that the presence of ermB (23 S rRNA methylase) and tet(M) (ribosome protective protein) resulted in inherent resistance to macrolides and tetracycline drugs, respectively. This was consistent with the results of erythromycin and doxycycline resistance in clinical drug susceptibility tests. The detection of lmrP suggests that this strain may have potential cross-resistance risk to other drugs such as lincoamides [17]. It is noteworthy that despite carrying the above resistance genes, the strain is still sensitive to beta-lactam, which is consistent with the lack of penicillin-binding protein (PBP) mutation in the S. pyogenes [18], emphasizing the need for early sufficient penicillin combined with clindamycin, which inhibiting toxin synthesis. Molecular epidemiological analysis further revealed that the M1(UK) lineage carries invasion-related genes such as mf/spd and scpA, which are highly homologous to the European endemic strains. This gene combination enhances bacterial penetration of subcutaneous soft tissue and mucosal barrier, resulting in multisite disseminated infection. It is particularly noteworthy that lmb may show abnormally high affinity in the highly sugar-modified basement membrane of T2DM patients, which provides a molecular basis for explaining the rare invasive scrotal infection in this patient [19].
T2DM serving as a significant predisposing factor for STSS, demonstrates a potential mechanistic association with hypervirulent bacterial infections. This connection may arise from compromised immune defenses in affected individuals due to suboptimal long-term disease management. First, chronic hyperglycemia critically impairs neutrophil function, including chemotaxis, phagocytosis, and neutrophil extracellular trap (NET) formation, thereby elevating susceptibility to invasive [16, 20]. Second, the accumulation of AGEs increased microvascular permeability, providing an anatomical conduit for bacterial dissemination [21]. Prediabetic vascularly compromised sites, such as the scrotum and lower extremities, served as preferential colonization targets for S. pyogenes [22]. From an immunological perspective, Th17/Treg imbalance and IL-10 overproduction further compromised mucosal defenses [23].
Despite aggressive treatment, the patient rapidly progressed to multi-organ failure and eventually succumbed. Given the high mortality rate associated with STSS, early diagnosis and prompt empirical treatment are critical in preventing further disease progression [24]. Although molecular techniques such as polymerase chain reaction (PCR) and WGS provide high sensitivity, conventional microbiological methods, including RADT and microscopy examination, remain indispensable for early diagnosis, especially in resource-limited settings [25]. In this case, during the diagnostic process, gram-positive cocci were first identified through microscopic examination, which raised suspicion of streptococcal infection. Subsequently, the RADT for group A/B streptococcus confirmed that the patient was infected with GAS. These conventional diagnostic methods are not only rapid but also provide preliminary pathogen information within a short period, thus significantly aiding in the timely diagnosis of STSS [26]. Integration of the patient’s clinical manifestations with ancillary diagnostic testing supports a provisional diagnosis of STSS, which attributed to GAS infection. Once STSS is suspected, treatment must be initiated in time. The standard regimen typically includes a combination of β-lactam antibiotics and clindamycin, supplemented by intravenous immunoglobulin (IVIG) to neutralize the superantigen [27]. This therapeutic approach is crucial for improving survival rates and reducing mortality in STSS patients.
In summary, we discuss a case of death from multiple organ failure resulting from poorly controlled T2DM complicated by STSS. WGS and phylogenetic analysis of each site identified S. pyogenes revealed that it belonged to the M1(UK) lineage and carried multiple antibiotic and virulence genes. Early diagnosis is essential for this disease. Moreover, We found that the combination of microscopic examination and RADT can provide early information for patients and play an important auxiliary role in the early diagnosis of STSS.
However, the single-case analysis limits generalizability to T2DM-related STSS populations. Future multi-center studies with larger cohorts are required to validate these conclusions. In addition, RADT and microscopy examination exhibit insufficient specificity for definitive diagnostic confirmation of STSS, necessitating cautious interpretation of their auxiliary role. Moreover, the persistent dependency on symptom-based diagnostic criteria may reduce sensitivity in cases with a typical clinical manifestations, underscoring the need for integrating advanced molecular diagnostics or imaging modalities to enhance detection accuracy.
Acknowledgements
Not applicable.
Abbreviations
- STSS
Streptococcal toxic shock syndrome
- T2DM
Type 2 diabetes mellitus
- RADT
Rapid antigen detection test
- GAS
Group A Streptococcus
- CRP
C-reactive protein
- PCT
Procalcitonin
- DIC
Disseminated intravascular coagulation
- AGEs
Advanced glycation end-products
- WGS
Whole genome sequencing
- MS
Mass spectrometry
- MDT
Multidisciplinary team
- AST
Antimicrobial susceptibility testing
- LB
Lysogeny broth
- SNPs
Single nucleotide polymorphisms
- PBP
Penicillin-binding protein
- NET
Neutrophil extracellular trap
- MIC
Minimum inhibitory concentration
- PCR
Polymerase chain reaction
- IVIG
Intravenous immunoglobulin
Author contributions
BD wrote the manuscript. LX, WW, ZW conducted the experiments. QM, LD, HZ, JY, XZ, YW, JW, ZZ, YT and LC analyzed the data. HL and XL designed and supervised the study. All the authors participated in reviewing the manuscript and gave approval before submission.
Funding
This research was funded by Scientific Research Grant Fund of Zhong Nanshan Medical Foundation of Guangdong Province (ZNSXS-20240010); Scientific and Technological Research Fund of Guangdong Province for Medical Science and Technology (A2021490); Medical Scientific Research Fund of Qingyuan People’s Hospital (202301-201,318).
Data availability
The datasets generated and analysed during the current study are available in the NCBI GeneBank repository, under accession number PRJNA1256115.
Declarations
Ethics approval and consent to participate
As a case report, our paper did not require any referral to our institutional clinical ethics committee.
Consent for publication
Written informed consent was obtained from the patient’s family members for publication of this report and any accompanying images.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Bishun Deng, Weihong Wen and Ziqi Wang contributed equally to this work.
Contributor Information
Huihui Lu, Email: huihui1998@139.com.
Lingqing Xu, Email: lingqing_xu@126.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analysed during the current study are available in the NCBI GeneBank repository, under accession number PRJNA1256115.