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Streptococcus pyogenes-purpura fulminans as an invasive form of group A streptococcal infection

  • Sayaka Okuzono
  • Masataka Ishimura
  • Shunsuke Kanno
  • Motoshi Sonoda
  • Noriyuki Kaku
  • Yoshitomo Motomura
  • Hisanori Nishio
  • Utako Oba
  • Masuo Hanada
  • Jun-ichi Fukushi
  • Michiyo Urata
  • Dongchon Kang
  • Hidetoshi Takada
  • Shouichi Ohga
Open Access
Case Report

Abstract

Background

Streptococcus pyogenes is an uncommon pathogen of purpura fulminans, and the pathogenesis of S. pyogenes-purpura fulminans remains unclear because of paucity of cases. We reported a pediatric case of S. pyogenes-purpura fulminans with literature review of the disease.

Case presentation

A 3-year-old boy showed limping, lethargy and acral gangrene within 24 h. A diagnosis of S. pyogenes-purpura fulminans was made for bacterial isolation from throat and peripheral blood. Intensive therapy led to a survival with amputation of the left distal metatarsal bone, and normal development. The isolated M12 carried no mutation of csrS/R or rgg. Thrombophilia or immunodeficiency was excluded.

Discussion

Twelve-reported cases (9 pediatric and 3 elderly) of S. pyogenes-purpura fulminans started with shock and coagulopathy. Five patients age < 8 years had no underlying disease and survived. One youngest and two immunocompromised patients died.

Conclusion

Streptococcus pyogenes-acute infectious purpura fulminans is a distinctive rare form of aggressive GAS infections.

Keywords

Acute infectious purpura fulminans Invasive group A β-Streptococcus Streptococcal toxic shock syndrome Disseminated intravascular coagulation Protein C deficiency 

Abbreviations

PF

purpura fulminans

GAS

group A Streptococcus

TSS

toxic shock syndrome

DIC

disseminated intravascular coagulation

ARDS

acute respiratory distress syndrome

MOF

multiple organ failure

JIA

juvenile idiopathic arthritis

TNF

tumor necrosis factor

NHL

non-Hodgkin’s lymphoma

TSS

toxic shock syndrome

NF

necrotizing fasciitis

Background

Streptococcus pyogenes (S. pyogenes) is the causative bacteria of scarlet fever, pharyngitis, impetigo, and cellulitis, as well as rheumatic fever and acute poststreptococcal glomerulonephritis [1]. The group A β-hemolytic Streptococcus (GAS) is associated with Sydenham’s chorea and pediatric acute-onset neuropsychiatric syndrome [2]. S. pyogenes is isolated from the throat of 10–30% children with acute pharyngitis, and healthy carriers are the source of outbreak. On the other hand, the most aggressive GAS infections comprise streptococcal toxic shock syndrome (TSS) and necrotizing fasciitis (NF) [3]. The invasive GAS infection occurs with high mortality and morbidity rates in both immunocompetent and immunocompromised adults irrespective of age, sex, and ethnicity. The ominous disease may thus account for the virulence of isolated strains. In particular, serotype M3 GAS isolates are known to be associated with severe invasive infection [4].

Purpura fulminans (PF) is a life-threatening condition characterized by sudden-onset progressive cutaneous hemorrhage and acral necrosis [5]. It is classified into neonatal, idiopathic, and acute infectious PFs. Neonatal PF develops within 72 h after birth, presenting with cerebral hemorrhage and/or thrombosis, purpuric skin lesions and symmetrical acral gangrene. It is caused by heritable protein C deficiency [6]. Idiopathic PF occurs 7–10 days after the onset of varicella or streptococcal infection, in the presence of transient autoantibodies directed against protein C and protein S [7]. The most common form, acute infectious PF, occurs superimposed on sepsis due to Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and rickettsiae [8]. S. pyogenes is an uncommon pathogen of PF in adults, and the pathogenesis of severe streptococcal disease remains unclear.

We herein report a rare case of acute infectious PF caused by S. pyogenes infection. The isolated strain of GAS from the previously healthy boy was M12 without high-virulent mutations of csrS/R or rgg [9, 10]. Twelve reviewed cases indicated that S. pyogenes is a weighty organism of acute infectious PF, occurring as a distinct type invasive GAS infection affecting children and elderly.

Materials and methods

Genetic study for the bacteria

Total DNA was extracted from bacterial cells and the nucleotide sequences of the csrS, csrR, and rgg genes were determined by automated sequencers, such as an Applied Biosystems 3130xl Genetic Analyzer (Applied Biosystems, Tokyo, Japan), as described previously [10]. The molecular characterization of the isolated strain was completed in the National Institute of Infectious Diseases (Tokyo, Japan).

Genetic and/or functional screening tests for the host

Genomic DNA was extracted from peripheral blood after obtaining informed consent from the patients. For screening of thrombophilia, after coagulation study, the direct sequencing of polymerase chain reaction (PCR) products was completed for the coding regions of protein C gene (PROC exons 1–9) and as described previously [11]. For screening of primary immunodeficiency diseases, flow-cytometric analyses were performed to diagnose phagocyte disorders and IRAK4/MyD88 deficiency [12]. Target-sequencing was then performed for the genes including STAT3, PIK3D, and PIK3R by the established method [13].

Case presentation

A previously healthy 3-year-old boy showed limping with the left leg pain, and then fever 6 h later. Next morning, he was transferred to an emergency hospital because of loss of consciousness and purpuric legs. Within a couple of hours, shock vital signs emerged and ecchymoses extended over the lower extremities. The patient was admitted to a pediatric intensive care unit on cardiopulmonary assist and catecholamine support. He had atopic dermatitis and one history of pneumonia in infancy. The growth and development were normal. There was neither consanguinity nor informative family history.

On admission, the comatose patient showed 180/min of tachycardia and unmeasurable blood pressure on the assist ventilation. Light reflex was prompt. The body temperature was 40.1 °C. Capillary refilling time was prolonged over 2 s, while cardiopulmonary sounds were normal. There was no hepatosplenomegaly or lymphadenopathy. Purpura and ecchymoses expanded to the both legs with necrotic toes (Fig. 1). Petechiae spread over the face, body and upper extremities. Complete blood counts showed a leukocyte count of 0.329 × 109/L with 80% neutrophils, 17% lymphocytes, 3% monocytes, a hemoglobin concentration of 11.0 g/dL, and a platelet count of 3.8 × 109/L. Schizocytosis and hemoglobinuria indicated hemolysis. Serum biochemistries revealed increased levels of blood urea nitrogen (24 mg/dL, reference range [rr]: 8–20), creatinine (0.5 mg/dL, rr: 0.2–0.45), total bilirubin (1.8 mg/dL, rr: 0.3–0.9), aspartate aminotransferase (381 U/L, rr: 24–43), alanine aminotransferase (99 U/L, rr: 9–30), lactate dehydrogenase (1203 U/L, rr: 190–365), creatine kinase (731 U/L, rr: 43–270), and C-reactive protein (12.83 mg/dL, rr: < 0.04). Coagulation studies showed hypofibrinogenemia (139 mg/dL, rr: 200–400), prolonged prothrombin time (PT 21.2 s, control 10–13.5 s) and activated partial thromboplastin time (APTT 53.1 s, control 26–41 s), and increased levels of fibrinogen degradation products (FDP 445.0 μg/mL, rr: 1–10) and D-dimer (142.1 μg/mL, rr: 0.15–1). Thrombin-antithrombin complex (TAT) was > 120.0 ng/mL (rr: < 4), plasmin α2–antiplasmin complex (PIC) was 25.2 μg/mL (rr: < 0.8) and thrombomodulin 37.7 FU/mL (rr: < 4.5). Plasma activities of protein C (13%, rr: 64–131) and protein S (52%, rr: 62–121) were respectively low, and those of antithrombin were normal (85%, rr: 68–130). The rapid antigen tests were positive for S. pyogenes and negative for Pneumococcus. S. pyogenes, determined later as the serotype M12, was isolated from throat and peripheral blood. Sterile cerebrospinal fluid showed no pleocytosis. These determined the diagnosis of acute infectious PF with S. pyogenes-septic shock. Antibiotic and anticoagulant therapy was started on the intensive care. Next day, leg purpura and acral gangrene extended. Anticoagulation with plasma-derived activated protein C (Anact C®), gabexate mesilate, fresh frozen plasma replacement, and platelet infusion, was intensified by the addition of a direct thrombin inhibitor (argatroban), antithrombin, recombinant thrombomodulin, and low-molecular heparin. The relaxing incisions were then conducted for the compartment syndrome of both legs on the 3rd day of illness. S. pyogenes was also isolated from the debridement tissues, and the histopathology indicated absent necrosis of the fascia and necrotic alteration of the muscle without specific inflammation. The continuous infusion of penicillin G led to the negative blood culture 24 h after the start of antibiotic therapy. Under controlled sepsis and coagulopathy, continuous irrigation and debridement were repeated. On the 13th day, debridement tissues showed necrotic muscle and fascia with chronic inflammatory changes. The histological changes indicated that the necrotic muscle tissues originated from ischemia rather than spreading infection of the fascia. The distal portions of the left metatarsal bone were finally amputated. Repeated skin-autografts resulted in the cosmetic and functional improvement of the extremities. There was no evidence of primary immunodeficiency diseases including asplenia, phagocyte disorders, hypogammaglobulinemia, immunoglobulin G subclass deficiency, complement deficiency or IRAK4/MyD88 deficiency, and absent mutation of STAT3, PI3KD, and PIK3RI genes. The genetic study of protein C or Factor V Leiden excluded heritable thrombophilia. He lives an active life for walking rehabilitation with no delayed development at 6 years of age. The isolated strain possessed T12 and M12 antigens, and emm12.0 gene, but no mutation of csrS/R or rgg.
Fig. 1

Treatment course of the pediatric patient with Streptococcus pyogenes-sepsis purpura fulminans. FFP fresh frozen plasma, Plt platelet, FDP fibrinogen and fibrin degradation products, CRP C-reactive protein, AT antithrombin, rTM recombinant thrombomodulin, MEPM meropenem, PCG penicillin G, CLDM clindamycin, TEIC teicoplanin

Twelve reported patients with acute infectious PF with S. pyogenes infection including the present case are shown in Table 1. Nine patients developed at age ≤ 10 years, and the remaining three were ≥ 50 years of age. All but one cases presented with septic shock and DIC, but not necrotizing fasciitis. Four immunocompromised patients were over 6 years. Five children age < 8 years had no underlying disease, and survived. The youngest one and two immunocompromised patients died.
Table 1

Reported cases of acute infectious purpura fulminans with Streptococcus pyogenes infection

Patient no

Sex

Age at onset

Underlying disease

Plasma activity of protein C (%)

Complications

Outcomes

Reports

 

Extremities

Neurological

1

M

2 months

No

NR

Shock, DIC

Death

NR

Death

Lloyd and Bolte [14]

2

M

4 months

No

6

Shock, DIC

Alive

All toes and 7 digits lost

No deficits

Dhodapkar et al. [15]

3

F

2.5 years

No

NR

Shock, DIC, ARDS, MOF

Alive

Preserved

Brain death

Daskalaki et al. [16]

4

M

3 years

No

13

Shock, DIC

Alive

Amputation

No deficits

Our case

5

M

5 years

No

60

Shock, DIC

Alive

Preserved

No deficits

Dhodapkar et al. [15]

6

M

7 years

No

NR

Shock, DIC

Alive

Amputation

NR

Davis et al. [17]

7

F

7 years

Chylothorax

NR

Shock, DIC, MOF

Alive

Amputation

NR

Cruz et al. [18]

8

F

8 years

JIA, TNFα-blocker

NR

Shock, DIC, Renal failure

Death

Amputation

Death

Renaud et al. [19]

9

F

10 years

JIA, TNFα-blocker

NR

Shock, DIC, ARDS

Alive

Amputation

NR

Lovell et al. [20]

10

M

50 years

No

Normal

Shock, DIC, Renal failure

Alive

Skin grafting

NR

Gupta [21]

11

F

62 years

Asplenia, NHL

NR

DIC

Death

NR

Death

Ward et al. [22]

12

F

72 years

No

NR

Shock, DIC

Alive

NR

NR

Ashokkumar et al. [23]

DIC disseminated intravascular coagulation, ARDS acute respiratory distress syndrome, MOF multiple organ failure, JIA juvenile idiopathic arthritis, TNF tumor necrosis factor, NHL non-Hodgkin’s lymphoma, NR not recorded

Discussion and conclusions

Streptococcus pyogenes is involved in both “acute infectious (sepsis-associated) PF” and “idiopathic (antibody-mediated) PF”. Neither of TSS or NF typified the present case. M types 1, 3, 12, and 28 are the common isolates associated with shock and multiorgan failure. However, the isolated strain in this case had no high-virulent mutation. The literature review first revealed no patients age 10–50 years, in contrast to the young adult patients with TTS and NF. No previous reports verified the bacteriological property or host predisposition [21]. Shock and coagulopathy was the hallmark of the disease onset, and half of them were previously healthy children. S. pyogenes-acute infectious PF may exemplify a distinct form of invasive GAS infection heralded by septic shock.

The pathogenesis of S. pyogenes -acute infectious PF remains unclear, because of the paucity of cases. Several toxins released from meningococci or pneumococci trigger the thrombotic action and subsequent hypercoagulability [24]. The streptococcal pyrogenic exotoxins (speA, speB and speC) induce cytotoxicity and pyrogenicity, and also enhance the lethal effects of endotoxins on the host [25]. S. pyogenes-derived superantigens cause TSS in healthy adults, but no thrombogenic toxins of GAS have been identified. S. pyogenes are considered to evolve the aggressive form via the horizontal crosstalk among the bacteria, although the precise mechanism has not been clarified [26]. The invasive GAS infection of TSS or NF makes a distinction in the clinical expression of patients. NF is an infection of the fascia and multiple layers of soft tissue from epidermis to muscle that characterized by extensive and rapidly spreading necrosis. Molecular studies [27] suggested that the injured muscle cells promote the adhesion of S. pyogenes that deteriorate local tissue infection. Streptococcal TSS is defined as any streptococcal infection associated with the sudden onset of shock and organ failure. Cytokine storm is crucial for the development of circulatory failure in bloodstream or deep tissue infection. In addition to the excessive T cell activation via superantigens, S. pyogenes exotoxins may induce the production of vasodilator or cardiac depressant leading to shock [28]. We demonstrated the skewed age distribution and the exclusive presentation of shock and coagulopathy at the onset of S. pyogenes-PF. A higher frequency of TSS has been noticed in S. pyogenes-PF than seen in S. pyogenes-NF [29]. The physiological low activity levels of protein C and protein S in infants raise the risk of thrombogenicity in severe infection [30]. It is not to say exaggerated that the rapid aggression of S. pyogenes-PF arises from the vulnerability to impaired circulation and hypercoagulability on toxic or, if any, septic shock (Fig. 2). The GAS virulence in S. pyogenes-PF may involve the ability to produce circulatory collapse-inducing factors rather than the tissue invasiveness of strain.
Fig. 2

A conceptual diagram of invasive group A Streptococcus infection and Streptococcus pyogenes-associated purpura fulminans. GAS, group A Streptococcus; TSS, toxic shock syndrome; PF, purpura fulminans; S. pyogenes, Streptococcus pyogenes

Antibiotic and anticoagulant therapy is the mainstay of acute infectious PF. The treatment goal is the survival free from amputation and neurological deficit. Our patient required repeated debridement of the legs to treat compartment syndrome but not for NF. The histopathologic study showed ischemic necrosis in the subcutaneous tissues and muscles. It may corroborate a pivotal role of the circulatory failure in the pathophysiology of S. pyogenes-PF. The pathogen was repeatedly isolated from the debridement tissues until the start of continuous PCG infusion with CLDM, that is usually used for the treatment of invasive GAS infection [31]. It accounted for the insufficient drug delivery in the ischemic tissues rather than the strain resistance. Our observations recommend the intensive circulatory support on invasive GAS-directed chemotherapy to minimize the chance of amputation in patients with S. pyogenes-PF.

In conclusion, S. pyogenes-acute infectious PF rarely occurred as the most severe form of S. pyogenes-TSS in healthy young children and the elderly. The first treatment of circulatory failure may be crucial for the outcomes of S. pyogenes-PF.

Notes

Authors’ contributions

The contributions of each author are as follows. SOk, MI and SK were the principal investigators, taking primary responsibility for the paper. MS, NK, YM and UO performed the clinical management with helpful discussion regarding the completion of the work. MH and JF completed clinical management with regard to the surgical intervention. MU and HN performed the thrombophilic investigation and the infection control, respectively. HT and SOh organized the case study and had the responsibility for the treatment. All authors read and approved the final manuscript.

Acknowledgements

We thank to all the staff who participated in the treatment of this patient in Kyushu University, Ms. Taeko Hotta and Associate Prof. Takeshi Uchiumi for performing the thrombophilic screening of the patient, Dr. Yoshihiro Ohishi and Prof. Yoshinao Oda for the Pathological diagnosis, Dr. Tadayoshi Ikebe (National Institute of Infectious Diseases) for investigating the molecular characterization of S. pyogenes, and Prof. Osamu Ohara and the staffs in Kazusa DNA Research Institution (Chiba, Japan) for performing the genetic screening of the patient.

Competing interests

The authors declare that they have no competing interests.

Availability of data and materials

Not applicable.

Consent for publication

A written informed consent for publication was obtained from the parents.

Ethics approval and consent to participate

Written informed consent for genetic screening was obtained from the parents. The procedures were approved by the Kyushu University Institutional Review Board for Human Genome/Gene Research (531-01).

Funding

This work was supported by Practical Research Project for Rare/Intractable Diseases (JP17ek0109260, JP18ek0109260) and Grant-in-Aids (S.O. 15545383, 15545623) from the Japan Agency for Medical Research and Development (AMED) and the Research on Measures for Intractable Diseases Project and Health and Labor Sciences Research grants (Research on Intractable Diseases) from the Ministry of Health, Labour and Welfare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Sayaka Okuzono
    • 1
  • Masataka Ishimura
    • 1
  • Shunsuke Kanno
    • 1
  • Motoshi Sonoda
    • 1
  • Noriyuki Kaku
    • 1
  • Yoshitomo Motomura
    • 1
  • Hisanori Nishio
    • 1
  • Utako Oba
    • 1
    • 2
  • Masuo Hanada
    • 3
    • 4
  • Jun-ichi Fukushi
    • 4
  • Michiyo Urata
    • 5
  • Dongchon Kang
    • 5
  • Hidetoshi Takada
    • 1
  • Shouichi Ohga
    • 1
  1. 1.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Division of PediatricsOita Prefectural HospitalOitaJapan
  3. 3.Department of Plastic SurgeryKyushu University HospitalFukuokaJapan
  4. 4.Department of Orthopaedic Surgery, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  5. 5.Department of Clinical Chemistry and Laboratory MedicineKyushu University HospitalFukuokaJapan

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