Advance Publication by J-STAGE
Japanese Journal of Infectious Diseases
Spontaneous non-traumatic Clostridium perfringens sepsis

Toru Hifumi

Received: September 10, 2019. Accepted: December 4, 2019
Published online: December 25, 2019
DOI:10.7883/yoken.JJID.2019.382

Advance Publication articles have been accepted by JJID but have not been copyedited
or formatted for publication.

Title page
Spontaneous non-traumatic Clostridium perfringens sepsis
Toru HifumitDepartment of Emergency and Critical Care Medicine, St. Luke’s International Hospital,cr

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9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japanus＊Corresponding author: Toru Hifumi

Department of Emergency and Critical Care Medicine, St. Luke’s International Hospital,an

9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, JapanM

Tel: +81-3-3541-5151; Fax: +81-3-5550-7066

edE-mail: hifumitoru@gmail.com

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Running title: Spontaneous sepsis due to C. perfringens

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Keywords: sepsis; Clostridium perfringens; intravascular hemolysis; gas gangrene1Title Page_日本語表記
特発性非外傷性 Clostridium perfringens 敗血症
一二三亨

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一二三亨
〒104-8560 東京都中央区明石町９-１
Tel. 03-3541-5151
Fax. 03-5550-7066
E-mail. hifumitoru@gmail.com

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責任著者連絡先

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‡

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聖路加国際病院 救急部

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SUMMARY
Clostridium species are gram-positive, spore-forming, anaerobic rods normally found inipt

the soil and the gastrointestinal tract of humans and animals. Spontaneous sepsis due tocr

C. perfringens is not caused by injury, which sets it apart from classic gas gangrene thatus

typically follows trauma. Spontaneous C. perfringens sepsis often develops as a rapidlyanprogressive intravascular hemolysis and metabolic acidosis, with high mortality rates ofover 70% with standard intensive care. In such cases, alpha-toxin secreted by C.

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perfringens is considered as the main toxin responsible for intravascular hemolysis,eddisseminated intravascular coagulopathy, and multiple organ failure. Theta-toxin causespt

a cytokine cascade which results in peripheral vasodilation similar to that seen in septicceshock. For C. perfringens infections, antibiotics, such as high-dose penicillin, andsurgical drainage as early as possible are the principal treatments of choice. However,Ac

considering the current mortality rate of sepsis, outcomes have not improved with thecurrent standard treatment for C. perfringens infections. Monoclonal antibody against
theta-toxin in combination with gas gangrene antitoxin are promising therapeutic
options.

3

1. Introduction
Clostridium perfringens is a gram-positive, anaerobic bacterium that grows in thegastrointestinal tract of humans and animals and is found soil (1). Spontaneous C.

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perfringens sepsis is not caused by injury, which sets it apart from classic gas gangrenecrthat typically follows trauma. Spontaneous sepsis due to C. perfringens often presents as

usa rapidly progressive intravascular hemolysis and metabolic acidosis, with high mortality

anrates of above 70% with standard intensive care (2-11). In these cases, alpha-toxin
secreted by C. perfringens is considered to be the main toxin, which is responsible forM

intravascular hemolysis, disseminated intravascular coagulopathy (DIC) (12, 13), anded

multiple organ failure. Although the number of reported cases with spontaneous C.

ceestablished.

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perfringens sepsis is increasing (14-27), appropriate treatment strategies have not been

In this review, we aim to clarify the pathophysiology and diagnosis ofAc

spontaneous C. perfringens sepsis and to provide insights regarding treatment strategies
including antitoxin therapy.

2. Pathophysiology
At least 12 toxins are produced by C. perfringens types A, B, C, D, and E, with alpha,4beta, epsilon, and iota as the major toxins (28). Recently, a French group was the first toreport the case of a patient with septic shock due to peritonitis caused by C. perfringens;the case was complicated by massive hemolysis secondary to the secretion of alpha-toxin

ipt

and theta-toxin by the bacterium (29). Alpha-toxin is a phospholipase C lecithinase thatcrdegrades phospholipids in the erythrocyte membrane, leading to subsequent accelerated

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destruction (14, 30). Phospholipase C lecithinase may also cause platelet destruction,anleading to thrombocytopenia. Conversely, theta-toxin is a cholesterol-dependent
cytolysin that forms transmembrane pores; it also inhibits chemotaxis and the organizedM

aggregation of neutrophilic granulocytes (29). Additionally, both alpha-toxin and theta-

contractility

whereastheta-toxin

inducessignificant

peripheralpt

myocardialedtoxin affect the circulatory system. Specifically, alpha-toxin directly inhibits

cevasodilation (31). These toxic effects explain the characteristic fulminant shockobserved in severe C. perfringens infection. The simultaneous presence of both toxins,

Ac

which act synergistically, is necessary for the development of serious C. perfringens
infections (31, 32). Thus, alpha-toxin and theta-toxin are considered as the principal
virulence factors of C. perfringens infection.

3. Diagnosis

5

Hemolysis is the first alarming sign of C. perfringens infection. The presence of a liverabscess with gas formation, accompanied with the signs of hemolysis, such as increased
levels of indirect bilirubin and lactate dehydrogenase, and anemia are typicaliptmanifestations; however, progression to gross hemolysis usually leads to death (Figurecr1) (33, 34). Therefore, rapid diagnosis is essential, and definitive diagnosis before theuspatient progresses to gross hemolysis is crucial. Considering the pathophysiology of C.

anperfringens infection, early detection of alpha-toxin and theta-toxin in the serum might
be the key for diagnosis. Monoclonal antibodies against these toxins, which have alreadyMbeen used in research settings, might be utilized for the development of diagnostic assays.

ed

Clinicians should always suspect C. perfringens sepsis in the absence of overt signs ofpthemolysis in patients with liver abscesses accompanied with gas formation.

ce

In addition to the analysis for the presence of toxins, the diagnosis of DIC is also
important for deciding on whether adjunctive therapy should be initiated. The diagnosis

Acof DIC is based on the criteria established by the Japanese Association for Acute
Medicine (35, 36), with a total score ≥ 4 indicating DIC.

4. General treatment strategies and adjunctive therapies
For the bacterial infection, antibiotics, such as high-dose penicillin, and surgical drainage

6

as early as possible are the two main treatments of choice (30). However, considering thehigh mortality rate of sepsis (37), the currently utilized standard treatments for C.
perfringens infection have not led to better outcomes. To further improve the patientcrtherapeutic strategies with acceptable clinical outcomes.

ipt

outcomes, focusing on specific treatments is a reasonable first step in establishingus

Recombinant human soluble thrombomodulin (rTM) has been shown asaneffective for sepsis-induced DIC in a meta-analysis (38). We previously examined theeffects of rTM on hemolysis, coagulation status, inflammation, and mortality in α-toxin-Mtreated rats (39) and found that rTM improved coagulation response induced by α-toxinedwith a significant difference in FDP level and platelet count in the rTM-treated grouppt

compared with the α-toxin-only group (39). These results suggest rTM as a candidate force

the treatment of C. perfringens-induced DIC because it serves as a negative feedback
regulator of blood coagulation (40).

Ac

Recently, Kubo et al. reported two patients with liver abscesses caused by C.

perfringens who were initiated on intensive plasma exchange and survived (41). The

application of plasma exchange to remove excess toxins produced by C. perfringens isreasonable. In fact, patients with Yamakagashi snake bites survived with aggressive
plasma exchange therapy (42). However, in the real-world clinical settings, especially for7

patients in septic shock, dialysis may cause severe hypotension, which may necessitate
therapy suspension. Thus, alternative therapies should be considered in patients withipt

septic shock due to C. perfringens.

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5. Antitoxin therapyus

The gas gangrene antitoxin, developed against the toxins produced by C. perfringens typean

A, C. septicum, and C. oedematiens, has been used as a treatment option for classic gas
gangrene following trauma. However, this product is no longer available in the United

M

States due to poor efficacy and severe allergic reactions. The gas gangrene antitoxin canedneutralize α-toxin secreted by C. perfringens. Therefore, we have introduced and strongly

pt

recommended the use of the gas gangrene antitoxin as the optimal therapy in C.

ceperfringens sepsis based on the pathophysiological mechanism (34, 43, 44). In a study
investigating the effects of gas gangrene antitoxin on hemolysis, coagulation status,Ac

inflammation, and mortality in α-toxin-treated rats, we demonstrated that the gas
gangrene antitoxin could stop hemolysis via the neutralization of α-toxin (39).
In a clinical setting, Yoshida et al. is the first to report a patient with C. perfringens
sepsis who was treated with the gas gangrene antitoxin (45). However, the efficacy of thegas gangrene antitoxin remains unknown because it was administered after the patient8

developed cardiopulmonary arrest and the patient died eight hours after the gas gangrene
antitoxin administration.
The gas gangrene antitoxin is owned by the government under the name of Kokuyu

ipt

vaccine (34)and stored at nine institutions that are spread across Japan. Therefore, rapid

cradministration of the gas gangrene antitoxin is not practical due to the supply limitations.

us

In the future, the gas gangrene antitoxin stocks at major hospitals such as the university

spontaneous C. perfringens sepsis.

anhospitals and national hospital organizations should be considered to treat patients withM

The clinical use of the monoclonal antibody against theta-toxin, developed and definededfirst by Sato et al. (46), in combination with the gas gangrene antitoxin is a promisingcepttherapeutic approach for spontaneous C. perfringens sepsis.

6. Prevention

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Considering the high mortality rate with the currently used standard therapy, prevention
strategies may be more practical than the development of promising monoclonal
antibodies. As the first step for prevention, vaccination is considered as a principal
component. Four doses of the diphtheria/tetanus/pertussis vaccine are administeredduring infancy, and a vaccine against diphtheria and tetanus is administered at the age of9

11–12 years under the Preventive Vaccination Law enacted in 1968 in Japan; this led tothe disappearance of the diphtheria infection from clinical practice (47, 48). Currently,
there are no licensed vaccines which are suitable for protection against C. perfringens

ipt

sepsis in humans (49). However, vaccines that are currently in development for use in

cranimals can potentially be developed further for use in humans (49, 50). Therefore,usvaccination might be considered as an effective strategy to protect from serious C.

M

7. Future considerations

anperfringens sepsis in humans.

ed

There is no nationwide registration for C. perfringens sepsis in Japan. Therefore, the exact

pt

number of patients with C. perfringens sepsis remains unknown. We recently launched aceresearch group supported by the Research Program on Emerging and Re-emerging
Infectious Disease of the Japan Agency for Medical Research and Development, with theAc

aim to examine spontaneous C. perfringens sepsis in 2019. The creation of a nationwide
registry for C. perfringens sepsis is the first step for the establishment of effective
treatment strategies, and further urgent work will be required.

8. Conclusion

10

In this review, we provided an overview of the pathophysiology and the diagnosis of
spontaneous C. perfringens sepsis and provided the currently utilized treatment strategies
including the gas gangrene antitoxin, which can be administered as early as possible in

cr

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combination with antibiotics to neutralize the toxins.

us

Acknowledgements

anThis research was supported by the Research Program on Emerging and Re-emerging
Infectious Disease from the Japan Agency for Medical Research and Development

AcceNone to declarept

Conflict of Interest

ed

M(AMED).

11

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Figure legends

Figure 1. Clinical manifestations of spontaneous, non-traumatic Clostridium
perfringens sepsis