1 Review

2 Title
3 Firstname Lastname 1, Firstname Lastname 2 and Firstname Lastname 2,*
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7 corresponding authors, add author initials) +xx-xxxx-xxx-xxxx (F.L.)

8 Received: date; Accepted: date; Published: date

9 Abstract: Clostridium sordellii is recently known to produce severe infections in human population,
10 especially in patients during postoperative period, durg users or trauma patiens. The sordellii
11 clostridial stain often causes death through systemic life-threatening manifestation as toxic shock,
12 leukemoid reaction (LR), diffuse capillary leak, refractory hypotension and tachycardia, all those in
13 a non-febrile context. The subject of interest in the present review is the Clostridium sordellii
14 infection in obstetrical and gynecological patients, these representing the majority of the cases.
15 Clostridial infection has a quite short latent period, after which the symptoms reveal a critical
16 clinical picture that leads rapidly towards exitus. Studies have reported cases of infection after
17 gynecological maneuvers such as medical abortion, hysteroscopies, obstetrical practice, surgery
18 and other traumas, that created a gate into the human organism for the clostridial stain to enter and
19 by the enymes and toxins produced, to multiply and damage the tisues. For the invasive character
20 are cited exotoxins: lethal and oedema-inducing toxin (LT) and hemorrhagic toxin (HT). Along
21 with these biochemical features are debated enzymes and bacterial proteins that aggressively
22 affects the human organism and its homeostasis heading to a poor outcome.

23 Keywords: Clostridium sordellii, lethal-toxin, toxic shock, female genital tract

24 Key Contribution: We present this review of the literature as the Clostridium sordellii infection and
25 its complication aren’t often found in clinical practice, being hard to recognize. Regarding the
26 severity and the poor prognosis, early diagnosis is mandatory for the patients’ survival.
27

28 1. Introduction
29 The sordellii stain (previousely named Clostridium welchii) is part of the Clostridium family that
30 represents anaerobe, Gram-positive, spore-forming bacterias that are ubiquitous in the environment.
31 [1] This type of clostridia is frequently found in soil and animal guts, and in human organism is
32 considered to be a saprophyte, colonizing the gastrointestinal tract, female genital tract [2] and less
33 frequent on skin, due to the anaerobe characteristic [3]. Soredellii, similar to other members of the
34 Clostridium family can cause myonecrosis, organ failure and toxic shock by producing bacterial
35 proteins helping the microorganism to enter, spread and damage the host. Although is considered a
36 rare disease, in the last decades more and more cases are presented, becoming a point of interest in
37 postoperative status care, traumatic injury or intravenous drug abuse . The disease occurs in young
38 healty individuals, within couple of days and breaks out into a severe symptomatology, rapidly
39 evolving and often lethal, despite supportive treatments. The clinical aspects are quite intriguing, the
40 infection launching with a prodrome of influenza-like symptoms, normal body temperature and no
41 purulent discharge and refractory hypotension [4]. In spite Gram-positive characteristic, the septic
42 shock induced by Clostridium sordellii is presented similar to one produced by Gram-negative
43 microorganism [5]. The amount of proinflammatory cytokines makes the inflammatory response

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44 inadequate and leads to respiratory distress, multiple organ failure and toxico-septic shock [6,7]. The
45 cytokines make the capillary endothelium more permeable for the macrophages, neutrophils and
46 other immune cells to invade the infected tissues. C.sordelli produces toxins responsible for the
47 lifethreatening injuries, the most important two are lethal toxin (TcsL) and hemorrhagic toxin
48 (TcsH), both part of the group of Large Clostridial Cytotoxins (LCC), that also include the
49 Clostridium difficile toxins A and B (TcdA and TcdB) [8,9,10]. The bacterial aggression is secondary to
50 the release of certain types of enzymes, that disrupt the cells’ membranes, spreading the infection
51 and cousing necrosis of the tissues. The enzymes don’t need proteolytic activation and are not
52 degraded by proteolytic enzymes from the host’s body, a special feature that enhances the
53 aggressivity of this bacteria. The pathogenic effect of these toxins depends on the toxin cell receptors
54 and by them sets a target to a specific tissue, for example, the large family of cytotoxins is divided
55 into neurotoxins that affects the neurons and other nervous structures, enterotoxins for the
56 gastrointestinal cells or leukotoxins that destroys the leukocytes [11].
57 The major health problem associated with the Clostridium sordellii infecton is the postpartum
58 and postabortum disease. Young healthy women are affected after undergoing gynecological and
59 obstetrical procedures, from the non-surgical ones like Misoprostol induced abortion [12,13] to
60 surgical ones like cessarian sections and vaginal delivery. The mechanism of the infection seems to
61 be the passage of the microorganisms through the open cervical canal that permits the bacteria to go
62 from the vagina to the uterus causing endometritis [14].
63 The onset of the clinical features occurs short after the infection as the toxins and enzymes
64 rapidly distroy the cells and tissues, in anaerobe circumstances, affecting the endothelial cell
65 permeability resulting in capillary leakage forming local oedemas, pleural and pericardial effusion
66 with abacterial fluid, anuria, tachycardia and substitute and vasopressor refractory hypotension,
67 leukemoid reaction with important left shift leukocytosis (majority neutrophils, promielocytes and
68 mielocytes), but interestingly associated with normal body temperature and the absence of purulent
69 discharge.
70 Because of the small frequency of the C.sordellii infection, for the moment are not available
71 specific and rapid tests, so the diagnosis is unfortunately delayed contributing to the fatal outcome
72 form the lack of the specific treatment. Otherwise, diagnosed on time, the infection requires surgical
73 treatment based on debridment of the dead tissue, combined with broad-spectrum antibiotics
74 similar to other clostridial stains and targeting the entire polymicrobic flora, hyperbar-oxigen
75 therapy specific for anaerobic bacterias, high-dose penicillin and intensive supportive care from the
76 beginning. A more specific therapy consist in administration of the immunoglobulin, this
77 toxin-neutralizing serum being the key of survival in this patients. Another mean of therapy might
78 be plasma exchange, but not fiable due to the already severe hypotensive state of the infected
79 individuals [15].
80
81 2. Physiopathology of Clostridium sordellii
82 For the first time, the sordellii stain was isolated from the acute edematous wound infection [16].
83 Beside LT and HT toxins, there been found another toxin, neuraminidase (NanS) responsible for
84 modification of the molecular adhesion of the cell in vascular endothelium and cell proliferation
85 leading to leukemoid reaction [2]. The activity of the NanS is objectified by the biochemical
86 modification, especially the production of hydrogen peroxide resulting from the degradation of the
87 desialylated galactose substrates by the galactose oxidase. Another aspect of the NanS activity is the
88 induced modification of vascular cell adhesion molecule (VCAM-1) and by that overrule the bone
89 marrow cell sequestration. By this mechanism, the premature cells are released into circulation,
90 developing the previous mentioned leukemoid reaction[17]. In the Aldape et al. study, a culture
91 made of C.sordellii and HL-60 cell was monitored 5 days and the results showed an increase of the
92 cell count due to sordellii toxin release. This reaction was similar to the cell response to GM-CSF. The
93 NanS along with phospholipase C have been proven to act like proliferative factors with a protein
94 structure of prokaryotic origin. Another mechanism of the mononuclear cell proliferation might be a
95 factor that stimulates the production of GM-CSF. Neuraminidase production facilitates the spread of
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96 the bacteria within epithelial cells by hydrolyzing the glycoproteins and glycolipids, removind the
97 therminal sialic acid from them[18,19]. By altering the sialic acids, neuraminidase affects the cell to
98 cell interaction and even masks cell surface receptors [20]. The production of the NanS begins right
99 away and can be found couple of hours after the infection. The glycoproteins altered that produces
100 the leukemoid reaction are P- and L- selectins, ligands responsible for the leukocyte migration and
101 adherence [21]. Through this molecular changes, the leukocytes can’t migrate and the diapedesis is
102 blocked, so the immune cells remain in the blood stream, not being able to pass the vascular
103 endothelium. On the other hand, changes in the VCAM-1 molecule from the bone marrow force the
104 immature leukocytes to enter in circulation, leveling up even more the white cell blood count [17].
105 The leukemoid reaction is not a specific manifestation of the sordellii stain, being observed in other
106 sialidase-producing clostridial stains such as C.difficile and C.novyi [18,19](Table 1) and other
107 bacterias like Salmonella typhimurium, Shigella dysenteriae and Mycobacterium tuberculosis [22, 23, 24].

108 Table 1. Toxins produced by clostridial stains

Clostridium sordellii Clostridium difficile Clostridium novyi

Collagenase Binary toxin γ-Phospholipase C (Type A toxin)

DNAse Collagenase Hemolysin (Type A toxin)

Hemolysin Hyaluronidase Tropomyosinase (Type B and D toxin)

Hemorrhagic toxin Toxin A β-Phospholipase C (Type B and D toxin)

Hyaluronidase Toxin B Lipase (Type D toxin)

Lethal toxin

Neuraminidase

Phospholipase C

109 3. Review of the literature regarding Clostridium sordellii infection in Obstetrics and Gynecology

110 3.1. Clostridium soredellii infection post medicamentous abortion

111 Medical abortion is a wide used procedure to terminate the first and second trimester pregnancies
112 and it is preffered by the patiens because of its’ noninvasive and nontraumatic characteristic. A
113 serious health problem risen by the medical induced abortion (MIA) is the postabortion infection
114 [25]Fischer et al. describes in 2005 four deaths in context of Clostridium sordellii infection after MIA,
115 all four receiving an antiprogestogen like Mifepristone followed by a prostaglandin analog –
116 Misoprostol.

117 Although the guideline of Royal College of Obstetricians and Gynecologists and other specific
118 association refer to MIA in Mifepristone-Misoprostol combination as being safe at any gestational
119 age, as the years pass by, studies show new cases of lethal Clostridium sordellii infection after this
120 procedure.

121 Mifepristone is both a glucocorticoid and progesterone blocker (Figure 1), used in MIA due to its
122 action of causing decidual ischemia resultin in death of the embryo [26]. Mifepristone mechanism
123 include blockage of the progesterone receptors in the decidua as well in the cells of cervical canal
124 undergoing cervical dilatation and elimination of the protective cervical mucus. By prior mentioned
125 actions, Mifepristone opens the gate for the combined aerobic and anaerobc vaginal flora and
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126 allowind to spread into the uterus, causing infection and necrosis. The anti-glucocorticoid
127 proprieties of Mifepristone disrupt the innate immune system, preventing it from clearing the
128 bacteria.

129 The study conducted by Meich in 2005 [26] proposes two theories by which Mifepristone can
130 facilitate the spread of Clostridium sordellii in utero, leading to lethal toxic shock. The first theory
131 implies that the anti-glucocorticoid effect of Mifepristone is responsible for the irreversible toxic
132 shock. In addition, Mifepristone is proved to alter the hypothalamic-pituitary-adrenal axis (HPA),
133 by dischargind load of cortisol in circulation [27]. Massive release of cortisol into the bloodstream
134 induce subsequently high levels of IL-10. This interleukine inhibits the production of early phase
135 proinflammatory cytokines, which in normal circumstances would activate the inflammation,
136 preventing the bacteria to spread [28,29,30,31]. This theory sustains that Mifepristone-induced septic
137 shock is based on the high levels of IL-10, inducing inflammatory reaction and allowing Clostridium
138 sordellii to grow. The second theory sustains quite the opposite: by suppressing the synthesis and
139 release of IL-10, as the result of glucocorticoid receptors lockade in macrophages, neutrophils and
140 monocytes, the inflammatory process increase incontrollable. As the proinflammatory cytokine
141 production increase, they are absorbed into the bloodstream and become an additional factor of the
142 irresponsive septic shock. The mass production of IL-1, IL-6 and TNFα caouse critical drop of blood
143 pressure by inducing systemic vasodilatation.

144
145 Figure 1. The action and the biochemical changes induced by Mifepristone in medical induced
146 abortions

147

148

149

150

151
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152 Table 2. Reported cases of Clostridium sordellii after MIA with specific regimen

Reference Year Regimen Gestational

age in weeks
Regimen: Mifepristone (MP) and vaginal misoprostol (MS)
[32] 2000 600 mg MP; 400 μg MS 7

[33] 2000 200 mg MP; 400 μg MS, up to 5 doses 14-20

[34] 2000 200 mg MP; 800 μg MS 8

[35] 2000 200 mg MP; 800 μg MS 9

[36] 2001 200 mg MP; 800 μg MS 9

[37] 2001 600 mg MP; 800 μg MS 9

[38] 2001 200 mg MP; 800 μg MS 9

[39] 2001 600 mg MP; 400 μg MS 8

Population Council study—Canadagg 2001 200 mg MP; 800 μg MS 8

[40] 2001 200 mg MP; 800 μg MS 9

[41] 2002 200 mg MP; 800 μg MS 9

[42] 2002 200 mg MP; 800 μg MS 9

[43] 2002 200 mg MP; 400 μg MS 9

[44] 2002 200 mg MP; 800 μg MS 9

[45] 2003 200 mg MP; 800 μg MS 9

[46] 2003 200 mg MP; 800 μg MS 7-13

Regimen: Mifepristone (MP) and oral misoprostol (MS)

[32] 2000 600 mg MP; 400 μg MS 7

[47] 2000 200 mg MP; 600 μg MS 4

[33] 2000 200 mg MP; 400 μg MS, up to 5 doses 5

[48] 2000 200 or 600 mg MP; 400 μg MS 5

[49] 2001 200 mg MP; 400 μg MS 8

Population Council study—Canadagg 2001 200 mg MP; 400 μg MS 319 8

Population Council study—Canadagg 2001 200 mg MP; 600 μg MS 8

[40] 2001 200 mg MP; 400 μg MS, 2 doses 9

[50] 2002 600 mg MP; 400 μg MS 9

Population Council study—USgg 2002 200 mg MP; 400 μg MS 7

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[42] 2002 200 mg MP; 400 μg MS, 800 μg MS 9

[44] 2002 200 mg MP; 800 μg MS 9

[43] 2002 200 mg MP; 800 μg MS 9

Regimen: vaginal misoprostol (MS) only

[51] 2000 800 μg MS 6

[52] 2001 1000 μg MS, up to 3 doses 7

[53] 2001 800 μg MS, up to 3 doses 8

[54] 2002 800 μg MS, up to 3 doses 8

153

154 The suspected link between MIA and Clostridium sordellii is the use of prostaglandin analogs, which
155 disruptsthe local immune balance when used intravaginal, allowing the saprophyte flora to grow
156 and climb into the uterus through the open cervix. The first mechanism in Clostridium sordellii
157 infection after MIA is the opening of the cervix due to local application of Misoprostol. Although not
158 intensive investigated, vaginal carriage of Clostridium sordellii has been reported in healthy women.

159 Setting Misoprostol use – Clostridium sordellii infection link as a start point, Aronoff et al. [55] studied
160 on animal model, the molecular changes in the immune system. The results concluded that
161 intravaginal use of prostaglandin analogs enhances the aggresivity of Clostridium sordellii genital
162 infection, rat model revealing an 80% rate of deaths within 4 days since the inoculum.

163 Misoprostol was found to interfere with bacterial clearance by reducing it, Aronoff’s study showing
164 the rise of bacterial load as well as the reduced production of TNFα in response of infection.
165 Clostridium sordellii by its LT, is known to create a distortion in intracellular communication. This
166 effect is combined with the suppression of proinflammatory cytokine production induced by
167 Misoprostol. Macrophages seem to be the target of the Misoprostol action, inhibiting the
168 phagocytosis and the cytokine production. Clostridium sordellii stain is proved to produce
169 hemocontcentration and a leukemoid reaction [56].In addition to that, the local application of
170 prostaglandin analogs ahows in infectes rats, a rise in circulating leukocyte count and secondary the
171 hematocrit level. By inhibiting the local production of TNFα, Misoprostol impare the uterine
172 macrophage function and allows the spreading of infection.

173 Another literature review found the frequency of Clostridium sordellii infection after MIA was less tha
174 1% (0.92%, N=46,421), categorized in endometritis (49%, 210/429) and undefined genital tract
175 infection (37%, 159,429) [2].

176 Fischer et al. describes in 2005 the characteristics of female infected with Clostridium sordellii and also
177 report previous cases. All four cases were young, previously healthy women in the age range 18-34,
178 all undergoing MIA, with fatal outcome after a rapid onset of the clinical picture (tachycardia,
179 hypotension, vomiting/diarrhea, abdominal pain, 3 out of 4 with peritoneal or pleural effusion and
180 only one with mild fever – 38o C). Paraclinical findings showed in all cases the evidence of
181 polymicrobial infection interesting the uterus, revealing acute inflammation and necrosis.

182 Aronoff et al. concluded in a study on animal model that the administration of topic Misoprostol has
183 dose-dependent effect regarding the infection with Clostridium sordellii, also rising the 7-day
184 mortality at a dose of 300 μg /kg. The human infection is presented with leukocytosis or leukemoid
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185 reaction and hemoconcentation [58] and the additive effect of Misoprostol suggest an increased
186 capillary leak which lead to a more dangerous infection.

187 According to all these findings, Mifepristone and Misoprostol used in MIA, increase the
188 susceptibility to developing sepsis in Clostridium sordellii infection context [2].

189 3.2. Clostridium soredellii infection post spontaneous abortion

190 Early pregnancy loss occurs before 20 weeks of gestation, the main causes being genetic
191 abnormalities or teratogenic factors, infection being an independent risk factor for miscarriage. The
192 onset is usually associated with heavy vaginal bleeding, with or without pelvic pain or passage of
193 tissue.

194 Cohen et al. [60] presented a case of spontaneous abortion complicated by Clostridium sordellii
195 infection. The patient was a young woman with a 18 weeks of pregnancy and history of spontaneous
196 abortion, hospitalized for pelvic pain, vaginal discharge and fever (38,4 oC). during hospitalization
197 she had spontaneous abortion without important vaginal bleeding, but right after, she became
198 hypotensive and tachycardiac. The blood culture and the PCR of placenta isolated the sordellii stain ,
199 but fortunately the PCR assays for LT were negative, leading to a favorable prognosis of the patient.
200 In addition, the WBC in the presented case, was not that high, reflected by the favorable outcome, as
201 the leukocytosis is a mortality factor in Clostridium sordellii infection [2].

202 In 2010, Hao [62] stipulated that the Clostridium sordellii production of LT, context of endometritis,
203 leads rapidly to death in secondary to massive pleural effusion [63,64]. Interestingly, the sordellii
204 stains without LT gene [65,66,60] or with deficient LT gene was found in patients who survived the
205 infection. Comparing to the other large toxin produced by sordellii clostridia - HT, was found that LT
206 has a higher mortality impact [68]. The result of the Hao study indicates a need for screening
207 in pregnant women, for Clostridium sordellii vaginal colonization, this population being
208 considered at high risk.

209 3.3. Clostridium soredellii postpartum infection

210 Both pregnancy and postpartum period represent relative immunecompromised statuses, infections
211 occurring more often and with a higher impact.

212 In the literature are presented several cases of Clostridium sordellii infection occurred after vaginal or
213 cesarian delivery. A noted by McGregor et al. [69] in 1989, the infection was presented in the context
214 of vaginal pack retention, endometritis and infected episiotomy. All 3 cases listed were found to
215 aquire the toxin-producing stain of sordellii and led rapidly to exitus. The patients were previously
216 healthy women with no medical record for important medical problems, admitted in the hospital
217 shortly after birth, with generalized weakness, nausea and vomiting. The evolution was infavorable
218 with the onset of refractory hypotension (case no.1 BP could not be obtained, case no.2 – 90/60
219 mmHg, case no.3 – 92/60 mmHg) accompanied with low urine output, tachycardia (case no.1 – 108
220 bpm, case no.2 – 180 bpm, case no.3 – 140 bmp), quick spreading edema, but intriguingly all afebrile
221 and with no purulent vaginal discharge. Laboratory findings were consistent in all three cases with
222 marked leukemoid reaction (case no.1 – WBC: 84.200 mm2, case no.2 – WBC: 66.000 mm2, case no.3 –
223 WBC: 93.600 mm2), elevated hematocrit due to hemoconcentration and leukocytosis (case no1. –
224 HCT: 52,5%, case no.2 – HCT: no data/high, case no.3 – HCT: 57%). Surgical treatment was
225 preformed in attempt to excise the inflammatory and necrotic tissue and and two cases
226 hysterectomy was the first choice. Culture from the biopsy specimen were found to be positive for
227 Clostridium sordellii .
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228 As observed in literature, not all stains of Clostridium sordellii induce the prior mentioned
229 laboratory findings in context of infection [70,71]. The production of exotoxins is proved to be
230 controlled bt plasmid or chromosomal mechanisms [72].

231 In 2016, Chong et al. [73] also outline the mechanism of vaginal colonization with Clostridum sordellii.
232 Both vaginal and rectal colonization can end up in pelvic infection due to the anatomical proximity.
233 The rectal presence of Clostridium sordellii was reported to be more common (3,2%) than vaginal
234 colonization (0,2%). Since 2016 all fatal cases presented in literature were due to LT production of
235 sordellii stain.

236 The Bitti [74] et al. case report study presents a patient with all usual clinical and laboratory findings
237 in the context of sordellii infection right after cesarian section for cervical dystocia at 41 weeks of
238 gestation. In addition, the authors performed microbiological studies and affirmed to be the first
239 study in which Clostridium sordellii was isolated from the patient’s blood during the toxic shock.
240 Experimental studies on mice and rats showed the cytotoxicity of the LT, the action and the outcome
241 of specific antiserum administration. Another obstetrical case was reported by Kruczynski et al. [75]
242 in 2000, describing atypical endometritis after vaginal delivery of twins. The remarkable aspect was
243 the unusual features of endometritis, described without febrile response, vaginal bleeding, discharge
244 or uterine tenderness. In the results and discussion section, Bitti concluded that are several condition
245 in which Clostridum sordellii produces a lethal infection: 1) Sordellii clostridia as a part of vaginal flora
246 (rare); 2) the LT producing stain; 3) the colonization to last long enough in vagina allowing the
247 microorganism to invade the tissues and 4) the local condition to be suitable for bacterial
248 multiplication.

249 Agraval [76] summarized that in peripartum women who develops toxic shock syndrome, without
250 fever and pain, but woth refractory hypotension, edema, ascites and pleural effusion, clostridial
251 infection with sordellii stain should be suspected for rapid and effective treatment.

252 In the obstetric literature, few authors described Clostridium sordellii infection post episiotomy
253 [77,78,79] and infected cesarian section wound [80] in all cases the clinical picture being consistent.

254 As a comment, in several cases studied in the literature, just before respiratory failure and cardiac
255 arrest that caused death, the pacients developed seizure activity, the mechanism not being
256 intensively investigated [81,82].

257 3.4. Clostridium soredellii infection post gynecological interventions

258 As previously mentioned, Clostridium sordellii is a vaginal saprophyte in a small number of

259 healthy women. But in case of suppressed or weak immunity, the microorganism becomes hifhly
260 pathogen, as shown that bacteremia occurs in, biliary tract disorders, gastrointestinal bleeding – as
261 the bacteria might be a part of gastrointestinal flora, and the small bleeding lessions become gates for
262 the clostridia to enter the bloodstream [83], oncologic patiens under chemotherapy and alcoholism
263 [84].

264 The majority of the reported cases with Clostridium sordellii infection were patients who
265 previously underwent invasive procedures or had different types of open lesions, but in 1989,
266 Hogan and Ireland [85] reported a unique case of spontaneous Clostridum sordellii infection in a
267 healthy woman with no recent history of surgery, chronic treatment, immunosupresive status or
268 traumas. The patient was admitted afebrile, for nausea, vomiting and diarrhea, with slight low blood
269 pressure (BP: 94/60 mmHg). Considering the negative evolution of her simptoms and paraclinical
270 data, was decided to perform an exploratory laparoscopy for final diagnosis. Due to the
271 intraabdominal findings (erythematous and dilated fallopian tubes, blue colored and slightly
272 enlarged uterus), a total hysterectomy with bilateral anexectomy it was elected to proceed. During
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273 the procedure, her hypotension was difficult to manage, and short after, in less than 24h from the
274 hospital admission, the pacient died from acute pulmonary edema. The cultures from the
275 endometrium were positive for Clostridium sordellii.

276 Clostridium sordelii toxic shock (CSTS) was found to lead to fatal outcome also in cases of
277 gynecological procedures being reported after endometrial ablation for heavy uterine bleeding in a
278 pre-climax patient [86], cervical cone, cervical laser [87] or hysterectomy [88]. Being a relatively rare
279 disease, not much is known about yet and with few indication regarding the prompt life-saving
280 treatment, gynecologist and obsteticians shoulf pay more attention and suspect Clostridium sordellii
281 infection in cases diagnosed with: septicemia (ICD-10: A419), toxic shock syndrome (ICD-10: A483),
282 puerperal sepsis (ICD-10: O85), other diseases and contitions complicating pregnancy, childbirth
283 and the puerperium (ICD-10: O998), therapeutic abortion complicated by genital tract and pelvic
284 infection (ICD-10: O045), acute inflammatory disease of uterus (ICD-10: N710), pelvic inflammatory
285 disease – PID (ICD-10: N739), inflammatory disease on cervix uteri (ICD-10: N72), other maternal
286 infection (ICD-1-: O988), other complication after therapeutic abortion (ICD-10: O068).

287 After laboratory tests, Clostridium sordellii is kown to be sensitive to some broad spectrum
288 antibiotics like tetracyclin, chloramphenicol, carbenicillin, penicillin and clindamycin, but at the
289 same time it is not available a guide for treatment [89] and the antitoxin serum it is not widely
290 accessible. The literature presents though a case of pleuropulmonary infection with Clostridium
291 sordellii treated successfully with penicillin and chest tube drainage [90].

292 4. Discussion

293 In the present review we combined the results of several papers, all regarding Clostridium
294 sordellii infection in obstetrics and gynecology. Because little is known yet about the topic, we
295 considered the need to draw attention to this pathology, even if it is a rare condition, but also lethal
296 in almost all the cases. Gathering the information, can be concluded that the clinical picture, even it
297 not specific, follows the same pattern in all cases, healty women can carry the stain which can lead to
298 infection in previously mentioned conditions, the evolution towards exitus is very rapid, in matter of
299 hours, the early recognition and testing should be performed from the start.

300 In conclusion, this review of literature aim to familiarize the practitioners with Clostridium
301 sordellii infection for better diagnosis and management.
302 Author Contributions: For research articles with several authors, a short paragraph specifying their individual
303 contributions must be provided. The following statements should be used “conceptualization, X.X. and Y.Y.;
304 methodology, X.X.; software, X.X.; validation, X.X., Y.Y. and Z.Z.; formal analysis, X.X.; investigation, X.X.;
305 resources, X.X.; data curation, X.X.; writing—original draft preparation, X.X.; writing—review and editing, X.X.;
306 visualization, X.X.; supervision, X.X.; project administration, X.X.; funding acquisition, Y.Y.”, please turn to the
307 CRediT taxonomy for the term explanation. Authorship must be limited to those who have contributed
308 substantially to the work reported.

309 Conflicts of Interest: The authors declare no conflict of interest.

310 Abbreviation

311 The following abbreviation are used in the manuscript:

BP Blood pressure
CSTS Clostridium sordelli toxic shock
GM-CSF granulocyte-macrophage colony–stimulating factor
HCT Hematocrit
HL-60 Human leukemia cell line
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HPA Hypotalamus-pituitary-adrenal
HT Hemorrhagic toxin
ICD-10 International Statistical Classification of Diseases and Related Health Problems
LT Lethal toxin
MIA Medical induced abortion
MOF Multiple organ failure
NanS Neuraminidase S
PCR Polymerase chain reaction
PID Pelvic inflammatory disease
TcdA Clostridium difficile toxin A
TcdB Clostridium difficile toxin B
TcsH Clostridium sordelli hemorrhagic toxin
TcsL Clostridium sordelli lethal toxin
TNFα Tumor necrosis factor α
VCAM-1 Vascular cell adhesion protein 1
WBC White blood cells

312 References

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314 [PMC]
315 2. Aldape, M.J; Bryant A.E; Stevens D.L. Clostridium sordellii infection: epidemiology, clinical findings,
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317 3. Browdie, D.A.; Davis J.H., Koplewitz, M.J.; Cordary L.; Leadbetter, A.W,. Clostridium sordellii
318 infection . J Trauma 1975; 15:5 15-9. [PubMed]
319 4. Bitti, A.; Mastrantonio, P.; Spigaglia, P.; Urru, G.; Spano, A.I.; Moretti, G.; Cherchi, G.B., A fatal
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