Fulminant Clostridium Difficile EnteritisCausing Abdominal Compartment Syndrome

Hue Thai,1 Alfredo D. Guerron,1 Kalman P. Bencsath,1 Xiuli Liu,2 and Michele Loor3

Abstract

Introduction: Clostridium difficile infection of the small bowel, or C. difficile enteritis (CDE), is an uncommoncondition. Cases reported previously have been described in patients with inflammatory bowel disease (IBD),compromised immune systems, or a history of colectomy or small bowel surgery.Case Description: We present a case of fulminant CDE causing abdominal compartment syndrome following aroutine outpatient inguinal hernia repair. This patient developed multiple organ failure dysfunction syndromerequiring surgical abdominal decompression and a small bowel resection. This case highlights the challenges inthe diagnosis of CDE, particularly in patients with intact colons and unusual presentations.Discussion: A high index of suspicion is required, as early recognition of CDE is essential in reducingmorbidity and mortality. This case report is followed by a review of the current literature on CDE, with a focuson the complexities inherent in the identification of this problem and the decision-making process for surgicalintervention.

Clostridium difficile is a gram-positive spore-formingorganism that produces clinical signs and symptoms

because of the binding of exotoxins A and B to intestinalmucosa. The toxins enter the cells, causing mucosal cellshedding and a severe inflammatory reaction that leads topseudomembrane formation [1,2]. The incidence of C. diffi-cile carriage in healthy adults in the community is estimatedto be 1%–3% [3]. However, stool carriage in hospitalized in-patients has been found to be as high as 50% (includingasymptomatic carrier status), with active infection resulting inmortality rates as high as 6.9% [4]. Traditionally recognized asan infection of the colon, C. difficile as an infection of the smallintestine, or C. difficile enteritis (CDE), is emerging as a lesscommon but life-threatening condition. A recent review of theliterature identified fifty-six reported cases, with more thanone-half of patients carrying a diagnosis of inflammatory bo-wel disease (IBD), approximately 30% of patients determinedto be immune compromised, and more than 80% of patientshaving altered gastrointestinal anatomy because of prior co-lectomy or small bowel surgery [5]. The overall mortality fromCDE in the pooled studies was approximately 32%, but hasranged in other series from 40–83% [3,6].

Abdominal compartment syndrome (ACS) is a well-de-scribed surgical emergency occurring in a variety of settings,including trauma and intra-abdominal infection, and result-

ing in hypoperfusion of abdominal organs [7,8]. The ACS hasbeen reported in association with C. difficile colitis [9], but toour knowledge, this is the first reported case in the setting ofCDE. It is generally believed that C. difficile does not have apredilection for infection of the small bowel. However, re-ceptors for C. difficile toxin A have been identified in humansmall bowel [1]. Here, we present a case of severe CDE,which occurred in a patient with no previous intestinal sur-gery, and was associated with the development of ACS.

Case report

A 49-year-old male developed fulminant CDE followinga laparoscopic inguinal hernia repair. The patient was anotherwise healthy male, with no prior surgery, who under-went a routine outpatient laparoscopic bilateral inguinalhernia repair and received one dose of perioperative cefa-zolin. He was readmitted four days later with nausea, vo-miting, and a computed tomography (CT) scan consistentwith a small bowel obstruction. He underwent exploratorylaparotomy. The distal ileum was thickened, but no me-chanical obstruction was identified, and the bowel appearedviable. No bowel resection was performed and the abdomenwas closed. He again received one dose of pre-operativecefazolin.

1Department of General Surgery, 2Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.3Department of Surgery, University of Minnesota, Minneapolis, Minnesota.

SURGICAL INFECTIONSVolume X, Number X, 2014ª Mary Ann Liebert, Inc.DOI: 10.1089/sur.2013.026

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Over the next 24 h, he continued to decompensate anddeveloped a severe metabolic acidosis, acute kidney injury,and respiratory failure. He underwent a second-look lapa-rotomy six hours later. Again, no areas of ischemia or ob-struction were found, and his abdomen was closed.Subsequently, the patient had one loose bowel movementwhich was sent for C. difficile antigen enzyme-linked im-munosorbent assay (ELISA) testing and returned positive.He was started on IV metronidazole. However, despite this,the patient deteriorated and developed profound multipleorgan dysfunction syndrome and shock requiring multiplevasopressors.

He was transferred subsequently to a tertiary-care facility.On arrival he was found to have acute kidney injury withanuria, respiratory failure, and progressive lactic acidosis. Onphysical examination, his abdomen was firm and distended,with concurrent elevated peak airway pressures (50 cm H2O).In addition, he demonstrated marked venous congestion ofhis chest wall, upper extremities, and face. Bladder pressuremeasurements between 35–40 mm Hg were obtained, con-firming intraabdominal hypertension. These findings wereconsistent with ACS, and he underwent emergent decom-pressive laparotomy. The operative findings included dilatedsmall bowel with areas of gross ischemia. One hundredeighty centimeters of small bowel were resected and thepatient was left in discontinuity with temporary abdominaldressings in place for planned re-exploration. Of note, thepatient’s colon was completely decompressed, well-per-fused, and without edema. At the time of bowel resection, asample of enteric contents from the distal ileum was sam-pled, and also found to be positive for C. difficile by ELISA.The patient’s vasopressor requirement resolved over thenext 24 h. Enteric vancomycin was administered via naso-gastric tube, in addition to parenteral metronidazole. He wasre-explored and washed out two days later and underwenthand-sewn anastomosis of his small bowel six days later.Because of persistent bowel edema and retraction of hisfascia, his abdominal wall could not be closed initially. Hereturned to the operating room three more times for se-quential closure of his fascia using negative-pressuredressings [10]. Complete fascial closure was achieved byday 12. His renal dysfunction resolved slowly and he wasdischarged 30 d after his bowel resection, tolerating a reg-ular diet.

Pathologic examination

On macroscopic examination, the resected small bowelwas markedly dilated. The serosal surface was duskywith prominent vascularity. The wall of the small bowelranged from 0.1 to 0.2 cm thickness and was edematous(Fig. 1). The mucosa was tan-pink and dusky when examinedin its fresh state. Scattered foci of gelatinous membrane werenoted. No obvious necrosis was identified. Sections throughthe gelatinous membrane showed a layer of luminal mucin,and necrotic debris, and mixed with mononuclear inflamma-tory cells attached to the necrotic mucosa (Fig. 2A&B). Therewas a relative lack of neutrophil inflammation in the pseudo-membrane. Random sections of the remaining small bowelshowed diffuse mucosal damage that was characterized bydilation of lacteals, blunting of villi, separation of surfaceepithelial cells from the lamina propria, and sloughing ofsurface epithelial cells at the tip of villi (Fig. 3A–C). Therewere atrophic glands (regenerative glands), crypt epithelialapoptosis, and mild hyalinization of the lamina propria in theareas affected most severely. In addition, there was submu-cosal hemorrhage and degeneration of muscularis propria (Fig.3D). The overall histopathologic feature was most consistent

FIG. 1. Macroscopic examination of the resected smallbowel shows marked, diffuse edema, and focal pseudo-membrane formation. Color image is available online atwww.liebertpub.com/sur

FIG. 2. Histologic examination of area with pseudomembrane. (A) The pseudomembrane was composed of mucin,necrotic debris, and a minor component of mononuclear inflammatory cells (H&E, 40X). (B) High-power view of pseu-domembrane showing mild hyalinization of lamina propria, coagulative necrosis of mucosa beneath the pseudomembrane(H&E, 200X). Color image is available online at www.liebertpub.com/sur

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with ischemic enteritis. No thromboembolic findings werepresent in the mesenteric vasculature.

Discussion

Clostridium difficile produces two toxins, A and B, whichplay a role in the pathogenesis of disease. Animal studieshave shown toxin A to be an enterotoxin that elicits increasedintestinal permeability, fluid secretion, and inflammation,and causes severe disruption of the intestinal epithelium [11].Studies on human colon biopsy specimens have shown thattoxin A causes epithelial cell rounding, detachment, andapoptosis [2] and forms a characteristic pseudomembraneunder endoscopic or macroscopic examination and hastherefore, been named pseudomembranous colitis histori-cally. In human beings, the colon is the main site of C. dif-ficile infection, but receptors for CD toxins have been isolatedfrom the human small bowel, with substantial variability insmall bowel toxin binding among individuals [1]. Animalstudies have demonstrated C. difficile induced enteritis be-cause of binding of toxin A to receptors in the small bowel[11–13]. In addition, as was demonstrated previously intransplanted human intestinal xenografts [14], C. difficile

toxin B is a potent inflammatory enterotoxin and may con-tribute to intestinal damage in CDE.

In the case of our patient, there was diffuse epithelial injuryinvolving the mucosal surface and the crypt epithelium, withmild hyalinization of the lamina propria. The pseudomem-brane was patchy and there was no neutrophil inflammation.Indeed, these features are also consistent with ischemic injurysecondary to ACS. However, the patient’s rapid developmentof ACS following a routine outpatient procedure is unusualwithout an underlying inciting condition. A positive ELISAfor C. difficile toxin on a sample obtained from the ileum,diffusely edematous small intestine, a normal appearing co-lon at the time of surgery, and the pathologic findings abovesuggest that this patient may have developed sepsis and ACSin the setting of CDE. In contrast to other cases that havethus far been presented in the literature, this is a patient whowas not immunosuppressed and who did not carry a diagnosisof IBD. He received only one dose of perioperative antibi-otics, and, yet, presented with diarrhea and sepsis, and testedpositive subsequently for C. difficile toxin.

Vigilance for CDE, with appropriate testing and prompttreatment, may aid in improving the clinical outcomes ofthese patients. In patients with underlying risk factors, such as

FIG. 3. Histologic examination of random small bowel section. (A) Villous blunting, surface epithelial injury, and dilatedlacteals (100X). (B) Separation of surface epithelial cells from lamina propria (H&E, 100X). (C) Sloughing of surfaceepithelial cells at the tip of villi and atrophic crypts (H&E, 100X). (D) Degeneration of muscularis propria (H&E, 100X).Color image is available online at www.liebertpub.com/sur

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IBD, immunosuppression, or a previous colectomy, appro-priate clinical signs and symptoms should prompt concern forCDE. This diagnosis is more challenging in patients with anintact colon, where the typical features of leukocytosis, di-arrhea, and abdominal pain may suggest C. difficile colitis,but involvement of the small bowel may not be apparent.Increased severity of presentation, including shock, or thepresence of a small bowel obstruction with wall thickeningon imaging may suggest CDE [6,15], but confirmation ofdiagnosis would be challenging. Laboratory testing, either bypolymerase chain reaction (PCR) or ELISA, would confirmthe presence of C. difficile toxin, but would not provide in-formation regarding the extent of gastrointestinal tract in-volvement. In general, treatment would be the sameregardless of the presence or absence of enteritis. An attemptat medical treatment would be made, with surgical inter-vention reserved for patients who develop fulminant disease.However, the presence of enteritis may put patients at higherrisk of requiring surgical intervention, and early recognitionmay lead to earlier surgical intervention, with perhaps im-proved outcomes. In addition, clinicians should be aware ofunusual presentations, such as ACS, which may manifest inpatients with underlying CDE.

Clostridium difficile infection has a broad range of sever-ity, ranging from the asymptomatic carrier state to toxicfulminant colitis requiring emergent surgery. Mortality ratesincrease with the severity of the disease state. Numerousfactors have been identified that may play a role in the degreeof severity, including strain type, host co-morbidity, priorantibiotic use, and use of acid suppressive medication. Al-though some of these factors have been substantiated by re-search, others are still in the process of being investigated. Ithas been proposed that CDE may be more severe than colitis.However, given the difficulty in diagnosis, particularly inpatients with intact GI tracts, this would be difficult to prove.

The case that we have presented here has brought up severalquestions regarding C. difficile infection. Firstly, does an al-teration in gastrointestinal motility contribute to the develop-ment of CDE? Wee et al. described the CT findings in fourpatients with CDE confirmed pathologically [6]. Mesentericstranding, ascites, small bowel distension, and mural thick-ening are prominent features on CT exam. These findings arenot specific, and can also be observed in the setting of bowelischemia. In addition, bowel distension is a hallmark feature ofbowel obstruction or ileus. This leads to a question of whetherslowing or stasis within the GI tract may promote C. difficilecolonization. Patients who have undergone surgery within 30 dare at increased risk for the progression of C. difficile to ful-minant disease [16]. Decreased GI motility that is commonin the post-operative period, particularly in patients usingnarcotics for pain control, may allow for the proliferationof C. difficile and toxin production, leading to clinical wors-ening.

Furthermore, C. difficile infection recurrence is common,with much recent research focused on how to clear the in-fection and restore normal GI flora. In response, several newmedical therapies have emerged, including rifaximin and fi-daxomycin [17], which both show improvements in recur-rence rates. Fecal transplant has also been proposed as noveltherapy in the setting of recurrent C. difficile infection. Is itpossible that the small intestine acts as a reservoir for C.difficile infection? Kralovich et al. published a case report in

1997 of a patient who developed fulminant C. difficile ileitisin a defunctionalized segment of ileum following jejuno-ilealbypass surgery, suggesting that this segment of small bowelwas serving as a reservoir for C. difficile infection [18]. If thesmall intestine does indeed act as a reservoir, perhaps therapyshould be targeted at eradication of C. difficile from the smallintestine, as this might help to prevent recurrences and pro-gression to fulminant disease. Mortality rates following co-lectomy remain high at 33% [19]. On multivariable analysis,this was associated mainly with host factors, such as ad-vanced age and underlying comorbid conditions. However,addressing CDE, if present at the time of laparotomy, mayimprove outcomes and guide medical treatment followingsurgical intervention.

As of yet, no study on the extent of gastrointestinal tractinvolvement in the setting C. difficile infection has been per-formed, and as such, we have no correlation with impact onprogression to fulminant disease or mortality. Although guide-lines exist for the treatment of C. difficile colitis, guidelines forthe treatment of CDE have not been established. In the future,defining the extent of C. difficile infection may aid in tailoringtreatment of this infection, ensuring that all sites along the GItract are clear and that normal flora has been restored. Thismay also help to direct therapy to distinct regions of the GItract, for example using enemas for colonic involvement andoral therapies when the small bowel is involved. In addition, ifindeed the site of involvement is associated with severity,defining the extent of involvement may be useful in deter-mining which patients would benefit from early surgical in-tervention. The case presented in this report is far fromstraightforward. Although CDE was diagnosed clinically, thepathologic specimens were equivocal for infectious versusischemic colitis. We present this case to highlight an unusualand dramatic presentation of what we believe was CDE, aswell as to bring up some interesting questions regarding thecomplexities of C. difficile infection. Future studies on CDEmay further elucidate its clinical importance and guide earlydiagnosis and treatment.

Author Disclosure Statement

No competing financial interests exist.

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Address correspondence to:Dr. Michele Loor

University of MinnesotaMMC 195

420 Delaware St. SEMinneapolis, MN 55455

Email: mmloor@umn.edu

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