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Fatal Spontaneous Clostridium septicum Gas Gangrene: A Possible Association With Iatrogenic Gastric Acid Suppression.

Proton pump inhibitors (PPIs) are used for the treatment of heartburn, gastroesophageal reflux disease (GERD), and peptic ulcer disease. The use of PPIs in the general population in the United States has increased dramatically since the approval by the US Food and Drug Administration as an "over the counter" drug in 2003. Although short-term use is generally well tolerated, protracted use of PPIs is associated with increased risk of hip fractures, pneumonia, (1) and Clostridium difficile colitis. (2) The risk for hip fracture has been shown to be related to poor absorption of calcium, (3) while pneumonia and colitis have been linked to proliferation of bacteria and possible selection for pathogenic bacteria as a result of decreased gastric acidity. (4) More recently, there have been reports of an association between gastric polyposis and long-term PPI use, although the mechanism is not completely clear. (5) Here we present a case of a 51-year-old woman with a prior history of GERD, treated with esomeprazole magnesium, who presented to the emergency department with rapidly progressive spontaneous gas gangrene and necrotizing fasciitis caused by Clostridium septicum and died within hours of her presentation to the hospital. This case report and literature review highlights the increasing incidence, high morbidity and mortality, and features suggestive of nontraumatic myonecrosis as a result of C septicum infection and a potential association with long-term PPI use. We suggest a role for PPIs in altering the gastrointestinal milieu, thereby selecting for pathogenic flora.

REPORT OF A CASE

A 51-year-old woman presented to the emergency department with a chief complaint of fever, chills, and severe bilateral leg pain that had awakened her from sleep. Five days before this presentation, she had been experiencing fever, abdominal pain, headache, earache, and a sore throat. She was seen by her primary care provider 1 day before her hospital presentation. A rapid strep test performed by her primary care provider yielded negative results. Her past medical history was significant for GERD, anemia, allergic rhinitis, and osteoarthritis of both knees. She did not have any prior history of Crohn disease, malignancy, neutropenia (cyclic, congenital, or acquired), or recent history of trauma. She had a history of esomeprazole magnesium use for GERD of greater than 3 years and was also taking meloxicam and ibuprofen for her osteoarthritis. Upon arrival at the emergency department, a quarter-sized erythematous and tender lesion was noted on the inner aspect of her right thigh. An initial complete blood count (CBC) demonstrated leukopenia (2.05 x [10.sup.3]/[mm.sup.3]; reference interval, 3.9-11.3 x [10.sup.3]/[mm.sup.3]) and slight thrombocytopenia (108 X [10.sup.3]/[mm.sup.3]; reference interval, 140-440 x [10.sup.3]/[mm.sup.3]). A repeated CBC for blood drawn 6 hours after presentation showed a leukocyte count of 9.75 x [10.sup.3]/[mm.sup.3] with 11% bands and a platelet count of 64 X [10.sup.3]/[mm.sup.3]. Hemoglobin and hematocrit levels, which were initially normal, declined to 4.5 g/dL (reference interval, 11.5-16.0 g/dL) and 13.9% (reference interval, 35%-47%), respectively. Coagulation study results were also abnormal with a prothrombin time of 24.4 seconds (reference interval, 9.8-12.2 seconds), a partial thromboplastin time of 196.3 seconds (reference interval, 23.1-33.9 seconds), and a fibrinogen concentration of 158.4 mg/dL (reference range, 203-397 mg/dL). A third CBC, for blood drawn 8 hours after presentation, showed a leukocyte count of 14.21 x [10.sup.3]/ [mm.sup.3] with 20% bands, 14% metamyelocytes, and 6% myelocytes; hemoglobin concentration of 3.9 g/dL; hematocrit of 12.2%; and platelet count of 58 x [10.sup.3]/[mm.sup.3]. Ultrasonography revealed deep venous thrombosis in the right lower extremity. Within hours, the ecchymotic lesion on her right thigh rapidly grew in size, with increased erythema and necrotic changes in the surrounding tissue (Figure 1, A and B). Clindamycin, vancomycin, cefepime, and meropenem were administered intravenously. Additional ecchymoses developed on the trunk and upper right shoulder, along with crepitus to palpation in the lower abdomen and both thighs. While awaiting transport to a facility with the capacity to treat with hyperbaric oxygen therapy, she developed tachypnea, hypotension, and cardiopulmonary decompensation. She underwent intubation and mechanical ventilation and was given multiple vasopressors. She became increasingly acidemic and anemic, and was taken to the operating room for bilateral thigh fasciotomies, debridement, and wound cultures. Intraoperatively, she sustained a cardiac arrest and died. Intraoperative wound cultures were positive for C septicum 1 day following her death. Postmortem examination was significant for evidence of bilateral lower limb debridement with open surgical incisions extending from the groin to the knees. Focal areas of dusky discoloration in the remaining viable muscle and soft tissue showed histologic evidence of ongoing myonecrosis. Epidermal ecchymosis, crepitus, and serosanguineous fluid-filled bullae were present involving the upper and lower extremities and trunk. On examination of her gastrointestinal tract, multiple well-demarcated, circular mucosal ulcers of varying sizes were found in the terminal ieum and at the ileocecal valve (Figure 2, A). The intervening ileal mucosa appeared normal and there was no evidence of strictures or perforation throughout the bowel. Microscopic sections from the areas of ileal ulceration showed necrosis, a transmural diffuse mononuclear infiltrate with a predominance of B cells, neutrophilic debris at the base of the ulcers, bowel wall gas, myonecrosis, and organizing serosal fat necrosis. There were no granulomas or features of chronic mucosal injury (Figure 2, B and C). Gram-Weigert stains of the intestinal ulcers showed spore-forming Gram-positive bacilli (Figure 2, D), which in conjunction with antemortem microbiologic identification of C septicum from the wound cultures, is morphologically consistent with C septicum. In addition, more than 50 fundic gland polyps were identified in the stomach. An aliquot of blood collected during the postmortem examination was tested for procalcitonin, with the KRYPTOR Compact analyzer chemiluminescent assay (Thermo-Fisher Scientific, Middletown, Virginia). The procalcitonin level was 9.6 ng/mL, indicating bacteremia and sepsis. The Clostridium isolate obtained from this patient's wound was sent to the Centers for Disease Control and Prevention, Antimicrobial Resistance and Characterization Laboratory, Division of Healthcare Quality Promotion, in Atlanta, Georgia, and the identification of the isolate was confirmed by 16S rRNA gene sequencing as C septicum; however, toxin typing was not performed.

COMMENT

The cause of death in this patient was attributed to C septicum sepsis with concurrent ulcerative terminal ileitis, necrotizing fasciitis, and myonecrosis. The elevated procalcitonin level is a biomarker of sepsis. (6) The history of recent abdominal pain, along with the presence of gas formation and large spore-forming Gram-positive bacilli within the ulcers of the terminal ileum, suggests that the gastrointestinal tract was the likely source of the infection. At initial presentation, this patient was leukopenic and her white blood cell count increased markedly (delta 9.75) during a period of 8 hours. The antemortem peripheral smears and postmortem bone marrow biopsy were consistent with leftshifted myeloid maturation likely due to mobilization of bone marrow stores in response to sepsis. Her terminal course (including anemia, thrombocytopenia, and disseminated intravascular coagulation) can be explained by the known effects of toxins elaborated by C septicum.

A variety of bacterial, viral, and parasitic infections have been shown to cause necrotizing fasciitis, including infections due to Group A streptococci, (7) methicillin-resistant Staphylococcus aureus strains producing Panton-Valentine leukocidin, (8) Vibrio vulnificus, Aeromonas hydrophila, (8) influenza A, and Coxsackie B, in addition to trichinellosis and cysticercosis. (9) Necrotizing fasciitis with crepitus is suggestive of gas-producing organisms, specifically clostridial species, anaerobic streptococcal species, and synergistic nonclostridial anaerobic infections. (10) Of the clostridial species, infections caused by Clostridium perfringens require devitalizing injury in order to cause pathology; on the other hand, spontaneous gas gangrene is most often associated with C septicum. (10) Symptoms that should increase suspicion for the diagnosis of C septicum necrotizing fasciitis include severe pain, rapidly progressive soft tissue infection, and crepitus in the absence of devitalizing trauma. (10)

Clostridium septicum is a large, Gram-positive, aerotolerant, gas-producing bacillus with subterminal spores. (11) It is the most common cause of nontraumatic gas gangrene, and classically presents as a primary infection of the perineum, scrotum, or extremity, following bacterial translocation from the gut. (10) The incidence of nontraumatic gas gangrene as a result of C septicum infection has increased in recent years. (10) Patients typically present with confusion followed by an acute course of excruciating pain, rapid tissue destruction characterized by spreading purple skin lesions with the formation of bullae filled with clear to hemorrhagic fluid, and gas formation within the tissues. (10) The prognosis of nontraumatic gas gangrene is extremely poor, with mortality ranging from 67% to 100%; most deaths occur within 24 hours of symptom onset. (10) Although antimicrobial therapy is an important component of therapy, aggressive surgical management is crucial, and thorough surgical debridement is the single best predictor of outcome. (12) Protein synthesis inhibitors (clindamycin, tetracycline, erythromycin, chloramphenicol), rifampin, metronidazole, cell wall inhibitors (such as piperacillin and imipenem), and b-lactams in combination with [beta]-lactamase inhibitors, have been shown to be active, although resistance has been described. In particular, clindamycin and tetracycline have been shown to inhibit toxin synthesis, and clindamycin down-modulates production of cytokines involved in shock and organ failure. (10) Use of hyperbaric oxygen therapy is controversial, owing to lack of data from randomized controlled trials and the ability of C septicum to survive aerotolerantly. (10)

The [alpha]-toxin produced by C septicum is the most potent and significant lethal factor with both hemolytic and necrotizing activity. It is responsible for the pathogenesis of gas gangrene and can cause a rapid decline in hemoglobin and hematocrit levels. (10) Clostridium septicum also produces a DNase ([beta]-toxin), a hyaluronidase ([gamma]-toxin), and septicolysin ([delta]-toxin). (10) Septicolysin has similar effects to the [theta]-toxin of C perfringens by promoting platelet/ neutrophil aggregation and impeding neutrophil migration into tissues. (13) It is plausible that the isolate from this patient also produced septicolysin, which may explain the paucity of a brisk neutrophilic response to tissue destruction seen in the postmortem tissues.

Although skin and soft tissue infections are the most common manifestation of C septicum infection, patients may also present with bowel ischemia (typically of the terminal ileum and/or proximal colon), vascular compromise, intraperitoneal infection, central nervous system infection, or infections of the head and neck. (12) A strong association exists between C septicum infection and the presence of a known or occult malignancy. More than half of the C septicum infections are associated with a gastrointestinal malignancy. (12) Other malignancies, including hematologic (leukemias and lymphoproliferative disorders) and various solid tumors (breast, melanoma), have been described in association.

Infection in the absence of malignancy has rarely been reported. (12) However, any compromise of the gastrointestinal mucosa-such as in Crohn disease (in combination with acquired neutropenia) (11) or diverticulitis (13)--may permit bacterial translocation and invasion. Decreased host defenses, specifically neutropenia (cyclic, congenital, or acquired), are associated with an increased incidence of spontaneous gas gangrene due to C septicum; these cases are also commonly associated with the presence of a necrotizing enterocolitis, cecitis, or distal ileitis. (10)

In this patient, multiple ulcers were visible in the terminal ileum and ileocecal junction. Microscopically, the lesions showed neutrophilic debris at the base of the ulcers in addition to a transmural lymphoplasmacytic infiltrate, which is typically seen in cases of C septicum infection. Moreover, the presence of gas-filled cysts and numerous sporeforming rod-shaped Gram-positive bacilli within the ulcers strongly suggest the gastrointestinal tract as the source for widespread dissemination. Interestingly, this patient had a history of long-term treatment with nonsteroidal antiinflammatory drugs (NSAIDs) for osteoarthritis and PPIs, specifically esomeprazole, for GERD.

Proton pump inhibitors are the second most commonly prescribed medications (after statins) and represent a significant health care expenditure. (2) Despite the existence of cost-effective and clinically sound step-down and ondemand treatment options, overprescription of PPIs has been recently described as a significant problem in both inpatient and outpatient settings. (2) Common side effects of PPI therapy include nausea, abdominal pain, and constipation or diarrhea. More serious sequelae include osteoporosis and bone fractures, malabsorption of B12, and impaired metabolism of antiplatelet agents. (2)

The mechanism of action in PPIs is reduction of hydrochloric acid secretion through the inhibition of [H.sup.+]/ K+ adenosine triphosphatase in parietal cells. While gastric acid (pH 1.4) is considered a protective factor against bacterial infections, an increase of the pH above 4.0 has been associated with increased vulnerability to a variety of enteric infections (eg, Vibrio cholerae, C difficile, Listeria, Campylobacter jejuni, Escherichia coli, and Salmonella). (4) Proton pump inhibitors are also known to slow gastric emptying and gastrointestinal motility, as well as decrease viscosity of the gastric mucous (4) -these effects increase transit time for gut bacteria, thereby increasing the likelihood of colonization. Furthermore, PPIs may also increase susceptibility to infection through their immunomodulatory effects. A number of PPIs inhibit chemotaxis of neutrophils in response to bacterial products, phagocytosis of organisms, expression of adhesion molecules, and subsequent cell killing. (4) As a consequence of PPI therapy, there is both increased colonization and decreased killing of bacteria in the gastrointestinal tract, thus predisposing individuals to development of enteric infections.

Importantly, PPI usage may select for unexpected microbial species. Clostridium septicum is usually a rare component of the gastrointestinal flora, found in only 2% of the healthy population. (11) Within the gastrointestinal tract, its distribution favors the cecum and ileocecal junction owing to the poor vascular supply and other environmental factors. (11) It has been demonstrated that production of C septicum [alpha]-toxin increases when pH is controlled at a more alkaline level than would result with free evolution in a batch culture. (14) Additionally, increased gastric pH supports survival of ingested vegetative forms of C difficile (4) that are present in the environment.

Patients with GERD, moreover, have detectable levels of bile salts in the gastric environment, which, together with select amino acids, have been shown to promote germination of spores. (4) Similar mechanisms of bacterial survival and selection may be at play in the case of C septicum infection under conditions of hypochlorhydria. It can be postulated that the increased pH resulting from chronic PPI therapy may increase the virulence and survival of C septicum within the gastrointestinal tract, thereby increasing risk of dissemination and gas gangrene.

Nonsteroidal anti-inflammatory drugs are another widely used class of medications and are commonly used in conjunction with PPIs for the treatment of osteoarthritis. An association between NSAIDs and gastrointestinal injury has been well described, particularly with involvement of the stomach and duodenum. NSAID-induced intestinal injury (eg, NSAID enteropathy) can result in inflammation, bleeding, ulceration, and rarely, perforation. Until recently, NSAID enteropathy was underappreciated owing to subclinical injury and difficulty in direct evaluation of the small intestine. With the advent of video capsule endoscopy and double-balloon enteroscopy, the ability to diagnose small intestinal lesions has improved and NSAID-induced injury has now been shown to occur more frequently in the intestines than in the upper gastrointestinal tract. (15) Recent evidence from animal models suggests that PPIs can exacerbate NSAID-induced intestinal injury and that bacteria residing in the small intestine may play a significant role in the pathogenesis. (15) Specifically, omeprazole treatment in rats resulted in a shift in the types of bacteria within the small bowel, thereby reducing Actinobacteria and increasing intestinal injury. (15)

In summary, this case illustrates a rare case of spontaneous gas gangrene from C septicum infection in a patient who received long-term therapy with PPIs and NSAIDs. In addition, there were multiple necrotic ulcers in the terminal ileum with associated invasion by C septicum that were likely the source of her disseminated infection. We hypothesize that chronic PPI therapy may have both exacerbated NSAID enteropathy by shifting the bacterial flora (eg, reducing Actinobacteria) and promoted survival and germination of Clostridium spores in the gastric environment. Ultimately, this resulted in translocation of the C septicum bacteria into the bloodstream causing systemic infection and spontaneous gas gangrene. Clostridium infections have been described in patients receiving long-term therapy with PPIs, although no association with C septicum has been previously described. While PPIs have a favorable safety profile and have significantly improved the therapy of upper gastrointestinal tract disorders, a number of pathologic conditions involving the gastrointestinal tract and other organ systems have been shown to be associated with long-term use.

We would like to thank Jon R. Christofersen, BS, for his help and expertise with the photography.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

(1.) Canani RB, Cirillo P, Roggero P, et al. Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children. Pediatrics. 2006; 117(5):e817-e820.

(2.) Heidelbaugh JJ, Kim AH, Chang R, Walker PC. Overutilization of protonpump inhibitors: what the clinician needs to know. Therap Adv Gastroenterol. 2012; 5(4):219-232.

(3.) Geller JL, Adams JS. Proton pump inhibitor therapy and hip fracture risk [author reply in JAMA. 2007; 297(13):1429-1430]. JAMA. 2007; 297(13):1429.

(4.) Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. 2011; 34(11-12):1269-1281.

(5.) Freeman HJ. Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis. World J Gastroenterol. 2008; 14(9):1318-1320.

(6.) Riedel S. Procalcitonin and the role of biomarkers in the diagnosis and management of sepsis. Diagn Microbiol Infect Dis. 2012; 73(3):221-227.

(7.) Ramos C, Whyte CM, Harris BH. Nontraumatic compartment syndrome of the extremities in children. J Pediatr Surg. 2006; 41(12):e5-e7.

(8.) Morgan MS. Diagnosis and management of necrotising fasciitis: a multiparametric approach. J Hosp Infect. 2010; 75(4):249-257.

(9.) Parasca I, Damian L, Albu A. Infectious muscle disease. Rom J Intern Med. 2006; 44(2):131-141.

(10.) Stevens DL, Aldape MJ, Bryant AE. Life-threatening clostridial infections. Anaerobe. 2012; 18(2):254-259.

(11.) Kiel N, Ho V, Pascoe A. A case of gas gangrene in an immunosuppressed Crohn's patient. World J Gastroenterol. 2011; 17(33):3856-3858.

(12.) Hermsen JL, Schurr MJ, Kudsk KA, Faucher LD. Phenotyping Clostridium septicum infection: asurgeon's infectious disease. J Surg Res. 2008; 148(1):67-76.

(13.) Bryant AE, Stevens DL. Clostridial myonecrosis: new insights in pathogenesis and management. Curr Infect Dis Rep. 2010; 12(5):383-391.

(14.) Cortinas TI, Mattar MA, Stefanini de Guzman AM. Alpha-toxin production by Clostridium septicum at different culture conditions. Anaerobe. 1997; 3(2-3): 199-202.

(15.) Wallace JL. Mechanisms, prevention and clinical implications of nonsteroidal anti-inflammatory drug-enteropathy. World J Gastroenterol. 2013; 19(12): 1861-1876.

Accepted for publication June 1 8, 2013.

From Johns Hopkins School of Medicine, Baltimore, Maryland (Ms Wu); and the Department of Pathology (Drs Baras, Cornish, Riedel, and Burton), Johns Hopkins Medicine, Baltimore, Maryland.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Elizabeth C. Burton, MD, Department of Pathology, Johns Hopkins Medicine, The Johns Hopkins Hospital, Pathology Building, Room B106, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: eburton3@jhmi.edu).

Caption: Figure 1. A and B, Knee/thigh lesion with expansion and central areas of necrosis over the course of hours.

Caption: Figure 2. A, Terminal ileum with multiple, irregularly distributed, circular, well-circumscribed ulcers of varying sizes. B, Terminal ileum with sharp demarcation between necrosis and viable intestine at ulcer site. There is necrosis that extends from the mucosa to the muscularis propria. Gas-filled cysts can be seen in the bowel wall also involving the muscularis propria. C, Terminal ileum with mixed, predominantly chronic inflammatory infiltrate and gas formation within the bowel wall. D, Terminal ileum with spore-forming Gram-positive bacilli (arrows indicate subterminal spores) morphologically consistent with Clostridium species (hematoxylin-eosin, original magnifications X20 [B and C]; Gram-Weigert, original magnification X100 oil immersion [D]).
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Author:Wu, Yiru E.; Baras, Alexander; Cornish, Toby; Riedel, Stefan; Burton, Elizabeth C.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2014
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