Hrev_master [page 14] [Emergency Care Journal 2025; 21:13852] Emergency Care Journal 2025 volume 21:13852 Abstract Clostridium Difficile Infection (CDI) is a prevalent healthcare- associated infection primarily affecting the gastrointestinal tract. However, extraintestinal manifestations, such as abscess forma- tion, are rare and pose significant diagnostic and therapeutic chal- lenges. Furthermore, Clostridium difficile-associated Leukemoid Reactions (LR) are infrequent and often indicative of severe disea- se with poor prognostic implications. This report presents a rare case of an extraintestinal CDI manifesting as an abscess accompa- nied by a leukemoid reaction. A 50-year-old male presented with a fever and gait imbalance. Clinical examination revealed a febrile, hemodynamically unstable patient with an inflamed abscess in the right lumbar region. Laboratory investigations demonstrated mar- ked leukocytosis and thrombocytosis. Despite initial empirical antimicrobial therapy with intravenous piperacillin-tazobactam and clindamycin, the patient exhibited persistent fever and pro- gressive leukocytosis. Surgical drainage of the abscess was perfor- med, and microbiological analysis identified Clostridium difficile. The antimicrobial regimen was modified to include intravenous metronidazole and vancomycin, resulting in clinical improvement and subsequent normalization of leukocyte counts. The patient made a complete recovery and was subsequently discharged. This case underscores the importance of considering atypical presenta- tions of CDI, particularly in the absence of classical gastrointesti- nal symptoms. Early recognition, prompt surgical intervention, and targeted antimicrobial therapy are critical for favorable clinical outcomes. This report highlights the need for heightened clinical awareness regarding atypical presentations of CDI to ensure prompt diagnosis and optimal patient outcomes. Introduction Clostridium difficile infection (CDI) is the most common healthcare-associated infection, capable of causing outbreaks, pos- ing significant treatment challenges, increasing healthcare costs, and contributing substantially to morbidity and mortality among hospitalized patients.1 While intestinal CDI is well documented, Correspondence: Asif Dabeer Jafri, Department of Emergency Medicine and Tele-ICU Service, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. E-mail: Asif_jafri2003@yahoo.co.in Key words: Clostridium difficile infection, abscess, leukemoid reaction. Conflict of interest: the authors declare no conflict of interest. Funding: None. Ethics approval and consent to participate: no ethical committee approval was required for this case report by the Department, because this article does not contain any studies with human partic- ipants or animals. Informed consent was obtained from the patient included in this study. Patient consent for publication: the patient gave his written consent to use his personal data for the publication of this case report and any accompanying images. Availability of data and materials: all data underlying the findings are fully available. Received: 17 April 2025. Accepted: 11 July 2025. Early view: 1 September 2025. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2025 Licensee PAGEPress, Italy Emergency Care Journal 2025; 21:13852 doi:10.4081/ecj.2025.13852 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Clostridium difficile infection presenting as a leukemoid reaction: a case report and mini-review of the literature Asif Dabeer Jafri,1 Muktesh Singh,2 Rehana Ansari,3 Ratender Kumar Singh4 1Department of Emergency Medicine and Tele-ICU Service, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh; 2Department of Anesthesiology and Critical Care, Moti Lal Nehru Medical College, Prayagraj, Uttar Pradesh; 3Department of Anaesthesia and Critical Care, BRD Medical College, Gorakhpur, Uttar Pradesh; 4Department of Emergency Medicine, Telemedicine and Digital Health, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India Highlights - Clinicians should consider CDI even in the absence of classical gastrointestinal symptoms, particularly in patients presenting with abscesses, sepsis, or unexplained leukemoid reactions. - Leukemoid reactions may serve as a surrogate marker of CDI severity and could aid in risk stratification. - Early microbiological identification and source control through surgical drainage play a crucial role in the management of extraintestinal CDI. - CDI spreads via contaminated hospital surfaces and equipment when infection control and cleaning protocols are poorly implemented. - Future studies are needed to establish standardized treatment protocols for extraintestinal CDI, including the role of intravenous versus oral antibiotics. extraintestinal manifestations of CDI are relatively rare.2 Reported cases of extraintestinal CDI have included the involvement of the small intestine, visceral abscess, reactive arthritis, septic arthritis, cellulitis, osteomyelitis, and empyema.3-7 CDI can lead to diarrhea, sepsis, multi-organ failure, and may be fatal in severe cases.8 However, unlike intestinal CDI, for which the Infectious Diseases Society of America (IDSA) has established treatment guidelines, no standardized protocols exist for the management of extraintesti- nal CDI.9 This lack of definitive guidelines poses a clinical chal- lenge in the diagnosis and treatment of such cases. Case Report A 50-year-old male presented with a two-day history of fever without chills or rigors, along with gait imbalance following a fall in the washroom one day prior. His medical history was unremar- kable, except for a prior Cerebrovascular Accident (CVA) from which he had partially recovered. On examination, he was con- scious, oriented, and febrile, with a temperature of 38.2°C. His vital signs included a pulse rate of 110 beats per minute, a respira- tory rate of 22 breaths per minute, blood pressure of 80/60 mmHg, and an oxygen saturation of 94% on room air. On general exami- nation, a 5×5 cm abscess was observed on his right lumbar region, which was warm but notably painless and nontender, as shown in Figure 1. A Non-Contrast Computed Tomography (NCCT) scan of the brain was performed to exclude the possibility of stroke due to the patient’s gait imbalance; however, the results were unremarka- ble. Laboratory investigations at the time of admission revealed a hemoglobin level of 10.5 g/dL, a total leukocyte count of 69,000/mm³, and a platelet count of 640,000/mm³. Liver function tests and coagulation parameters were within normal limits. Renal function was impaired, as evidenced by a serum creatinine level of 2.4 mg/dL and a urea level of 120 mg/dL. Additionally, hyponatre- mia was present, with a serum sodium level of 128 mEq/L. Peripheral blood smear revealed a markedly elevated total leuko- cyte count with a left shift extending up to the promyelocyte stage and the presence of toxic granulations. No blasts were observed, and BCR-ABL testing for Chronic Myeloid Leukemia (CML) was negative. A comprehensive infectious disease workup, including Computed Tomography (CT) imaging of the abdomen and chest, did not reveal any significant abnormalities. Additionally, a two- dimensional echocardiographic assessment was also normal. Blood and urine cultures yielded no growth. Notably, inflammato- ry markers, including serum procalcitonin and C-Reactive Protein (CRP), were elevated. The patient initially received a bolus of intravenous fluids and was started on vasopressor support, along with broad-spectrum intravenous antibiotics, including piperacil- lin-tazobactam and clindamycin, in conjunction with other suppor- tive measures. While the patient’s shock was resolved with the instituted treatment, he remained febrile, and his leukocyte count continued to rise, reaching 85,000/mm³ despite ongoing therapy. The next day, the abscess was surgically drained. Although the patient became afebrile after the procedure, his leukocyte count continued to increase. Culture analysis of the drained abscess revealed the presence of Clostridium difficile. In response, antimi- crobial therapy was escalated to include intravenous metronidazole and vancomycin while piperacillin-tazobactam was continued. After a two-week course of antibiotics, the patient showed gradual clinical improvement and achieved hemodynamic stability. Leukocyte counts normalized, and the acute kidney injury resol- ved. He was successfully discharged from our institution. At the two-week follow-up, his laboratory parameters remained within normal limits, he was hemodynamically stable, and he reported no new complaints. This case is of particular interest due to the rarity of Clostridium difficile-associated abscess leading to a leukemoid reaction. The successful management included a combination of surgical drainage and targeted antibiotic therapy, resulting in clini- cal resolution. This case highlights the importance of considering atypical infectious sources in patients presenting with persistent leukocytosis despite broad-spectrum antibiotics. Discussion Clostridium difficile is primarily recognized for its role in anti- biotic-associated diarrhea and pseudomembranous colitis; howe- ver, its potential to cause extraintestinal infections remains uncom- mon. The incidence and severity of CDI have increased in recent years. The occurrence of a leukemoid reaction in conjunction with CDI is uncommon and signifies a serious condition with a poor prognosis.10 One of the rarest presentations is C. difficile-associa- ted leukemoid reaction, which refers to an extreme elevation in White Blood Cell (WBC) count, often exceeding 50,000 cells/mm³, in response to infection. Leukemoid reactions have been widely reported in severe infections, malignancies, and stress responses. Leukocytosis in CDI is thought to be driven by severe systemic inflammation, cytokine release, and toxin production. Studies suggest that extreme WBC elevations may correlate with disease severity, potentially serving as a prognostic marker for adverse outcomes, including septic shock, multi-organ dysfun- ction, and mortality.11,12 The most significant risk factor for developing CDI is the use of broad-spectrum antibiotics such as penicillins, cephalosporins, fluoroquinolones, and clindamycin which disrupt the normal gut microbiota, leading to dysbiosis and allowing C. difficile to proli- ferate and cause infection.13,14 Other risk factors include proton pump inhibitor use, advanced age, immunosuppression, under- lying comorbidities, previous CDI, renal or hepatic failure, recent hospitalization, and prolonged hospital stays.15,16 Mini Review Figure 1. Abscess in the right lumbar region. [Emergency Care Journal 2025; 21:13852] [page 15] Although C. difficile is predominantly linked to gastrointesti- nal pathology, extra-intestinal manifestations, including abscess formation due to CDI, are exceedingly rare, with only a few cases documented in the literature.17 The mechanism behind extraintesti- nal dissemination remains unclear but may involve hematogenous spread, direct inoculation, or translocation from the gastrointesti- nal tract. In this case, the lack of gastrointestinal symptoms (such as diarrhea or colitis) initially obscured the diagnosis, emphasizing the importance of considering CDI in patients with soft tissue infections and systemic inflammatory responses. The identification of C. difficile in the abscess culture was unexpected, reinforcing the need for broad-spectrum microbiological testing in cases of persistent sepsis with unusual presentations. Reports in the literature describe cases of C. difficile bactere- mia without associated diarrhea, highlighting its ability to dissemi- nate systemically.18 Furthermore, a documented case of C. difficile spinal epidural abscess illustrates its capacity to infect soft tissues, albeit infrequently.19 The study by Albrich and Rimland found that among 162 CDI patients, 22% had thrombocytosis, and 60% had leukocytosis. C. difficile toxin A was more common in thrombocy- tosis with leukocytosis, suggesting these markers may help diagno- se infections.20 Unlike intestinal CDI, for which treatment guidelines are well established, there are no standardized protocols for extraintestinal CDI. Current guidelines for treating intestinal CDI recommend oral vancomycin or fidaxomicin for first episodes, recurrences, and severe cases. Metronidazole is now reserved for mild infections and should only be considered when vancomycin or fidaxomicin, are unavailable, as it is no longer recommended as first-line thera- py. However, the role of oral versus intravenous antibiotics in extraintestinal infections remains uncertain. While CDI is traditionally linked to healthcare settings, recent reports highlight a rising incidence in the community even among individuals without prior healthcare exposure or antibiotic use, as seen in our case.21-22 In our case, initial empiric therapy with piperacillin-tazobac- tam and clindamycin was insufficient, as evidenced by progressive leukocytosis and persistent fever. The turning point in management was the identification of C. difficile in the abscess culture, prom- pting a switch to intravenous metronidazole and vancomycin, which led to clinical resolution. This case underscores the impor- tance of early surgical intervention for abscess drainage, as source control is essential in managing deep-seated infections. Additionally, risk factors for extraintestinal CDI should be careful- ly evaluated. Although our patient had no prior history of hospita- lization or antibiotic use, further research is warranted to clarify host susceptibility, bacterial virulence mechanisms, and optimal treatment approaches for extraintestinal CDI. This case highlights the importance of considering atypical infectious sources in patients with leukocytosis and fever. Clinicians should remain vigilant in recognizing unusual infectious presentations of C. difficile, especially in patients lacking classical gastrointestinal manifestations. CDI is commonly transmitted through contaminated surfaces in hospitals. Inadequately cleaned surfaces and medical equipment can serve as reservoirs for its spores, facilitating transmission to patients when infection prevention and control measures, inclu- ding effective cleaning protocols, are not properly implemented.23 Conclusions Clinicians should consider CDI even in the absence of classical gastrointestinal symptoms, particularly in patients presenting with abscesses, sepsis, or unexplained leukemoid reactions. Leukemoid reactions may serve as a surrogate marker of CDI severity and could aid in risk stratification. References 1. Kyne L, Hamel MB, Polavaram R, Kelly CP. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346-53. 2. Gupta A, Patel R, Baddour LM, et al. Extraintestinal Clostridium difficile infections: a single-center experience. Mayo Clin Pro 2014;89:1525–36. 3. Jacobs A, Barnard K, Fishel R, Gradon JD. Extracolonic man- ifestations of Clostridium difficile infections: presentation of 2 cases and review of the literature. Medicine (Baltimore) 2001;80:88–101. 4. Amaya SL, Rosa ES, Sergio GF, et al. Extraintestinal Clostridioides difficile Infection: Septic Arthritis 12 Months after Colitis. Anaerobe 2021;69:102318. 5. Hudson DA, Gibb AP, Gill MJ. Empyema caused by Clostridium difficile. Can J Infect Dis 1999;10:170–1. 6. Bhargava A, Sen P, Swaminathan A, Ogbolu C, Chechko S, Stone F. Rapidly progressive necrotizing fasciitis and gangrene due to Clostridium difficile: case report. Clin Infect Dis 2000;30:954-5. 7. Incavo SJ, Muller DL, Krag MH, Gump D. Vertebral osteomyelitis caused by Clostridium difficile: a case report and review of the literature. Spine 1988;13:111-3. 8. Bartlett JG. Narrative review: the new epidemic of Clostridium difficile–associated enteric disease. Ann Int Med 2006;145: 758-64. 9. Johnson S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis 2021;73:e1029–e1044. 10. Naaraayan A, Aleta M, Basak P, et al. Leukemoid reaction to Clostridium difficile infection. Anaerobe 2015;34:158–60. 11. Wanahita A, Goldsmith EA, Musher DM, et al. Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by Clostridium difficile. Clin Infect Dis 2002;34:1585–92. 12. Walker J, Sawhney R, O’Sullivan D, et al. Leukemoid Reactions Complicating Colitis Due to Clostridium difficile. South Med J 2004;97:775–8. 13. Gorbach SL, Bartlett JG. Contributions to the discovery of Clostridium difficile antibiotic-associated diarrhea. Clin Infect Dis 2014;59:S66-70. 14. Kelly CR, Allegretti JR. gastroenterology and Clostridium dif- ficile infection: past, present, and future. Clin Infect Dis 2023;77:S463-70. 15. Khanafer N, Vanhems P, Barbut F, Luxemburger C, CDI01 Study Group. Factors associated with Clostridium difficile infection: a nested case-control study in a three year prospec- tive cohort. Anaerobe 2017;44:117-23. Mini Review [page 16] [Emergency Care Journal 2025; 21:13852] 16. Eeuwijk J, Ferreira G, Yarzabal JP, et al. A systematic literature review on risk factors for and timing of Clostridioides difficile infection in the United States. Infect Dis Ther 2024;13:273-98. 17. Libby DB, Bearman G. Bacteremia due to Clostridium diffi- cile—review of the literature. Int J Infect Dis 2009;13:e305-9. 18. Lee NY, Huang YT, Hsueh PR, Ko WC. Clostridium difficile bacteremia, Taiwan. Emerg Infect Dis 2010;16:1204. 19. Al-Hourani K, Reddy S, Parker A. Primary Clostridium diffi- cile spinal epidural abscess. J R Soc Med Sh Rep 2010;1:41. 20. Albrich, W.C.; Rimland, D. Clostridium difficile: Association with Thrombocytosis and Leukocytosis. South Med J 2007;100:149-51. 21. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. New England J Med 2015;372:825-34. 22. Khanna S, Baddour LM, Huskins WC, et al. The epidemiology of Clostridium difficile infection in children: a population- based study. Clin Infect Dis 2013;56:1401-6. 23. Carling PC, Parry MF, Olmstead R. Environmental approaches to controlling Clostridioides difficile infection in healthcare settings. Antimicrob Resist Infection Control 2023;12:94. Mini Review [Emergency Care Journal 2025; 21:13852] [page 17]