Open Forum Infectious Diseases ID CASE physicians at the time believed the positive cultures in March Bacteremia and Septic Arthritis due to reflected contamination, 2 sets of blood cultures drawn at the a Nontoxigenic Strain of Clostridium time of her ED visit in July were sterile, and she was discharged difficile in a Patient With Sickle Cell home again with pain medications. However, ultimately, she was admitted in September with persistent symptoms as well as Disease new-onset diarrhea. 1 2 1,2,3 Emilie Hill, Adrienne D. Workman, Francesca Lee, 1 1 2 On examination at the time of admission to the hospital, Rita Hollaway, Dominick Cavuoti, and Bonnie C. Prokesch 1 2 3 she was moaning in pain, lethargic, and unable to follow com- Departments of Pathology, Internal Medicine, and Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas mands. Significant musculoskeletal findings included bilat- eral lower extremity edema and tender bilateral knee effusions A 22-year-old female with sickle cell disease presented with without warmth nor erythema. Computed tomography scan fevers, bilateral knee pain, and lethargy. Laboratory data revealed of her abdomen with oral and intravenous contrast revealed a leukocytosis and lactic acidosis. Blood and synovial fluid cul- nodularity of the liver as well as mild diffuse wall thickening tures grew a non-toxin-producing strain of Clostridium difficile . of the colon and mid to distal small bowel loops consistent This case highlights the fact that nontoxigenic Clostridium diffi - with enterocolitis. Laboratory data upon admission were nota- cile can cause significant disease. ble for a leukocytosis of 20.25 K/μL, a hemoglobin of 6.4 g/ Keywords. bacteremia; Clostridium difficile ; hemoglobin SS disease; septic arthritis; sickle cell disease. dL, and an elevated lactic acid of 5.8 mmol/L. Examination of right knee synovial fluid revealed 145 000 red blood cells and 170 500 nucleated cells/mm with a neutrophilic predominance. CASE Gram stain of the synovial fluid was negative. Blood cultures revealed Gram-variable rods aer 1 ft day of incubation, which A 22-year-old African American female with sickle cell were identified as C. difficile by MALDI-TOF. The synovial fluid (Hemoglobin SS) disease and biopsy-proven autoimmune hep- was cultured aerobically and anaerobically. There was no aer - atitis on prednisone and azathioprine presented to the emer- gency department (ED) twice in early March with fevers and obic growth. However, aer 72 h ft ours of incubation, growth was intermittent bilateral knee pain and swelling. Both times she was present in the anaerobic culture. A Gram stain of the colonies treated for a sickle cell pain crisis and discharged home. Blood growing on Brucella blood agar revealed Gram-variable rods, cultures from her first presentation and second presentation which were also identified as C. difficile by MALDI-TOF. Stool grew Clostridium species in 1 out of 2 sets of aerobic and anaer- studies, including C. difficile polymerase chain reaction (PCR) obic bottles and 3 out of 3 sets of aerobic and anaerobic bottles, testing, were ordered but never sent before the patient’s diarrhea respectively. The positive cultures were obtained prior to the abated. While intravenous metronidazole 500 mg every 8 hours initiation of matrix-assisted laser desorption/ionization time was initially prescribed, the antibiotic was changed to the oral of flight (MALDI-TOF) mass spectrometry, and thus they were route of administration within 72 hours, as she was less lethar- not identified to species. The patient continued to have bilateral gic and able to reliably take medication by mouth. Although the knee pain and subjective fevers for months, prompting her to orthopedic service initially considered performing an arthro- present again to the ED in July. Despite not having received any centesis of her left knee as well as incision and drainage of both antibiotics or further work-up of her prior bacteremia, as her knees, in light of her dramatic and rapid clinical improvement with metronidazole therapy, no further invasive interventions were pursued. Because of concern for possible perforation in the setting of active colitis, a colonoscopy was not performed. Received 13 June 2017; editorial decision 17 December 2017; accepted 29 December 2017. Correspondence: B. C. Prokesch, MD, Department of Internal Medicine, Division of Ultimately, the patient completed a 4-week course of metroni- Infectious Diseases, 5323 Harry Hines Boulevard, Dallas, TX 75390-9113 (bonnie.prokesch@ dazole 500 mg 3 times daily, with no adverse effects and full UTSouthwestern.edu) ® resolution of symptoms. Open Forum Infectious Diseases © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases A subculture of the C. difficile isolate from blood was sent Society of America. This is an Open Access article distributed under the terms of the Creative to the Centers for Disease Control and Prevention for ribo- Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any typing. The isolate tested negative for toxin genes tcdA, tcdB, medium, provided the original work is not altered or transformed in any way, and that the work cdtA, and cdtB by multiplex real-time PCR, and positive for the is properly cited. For commercial re-use, please contact firstname.lastname@example.org 115bp DNA sequence that replicates the pathogenicity locus in DOI: 10.1093/ofid/ofx278 ID CASE • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofx278/4782666 by Ed 'DeepDyve' Gillespie user on 16 March 2018 nontoxigenic strains. As a result, this isolate had no amplifica- Administration–approved molecular tests that detect genes tion for the tcdC-encoding gene. PCR ribotyping confirmed encoding C. difficile toxins. These nucleic acid amplification that the isolate was Ribotype 039. The isolate was sent to ARUP tests are rapid and highly sensitive, yet the positive predictive laboratories for a cytotoxin cell assay, which provided confirm- value can be low if the test is not ordered in the appropriate ation that, phenotypically, no toxin was being produced. clinical context. The ProGastro Cd test (Prodesse, Waukesha, WI) and the GeneOhm Cdiff assay (BD Diagnostics, San DISCUSSION Diego, CA) target toxin B (tcdB), while the Xpert C. difficile The genus Clostridium comprises obligately anaerobic (or occa- test (Cepheid) is a multiplex assay that amplifies 2 genes, tcdB sionally aerotolerant), Gram-positive rods. C. difficile causes and a gene that regulates toxin production (tcdC). In addition, symptoms ranging from mild self-limiting diarrhea to the multiplex gastrointestinal panels such as BioFire FilmArray development of full-scale pseudomembranous colitis . Extra- (Biomerieux, Inc., Durham, NC) include a C. difficile toxin intestinal C. difficile infections account for less than 0.2% of all gene as one of its targets. Less expensive, less sensitive mem- C. difficile infections . C. difficile bacteremia is even more brane enzyme immunoassays like the C. DIFF QUIK CHEK uncommon and is generally part of a polymicrobial bacteremia COMPLETE (Alere North America, LLC, Orlando, FL) involving other intestinal flora . A recent literature review have been used in some laboratories as screening tests before identified only 44 cases of C. difficile bacteremia between 1962 performing the molecular tests. In addition to assaying for and 2015 . Moreover, while review of the literature describes toxins A and B in fecal samples, the test detects C. difficile postinfectious sterile inflammatory arthritis as a complication antigen, glutamate dehydrogenase, as a screen for the presence of gastrointestinal C. difficile infection [3–5], cases of septic of C. difficile in the stool. Clinicians may attempt to recover arthritis due to the organism itself are rare (Table 1). When it C. difficile from clinical samples, also called toxigenic culture, does occur, the majority of published septic arthritis cases [3, but the process is laborious and time consuming, requiring 6] involve prosthetic joints [7–12]. Review of the literature multiple days for isolation and identification. If isolates are yielded only 1 case report of native large joint septic arthritis recovered, whole-genome sequencing and ribotyping may be in an 11-year-old boy, also with Hemoglobin SS disease, who performed using research-only assays. experienced right-sided shoulder discomfort and was found to Only strains that carry the pathogenicity locus (PaLoc) pos- be bacteremic with C. difficile despite having no gastrointestinal sess the genetic information for the C. difficile enterotoxin, symptoms . This publication did not describe ribotyping on TcdA, and the cytotoxin, TcdB. Historically, only strains pro- the bacterial isolate in that case to assess for toxin production. ducing TcdA and/or TcdB were thought to cause C. difficile C. difficile diagnostic assays are designed to detect the infection . Outbreaks with more virulent strains such as B1/ absence or presence of organisms or toxins in patient fecal NAP1/027 and ribotype78 are associated with significant mor - samples. However, these tests are unable to differentiate asymp- tality [14, 15]. This case highlights that a non-toxin-producing tomatic carriers from those patients with veritable disease. isolate can be responsible for severe extra-intestinal disease due The majority of clinical laboratories utilize Food and Drug to C. difficile. Table 1. Review of Cases of Septic Arthritis due to C. difficile Case Prosthetic Comorbid C. difficile C. difficile Surgical No. Ref Year Sex Age Joint Joint Conditions Diarrhea Bacteremia Therapy Intervention Outcome 1 13 1994 F 31 Hip Yes Sickle cell disease No No Metronidazole Incision and Died drainage 2 8 1995 M 16 Knee Yes Osteosarcoma No No Ornidazole Above knee Survived of femur on amputation chemotherapy 3 12 1999 F 83 Hip Yes Unknown Yes (toxin No Metronidazole Prosthesis Survived negative) removal 4 15 2009 M 11 Shoulder No Sickle cell disease No No Metronidazole Incision and Survived drainage 5 14 2010 F 66 Hip Yes Chronic kidney Unknown Yes Metronidazole Incision and Survived disease drainage 6 11 2013 F 61 Knee Yes Hypothyroidism No No Metronidazole Above knee Survived amputation 7 10 2013 F 47 Shoulder Yes Alcoholic hepatitis No No Metronidazole Prosthesis Unknown removal 8 9 2013 M 61 Hip Yes AIDS, type 2 No Yes Metronidazole Incision and Survived diabetes drainage 2 • OFID • ID CASE Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofx278/4782666 by Ed 'DeepDyve' Gillespie user on 16 March 2018 3. Jacobs A, Barnard K, Fishel R, Gradon JD. Extracolonic manifestations of CONCLUSION Clostridium difficile infections. Presentation of 2 cases and review of the literature. Medicine (Baltimore) 2001; 80:88–101. To our knowledge, this is the first reported case indicating that 4. Legendre P, Lalande V, Eckert C, et al. Clostridium difficile associated reactive non-toxin-producing strains of C. difficile can cause severe arthritis: case report and literature review. Anaerobe 2016; 38:76–80. extraintestinal disease, including septic arthritis of a native 5. Townes JM. Reactive arthritis after enteric infections in the United States: the problem of definition. Clin Infect Dis 2010; 50:247–54. large joint. In order to provide timely and appropriate ther- 6. Pron B, Merckx J, Touzet P, et al. Chronic septic arthritis and osteomyelitis in a apy, it is important for clinicians and microbiologists to be prosthetic knee joint due to Clostridium difficile. Eur J Clin Microbiol Infect Dis 1995; 14:599–601. aware of the various potential manifestations of infection with 7. Brassinne L, Rodriguez-Villalobos H, Jonckheere S, et al. Early infection of hip C. difficile. joint prosthesis by Clostridium difficile in an HIV-1 infected patient. Anaerobe 2014; 27:96–9. 8. Ranganath S, Midturi JK. Unusual case of prosthetic shoulder joint infection due Acknowledgments to Clostridium difficile. Am J Med Sci 2013; 346:422–3. e a Th uthors would like to acknowledge the microbiology technicians 9. Curtis L, Lipp MJ. Clostridium difficile infection of a prosthetic knee joint requir- at Clements University Hospital and David Lonsway, Ashley Paulick, and ing amputation. Surg Infect (Larchmt) 2013; 14:163–4. Preeta Kutty at the Centers for Disease Control and Prevention, Atlanta, 10. McCarthy J, Stingemore N. Clostridium difficile infection of a prosthetic joint pre- Georgia, for their assistance. senting 12 months after antibiotic-associated diarrhoea. J Infect 1999; 39:94–6. Potential conifl cts of interest. All authors: no reported conflicts of 11. Achong DM, Oates E. Periprosthetic Clostridium difficile hip abscess imaged with In-111 WBCs. Clin Nucl Med 1994; 19:860–2. interest. All authors have submitted the ICMJE Form for Disclosure of 12. Lee NY, Huang YT, Hsueh PR, Ko WC. Clostridium difficile bacteremia, Taiwan. Potential Conflicts of Interest. Conflicts that the editors consider relevant to Emerg Infect Dis 2010; 16:1204–10. the content of the manuscript have been disclosed. 13. Gregg KS, Alexander KA. Native joint septic arthritis caused by Clostridium dif- ficile in an 11-year old with hemoglobin SS disease. Pediatr Infect Dis J 2009; References 28:853. 1. Jorgensen J, Pfaller M, Carroll K, et al. Manual of Clinical Microbiology. 11th ed. 14. Dubberke ER, Haslam DB, Lanzas C, et al. The ecology and pathobiology of Washington, DC: ASM Press; 2015. Clostridium difficile infections: an interdisciplinary challenge. Zoonoses Public 2. Kazanji N, Gjeorgjievski M, Yadav S, et al. Monomicrobial vs polymicrobial Health 2011; 58:4–20. Clostridium difficile bacteremia: a case report and review of the literature. Am J 15. Kuijper EJ, van den Berg RJ, Debast S, et al. Clostridium difficile ribotype 027, Med 2015; 128:e19–26. toxinotype III, the Netherlands. Emerg Infect Dis 2006; 12:827–30. ID CASE • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/2/ofx278/4782666 by Ed 'DeepDyve' Gillespie user on 16 March 2018
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Published: Feb 1, 2018
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