Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review

Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review Karan Bir Singh, Anas Khouri, Deepak Singh, Jose Prieto, Priyata Dutta, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3928202/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Apr, 2024 Read the published version in Cureus → Version 1 posted You are reading this latest preprint version Abstract Aim To evaluate Clostridioides difficile testing and diagnosis in specific patient populations. Background Clostridioides difficile infection (CDI) is a biochemical and clinical diagnosis. Certain patient populations are at higher risk and testing must be interpreted correctly to avoid overdiagnosis and overtreatment. Consequently, we need to understand the limitations of the tests used to avoid increase morbidity and mortality due to false negative test results. Diagnostic assays should be ordered in a step wise approach in specific patient populations to confirm CDI. Methods Manuscripts were extracted from three different databases based on keywords. Data were extracted based on the PRISMA 2020 guidelines. Each manuscript was analyzed using appropriate critical appraisal tools. Results A total of 70 reports were evaluated. 18 review articles, 4 retrospective cohorts, 3 guidelines, 1 experimental, and 1 cross sectional study were eligible for inclusion. A total of 27 reports were included. Discussion CDI should be considered in all patients with traditional risk factors. Increased clinical suspicion of CDI is required in special populations such as hypogammaglobulinemia, transplant recipients, surgery, and inflammatory bowel disease. Testing should be limited to patients with the clinical manifestations of CDI to ensure a high pre-test probability for test interpretation. Diagnostic assays should follow a sequential, stepwise approach to accurately categorize the toxin expression status of the bacteria. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Clostridioides difficile (formerly known as Clostridium difficile ) is a gram positive, spore forming, strict anaerobic bacillus.( 1 , 2 ) The organism lives harmoniously in the colon with its growth and production suppressed by normal gut flora. This bacterium was discovered in 1935 and later the first case of antibiotic associated pseudomembranous colitis was diagnosed in 1978. At this time, the strain was originally named Bacillus difficilis due to its microscopic appearance and difficult cultivation.( 3 ) This organism is a leading cause of gastrointestinal disease and costs the health system 4 billion dollars annually.( 2 ) Since the 20th century, CDI rates have been increasing worldwide with increasing incidence in adults. In 2002, high mortality rates were attributed to a strain called ribotype 027/B1, also known as NAP-1.( 3 ) There was a lack of systematic surveillance for CDI prior to 2003. After the worldwide outbreak of the NAP-1 strain, the Centres for Disease Control and Prevention (CDC) approximated that there were 500,000 CDI cases and 29,000 deaths in the America in 2011.( 3 ) In 2010 study found that 97% of cases were related to healthcare and 75% of these patients had a history of previous hospitalizations.( 4 ) Trends from another study demonstrated incidence increasing from 5.5/10,000 to 11.2/10,000, with more dramatic increases in adults aged adults aged ≥ 65 of age.( 4 ) The emergence of NAP-1 variant of Clostridioides difficile (C.diff) has been as high as 30% in hospitalized patients, accounts for more than 300,000 newly diagnosed cases per year, and up to 40% of community acquired infections required hospitalization.( 3 ) Since the discovery of the NAP-1 strain, testing for C.diff has increased. The virulence of C.diff is from two clostridial toxins, enterotoxin (toxin A) and cytotoxin (toxin B). These toxins are encoded by genes, cdtA and cdtB, on the pathogenicity locus (PaLoc).( 2 ) All strains of C.diff have the ability to ferment and produce glutamate dehydrogenase (GDH) irrespective of toxigenic properties. This has led to the test for GDH which has a sensitivity (Sn) ranging from 79.5–100%, specificity (Sp) of 82.7–100%, negative predictive value (NPV) of 100%.( 5 ) GDH testing does not distinguish between toxigenic and non-toxigenic strains, therefore, a confirmatory test is required for toxin analysis. The best test for detecting toxin production is a toxigenic culture (TC) due to its high Sn and Sp, but due to its turnaround times, other assays are preferred in the modern era.( 5 – 7 ) The toxin A/B enzyme immunoassay (EIA) is a common confirmatory test which detects antibodies directed against both virulent clostridial toxins. The Sn varies from 53–85% with a Sp of 91–98%.( 6 ) Due to poor Sn, combination of rapid turn-over tests and a multi-step approach are considered to avoid false positives and false negatives.( 8 ) In addition, sole reliance on molecular testing for toxins increases the likelihood of over-diagnosis and over-treatment of C.diff. This conclusion is most important in patients that have asymptomatic colonization or carriage of C.diff. This carriage is common in healthcare associated facilities and in the community and it is estimated that prevalence ranges from 7–18%.( 9 ) Methods Design: This systematic review was created to establish a comprehensive collection of current data from different databases to align with the most up to date evidence-based practice patterns for the workup of CDI. This study followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist. Our research was not registered online. Search strategy and selection: We evaluated studies that identified the roles of biochemical testing of C. diff and implications of disease severity and development of toxic megacolon in a subset of patient populations. On 2 February 2023 author CC searched the databases PubMed (1946-present), Scopus (1788-present), and the Cumulative Index of Nursing and Allied Health Literature (CINAHL Complete, 1937-present) to identify relevant reports. Search terms used included index and keyword terms for “clostridioides difficile”, “toxin assay”, and “toxic megacolon”. The search strategy is listed in Table 1. Inclusion criteria were English language articles published between the years 2012 to 2023, with eligibility based on population, type of study, and outcomes. Exclusion criteria were non-English language reports that were experimental (except for one study which was deemed necessary for this review) or basic science, poor quality appraisal, pediatric population, and outdated guidelines. All six investigators had to agree to including and/or excluding the studies based on these criteria before they were finalized into this paper. One experimental study was included in this systematic review for the purpose of identifying the hypervirulent strain NAP-1. After removing duplicates, the full text articles of the search results (n = 76) were uploaded to Rayyan, a Web-based platform used to organize and manage articles for systematic reviews. Data extraction: All five investigators (A.K, J.A, M.N, P.D, D.S) extracted five reports each and two investigators (K.S and G.M) extracted three reports from the eligible studies based on: last name of author, publication year, number of patients, purpose of the study, and results. All appropriate records and studies grouped based on study type and listed in Table 2 in descending year of publication. Quality appraisal: Two investigators (K.S and A.K) independently reviewed each of the thirty included reports for authenticity and quality. We utilized the JBI global website to methodologically assess the transparency of each included report. Review articles ( 18 ), retrospective cohorts ( 4 ), guidelines ( 3 ), experimental ( 1 ), and cross-sectional study ( 1 ) were criticized to have excellent appraisal. The following instruments were used: Text and opinion for review articles, the revised A ppraisal of G uidelines for RE search & E valuation (AGREE) II for guidelines, diagnostic accuracy tool for the cross-sectional study, experimental study checklist for the experimental study, and cohort study checklist for the cohort studies. Results After identifying 85 records from Scopus, 24 records from PubMed, and 37 records from CINAHL we removed 70 duplicate records using an excel spreadsheet. We manually excluded 6 records based on publication year. Lastly, we excluded records based on abstract screening and not meeting eligibility criteria. Overall, 27 reports were eligible for inclusion in this systematic review as listed in Fig. 1 . Discussion In this part of the manuscript, we discuss definitions, risk factors, emphasis on specific patient populations, diagnosis, and testing. Risk factors: Table 3 Risk factor table for initial and recurrent clostridioides difficile. Increased risk Reduced risk Initial CDI rCDI -Pulsed dose (every 48 hours) in rCDI -Hand hygiene, barrier precautions, and infection control programs -Antibiotic stewardship Independent Dependent Dependent Independent -Recent gastro-intestinal surgery (particularly colectomy, ileo-anal pouch, and ileostomy) -Recent exposure to anti-neoplastic agents -IBD -Previous hospitalization -Advanced age (> 60) -Greater co-morbid conditions -Solid and hematopoietic transplant -Antibiotics -PPI in cirrhosis -Sharing room with CDI patient -Non-C.diff antibiotics -Sharing room with CDI patient -Advanced age (> 65) -Poor health status Solid and hematopoietic transplant CDI, clostridioides difficile infection; PPI, proton pump inhibitors; IBD, inflammatory bowel disease; rCDI, recurrent clostridioides difficile infection; C. diff, clostridioides difficile. Antimicrobials: Predisposing risk factors for CDI are listed on Table 3 but, the two main risk factors for CDI are exposure to antibiotics and C.diff.( 1 , 3 , 10 – 14 ) Antibiotic use is the strongest risk factor for development of CDI and the most common include clindamycin, fluoroquinolones, and cephalosporins. Optimization of antimicrobials and antibiotic stewardship have been shown to reduce CDI incidence by up to 60%.( 4 , 15 ) In the Netherlands, a three-year case control study studied the association between duration and dosage of antibiotics. Third-generation cephalosporins had the highest odds followed by carbapenems, and second-generation cephalosporins of developing CDI (OR 5.3, 4.7, 3.3, respectively).( 16 ) Those currently on antibiotics and within 30 days of completion had the greatest risk (OR 6.7–10.4).( 10 ) Interestingly, linezolid has conflicting data on C.diff risk as some research has shown a theoretical inhibition of exotoxin production and reduction in CDI inhibited.( 17 , 18 ) The study in Main Medical Center was primarily experimental in vitro gut model and the second study lacked external validity as the patient population of interests were principally heart transplant recipient and had a small sample size (n = 91). On the other hand, one study found patients who underwent HSCT more prone to developing CDI with linezolid.( 12 ) Along depressed immune system due to multiple other comorbities, these patients lose their protective gut microbiome from gastrointestinal inflammation.( 3 , 12 ) Nonantimicrobial risk factors: Proton pump inhibitors (PPIs) are common medications used in all clinical settings that have been associated to CDI. A meta-analysis of approximately 299,000 participants from 23 retrospective studies demonstrated CDI incidence of 64.9% in PPI users.( 19 ) The meta-analysis concluded with judicious PPI prescriptions. The study has limitations as the length of duration of PPIs was not defined. In addition, the study incorporated the ‘trim and fill’ method to adjust the asymmetrical funnel plot which can lead to over- or under-estimation of true measures in this meta-analysis. Other retrospective studies or systematic/meta-analysis that determined both PPIs and histamine receptor-2 blockers increase CDI. Although it is generally accepted by the Federal of Drug Administration (FDA) that PPIs increase CDI, there is considerable controversy based on the current available literature.( 1 , 3 , 4 , 11 ) Reduced risk: A detailed list of factors that decrease the risk of CDI are listed in Table 3 . Binders that are commonly used for bile sequestration such as cholestyramine and colestipol have been shown to decrease risk of CDI. In lieu of these resins, vancomycin is highly efficacious and clinicians should be reminded to set a timing interval between oral vancomycin and bile resins. Currently, 4,000 mg of cholestyramine is given three to four times daily and two to three hours after oral vancomycin.( 10 , 20 ) Apart from medications, asymptomatic colonization is thought to be immunoprotective. Approximately 40% of patients with community care associated C.diff do not have antibiotic exposure.( 10 ) In fact, 10% of healthy adults, up to 50% of institutionalized patients, and neonates become asymptomatic reservoir and spread this bacteria throughout the healthcare system.( 21 ) Carriers have immunoglobulin G (IgG) antitoxin A and B antibodies against C.diff, thereby, inhibiting toxin production. It has been postulated that earlier colonization of asymptomatic C.diff may lead to a robust memory immunity until the later decades of life. As antitoxin A and B antibodies production weans with aging and apoptosis, this poses a risk factor for CDI in the elderly.( 1 , 22 ) Special risk populations: Hypogammaglobulinemia: As forementioned, humoral immunity protects against toxicogenic colonization of C.diff. Patients with solid organ transplant(s) (liver, kidney, heart and lung), may benefit from passive immunization for C.diff. These immunosuppressed receipts receiving prophylactic antibiotics post-transplant have a prevalence of 1.0–30% for CDI.( 3 ) In addition, hypogammaglobulinemia has been found to be an independent risk factor for CDI and rCDI. In a prospective study, 235 patients underwent heart transplant and 35 developed CDI. Of these 35 patients, immunoglobulin levels were determined to be low in 6 of the 7 tested individuals.( 3 , 10 , 23 ) Although routine IVIG administration is not recommended, it should be considered in patients with hypogammaglobulinemia that have other conferring comorbid conditions for CDI. Surgical: In the surgical patient, there are multiple risk factors that both confound and modify the effect of CDI such as gastrointestinal surgery, emergent surgery, organ transplant, and nasogastric tube feeds. Gastrointestinal surgeons influence CDI both directly (by surgical treatment) and indirectly (by inadvertently contributing to CDI by an unrelated surgery). There is evidence that enteral tube feeding in patients with anatomical or dynamic obstructions increases the risk of CDI. The transit time of stool is decreased and allows for proliferation of toxins resulting in toxin proliferation.( 24 ) According to the 2017 Infectious Disease Society Association (IDSA), a match cohort study demonstrated enteral feeds increase the risk of CDI.( 25 ) Therefore, it is best practice to discontinue NGT early to reduce the possibility of cross-contamination from hospital instruments.( 1 , 3 ) Inflammatory bowel disease: Inflammatory bowel disease (IBD) harbors a pro-inflammatory state that causes physiological, anatomical, and immunological changes to the gastrointestinal tract. As opposed to HCO-HFA and CAO-HFA CDI, IBD specific populations present with CAA CDI. A national prevalence survey found CDI in ulcerative colitis (UC) to be 37 per 1,000, 11 per 1,000 in Crohn’s disease (CD)m and 4 per 1,000 in general medical patients.( 26 ) IBD patients suffer from acute flares leading to increased hospitalizations, immunosuppression with corticosteroids, and increased prescription of antimicrobials. Of all the forementioned factors, corticosteroid administration has the greatest risk, with a threefold increase in CDI incidence.( 4 ) A study in British Columbia determined that corticosteroids to be an independent risk factor in IBD.( 27 ) Interestingly, it is unclear what risk immunotherapy poses in this population. The complications of CDI are much higher in UC (9.5%) than with CD (7%) partly due to more extensive involvement of the colonic mucosa in UC.( 27 ) Patients with colectomy and have ileo-anal pouch or ileostomy remain at an elevated risk of CDI as well. Symptoms such as increasing ostomy output, bleeding, changes in stool consistency and frequency, and along with systemic markers of inflammation should prompt evaluation of an infectious source. Healthcare professionals should have a low threshold to initiate therapy however should be aware of rising metronidazole resistance in this group of patients.( 3 ) In terms of testing, IBD patients are more likely to have toxin positive strains if there is one or more classic risk factor for CDI (antibiotic exposure, recent hospitalization, institutionalized, history of surgery) in comparison to toxin negative strains (68% vs 31%).( 13 ) Intensive care unit (ICU): Patients that are directly admitted to the ICU have been found to be colonized with toxicogenic C.diff strains. Approximately 15% of 5,300 admitted patients were confirmed to have CDI and this correlates to the increased incidence of community acquired CDI.( 28 ) Patients found to have CDI at the time of ICU admission were much more likely to have subsequent CDI in the future (p < 0.01).( 29 ) A retrospective study in Taiwan found that the diarrheal group had a longer length of ICU stay than the ileal group (28 vs 12 days, p < 0.01).( 30 ) A cohort study determined that the size of the unity and capacity of rooms were related to horizontal transmission.( 31 ) Therefore, hand hygiene is the cornerstone in the ICU to decrease transmission of spores. In the ICU, there is accumulation of co-morbid conditions, virulent organisms, and use of broad-spectrum antibiotic that increase CDI risk. Diagnosis of Clostridium Difficile infection CDI diagnosis requires a clinical syndrome accompanied by a biochemical test for confirmation. CDI is defined as the presence of detectable toxicogenic C.diff strain and clinical syndrome of acute diarrhea consistent with ≥ 3 unformed Bristol 5–7 stools in the last 24 hours without another explanation and prior exposure of antibiotics in the last 2 months. Each test must be accurate to diagnose the pathogen and timely to ensure rapid isolation for infection control and preventing progression. C.diff colitis can be a challenge to diagnose as symptoms can overlap with other general diarrheal illnesses and detection of nontoxigenic strains of C.diff which do not require treatment. To diagnose a clostridium difficile infection, patients must have acute diarrhea in addition to either toxigenic difficile strain or C.diff toxins in stool samples.( 34 ) C.diff tests include toxigenic culture (TC), Glutamate dehydrogenase (GDH) detection assays, nucleic acid amplification tests (NAATs), cell cytotoxicity neutralization assays (CCNAs), and toxin detection tests (EIA). Each test is compared in details in Table 4 . Patients who are at high risk for CDI are the ones that have received antibiotics in the last 3 months, hospitalized for more than 3 days, and atleast 65 years of age.( 3 ) Table 4 Clostridioides difficile tests, turnaround time, sensitivity/specificity, and important details regarding each test. Type of tests Turnaround (h) Sn/Sp Details TC 48-120h (5,6) 87–100%/94–100% (7) This is a gold standard test. Isolates toxigenic strains of C.diff from the stool culture or rectal swab. GDH/EIA 90%/80–100% (7,14,32,33) Considered the first test to order for screening.(34) Quicker and more sensitive than toxin EIAs. Test uses antibodies to detect the presence of GDH, a cell wall-associated enzyme that is present in both toxigenic and nontoxigenic strains. Therefore, cannot be used alone in the diagnosis of CDI. NAAT < 4h (6) 100%/70% (14,35) Detects nucleic acid sequences through amplifications of the genes that produce toxins A and B (TcdA and TcdB respectively). Detects toxin genes instead of active toxin, it cannot differentiate between CDI and asymptomatic carriage.(35) NAAT can be done by PCR (polymerase chain reaction) or LAMP (loop-mediated isothermal amplification). CCNAs 72-96h (34) 90–100%/98–99% (7) This test works by inoculating a stool sample onto two sets of sensitive tissue culture cells, first set without C.diff anti-toxin and the second set with the anti-toxin. Positive if cytopathic effect in the first set. Toxin ELISA < 2h (6) 53–85%/91–98% (7) This test uses antibodies to detect the presence of C.diff toxins A/B. A negative toxin assay does not rule out toxigenic strains. Combining a high sensitivity test (like GDH) with EIA can make up for the low sensitivity of this test. Hours (h); Sensitivity/Specificity (Sn/Sp); Toxigenic culture (TC); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA); Nucleic acid amplification test (NAAT); Cytotoxicity neutralization assays (CCNAs); Toxin A B enzyme-linked immunosorbent assay (ELISA). Diagnostic algorithms No stand alone test can distinguish between toxigenic/nontoxigenic strains and asymptomatic colonization as described in Table 5 .( 5 ) Therefore, a 2-step or multi step diagnostic algorithms have been used to improve the diagnosis of CDI. The 2-step approach starts by a high sensitive test (GDH EIA or NAAT) followed by a high specificity confirmatory test (TcdA /TcdB EIAs) per the 2016 Europe and UK guidelines (ESCMID).( 8 , 36 ) Table 5 Clostridium difficile testing with specific aim of testing Detection of C.diff Detection of toxins A and/or B TC (toxigenic C.diff strain) CCNAs: Detects TcdA and TcdB GDH EIA (Toxigenic and nontoxigenic strains) Toxin A B immunoassays (ELISA) PCR-NAAT: Detects TcdA and TcdB genes (Toxigenic strains) Clostridioides difficile (C.diff); Toxigenic culture (TC); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA); Polymerase chain reaction nucleic acid amplification test (PCR-NAAT); Toxin A gene (TcdA) and Toxin B gene (TcdB); Cytotoxicity neutralization assays (CCNAs). Most algorithms start with a GDH test followed by toxin EIA as shown in Fig. 2 . Some algorithms start with NAAT instead of GDH followed by toxin EIA which is more expensive but has a higher diagnostic accuracy. Economic studies showed that starting with GDH costs approximately $ 10 per algorithm vs $ 30 per algorithm starting with PCR.( 5 ) Therefore, many small community hospitals and long term care facilities perform GDH with toxin A/B EIA and subsequent NAAT for inconsistent results. This is referred to as the “multi-step approach” where the NAAT is used to differentiate if the positive GDH was due to toxigenic strain or nontoxigenic strain as illustrated in Fig. 3 .( 7 ) Another modification of the multistep algorithm is to combine step 1 and step 2 together by testing for GDH and toxins at the same time, followed by NAAT if inconsistent results as described in Fig. 4 . The advantage of this modification is saving time by combining steps 1 and 2 together as described in Table 6 . The disadvantage is the cost of the Toxins EIA test which is usually unnecessary if the GDH is negative. The previous 3 algorithms summarize the recommended testing by the ESGCD and ESCMID.( 8 ) Table 6 Comparison of 2-step, multi-step, and modified multi-step algorithm Algorithm First test Second test Third test Advantages/Disadvantages 2 step NAAT Toxin A/B EIA N/A Pros: Faster Cons: More expensive Multi-step GDH Toxin A/B EIA NAAT Pros: Most cost effective. Cons: Time consuming, Multiple steps. Modified multi-step GDH and Toxin A/B EIA NAAT Pros: Fast turn around time. Cons: Unnecessary toxins test with GDH is negative Nucleic acid amplification test (NAAT); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA) Who should be tested? C.diff colonization has been reported to be between 0–15% in healthy and 10–15% in hospitalized patients.( 7 , 37 )Therefore, it is important to only screen symptomatic individuals to avoid false positives as laboratory tests alone cannot differentiate between an actual infection and asymptomatic colonization.( 7 ) Fecal swabs cannot be used for toxin detection (inadequate sample) due to inadequate sample, instead they can only be used for culture or NAAT.( 2 , 5 ) Candidates for testing are those that are laxative free for 48 hours, Bristol 5 or more ≥ 3 bowel movements in 24 hours, abdominal pain/cramps, with no other clear cause of diarrhea.( 7 ) Patients with findings of colitis, severe ileus, or megacolon on imaging should be prioritized.( 5 ) Also, early surgery consult is recommended for those showing evidence of megacolon or ileus on imaging.( 4 ) Retesting individuals within 7 days of previous negative test is not recommended. Repeated testing can increase healthcare costs and false-positive results. Diagnostic yield of repeat testing is approximately 2%. It is also not recommended to repeat testing to check for cure, as greater than 60% of patients will remain positive after successful treatment.( 2 , 25 ) Limitation: Systematic review is limited by the inclusion and exclusion criteria. This systematic review was governed by testing and diagnosis in specific populations only. The majority of the included reports in this manuscript were review articles and guidelines. In addition, there is significant heterogenicity in different studies that evaluated the risk factors and correlation of CDI. More randomized controlled and blinded studies need to be conducted in the future for specific risk factor attributes that may increase and/or decrease CDI prevalence and incidence. Conclusion Clostridium difficile is a major cause of health care associated infections. There is an increased prevalence of this bacteria in the community from widespread contamination and transmission. The new emergence of the B1/NAP1/027 strain has caused widespread mortality and increased testing. The infection is a clinical syndrome that is defined by ≥ 3 unformed Bristol 5–7 bowel movements in the last 24 hours without another identifiable cause and positive stool testing. There are a wide variety of available diagnostic tests and the preferred tests are GDH antigen, toxin A/B EIA, and NAAT. These tests are accurate and make a timely diagnosis in the patient but it is imperative that we are aware of the limitations of each test. Toxin A/B EIA is not very sensitive while NAAT detects both toxigenic and non-toxigenic strains and does not differentiate between active disease or carrier state. The 2-step approach, multi-step approach, and modified multistep approach are the different algorithms used for testing and vary due to cost and institution. Specific populations are more predisposed to C. diff colitis due to dysregulation in the immune system, medications, and the acuity of care. There is a need for further research in specific disease groups as studies have numerous variables that produce heterogeneity and poor external validity. Declarations Author Contribution K.S: The corresponding author, wrote the methodology and results section and created Table 2, . Proofread and double-checked the final manuscript.A.K: prepared diagnosis section in Discussion and created Figures 3-4.D.S: Prepared the abstract for the manuscriptJ.P: Prepared the PRISMA 2020 flow diagram and Table 1.P.D: Wrote the risk factor part of the discussion along with Table 3.M.N: Wrote the ICU and IBD section in the discussion of this manuscript.C.C: Extracted all the files and removed duplicates in the result section of this paper and uploaded to Rayyan. Formated the references in APA.E.M: Dr. Morrison is an Infectious Disease physician and she provided edits to further clarify information throughout the manuscript from an infectious disease standpointW.S: Gastroenterologist and was the main mentor of this manuscript. Guided and provided assistance in edits to decrease the length of the manuscript. Also recommended this journal for submission. References Kodadek, L. M., & Lipsett, P. A. (2018). Prevention and treatment of Clostridium difficile enterocolitis. Advances in Surgery , 52 (1), 29–42. https://doi.org/10.1016/j.yasu.2018.04.001 Martínez-Meléndez, A., Camacho-Ortiz, A., Morfin-Otero, R., Maldonado-Garza, H. J., Villarreal-Treviño, L., & Garza-González, E. (2017). Current knowledge on the laboratory diagnosis of Clostridium difficile infection. World Journal of Gastroenterology , 23 (9), 1552–1567. https://doi.org/10.3748/wjg.v23.i9.1552 Smits, W. K., Lyras, D., Lacy, D. B., Wilcox, M. H., & Kuijper, E. J. (2016). Clostridium difficile infection. Nature Reviews Disease Primers , 2 , 16020. https://doi.org/10.1038/nrdp.2016.20 Stanley, J. D., Bartlett, J. G., Dart, B. W., 4th, & Ashcraft, J. H. (2013). Clostridium difficile infection. Current Problems in Surgery , 50 (7), 302–337. https://doi.org/10.1067/j.cpsurg.2013.02.004 Surawicz, C. M., Brandt, L. J., Binion, D. G., Ananthakrishnan, A. N., Curry, S. R., Gilligan, P. H., McFarland, L. V., Mellow, M., & Zuckerbraun, B. S. (2013). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. The American Journal of Gastroenterology , 108 (4), 478–499. https://doi.org/10.1038/ajg.2013.4 Xiao, Z., Chen, H., Chen, H., Wu, L., Yang, G., Wu, Y., & He, N. (2019). Advanced diagnostic strategies for Clostridium difficile Infection (CDI). Journal of Biomedical Nanotechnology , 15 (6), 1113–1134. https://doi.org/10.1166/jbn.2019.2782 Lübbert, C., John, E., & von Müller, L. (2014). Clostridium difficile infection: guideline-based diagnosis and treatment. Deutsches Arzteblatt International , 111 (43), 723–731. https://doi.org/10.3238/arztebl.2014.0723 Abreu Y Abreu, A. T., Velarde-Ruiz Velasco, J. A., Zavala-Solares, M. R., Remes-Troche, J. M., Carmona-Sánchez, R. I., Aldana-Ledesma, J. M., Camacho-Ortiz, A., Contreras-Omaña, R., Díaz-Seoane, R., Elizondo-Vázquez, C. T., Garza-González, E., Grajales-Figueroa, G., Gómez-Escudero, O., Jacobo-Karam, J. S., Morales-Arámbula, M., Olivares-Guzmán, L. O., Sifuentes-Osornio, J., Siu-Moguel, A. G., Soto-Solís, R., Valdovinos-García, L. R., … Lazo-de la Vega Jasso, S. A. (2019). Consensus on the prevention, diagnosis, and treatment of Clostridium difficile infection. Revista de Gastroenterologia de Mexico (English Edition) , 84 (2), 204–219. https://doi.org/10.1016/j.rgmx.2018.12.001 European Centre for Disease Prevention and Control (2018, October 19). Laboratory procedures for diagnosis and typing of human Clostridium difficile infection. https://www.ecdc.europa.eu/en/publications-data/laboratory-procedures-diagnosis-and-typing-human-clostridium-difficile-infection Guery, B., Barbut, F., & Tschudin-Sutter, S. (2020). Diagnostic and therapy of severe Clostridioides difficile infections in the ICU. Current Opinion in Critical Care , 26 (5), 450–458. https://doi.org/10.1097/MCC.0000000000000753 Srisajjakul, S., Prapaisilp, P., & Bangchokdee, S. (2022). Drug-induced bowel complications and toxicities: imaging findings and pearls. Abdominal Radiology , 47 (4), 1298–1310. https://doi.org/10.1007/s00261-022-03452-1 Guery, B., Galperine, T., & Barbut, F. (2019). Clostridioides difficile: Diagnosis and treatments. BMJ , 366 , l4609. https://doi.org/10.1136/bmj.l4609 Mileto, S., Das, A., & Lyras, D. (2019). Enterotoxic Clostridia: Clostridioides difficile infections. Microbiology Spectrum , 7 (3), https://doi.org/10.1128/microbiolspec.gpp3-0015-2018 Ong, G. K., Reidy, T. J., Huk, M. D., & Lane, F. R. (2017). Clostridium difficile colitis: a clinical review. American Journal of Surgery , 213 (3), 565–571. https://doi.org/10.1016/j.amjsurg.2016.10.035 Usacheva, E. A., Jin, J. P., & Peterson, L. R. (2016). Host response to Clostridium difficile infection: Diagnostics and detection. Journal of Global Antimicrobial Resistance , 7 , 93–101. https://doi.org/10.1016/j.jgar.2016.08.002 Bouza, E., Alcalá, L., & Reigadas, E. (2016). Optimizing the diagnostic testing of Clostridium difficile infection. Expert Review of Anti-Infective Therapy , 14 (9), 801–808. https://doi.org/10.1080/14787210.2016.1216313 Kaiser, A. M., Hogen, R., Bordeianou, L., Alavi, K., Wise, P. E., Sudan, R., & CME Committee of the SSAT (2015). Clostridium difficile infection from a surgical perspective. Journal of Gastrointestinal Surgery , 19 (7), 1363–1377. https://doi.org/10.1007/s11605-015-2785-4 Korman T. M. (2015). Diagnosis and management of Clostridium difficile infection. Seminars in Respiratory and Critical Care Medicine , 36 (1), 31–43. https://doi.org/10.1055/s-0034-1398741 Rineh, A., Kelso, M. J., Vatansever, F., Tegos, G. P., & Hamblin, M. R. (2014). Clostridium difficile infection: Molecular pathogenesis and novel therapeutics. Expert Review of Anti-Infective Therapy , 12 (1), 131–150. https://doi.org/10.1586/14787210.2014.866515 Berg, A. M., Kelly, C. P., & Farraye, F. A. (2013). Clostridium difficile infection in the inflammatory bowel disease patient. Inflammatory Bowel Diseases , 19 (1), 194–204. https://doi.org/10.1002/ibd.22964 Bloukh, S. I., & Bloukh, S. H. (2013). Clostridium difficile infection: an overview of the disease and its pathogenesis, diagnosis, treatment, prevention and management. Research Journal of Pharmaceutical, Biological and Chemical Sciences 4 (4), 1219-1232. Alrabaa, S., Noel, P.R., Wills, T. (2013, June). Clostridium difficile infection: What you need to know. Consultant360. 53(6):389–95. https://www.consultant360.com/article/clostridium-difficile-infection-what-you-need-know Kucharzik, T., Ellul, P., Greuter, T., Rahier, J. F., Verstockt, B., Abreu, C., Albuquerque, A., Allocca, M., Esteve, M., Farraye, F. A., Gordon, H., Karmiris, K., Kopylov, U., Kirchgesner, J., MacMahon, E., Magro, F., Maaser, C., de Ridder, L., Taxonera, C., Toruner, M., … Vavricka, S. (2021). ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease. Journal of Crohn's and Colitis , 15 (6), 879–913. https://doi.org/10.1093/ecco-jcc/jjab052 Lee, J. C., Hung, Y. P., Tsai, B. Y., Tsai, P. J., & Ko, W. C. (2021). Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations. Journal of Microbiology, Immunology, and Infection , 54 (6), 1111–1117. https://doi.org/10.1016/j.jmii.2020.07.012 Gupta, A., Wash, C., Wu, Y., Sorrentino, D., & Nguyen, V. Q. (2021). Diagnostic modality of Clostridioides difficile infection predicts treatment response and outcomes in inflammatory bowel disease. Digestive Diseases and Sciences , 66 (2), 547–553. https://doi.org/10.1007/s10620-020-06205-6 Sheitoyan-Pesant, C., Abou Chakra, C. N., Pépin, J., Marcil-Héguy, A., Nault, V., & Valiquette, L. (2016). Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection. Clinical Infectious Diseases , 62 (5), 574–580. https://doi.org/10.1093/cid/civ958 Spadão, F., Gerhardt, J., Guimarães, T., Dulley, F., Almeida Junior, J. N., Batista, M. V., Shikanai-Yasuda, M. A., Levin, A. S., & Costa, S. F. (2014). Incidence of diarrhea by Clostridium difficile in hematologic patients and hematopoietic stem cell transplantation patients: Risk factors for severe forms and death. Revista do Instituto de Medicina Tropical de Sao Paulo , 56 (4), 325–331. https://doi.org/10.1590/s0036-46652014000400010 Mostafa M.S., Abd El Hamid H.S.. (2022). PCR versus toxigenic culture in diagnosis of antibiotic-associated diarrhea due to Clostridium difficile infection. The Egyptian Journal of Hospital Medicine, 88 (1):3396–400. Lanis, J. M., Heinlen, L. D., James, J. A., & Ballard, J. D. (2013). Clostridium difficile 027/BI/NAP1 encodes a hypertoxic and antigenically variable form of TcdB. PLoS Pathogens , 9 (8), e1003523. https://doi.org/10.1371/journal.ppat.1003523 Valiquette, L., Cossette, B., Garant, M. P., Diab, H., & Pépin, J. (2007). Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain. Clinical Infectious Diseases , 45( Suppl 2), S112–S121. https://doi.org/10.1086/519258 Hensgens, M. P., Goorhuis, A., Dekkers, O. M., & Kuijper, E. J. (2012). Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. The Journal of Antimicrobial Chemotherapy , 67 (3), 742–748. https://doi.org/10.1093/jac/dkr508 Baines, S. D., Noel, A. R., Huscroft, G. S., Todhunter, S. L., O'Connor, R., Hobbs, J. K., Freeman, J., Lovering, A. M., & Wilcox, M. H. (2011). Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. The Journal of Antimicrobial Chemotherapy . 66 (7):1537-1546. https://doi.org/10.1093/jac/dkr155 Valerio, M., Pedromingo, M., Muñoz, P., Alcalá, L., Marin, M., Peláez, T., Giannella, M., & Bouza, E. (2012). Potential protective role of linezolid against Clostridium difficile infection. International Journal of Antimicrobial Agents , 39 (5), 414–419. https://doi.org/10.1016/j.ijantimicag.2012.01.005 Janarthanan S., Ditah I., Adler D.G., Ehrinpreis M.N. (2012). Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. American Journal of Gastroenterology , 107 (7):1001–10. https://doi.org/ 10.1038/ajg.2012.179 Weiss K. (2009). Toxin-binding treatment for Clostridium difficile: a review including reports of studies with tolevamer. International Journal of Antimicrobial Agents , 33 (1), 4–7. https://doi.org/10.1016/j.ijantimicag.2008.07.011 Galdys, A. L., Nelson, J. S., Shutt, K. A., Schlackman, J. L., Pakstis, D. L., Pasculle, A. W., Marsh, J. W., Harrison, L. H., & Curry, S. R. (2014). Prevalence and duration of asymptomatic Clostridium difficile carriage among healthy subjects in Pittsburgh, Pennsylvania. Journal of Clinical Microbiology , 52 (7), 2406–2409. https://doi.org/10.1128/JCM.00222-14 Napolitano, L. M., & Edmiston, C. E., Jr (2017). Clostridium difficile disease: Diagnosis, pathogenesis, and treatment update. Surgery , 162 (2), 325–348. https://doi.org/10.1016/j.surg.2017.01.018 Muñoz, P., Giannella, M., Alcalá, L., Sarmiento, E., Fernandez Yañez, J., Palomo, J., Catalán, P., Carbone, J., & Bouza, E. (2007). Clostridium difficile-associated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer? The Journal of Heart and Lung Transplantation , 26 (9), 907–914. https://doi.org/10.1016/j.healun.2007.07.010 Kent, K. C., Rubin, M. S., Wroblewski, L., Hanff, P. A., & Silen, W. (1998). The impact of Clostridium difficile on a surgical service: a prospective study of 374 patients. Annals of Surgery , 227 (2), 296–301. https://doi.org/10.1097/00000658-199802000-00021 McDonald, L. C., Gerding, D. N., Johnson, S., Bakken, J. S., Carroll, K. C., Coffin, S. E., Dubberke, E. R., Garey, K. W., Gould, C. V., Kelly, C., Loo, V., Shaklee Sammons, J., Sandora, T. J., & Wilcox, M. H. (2018). Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical Infectious Diseases , 66 (7), e1–e48. https://doi.org/10.1093/cid/cix1085 Nguyen, G. C., Kaplan, G. G., Harris, M. L., & Brant, S. R. (2008). A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. The American Journal of Gastroenterology , 103 (6), 1443–1450. https://doi.org/10.1111/j.1572-0241.2007.01780.x Freedberg, D. E., Zhou, M. J., Cohen, M. E., Annavajhala, M. K., Khan, S., Moscoso, D. I., Brooks, C., Whittier, S., Chong, D. H., Uhlemann, A. C., Abrams, J. A. (2018). Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. Intensive Care Medicine, 44 , 1203–1211 (2018). https://doi.org/10.1007/s00134-018-5268-8 Chang, V. T., & Nelson, K. (2000). The role of physical proximity in nosocomial diarrhea. Clinical Infectious Diseases , 31 (3), 717–722. https://doi.org/10.1086/314030 Arimoto, J., Horita, N., Kato, S., Fuyuki, A., Higurashi, T., Ohkubo, H., Endo, H., Takashi, N., Kaneko, T., Nakajima, A. (2016). Diagnostic test accuracy of glutamate dehydrogenase for Clostridium difficile: Systematic review and meta-analysis. Scientific Reports , 6:29754. https://doi.org/10.1038/srep29754 Crobach, M. J., Planche, T., Eckert, C., Barbut, F., Terveer, E. M., Dekkers, O. M., Wilcox, M. H., & Kuijper, E. J. (2016). European Society of Clinical Microbiology and Infectious Diseases: Update of the diagnostic guidance document for Clostridium difficile infection. Clinical Microbiology and Infection , 22( Suppl 4), S63–S81. https://doi.org/10.1016/j.cmi.2016.03.010 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.pdf Table2.pdf Cite Share Download PDF Status: Published Journal Publication published 24 Apr, 2024 Read the published version in Cureus → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3928202","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":271704391,"identity":"62fe26e8-5d5a-4d26-a771-6b9042921382","order_by":0,"name":"Karan Bir 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1","display":"","copyAsset":false,"role":"figure","size":468751,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA 2020 flow diagram for systematic review.\u003c/p\u003e","description":"","filename":"FigurePage1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/10e5e0c3ff984df879037abd.jpg"},{"id":51017293,"identity":"5067a0b1-5dbe-4fe0-9b4c-3e6954af96a1","added_by":"auto","created_at":"2024-02-12 19:15:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":370830,"visible":true,"origin":"","legend":"\u003cp\u003e2 step diagnostic approach for C.diff\u003c/p\u003e","description":"","filename":"FigurePage2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/df715fa583819ae148f861dc.jpg"},{"id":51017294,"identity":"8230f731-a055-48c7-a545-af3d1eb129fb","added_by":"auto","created_at":"2024-02-12 19:15:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":396173,"visible":true,"origin":"","legend":"\u003cp\u003eMulti-step approach of the original 2-step algorithm\u003c/p\u003e","description":"","filename":"FigurePage3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/de93f372499830aa5e06863e.jpg"},{"id":51017295,"identity":"55724c3f-9a7e-4259-b137-90e4842ea32c","added_by":"auto","created_at":"2024-02-12 19:15:05","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":409430,"visible":true,"origin":"","legend":"\u003cp\u003eModification of the multi-step approach\u003c/p\u003e","description":"","filename":"FigurePage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/b536fd709b21b9161195b4c1.jpg"},{"id":55337305,"identity":"b5960259-d368-492e-9364-9a386e68057e","added_by":"auto","created_at":"2024-04-26 00:38:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":616535,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/7699e1e3-3685-40fa-9c66-944fea75340a.pdf"},{"id":51017292,"identity":"69a91c3b-01c1-42c5-a4b7-9a637299ec39","added_by":"auto","created_at":"2024-02-12 19:15:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":83445,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/9a1b7e9049264eeab6dd9069.pdf"},{"id":51017296,"identity":"88ebccc0-71c0-44be-a73b-b88576a58092","added_by":"auto","created_at":"2024-02-12 19:15:05","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":145136,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3928202/v1/732da58db47a869bdc3d47de.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review","fulltext":[{"header":"Introduction","content":"\u003cp\u003e \u003cem\u003eClostridioides difficile\u003c/em\u003e (formerly known as \u003cem\u003eClostridium difficile\u003c/em\u003e) is a gram positive, spore forming, strict anaerobic bacillus.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) The organism lives harmoniously in the colon with its growth and production suppressed by normal gut flora. This bacterium was discovered in 1935 and later the first case of antibiotic associated pseudomembranous colitis was diagnosed in 1978. At this time, the strain was originally named \u003cem\u003eBacillus difficilis\u003c/em\u003e due to its microscopic appearance and difficult cultivation.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) This organism is a leading cause of gastrointestinal disease and costs the health system 4\u0026nbsp;billion dollars annually.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) Since the 20th century, CDI rates have been increasing worldwide with increasing incidence in adults. In 2002, high mortality rates were attributed to a strain called ribotype 027/B1, also known as NAP-1.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) There was a lack of systematic surveillance for CDI prior to 2003. After the worldwide outbreak of the NAP-1 strain, the Centres for Disease Control and Prevention (CDC) approximated that there were 500,000 CDI cases and 29,000 deaths in the America in 2011.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) In 2010 study found that 97% of cases were related to healthcare and 75% of these patients had a history of previous hospitalizations.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) Trends from another study demonstrated incidence increasing from 5.5/10,000 to 11.2/10,000, with more dramatic increases in adults aged adults aged\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;65 of age.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) The emergence of NAP-1 variant of \u003cem\u003eClostridioides difficile\u003c/em\u003e (C.diff) has been as high as 30% in hospitalized patients, accounts for more than 300,000 newly diagnosed cases per year, and up to 40% of community acquired infections required hospitalization.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSince the discovery of the NAP-1 strain, testing for C.diff has increased. The virulence of C.diff is from two clostridial toxins, enterotoxin (toxin A) and cytotoxin (toxin B). These toxins are encoded by genes, cdtA and cdtB, on the pathogenicity locus (PaLoc).(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) All strains of C.diff have the ability to ferment and produce glutamate dehydrogenase (GDH) irrespective of toxigenic properties. This has led to the test for GDH which has a sensitivity (Sn) ranging from 79.5\u0026ndash;100%, specificity (Sp) of 82.7\u0026ndash;100%, negative predictive value (NPV) of 100%.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) GDH testing does not distinguish between toxigenic and non-toxigenic strains, therefore, a confirmatory test is required for toxin analysis. The best test for detecting toxin production is a toxigenic culture (TC) due to its high Sn and Sp, but due to its turnaround times, other assays are preferred in the modern era.(\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) The toxin A/B enzyme immunoassay (EIA) is a common confirmatory test which detects antibodies directed against both virulent clostridial toxins. The Sn varies from 53\u0026ndash;85% with a Sp of 91\u0026ndash;98%.(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) Due to poor Sn, combination of rapid turn-over tests and a multi-step approach are considered to avoid false positives and false negatives.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e) In addition, sole reliance on molecular testing for toxins increases the likelihood of over-diagnosis and over-treatment of C.diff. This conclusion is most important in patients that have asymptomatic colonization or carriage of C.diff. This carriage is common in healthcare associated facilities and in the community and it is estimated that prevalence ranges from 7\u0026ndash;18%.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eDesign:\u003c/h2\u003e\n \u003cp\u003eThis systematic review was created to establish a comprehensive collection of current data from different databases to align with the most up to date evidence-based practice patterns for the workup of CDI. This study followed the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) checklist. Our research was not registered online.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eSearch strategy and selection:\u003c/h2\u003e\n \u003cp\u003eWe evaluated studies that identified the roles of biochemical testing of C. diff and implications of disease severity and development of toxic megacolon in a subset of patient populations. On 2 February 2023 author CC searched the databases PubMed (1946-present), Scopus (1788-present), and the Cumulative Index of Nursing and Allied Health Literature (CINAHL Complete, 1937-present) to identify relevant reports. Search terms used included index and keyword terms for \u0026ldquo;clostridioides difficile\u0026rdquo;, \u0026ldquo;toxin assay\u0026rdquo;, and \u0026ldquo;toxic megacolon\u0026rdquo;. The search strategy is listed in Table\u0026nbsp;1. Inclusion criteria were English language articles published between the years 2012 to 2023, with eligibility based on population, type of study, and outcomes. Exclusion criteria were non-English language reports that were experimental (except for one study which was deemed necessary for this review) or basic science, poor quality appraisal, pediatric population, and outdated guidelines. All six investigators had to agree to including and/or excluding the studies based on these criteria before they were finalized into this paper. One experimental study was included in this systematic review for the purpose of identifying the hypervirulent strain NAP-1. After removing duplicates, the full text articles of the search results (n\u0026thinsp;=\u0026thinsp;76) were uploaded to Rayyan, a Web-based platform used to organize and manage articles for systematic reviews.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n \u003ch2\u003eData extraction:\u003c/h2\u003e\n \u003cp\u003eAll five investigators (A.K, J.A, M.N, P.D, D.S) extracted five reports each and two investigators (K.S and G.M) extracted three reports from the eligible studies based on: last name of author, publication year, number of patients, purpose of the study, and results. All appropriate records and studies grouped based on study type and listed in Table\u0026nbsp;2 in descending year of publication.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eQuality appraisal:\u003c/h2\u003e\n \u003cp\u003eTwo investigators (K.S and A.K) independently reviewed each of the thirty included reports for authenticity and quality. We utilized the JBI global website to methodologically assess the transparency of each included report. Review articles (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), retrospective cohorts (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e), guidelines (\u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e), experimental (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e), and cross-sectional study (\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e) were criticized to have excellent appraisal. The following instruments were used: Text and opinion for review articles, the revised \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eA\u003c/span\u003eppraisal of \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eG\u003c/span\u003euidelines for \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eRE\u003c/span\u003esearch \u0026amp; \u003cspan type=\"BoldUnderline\" class=\"BoldUnderline\" name=\"Emphasis\"\u003eE\u003c/span\u003evaluation (AGREE) II for guidelines, diagnostic accuracy tool for the cross-sectional study, experimental study checklist for the experimental study, and cohort study checklist for the cohort studies.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAfter identifying 85 records from Scopus, 24 records from PubMed, and 37 records from CINAHL we removed 70 duplicate records using an excel spreadsheet. We manually excluded 6 records based on publication year. Lastly, we excluded records based on abstract screening and not meeting eligibility criteria. Overall, 27 reports were eligible for inclusion in this systematic review as listed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this part of the manuscript, we discuss definitions, risk factors, emphasis on specific patient populations, diagnosis, and testing.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRisk factors:\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRisk factor table for initial and recurrent clostridioides difficile.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eIncreased risk\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eReduced risk\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eInitial CDI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003erCDI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e-Pulsed dose (every 48 hours) in rCDI\u003c/p\u003e \u003cp\u003e-Hand hygiene, barrier precautions, and infection control programs\u003c/p\u003e \u003cp\u003e-Antibiotic stewardship\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDependent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIndependent\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e-Recent gastro-intestinal surgery (particularly colectomy, ileo-anal pouch, and ileostomy)\u003c/p\u003e \u003cp\u003e-Recent exposure to anti-neoplastic agents\u003c/p\u003e \u003cp\u003e-IBD\u003c/p\u003e \u003cp\u003e-Previous hospitalization\u003c/p\u003e \u003cp\u003e-Advanced age (\u0026gt;\u0026thinsp;60)\u003c/p\u003e \u003cp\u003e-Greater co-morbid conditions\u003c/p\u003e \u003cp\u003e-Solid and hematopoietic transplant\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-Antibiotics\u003c/p\u003e \u003cp\u003e-PPI in cirrhosis\u003c/p\u003e \u003cp\u003e-Sharing room with CDI patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-Non-C.diff antibiotics\u003c/p\u003e \u003cp\u003e-Sharing room with CDI patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-Advanced age (\u0026gt;\u0026thinsp;65)\u003c/p\u003e \u003cp\u003e-Poor health status\u003c/p\u003e \u003cp\u003eSolid and hematopoietic transplant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCDI, clostridioides difficile infection; PPI, proton pump inhibitors; IBD, inflammatory bowel disease; rCDI, recurrent clostridioides difficile infection; C. diff, clostridioides difficile.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eAntimicrobials:\u003c/h2\u003e \u003cp\u003ePredisposing risk factors for CDI are listed on Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\u003c/span\u003e but, the two main risk factors for CDI are exposure to antibiotics and C.diff.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11 CR12 CR13\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e) Antibiotic use is the strongest risk factor for development of CDI and the most common include clindamycin, fluoroquinolones, and cephalosporins. Optimization of antimicrobials and antibiotic stewardship have been shown to reduce CDI incidence by up to 60%.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e) In the Netherlands, a three-year case control study studied the association between duration and dosage of antibiotics. Third-generation cephalosporins had the highest odds followed by carbapenems, and second-generation cephalosporins of developing CDI (OR 5.3, 4.7, 3.3, respectively).(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e) Those currently on antibiotics and within 30 days of completion had the greatest risk (OR 6.7\u0026ndash;10.4).(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) Interestingly, linezolid has conflicting data on C.diff risk as some research has shown a theoretical inhibition of exotoxin production and reduction in CDI inhibited.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) The study in Main Medical Center was primarily experimental in vitro gut model and the second study lacked external validity as the patient population of interests were principally heart transplant recipient and had a small sample size (n\u0026thinsp;=\u0026thinsp;91). On the other hand, one study found patients who underwent HSCT more prone to developing CDI with linezolid.(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e) Along depressed immune system due to multiple other comorbities, these patients lose their protective gut microbiome from gastrointestinal inflammation.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eNonantimicrobial risk factors:\u003c/h2\u003e \u003cp\u003eProton pump inhibitors (PPIs) are common medications used in all clinical settings that have been associated to CDI. A meta-analysis of approximately 299,000 participants from 23 retrospective studies demonstrated CDI incidence of 64.9% in PPI users.(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e) The meta-analysis concluded with judicious PPI prescriptions. The study has limitations as the length of duration of PPIs was not defined. In addition, the study incorporated the \u0026lsquo;trim and fill\u0026rsquo; method to adjust the asymmetrical funnel plot which can lead to over- or under-estimation of true measures in this meta-analysis. Other retrospective studies or systematic/meta-analysis that determined both PPIs and histamine receptor-2 blockers increase CDI. Although it is generally accepted by the Federal of Drug Administration (FDA) that PPIs increase CDI, there is considerable controversy based on the current available literature.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eReduced risk:\u003c/h2\u003e \u003cp\u003eA detailed list of factors that decrease the risk of CDI are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Binders that are commonly used for bile sequestration such as cholestyramine and colestipol have been shown to decrease risk of CDI. In lieu of these resins, vancomycin is highly efficacious and clinicians should be reminded to set a timing interval between oral vancomycin and bile resins. Currently, 4,000 mg of cholestyramine is given three to four times daily and two to three hours after oral vancomycin.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) Apart from medications, asymptomatic colonization is thought to be immunoprotective. Approximately 40% of patients with community care associated C.diff do not have antibiotic exposure.(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) In fact, 10% of healthy adults, up to 50% of institutionalized patients, and neonates become asymptomatic reservoir and spread this bacteria throughout the healthcare system.(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) Carriers have immunoglobulin G (IgG) antitoxin A and B antibodies against C.diff, thereby, inhibiting toxin production. It has been postulated that earlier colonization of asymptomatic C.diff may lead to a robust memory immunity until the later decades of life. As antitoxin A and B antibodies production weans with aging and apoptosis, this poses a risk factor for CDI in the elderly.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSpecial risk populations:\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003eHypogammaglobulinemia:\u003c/h2\u003e \u003cp\u003eAs forementioned, humoral immunity protects against toxicogenic colonization of C.diff. Patients with solid organ transplant(s) (liver, kidney, heart and lung), may benefit from passive immunization for C.diff. These immunosuppressed receipts receiving prophylactic antibiotics post-transplant have a prevalence of 1.0\u0026ndash;30% for CDI.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) In addition, hypogammaglobulinemia has been found to be an independent risk factor for CDI and rCDI. In a prospective study, 235 patients underwent heart transplant and 35 developed CDI. Of these 35 patients, immunoglobulin levels were determined to be low in 6 of the 7 tested individuals.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) Although routine IVIG administration is not recommended, it should be considered in patients with hypogammaglobulinemia that have other conferring comorbid conditions for CDI.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSurgical:\u003c/h2\u003e \u003cp\u003eIn the surgical patient, there are multiple risk factors that both confound and modify the effect of CDI such as gastrointestinal surgery, emergent surgery, organ transplant, and nasogastric tube feeds. Gastrointestinal surgeons influence CDI both directly (by surgical treatment) and indirectly (by inadvertently contributing to CDI by an unrelated surgery). There is evidence that enteral tube feeding in patients with anatomical or dynamic obstructions increases the risk of CDI. The transit time of stool is decreased and allows for proliferation of toxins resulting in toxin proliferation.(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e) According to the 2017 Infectious Disease Society Association (IDSA), a match cohort study demonstrated enteral feeds increase the risk of CDI.(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) Therefore, it is best practice to discontinue NGT early to reduce the possibility of cross-contamination from hospital instruments.(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eInflammatory bowel disease:\u003c/h2\u003e \u003cp\u003eInflammatory bowel disease (IBD) harbors a pro-inflammatory state that causes physiological, anatomical, and immunological changes to the gastrointestinal tract. As opposed to HCO-HFA and CAO-HFA CDI, IBD specific populations present with CAA CDI. A national prevalence survey found CDI in ulcerative colitis (UC) to be 37 per 1,000, 11 per 1,000 in Crohn\u0026rsquo;s disease (CD)m and 4 per 1,000 in general medical patients.(\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e) IBD patients suffer from acute flares leading to increased hospitalizations, immunosuppression with corticosteroids, and increased prescription of antimicrobials. Of all the forementioned factors, corticosteroid administration has the greatest risk, with a threefold increase in CDI incidence.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) A study in British Columbia determined that corticosteroids to be an independent risk factor in IBD.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Interestingly, it is unclear what risk immunotherapy poses in this population. The complications of CDI are much higher in UC (9.5%) than with CD (7%) partly due to more extensive involvement of the colonic mucosa in UC.(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e) Patients with colectomy and have ileo-anal pouch or ileostomy remain at an elevated risk of CDI as well. Symptoms such as increasing ostomy output, bleeding, changes in stool consistency and frequency, and along with systemic markers of inflammation should prompt evaluation of an infectious source. Healthcare professionals should have a low threshold to initiate therapy however should be aware of rising metronidazole resistance in this group of patients.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) In terms of testing, IBD patients are more likely to have toxin positive strains if there is one or more classic risk factor for CDI (antibiotic exposure, recent hospitalization, institutionalized, history of surgery) in comparison to toxin negative strains (68% vs 31%).(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eIntensive care unit (ICU):\u003c/h2\u003e \u003cp\u003ePatients that are directly admitted to the ICU have been found to be colonized with toxicogenic C.diff strains. Approximately 15% of 5,300 admitted patients were confirmed to have CDI and this correlates to the increased incidence of community acquired CDI.(\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e) Patients found to have CDI at the time of ICU admission were much more likely to have subsequent CDI in the future (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e) A retrospective study in Taiwan found that the diarrheal group had a longer length of ICU stay than the ileal group (28 vs 12 days, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01).(\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) A cohort study determined that the size of the unity and capacity of rooms were related to horizontal transmission.(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) Therefore, hand hygiene is the cornerstone in the ICU to decrease transmission of spores. In the ICU, there is accumulation of co-morbid conditions, virulent organisms, and use of broad-spectrum antibiotic that increase CDI risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eDiagnosis of Clostridium Difficile infection\u003c/h2\u003e \u003cp\u003eCDI diagnosis requires a clinical syndrome accompanied by a biochemical test for confirmation. CDI is defined as the presence of detectable toxicogenic C.diff strain and clinical syndrome of acute diarrhea consistent with \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;3 unformed Bristol 5\u0026ndash;7 stools in the last 24 hours without another explanation and prior exposure of antibiotics in the last 2 months. Each test must be accurate to diagnose the pathogen and timely to ensure rapid isolation for infection control and preventing progression. C.diff colitis can be a challenge to diagnose as symptoms can overlap with other general diarrheal illnesses and detection of nontoxigenic strains of C.diff which do not require treatment.\u003c/p\u003e \u003cp\u003eTo diagnose a clostridium difficile infection, patients must have acute diarrhea in addition to \u003cem\u003eeither\u003c/em\u003e toxigenic difficile strain \u003cem\u003eor\u003c/em\u003e C.diff toxins in stool samples.(\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) C.diff tests include toxigenic culture (TC), Glutamate dehydrogenase (GDH) detection assays, nucleic acid amplification tests (NAATs), cell cytotoxicity neutralization assays (CCNAs), and toxin detection tests (EIA). Each test is compared in details in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Patients who are at high risk for CDI are the ones that have received antibiotics in the last 3 months, hospitalized for more than 3 days, and atleast 65 years of age.(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClostridioides difficile tests, turnaround time, sensitivity/specificity, and important details regarding each test.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eType of tests\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTurnaround (h)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSn/Sp\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDetails\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48-120h (5,6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87\u0026ndash;100%/94\u0026ndash;100% (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThis is a gold standard test. Isolates toxigenic strains of C.diff from the stool culture or rectal swab.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDH/EIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2h (6,14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;90%/80\u0026ndash;100% (7,14,32,33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eConsidered the first test to order for screening.(34) Quicker and more sensitive than toxin EIAs. Test uses antibodies to detect the presence of GDH, a cell wall-associated enzyme that is present in both toxigenic and nontoxigenic strains. Therefore, cannot be used alone in the diagnosis of CDI.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNAAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4h (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%/70% (14,35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDetects nucleic acid sequences through amplifications of the genes that produce toxins A and B (TcdA and TcdB respectively). Detects toxin genes instead of active toxin, it cannot differentiate between CDI and asymptomatic carriage.(35) NAAT can be done by PCR (polymerase chain reaction) or LAMP (loop-mediated isothermal amplification).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCNAs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72-96h (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u0026ndash;100%/98\u0026ndash;99% (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThis test works by inoculating a stool sample onto two sets of sensitive tissue culture cells, first set without C.diff anti-toxin and the second set with the anti-toxin. Positive if cytopathic effect in the first set.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxin ELISA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;2h (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53\u0026ndash;85%/91\u0026ndash;98% (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThis test uses antibodies to detect the presence of C.diff toxins A/B. A negative toxin assay does not rule out toxigenic strains. Combining a high sensitivity test (like GDH) with EIA can make up for the low sensitivity of this test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHours (h); Sensitivity/Specificity (Sn/Sp); Toxigenic culture (TC); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA); Nucleic acid amplification test (NAAT); Cytotoxicity neutralization assays (CCNAs); Toxin A B enzyme-linked immunosorbent assay (ELISA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic algorithms\u003c/h2\u003e \u003cp\u003eNo stand alone test can distinguish between toxigenic/nontoxigenic strains and asymptomatic colonization as described in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e5\u003c/span\u003e.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Therefore, a 2-step or multi step diagnostic algorithms have been used to improve the diagnosis of CDI. The 2-step approach starts by a high sensitive test (GDH EIA or NAAT) followed by a high specificity confirmatory test (TcdA /TcdB EIAs) per the 2016 Europe and UK guidelines (ESCMID).(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClostridium difficile testing with specific aim of testing\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDetection of C.diff\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDetection of toxins A and/or B\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTC (toxigenic C.diff strain)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCCNAs: Detects TcdA and TcdB\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDH EIA (Toxigenic and nontoxigenic strains)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eToxin A B immunoassays (ELISA)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCR-NAAT: Detects TcdA and TcdB genes (Toxigenic strains)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eClostridioides difficile (C.diff); Toxigenic culture (TC); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA); Polymerase chain reaction nucleic acid amplification test (PCR-NAAT); Toxin A gene (TcdA) and Toxin B gene (TcdB); Cytotoxicity neutralization assays (CCNAs).\u003c/p\u003e \u003cp\u003eMost algorithms start with a GDH test followed by toxin EIA as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Some algorithms start with NAAT instead of GDH followed by toxin EIA which is more expensive but has a higher diagnostic accuracy. Economic studies showed that starting with GDH costs approximately \u003cspan\u003e$\u003c/span\u003e10 per algorithm vs \u003cspan\u003e$\u003c/span\u003e30 per algorithm starting with PCR.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Therefore, many small community hospitals and long term care facilities perform GDH with toxin A/B EIA and subsequent NAAT for inconsistent results. This is referred to as the \u0026ldquo;multi-step approach\u0026rdquo; where the NAAT is used to differentiate if the positive GDH was due to toxigenic strain or nontoxigenic strain as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Another modification of the multistep algorithm is to combine step 1 and step 2 together by testing for GDH and toxins at the same time, followed by NAAT if inconsistent results as described in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The advantage of this modification is saving time by combining steps 1 and 2 together as described in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e6\u003c/span\u003e. The disadvantage is the cost of the Toxins EIA test which is usually unnecessary if the GDH is negative. The previous 3 algorithms summarize the recommended testing by the ESGCD and ESCMID.(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of 2-step, multi-step, and modified multi-step algorithm\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlgorithm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSecond test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eThird test\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdvantages/Disadvantages\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 step\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNAAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToxin A/B EIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN/A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePros: Faster\u003c/p\u003e \u003cp\u003eCons: More expensive\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMulti-step\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGDH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eToxin A/B EIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNAAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePros: Most cost effective.\u003c/p\u003e \u003cp\u003eCons: Time consuming, Multiple steps.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModified multi-step\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eGDH and Toxin A/B EIA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNAAT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePros: Fast turn around time.\u003c/p\u003e \u003cp\u003eCons: Unnecessary toxins test with GDH is negative\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNucleic acid amplification test (NAAT); Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eWho should be tested?\u003c/h2\u003e \u003cp\u003eC.diff colonization has been reported to be between 0\u0026ndash;15% in healthy and 10\u0026ndash;15% in hospitalized patients.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e)Therefore, it is important to only screen symptomatic individuals to avoid false positives as laboratory tests alone cannot differentiate between an actual infection and asymptomatic colonization.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Fecal swabs cannot be used for toxin detection (inadequate sample) due to inadequate sample, instead they can only be used for culture or NAAT.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eCandidates for testing are those that are laxative free for 48 hours, Bristol 5 or more\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;3 bowel movements in 24 hours, abdominal pain/cramps, with no other clear cause of diarrhea.(\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) Patients with findings of colitis, severe ileus, or megacolon on imaging should be prioritized.(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) Also, early surgery consult is recommended for those showing evidence of megacolon or ileus on imaging.(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eRetesting individuals within 7 days of previous negative test is not recommended. Repeated testing can increase healthcare costs and false-positive results. Diagnostic yield of repeat testing is approximately 2%. It is also not recommended to repeat testing to check for cure, as greater than 60% of patients will remain positive after successful treatment.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eLimitation:\u003c/h2\u003e \u003cp\u003e Systematic review is limited by the inclusion and exclusion criteria. This systematic review was governed by testing and diagnosis in specific populations only. The majority of the included reports in this manuscript were review articles and guidelines. In addition, there is significant heterogenicity in different studies that evaluated the risk factors and correlation of CDI. More randomized controlled and blinded studies need to be conducted in the future for specific risk factor attributes that may increase and/or decrease CDI prevalence and incidence.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eClostridium difficile is a major cause of health care associated infections. There is an increased prevalence of this bacteria in the community from widespread contamination and transmission. The new emergence of the B1/NAP1/027 strain has caused widespread mortality and increased testing. The infection is a clinical syndrome that is defined by \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;3 unformed Bristol 5\u0026ndash;7 bowel movements in the last 24 hours without another identifiable cause and positive stool testing. There are a wide variety of available diagnostic tests and the preferred tests are GDH antigen, toxin A/B EIA, and NAAT. These tests are accurate and make a timely diagnosis in the patient but it is imperative that we are aware of the limitations of each test. Toxin A/B EIA is not very sensitive while NAAT detects both toxigenic and non-toxigenic strains and does not differentiate between active disease or carrier state. The 2-step approach, multi-step approach, and modified multistep approach are the different algorithms used for testing and vary due to cost and institution. Specific populations are more predisposed to C. diff colitis due to dysregulation in the immune system, medications, and the acuity of care. There is a need for further research in specific disease groups as studies have numerous variables that produce heterogeneity and poor external validity.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eK.S: The corresponding author, wrote the methodology and results section and created Table 2, . Proofread and double-checked the final manuscript.A.K: prepared diagnosis section in Discussion and created Figures 3-4.D.S: Prepared the abstract for the manuscriptJ.P: Prepared the PRISMA 2020 flow diagram and Table 1.P.D: Wrote the risk factor part of the discussion along with Table 3.M.N: Wrote the ICU and IBD section in the discussion of this manuscript.C.C: Extracted all the files and removed duplicates in the result section of this paper and uploaded to Rayyan. Formated the references in APA.E.M: Dr. Morrison is an Infectious Disease physician and she provided edits to further clarify information throughout the manuscript from an infectious disease standpointW.S: Gastroenterologist and was the main mentor of this manuscript. Guided and provided assistance in edits to decrease the length of the manuscript. Also recommended this journal for submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKodadek, L. M., \u0026amp; Lipsett, P. A. (2018). Prevention and treatment of Clostridium difficile enterocolitis. \u003cem\u003eAdvances in Surgery\u003c/em\u003e, \u003cem\u003e52\u003c/em\u003e(1), 29\u0026ndash;42. https://doi.org/10.1016/j.yasu.2018.04.001\u003c/li\u003e\n\u003cli\u003eMart\u0026iacute;nez-Mel\u0026eacute;ndez, A., Camacho-Ortiz, A., Morfin-Otero, R., Maldonado-Garza, H. J., Villarreal-Trevi\u0026ntilde;o, L., \u0026amp; Garza-Gonz\u0026aacute;lez, E. (2017). Current knowledge on the laboratory diagnosis of Clostridium difficile infection. \u003cem\u003eWorld Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(9), 1552\u0026ndash;1567. https://doi.org/10.3748/wjg.v23.i9.1552\u003c/li\u003e\n\u003cli\u003eSmits, W. K., Lyras, D., Lacy, D. B., Wilcox, M. H., \u0026amp; Kuijper, E. J. (2016). Clostridium difficile infection. \u003cem\u003eNature Reviews Disease Primers\u003c/em\u003e, \u003cem\u003e2\u003c/em\u003e, 16020. https://doi.org/10.1038/nrdp.2016.20\u003c/li\u003e\n\u003cli\u003eStanley, J. D., Bartlett, J. G., Dart, B. W., 4th, \u0026amp; Ashcraft, J. H. (2013). Clostridium difficile infection. \u003cem\u003eCurrent Problems in Surgery\u003c/em\u003e, \u003cem\u003e50\u003c/em\u003e(7), 302\u0026ndash;337. https://doi.org/10.1067/j.cpsurg.2013.02.004 \u003c/li\u003e\n\u003cli\u003eSurawicz, C. M., Brandt, L. J., Binion, D. G., Ananthakrishnan, A. N., Curry, S. R., Gilligan, P. H., McFarland, L. V., Mellow, M., \u0026amp; Zuckerbraun, B. S. (2013). Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. \u003cem\u003eThe American Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e108\u003c/em\u003e(4), 478\u0026ndash;499. https://doi.org/10.1038/ajg.2013.4\u003c/li\u003e\n\u003cli\u003eXiao, Z., Chen, H., Chen, H., Wu, L., Yang, G., Wu, Y., \u0026amp; He, N. (2019). Advanced diagnostic strategies for Clostridium difficile Infection (CDI). \u003cem\u003eJournal of Biomedical Nanotechnology\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(6), 1113\u0026ndash;1134. https://doi.org/10.1166/jbn.2019.2782 \u003c/li\u003e\n\u003cli\u003eL\u0026uuml;bbert, C., John, E., \u0026amp; von M\u0026uuml;ller, L. (2014). Clostridium difficile infection: guideline-based diagnosis and treatment. \u003cem\u003eDeutsches Arzteblatt International\u003c/em\u003e, \u003cem\u003e111\u003c/em\u003e(43), 723\u0026ndash;731. https://doi.org/10.3238/arztebl.2014.0723\u003c/li\u003e\n\u003cli\u003eAbreu Y Abreu, A. T., Velarde-Ruiz Velasco, J. A., Zavala-Solares, M. R., Remes-Troche, J. M., Carmona-S\u0026aacute;nchez, R. I., Aldana-Ledesma, J. M., Camacho-Ortiz, A., Contreras-Oma\u0026ntilde;a, R., D\u0026iacute;az-Seoane, R., Elizondo-V\u0026aacute;zquez, C. T., Garza-Gonz\u0026aacute;lez, E., Grajales-Figueroa, G., G\u0026oacute;mez-Escudero, O., Jacobo-Karam, J. S., Morales-Ar\u0026aacute;mbula, M., Olivares-Guzm\u0026aacute;n, L. O., Sifuentes-Osornio, J., Siu-Moguel, A. G., Soto-Sol\u0026iacute;s, R., Valdovinos-Garc\u0026iacute;a, L. R., \u0026hellip; Lazo-de la Vega Jasso, S. A. (2019). Consensus on the prevention, diagnosis, and treatment of Clostridium difficile infection. \u003cem\u003eRevista de Gastroenterologia de Mexico (English Edition)\u003c/em\u003e, \u003cem\u003e84\u003c/em\u003e(2), 204\u0026ndash;219. https://doi.org/10.1016/j.rgmx.2018.12.001\u003c/li\u003e\n\u003cli\u003eEuropean Centre for Disease Prevention and Control (2018, October 19). \u003cem\u003eLaboratory procedures for diagnosis and typing of human Clostridium difficile infection.\u003c/em\u003e https://www.ecdc.europa.eu/en/publications-data/laboratory-procedures-diagnosis-and-typing-human-clostridium-difficile-infection\u003c/li\u003e\n\u003cli\u003eGuery, B., Barbut, F., \u0026amp; Tschudin-Sutter, S. (2020). Diagnostic and therapy of severe Clostridioides difficile infections in the ICU. \u003cem\u003eCurrent Opinion in Critical Care\u003c/em\u003e, \u003cem\u003e26\u003c/em\u003e(5), 450\u0026ndash;458. https://doi.org/10.1097/MCC.0000000000000753 \u003c/li\u003e\n\u003cli\u003eSrisajjakul, S., Prapaisilp, P., \u0026amp; Bangchokdee, S. (2022). Drug-induced bowel complications and toxicities: imaging findings and pearls. \u003cem\u003eAbdominal Radiology\u003c/em\u003e, \u003cem\u003e47\u003c/em\u003e(4), 1298\u0026ndash;1310. https://doi.org/10.1007/s00261-022-03452-1 \u003c/li\u003e\n\u003cli\u003eGuery, B., Galperine, T., \u0026amp; Barbut, F. (2019). Clostridioides difficile: Diagnosis and treatments. \u003cem\u003eBMJ\u003c/em\u003e, \u003cem\u003e366\u003c/em\u003e, l4609. https://doi.org/10.1136/bmj.l4609 \u003c/li\u003e\n\u003cli\u003eMileto, S., Das, A., \u0026amp; Lyras, D. (2019). Enterotoxic Clostridia: \u003cem\u003eClostridioides difficile\u003c/em\u003e infections. \u003cem\u003eMicrobiology Spectrum\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e(3), https://doi.org/10.1128/microbiolspec.gpp3-0015-2018 \u003c/li\u003e\n\u003cli\u003eOng, G. K., Reidy, T. J., Huk, M. D., \u0026amp; Lane, F. R. (2017). Clostridium difficile colitis: a clinical review. \u003cem\u003eAmerican Journal of Surgery\u003c/em\u003e, \u003cem\u003e213\u003c/em\u003e(3), 565\u0026ndash;571. https://doi.org/10.1016/j.amjsurg.2016.10.035\u003c/li\u003e\n\u003cli\u003eUsacheva, E. A., Jin, J. P., \u0026amp; Peterson, L. R. (2016). Host response to Clostridium difficile infection: Diagnostics and detection. \u003cem\u003eJournal of Global Antimicrobial Resistance\u003c/em\u003e, \u003cem\u003e7\u003c/em\u003e, 93\u0026ndash;101. https://doi.org/10.1016/j.jgar.2016.08.002 \u003c/li\u003e\n\u003cli\u003eBouza, E., Alcal\u0026aacute;, L., \u0026amp; Reigadas, E. (2016). Optimizing the diagnostic testing of Clostridium difficile infection. \u003cem\u003eExpert Review of Anti-Infective Therapy\u003c/em\u003e, \u003cem\u003e14\u003c/em\u003e(9), 801\u0026ndash;808. https://doi.org/10.1080/14787210.2016.1216313 \u003c/li\u003e\n\u003cli\u003eKaiser, A. M., Hogen, R., Bordeianou, L., Alavi, K., Wise, P. E., Sudan, R., \u0026amp; CME Committee of the SSAT (2015). Clostridium difficile infection from a surgical perspective. \u003cem\u003eJournal of Gastrointestinal Surgery\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(7), 1363\u0026ndash;1377. https://doi.org/10.1007/s11605-015-2785-4\u003c/li\u003e\n\u003cli\u003eKorman T. M. (2015). Diagnosis and management of Clostridium difficile infection. \u003cem\u003eSeminars in Respiratory and Critical Care Medicine\u003c/em\u003e, \u003cem\u003e36\u003c/em\u003e(1), 31\u0026ndash;43. https://doi.org/10.1055/s-0034-1398741 \u003c/li\u003e\n\u003cli\u003eRineh, A., Kelso, M. J., Vatansever, F., Tegos, G. P., \u0026amp; Hamblin, M. R. (2014). Clostridium difficile infection: Molecular pathogenesis and novel therapeutics. \u003cem\u003eExpert Review of Anti-Infective Therapy\u003c/em\u003e, \u003cem\u003e12\u003c/em\u003e(1), 131\u0026ndash;150. https://doi.org/10.1586/14787210.2014.866515 \u003c/li\u003e\n\u003cli\u003eBerg, A. M., Kelly, C. P., \u0026amp; Farraye, F. A. (2013). Clostridium difficile infection in the inflammatory bowel disease patient. \u003cem\u003eInflammatory Bowel Diseases\u003c/em\u003e, \u003cem\u003e19\u003c/em\u003e(1), 194\u0026ndash;204. https://doi.org/10.1002/ibd.22964\u003c/li\u003e\n\u003cli\u003eBloukh, S. I., \u0026amp; Bloukh, S. H. (2013). Clostridium difficile infection: an overview of the disease and its pathogenesis, diagnosis, treatment, prevention and management. \u003cem\u003eResearch Journal of Pharmaceutical, Biological and Chemical Sciences 4\u003c/em\u003e(4), 1219-1232. \u003c/li\u003e\n\u003cli\u003eAlrabaa, S., Noel, P.R., Wills, T. (2013, June). \u003cem\u003eClostridium difficile infection: What you need to know.\u003c/em\u003e Consultant360. 53(6):389\u0026ndash;95. https://www.consultant360.com/article/clostridium-difficile-infection-what-you-need-know\u003c/li\u003e\n\u003cli\u003eKucharzik, T., Ellul, P., Greuter, T., Rahier, J. F., Verstockt, B., Abreu, C., Albuquerque, A., Allocca, M., Esteve, M., Farraye, F. A., Gordon, H., Karmiris, K., Kopylov, U., Kirchgesner, J., MacMahon, E., Magro, F., Maaser, C., de Ridder, L., Taxonera, C., Toruner, M., \u0026hellip; Vavricka, S. (2021). ECCO guidelines on the prevention, diagnosis, and management of infections in inflammatory bowel disease. \u003cem\u003eJournal of Crohn\u0026apos;s and Colitis\u003c/em\u003e, \u003cem\u003e15\u003c/em\u003e(6), 879\u0026ndash;913. https://doi.org/10.1093/ecco-jcc/jjab052 \u003c/li\u003e\n\u003cli\u003eLee, J. C., Hung, Y. P., Tsai, B. Y., Tsai, P. J., \u0026amp; Ko, W. C. (2021). Severe Clostridium difficile infections in intensive care units: Diverse clinical presentations. \u003cem\u003eJournal of Microbiology, Immunology, and Infection\u003c/em\u003e, \u003cem\u003e54\u003c/em\u003e(6), 1111\u0026ndash;1117. https://doi.org/10.1016/j.jmii.2020.07.012 \u003c/li\u003e\n\u003cli\u003eGupta, A., Wash, C., Wu, Y., Sorrentino, D., \u0026amp; Nguyen, V. Q. (2021). Diagnostic modality of Clostridioides difficile infection predicts treatment response and outcomes in inflammatory bowel disease. \u003cem\u003eDigestive Diseases and Sciences\u003c/em\u003e, \u003cem\u003e66\u003c/em\u003e(2), 547\u0026ndash;553. https://doi.org/10.1007/s10620-020-06205-6 \u003c/li\u003e\n\u003cli\u003eSheitoyan-Pesant, C., Abou Chakra, C. N., P\u0026eacute;pin, J., Marcil-H\u0026eacute;guy, A., Nault, V., \u0026amp; Valiquette, L. (2016). Clinical and healthcare burden of multiple recurrences of Clostridium difficile infection. \u003cem\u003eClinical Infectious Diseases\u003c/em\u003e, \u003cem\u003e62\u003c/em\u003e(5), 574\u0026ndash;580. https://doi.org/10.1093/cid/civ958 \u003c/li\u003e\n\u003cli\u003eSpad\u0026atilde;o, F., Gerhardt, J., Guimar\u0026atilde;es, T., Dulley, F., Almeida Junior, J. N., Batista, M. V., Shikanai-Yasuda, M. A., Levin, A. S., \u0026amp; Costa, S. F. (2014). Incidence of diarrhea by Clostridium difficile in hematologic patients and hematopoietic stem cell transplantation patients: Risk factors for severe forms and death. \u003cem\u003eRevista do Instituto de Medicina Tropical de Sao Paulo\u003c/em\u003e, \u003cem\u003e56\u003c/em\u003e(4), 325\u0026ndash;331. https://doi.org/10.1590/s0036-46652014000400010 \u003c/li\u003e\n\u003cli\u003eMostafa M.S., Abd El Hamid H.S.. (2022). PCR versus toxigenic culture in diagnosis of antibiotic-associated diarrhea due to Clostridium difficile infection. \u003cem\u003eThe Egyptian Journal of Hospital Medicine, 88\u003c/em\u003e(1):3396\u0026ndash;400. \u003c/li\u003e\n\u003cli\u003eLanis, J. M., Heinlen, L. D., James, J. A., \u0026amp; Ballard, J. D. (2013). Clostridium difficile 027/BI/NAP1 encodes a hypertoxic and antigenically variable form of TcdB. \u003cem\u003ePLoS Pathogens\u003c/em\u003e, \u003cem\u003e9\u003c/em\u003e(8), e1003523. https://doi.org/10.1371/journal.ppat.1003523 \u003c/li\u003e\n\u003cli\u003eValiquette, L., Cossette, B., Garant, M. P., Diab, H., \u0026amp; P\u0026eacute;pin, J. (2007). Impact of a reduction in the use of high-risk antibiotics on the course of an epidemic of Clostridium difficile-associated disease caused by the hypervirulent NAP1/027 strain. \u003cem\u003eClinical Infectious Diseases\u003c/em\u003e, \u003cem\u003e45(\u003c/em\u003eSuppl 2), S112\u0026ndash;S121. https://doi.org/10.1086/519258 \u003c/li\u003e\n\u003cli\u003eHensgens, M. P., Goorhuis, A., Dekkers, O. M., \u0026amp; Kuijper, E. J. (2012). Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. \u003cem\u003eThe Journal of Antimicrobial Chemotherapy\u003c/em\u003e, \u003cem\u003e67\u003c/em\u003e(3), 742\u0026ndash;748. https://doi.org/10.1093/jac/dkr508 \u003c/li\u003e\n\u003cli\u003eBaines, S. D., Noel, A. R., Huscroft, G. S., Todhunter, S. L., O\u0026apos;Connor, R., Hobbs, J. K., Freeman, J., Lovering, A. M., \u0026amp; Wilcox, M. H. (2011). Evaluation of linezolid for the treatment of Clostridium difficile infection caused by epidemic strains using an in vitro human gut model. \u003cem\u003eThe Journal of Antimicrobial Chemotherapy\u003c/em\u003e. \u003cem\u003e66\u003c/em\u003e(7):1537-1546. https://doi.org/10.1093/jac/dkr155 \u003c/li\u003e\n\u003cli\u003eValerio, M., Pedromingo, M., Mu\u0026ntilde;oz, P., Alcal\u0026aacute;, L., Marin, M., Pel\u0026aacute;ez, T., Giannella, M., \u0026amp; Bouza, E. (2012). Potential protective role of linezolid against Clostridium difficile infection. \u003cem\u003eInternational Journal of Antimicrobial Agents\u003c/em\u003e, \u003cem\u003e39\u003c/em\u003e(5), 414\u0026ndash;419. https://doi.org/10.1016/j.ijantimicag.2012.01.005 \u003c/li\u003e\n\u003cli\u003eJanarthanan S., Ditah I., Adler D.G., Ehrinpreis M.N. (2012). Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. \u003cem\u003eAmerican Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e107\u003c/em\u003e(7):1001\u0026ndash;10. https://doi.org/ 10.1038/ajg.2012.179\u003c/li\u003e\n\u003cli\u003eWeiss K. (2009). Toxin-binding treatment for Clostridium difficile: a review including reports of studies with tolevamer. \u003cem\u003eInternational Journal of Antimicrobial Agents\u003c/em\u003e, \u003cem\u003e33\u003c/em\u003e(1), 4\u0026ndash;7. https://doi.org/10.1016/j.ijantimicag.2008.07.011 \u003c/li\u003e\n\u003cli\u003eGaldys, A. L., Nelson, J. S., Shutt, K. A., Schlackman, J. L., Pakstis, D. L., Pasculle, A. W., Marsh, J. W., Harrison, L. H., \u0026amp; Curry, S. R. (2014). Prevalence and duration of asymptomatic Clostridium difficile carriage among healthy subjects in Pittsburgh, Pennsylvania. \u003cem\u003eJournal of Clinical Microbiology\u003c/em\u003e, \u003cem\u003e52\u003c/em\u003e(7), 2406\u0026ndash;2409. https://doi.org/10.1128/JCM.00222-14 \u003c/li\u003e\n\u003cli\u003eNapolitano, L. M., \u0026amp; Edmiston, C. E., Jr (2017). Clostridium difficile disease: Diagnosis, pathogenesis, and treatment update. \u003cem\u003eSurgery\u003c/em\u003e, \u003cem\u003e162\u003c/em\u003e(2), 325\u0026ndash;348. https://doi.org/10.1016/j.surg.2017.01.018 \u003c/li\u003e\n\u003cli\u003eMu\u0026ntilde;oz, P., Giannella, M., Alcal\u0026aacute;, L., Sarmiento, E., Fernandez Ya\u0026ntilde;ez, J., Palomo, J., Catal\u0026aacute;n, P., Carbone, J., \u0026amp; Bouza, E. (2007). Clostridium difficile-associated diarrhea in heart transplant recipients: is hypogammaglobulinemia the answer? \u003cem\u003eThe Journal of Heart and Lung Transplantation\u003c/em\u003e, \u003cem\u003e26\u003c/em\u003e(9), 907\u0026ndash;914. https://doi.org/10.1016/j.healun.2007.07.010 \u003c/li\u003e\n\u003cli\u003eKent, K. C., Rubin, M. S., Wroblewski, L., Hanff, P. A., \u0026amp; Silen, W. (1998). The impact of Clostridium difficile on a surgical service: a prospective study of 374 patients. \u003cem\u003eAnnals of Surgery\u003c/em\u003e, \u003cem\u003e227\u003c/em\u003e(2), 296\u0026ndash;301. https://doi.org/10.1097/00000658-199802000-00021 \u003c/li\u003e\n\u003cli\u003eMcDonald, L. C., Gerding, D. N., Johnson, S., Bakken, J. S., Carroll, K. C., Coffin, S. E., Dubberke, E. R., Garey, K. W., Gould, C. V., Kelly, C., Loo, V., Shaklee Sammons, J., Sandora, T. J., \u0026amp; Wilcox, M. H. (2018). Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). \u003cem\u003eClinical Infectious Diseases\u003c/em\u003e, \u003cem\u003e66\u003c/em\u003e(7), e1\u0026ndash;e48. https://doi.org/10.1093/cid/cix1085 \u003c/li\u003e\n\u003cli\u003eNguyen, G. C., Kaplan, G. G., Harris, M. L., \u0026amp; Brant, S. R. (2008). A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. \u003cem\u003eThe American Journal of Gastroenterology\u003c/em\u003e, \u003cem\u003e103\u003c/em\u003e(6), 1443\u0026ndash;1450. https://doi.org/10.1111/j.1572-0241.2007.01780.x \u003c/li\u003e\n\u003cli\u003eFreedberg, D. E., Zhou, M. J., Cohen, M. E., Annavajhala, M. K., Khan, S., Moscoso, D. I., Brooks, C., Whittier, S., Chong, D. H., Uhlemann, A. C., Abrams, J. A. (2018). Pathogen colonization of the gastrointestinal microbiome at intensive care unit admission and risk for subsequent death or infection. \u003cem\u003eIntensive Care Medicine,\u003c/em\u003e \u003cem\u003e44\u003c/em\u003e, 1203\u0026ndash;1211 (2018). https://doi.org/10.1007/s00134-018-5268-8\u003c/li\u003e\n\u003cli\u003eChang, V. T., \u0026amp; Nelson, K. (2000). The role of physical proximity in nosocomial diarrhea. \u003cem\u003eClinical Infectious Diseases\u003c/em\u003e, \u003cem\u003e31\u003c/em\u003e(3), 717\u0026ndash;722. https://doi.org/10.1086/314030 \u003c/li\u003e\n\u003cli\u003eArimoto, J., Horita, N., Kato, S., Fuyuki, A., Higurashi, T., Ohkubo, H., Endo, H., Takashi, N., Kaneko, T., Nakajima, A. (2016). Diagnostic test accuracy of glutamate dehydrogenase for Clostridium difficile: Systematic review and meta-analysis. \u003cem\u003eScientific Reports\u003c/em\u003e, 6:29754. https://doi.org/10.1038/srep29754 \u003c/li\u003e\n\u003cli\u003eCrobach, M. J., Planche, T., Eckert, C., Barbut, F., Terveer, E. M., Dekkers, O. M., Wilcox, M. H., \u0026amp; Kuijper, E. J. (2016). European Society of Clinical Microbiology and Infectious Diseases: Update of the diagnostic guidance document for Clostridium difficile infection. \u003cem\u003eClinical Microbiology and Infection\u003c/em\u003e, \u003cem\u003e22(\u003c/em\u003eSuppl 4), S63\u0026ndash;S81. https://doi.org/10.1016/j.cmi.2016.03.010 \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3928202/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3928202/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eAim\u003c/h2\u003e \u003cp\u003eTo evaluate \u003cem\u003eClostridioides difficile\u003c/em\u003e testing and diagnosis in specific patient populations.\u003c/p\u003e\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003e \u003cem\u003eClostridioides difficile\u003c/em\u003e infection (CDI) is a biochemical and clinical diagnosis. Certain patient populations are at higher risk and testing must be interpreted correctly to avoid overdiagnosis and overtreatment. Consequently, we need to understand the limitations of the tests used to avoid increase morbidity and mortality due to false negative test results. Diagnostic assays should be ordered in a step wise approach in specific patient populations to confirm CDI.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eManuscripts were extracted from three different databases based on keywords. Data were extracted based on the PRISMA 2020 guidelines. Each manuscript was analyzed using appropriate critical appraisal tools.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 70 reports were evaluated. 18 review articles, 4 retrospective cohorts, 3 guidelines, 1 experimental, and 1 cross sectional study were eligible for inclusion. A total of 27 reports were included.\u003c/p\u003e\u003ch2\u003eDiscussion\u003c/h2\u003e \u003cp\u003eCDI should be considered in all patients with traditional risk factors. Increased clinical suspicion of CDI is required in special populations such as hypogammaglobulinemia, transplant recipients, surgery, and inflammatory bowel disease. Testing should be limited to patients with the clinical manifestations of CDI to ensure a high pre-test probability for test interpretation. Diagnostic assays should follow a sequential, stepwise approach to accurately categorize the toxin expression status of the bacteria.\u003c/p\u003e","manuscriptTitle":"Testing and diagnosis of Clostridioides difficile infection in special scenarios: A systematic review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-12 19:14:59","doi":"10.21203/rs.3.rs-3928202/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7ddb01b2-9499-4673-9df3-14b3b7cf290c","owner":[],"postedDate":"February 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-04-26T00:38:48+00:00","versionOfRecord":{"articleIdentity":"rs-3928202","link":"https://doi.org/10.7759/cureus.59016","journal":{"identity":"cureus","isVorOnly":true,"title":"Cureus"},"publishedOn":"2024-04-25 00:38:48","publishedOnDateReadable":"April 25th, 2024"},"versionCreatedAt":"2024-02-12 19:14:59","video":"","vorDoi":"10.7759/cureus.59016","vorDoiUrl":"https://doi.org/10.7759/cureus.59016","workflowStages":[]},"version":"v1","identity":"rs-3928202","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3928202","identity":"rs-3928202","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}