Maribeth R. Nicholson, Curtis J. Donskey<\/h3>\n\n\n\nJAMA. <\/em>Published online August 21, 2023. doi:10.1001\/jama.2023.15875<\/h3>\n\n\n\nCase<\/p>\n\n\n\n
A10-year-old female with spina bifida and neurogenic bowel was hospitalized for abdominal pain, dehydration, and more than 20 episodes of watery diarrhea per day. Her symptoms began 5 days after completing a course of amoxicillin for streptococcal pharyngitis. Results of a gastrointestinal pathogen panel that included 18 bacterial, viral, and parasitic pathogens were negative. A stool sample result was positive for Clostridioides difficile<\/em> by polymerase chain reaction (PCR) testing and an enzyme immunoassay test for C difficile<\/em> toxin A and B had a negative result.<\/a><\/a><\/p>\n\n\n\nHow Do You Interpret These Test Results?<\/h4>\n\n\n\n\n- Antibiotic treatment for C difficile<\/em> infection is not indicated.<\/li>\n\n\n\n
- Antibiotic treatment for C difficile<\/em> infection is warranted.<\/li>\n\n\n\n
- Stool testing for fecal leukocytes is necessary.<\/li>\n\n\n\n
- The gastrointestinal pathogen panel is likely a false-negative result.<\/li>\n<\/ol>\n\n\n\n
Discussion<\/a><\/p>\n\n\n\nAnswer<\/a><\/p>\n\n\n\nB. Antibiotic treatment for C difficile<\/em> infection is warranted.<\/a><\/p>\n\n\n\nTest Characteristics<\/a><\/p>\n\n\n\nFew studies are available to guide best testing practices for the diagnosis of C difficile<\/em> infection (CDI) in children.1<\/a><\/sup>Colonization with toxigenic and nontoxigenic C difficile<\/em> affects 3% to 40% of children younger than 3 years and 3% to 26% of hospitalized children and adults.2<\/a><\/sup> Therefore, diarrhea from causes other than CDI, such as laxatives, viral infections, and prior antibiotic use, should be considered.3<\/a><\/sup><\/a><\/p>\n\n\n\nCommonly used diagnostic stool tests for detection of CDI are summarized in the\u00a0Table<\/a>. Nucleic acid amplification tests (NAAT), such as PCR, detect genes that encode for toxins produced by toxigenic\u00a0C difficile<\/em>. Enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) antigen detects GDH protein, which is present in both toxigenic and nontoxigenic\u00a0C difficile<\/em>. NAAT and GDH antigen tests have high sensitivity (96% and 94%, respectively) for detection of\u00a0C difficile<\/em>, but lower specificity (94% and 90%, respectively) because they do not detect\u00a0C difficile<\/em>\u00a0toxin.2<\/a>-4<\/a><\/sup>\u00a0EIAs for\u00a0C difficile<\/em>\u00a0toxins A and B have a high specificity for CDI (99%), but should not be used alone due to their low sensitivity for CDI (83%).2<\/a>-4<\/a><\/sup><\/p>\n\n\n\n![\"\"\/](\"https:\/\/cdn.jamanetwork.com\/ama\/content_public\/journal\/jama\/0\/jdt230002t1_1692397736.49022.png?Expires=1695678574&Signature=nx26WCGex1O2LIT4P7k8AYLf2V-fvgkL~xZ~WK-Z0ihMNzPJA1YgEfhI~eM1BVR6ASMpW3Dye-7rn8-bznejbUUteoSFcaUcExB1MXCPqfS3ujsCtvdxFMDKcTFHvZuJZHLFcZOMVx~REnd9XusOadbtB9gedIdWHR8Thyrf9YDgIIUb8SNkVgHoiVCtvdxxR3skcrz39v50J71ALMoGYvtjm1qsBHH8-mwAcvMYa5HloLw-k9nWcHn3Fs12zoZf3m9zER3w0ftyav8xw5xV1tmpu1gt-dogFIlwfUCYDyvpC8ltzf6-u-C8fYhGI7xMNTDJdHBFv16AXXK6eUoFWw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA\")
<\/figure>\n\n\n\nMultistep algorithms typically include a test with high sensitivity (NAAT or GDH antigen test) and a test with high specificity (toxin EIA).1<\/a><\/sup>-5<\/a><\/sup> A potential benefit of multistep algorithm testing, compared with NAAT or GDH antigen testing alone, is an improved ability to distinguish CDI from C difficile<\/em> colonization, which may facilitate avoiding unnecessary antibiotics.5<\/a><\/sup> Negative screening test results have high negative predictive value (>98% at CDI prevalence of 5% to 10%) and reliably exclude CDI.3<\/a><\/sup> Patients with a positive toxin EIA result are classified as likely to have CDI, although some may be asymptomatic carriers of toxigenic C difficile<\/em>.6<\/a><\/sup>,7<\/a><\/sup><\/a><\/p>\n\n\n\nDiscordant results on multistep screening testing (ie, a positive NAAT or GDH antigen test result and a negative toxin EIA result) may be due to CDI or asymptomatic C difficile<\/em> carriage. Individuals with test results positive for GDH antigen and negative for toxin EIA can undergo NAAT to determine whether they have a toxigenic strain of C difficile<\/em>. Many patients with discordant results on multistep screening testing have risk factors for C difficile<\/em> and a clinical presentation consistent with CDI, and approximately 70% are treated with antibiotics for CDI.8<\/a><\/sup>-10<\/a><\/sup> Compared with patients who have positive results on both C difficile<\/em> multistep screening tests, patients with discordant results have less severe illness, reduced recurrence rates, and a lower mortality rate,8<\/a><\/sup>,9<\/a><\/sup> although fulminant CDI can occur.10<\/a><\/sup> Therefore, treatment should not be withheld if there is high clinical suspicion of CDI.2<\/a><\/sup>-4<\/a>,8<\/a><\/sup><\/a><\/p>\n\n\n\nHospitals and clinics that use multistep algorithms for CDI should inform clinicians about optimal interpretation of these test results. In 2023, Medicare reimbursements were $37.27 for NAAT, $13.15 for GDH antigen testing, and $16 for toxin EIA.<\/a><\/p>\n\n\n\nApplication of Test Results to This Patient<\/a><\/p>\n\n\n\nThis patient had a high pretest probability for CDI due to voluminous diarrhea that developed after a recent course of antibiotics. Therefore, her positive PCR test result and negative toxin EIA result were unlikely to be due to C difficile<\/em> colonization, and treatment for CDI was warranted.<\/a><\/p>\n\n\n\nAlternative Diagnostic Testing Approaches<\/a><\/p>\n\n\n\nAccording to the Infectious Diseases Society of America 2017 CDI practice guidelines, NAAT can be used alone for CDI testing in hospitals with a diagnostic stewardship program that educates clinicians and laboratory personnel to perform NAAT only for unexplained new-onset diarrhea (\u22653 unformed stools in 24 hours) in patients not taking laxatives.2<\/a><\/sup> Cell cytotoxicity neutralization assay for toxin and toxigenic culture are the reference tests for C difficile<\/em>. However, these tests are rarely used in clinical laboratories because results are not available until several days after testing.3<\/a><\/sup><\/a><\/p>\n\n\n\nPatient Outcome<\/a><\/p>\n\n\n\nThe patient was treated with 10 days of oral vancomycin. Her diarrhea and abdominal pain improved within 2 days and resolved after 10 days. However, 7 days after completing the vancomycin, she developed recurrent copious diarrhea and was hospitalized for dehydration. Results of stool test were positive for C difficile<\/em> PCR and negative for toxin EIA. Due to the high suspicion of recurrent CDI, she was prescribed fidaxomicin, 200 mg, twice daily. Her diarrhea improved within 2 days and resolved after 10 days of fidaxomicin. At her most recent clinic visit, 2 months after initial presentation, the patient had no recurrent diarrhea.<\/a><\/a><\/p>\n\n\n\nClinical Bottom Line<\/h4>\n\n\n\n\n- Multistep CDI test algorithms include a sensitive stool screening test, such as a nucleic acid amplification test (NAAT) or glutamate dehydrogenase (GDH) antigen testing, and a more specific test, enzyme immunoassay (EIA), for C difficile<\/em> toxin A and B.<\/li>\n\n\n\n
- Multistep CDI testing may help distinguish CDI vs colonization, potentially avoiding unnecessary antibiotics compared with NAAT or GDH antigen testing alone.<\/li>\n\n\n\n
- Patients with a positive NAAT or GDH antigen test result and a negative toxin EIA result may have symptomatic CDI or may be asymptomatic carriers of C difficile<\/em>.<\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"
JAMA Diagnostic Test Interpretation August 2 […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[13,18],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=24586"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586\/revisions"}],"predecessor-version":[{"id":24588,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586\/revisions\/24588"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=24586"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=24586"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=24586"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
Case<\/p>\n\n\n\n
A10-year-old female with spina bifida and neurogenic bowel was hospitalized for abdominal pain, dehydration, and more than 20 episodes of watery diarrhea per day. Her symptoms began 5 days after completing a course of amoxicillin for streptococcal pharyngitis. Results of a gastrointestinal pathogen panel that included 18 bacterial, viral, and parasitic pathogens were negative. A stool sample result was positive for Clostridioides difficile<\/em> by polymerase chain reaction (PCR) testing and an enzyme immunoassay test for C difficile<\/em> toxin A and B had a negative result.<\/a><\/a><\/p>\n\n\n\n Discussion<\/a><\/p>\n\n\n\n Answer<\/a><\/p>\n\n\n\n B. Antibiotic treatment for C difficile<\/em> infection is warranted.<\/a><\/p>\n\n\n\n Test Characteristics<\/a><\/p>\n\n\n\n Few studies are available to guide best testing practices for the diagnosis of C difficile<\/em> infection (CDI) in children.1<\/a><\/sup>Colonization with toxigenic and nontoxigenic C difficile<\/em> affects 3% to 40% of children younger than 3 years and 3% to 26% of hospitalized children and adults.2<\/a><\/sup> Therefore, diarrhea from causes other than CDI, such as laxatives, viral infections, and prior antibiotic use, should be considered.3<\/a><\/sup><\/a><\/p>\n\n\n\n Commonly used diagnostic stool tests for detection of CDI are summarized in the\u00a0Table<\/a>. Nucleic acid amplification tests (NAAT), such as PCR, detect genes that encode for toxins produced by toxigenic\u00a0C difficile<\/em>. Enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) antigen detects GDH protein, which is present in both toxigenic and nontoxigenic\u00a0C difficile<\/em>. NAAT and GDH antigen tests have high sensitivity (96% and 94%, respectively) for detection of\u00a0C difficile<\/em>, but lower specificity (94% and 90%, respectively) because they do not detect\u00a0C difficile<\/em>\u00a0toxin.2<\/a>-4<\/a><\/sup>\u00a0EIAs for\u00a0C difficile<\/em>\u00a0toxins A and B have a high specificity for CDI (99%), but should not be used alone due to their low sensitivity for CDI (83%).2<\/a>-4<\/a><\/sup><\/p>\n\n\n\n Multistep algorithms typically include a test with high sensitivity (NAAT or GDH antigen test) and a test with high specificity (toxin EIA).1<\/a><\/sup>-5<\/a><\/sup> A potential benefit of multistep algorithm testing, compared with NAAT or GDH antigen testing alone, is an improved ability to distinguish CDI from C difficile<\/em> colonization, which may facilitate avoiding unnecessary antibiotics.5<\/a><\/sup> Negative screening test results have high negative predictive value (>98% at CDI prevalence of 5% to 10%) and reliably exclude CDI.3<\/a><\/sup> Patients with a positive toxin EIA result are classified as likely to have CDI, although some may be asymptomatic carriers of toxigenic C difficile<\/em>.6<\/a><\/sup>,7<\/a><\/sup><\/a><\/p>\n\n\n\n Discordant results on multistep screening testing (ie, a positive NAAT or GDH antigen test result and a negative toxin EIA result) may be due to CDI or asymptomatic C difficile<\/em> carriage. Individuals with test results positive for GDH antigen and negative for toxin EIA can undergo NAAT to determine whether they have a toxigenic strain of C difficile<\/em>. Many patients with discordant results on multistep screening testing have risk factors for C difficile<\/em> and a clinical presentation consistent with CDI, and approximately 70% are treated with antibiotics for CDI.8<\/a><\/sup>-10<\/a><\/sup> Compared with patients who have positive results on both C difficile<\/em> multistep screening tests, patients with discordant results have less severe illness, reduced recurrence rates, and a lower mortality rate,8<\/a><\/sup>,9<\/a><\/sup> although fulminant CDI can occur.10<\/a><\/sup> Therefore, treatment should not be withheld if there is high clinical suspicion of CDI.2<\/a><\/sup>-4<\/a>,8<\/a><\/sup><\/a><\/p>\n\n\n\n Hospitals and clinics that use multistep algorithms for CDI should inform clinicians about optimal interpretation of these test results. In 2023, Medicare reimbursements were $37.27 for NAAT, $13.15 for GDH antigen testing, and $16 for toxin EIA.<\/a><\/p>\n\n\n\n Application of Test Results to This Patient<\/a><\/p>\n\n\n\n This patient had a high pretest probability for CDI due to voluminous diarrhea that developed after a recent course of antibiotics. Therefore, her positive PCR test result and negative toxin EIA result were unlikely to be due to C difficile<\/em> colonization, and treatment for CDI was warranted.<\/a><\/p>\n\n\n\n Alternative Diagnostic Testing Approaches<\/a><\/p>\n\n\n\n According to the Infectious Diseases Society of America 2017 CDI practice guidelines, NAAT can be used alone for CDI testing in hospitals with a diagnostic stewardship program that educates clinicians and laboratory personnel to perform NAAT only for unexplained new-onset diarrhea (\u22653 unformed stools in 24 hours) in patients not taking laxatives.2<\/a><\/sup> Cell cytotoxicity neutralization assay for toxin and toxigenic culture are the reference tests for C difficile<\/em>. However, these tests are rarely used in clinical laboratories because results are not available until several days after testing.3<\/a><\/sup><\/a><\/p>\n\n\n\n Patient Outcome<\/a><\/p>\n\n\n\n The patient was treated with 10 days of oral vancomycin. Her diarrhea and abdominal pain improved within 2 days and resolved after 10 days. However, 7 days after completing the vancomycin, she developed recurrent copious diarrhea and was hospitalized for dehydration. Results of stool test were positive for C difficile<\/em> PCR and negative for toxin EIA. Due to the high suspicion of recurrent CDI, she was prescribed fidaxomicin, 200 mg, twice daily. Her diarrhea improved within 2 days and resolved after 10 days of fidaxomicin. At her most recent clinic visit, 2 months after initial presentation, the patient had no recurrent diarrhea.<\/a><\/a><\/p>\n\n\n\n JAMA Diagnostic Test Interpretation August 2 […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[13,18],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=24586"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586\/revisions"}],"predecessor-version":[{"id":24588,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24586\/revisions\/24588"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=24586"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=24586"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=24586"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}How Do You Interpret These Test Results?<\/h4>\n\n\n\n
\n
<\/figure>\n\n\n\nClinical Bottom Line<\/h4>\n\n\n\n
\n