AMR in focus: Deep dive into the laboratory diagnosis of Clostridioides difficile infection

Clostridioides difficile infection (CDI) is well-recognized to cause severe morbidity and mortality, especially in the highest risk populations such as the elderly and those receiving antibiotics, however the best way to diagnose CDI remains controversial. The reasons for this are complex but mainly relate to the fact that C. difficile can be carried asymptomatically and treatment in this case is unnecessary and may itself cause infection or other unwanted effects. Detection of asymptomatic carriage by sensitive methods such as NAAT testing therefore carries a risk of incorrect diagnosis unless careful attention is paid to only testing those with symptoms compatible with CDI. On the other hand, antigen detection for toxin B tends to lack sensitivity when compared to other detection methods.

International guidelines regarding the optimum diagnostic methods for CDI have attempted to balance these concerns. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidance (i) considers that there are no tests, when used alone, that could provide the required performance when tested in an endemic situation, and recommends using unformed stool samples only and a two-step approach to improve the positive percent agreement. The two-step approach would allow negative results to be reported directly, but positive results from any method (GDH, antigen-based detection of toxins A or B, or NAAT testing) would need to be confirmed by an alternative method, nevertheless consider that when free feces are absent CDI cannot be confidently distinguished from asymptomatic on the basis of the result alone.

Infectious Diseases Society of America (IDSA) guidance, (ii) on the other hand, allows for a positive stool toxin test as part of a multi-step algorithm, but also allows for a NAAT on its own where there are pre-agreed institutional criteria for patient stool submission.

A very interesting recent publication by Ramirez et al (iii) sought to address the controversies surrounding the diagnosis of CDI by evaluating the potential for misdiagnosis of CDI as a result of standard of care (SOC) stool collection and testing practices on CDI incidence estimates on a cohort of patients in Louisville, Kentucky.

The investigators undertook careful daily active surveillance for diarrhea cases that could reflect CDI among eligible patients (adults >50 years of age) in the relevant hospitals. All patients who had relevant symptoms were enrolled in the study and had stool samples taken for a range of diagnostic tests including GDH, antigen detection, NAAT, and a cell cytotoxicity neutralization assay. Standard of care (SOC) sampling and testing went on in these hospitals completely independent of the study process and results were used for patient management.

When the two diagnostic processes were compared head to head it was clear that there were differences between SOC and study diagnoses. Of 75 SOC-diagnosed cases, 12 (16%) were not study-diagnosed, whereas of 109 study CDI diagnoses, 44 (40.4%) were not study-diagnosed, and these findings led to differences in hospitalized CDI incidence. The authors make the important point that although current guidance starts from the perspective of avoiding over-diagnosis of CDI, it seems likely that in fact, under-diagnosis may be more of a problem, leading to under-estimation of the number of cases found through public health surveillance. They note that underdiagnosis can result from both SOC testing missing a case of CDI, or from a lack of sample collection, with the latter being more frequently found in this study, mainly as a result of these patients receiving laxatives at the time of assessment.

While the authors do not make any specific recommendations for changes to CDI diagnostic guidance or current practice, it is important to note that current SOC approaches may lead to cases of CDI being missed, with important impacts both for individual patient management and public health surveillance. Learn more here.

Dr. Beryl Oppenheim is a Senior Director, Medical Affairs at Cepheid.

Beryl is a medically qualified microbiologist who has worked in the

National Health Service in England for many years, leading

laboratories and infection control teams. Dr. Oppenheim has published

widely with more than 100 peer-reviewed publications, and her main research

interests include healthcare-associated infections (HAIs), antimicrobial resistance,

and infections in the critically ill and immunocompromised host.

References

(i). Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficile infection (CDI). Clin Microbiol Infect. 2009 Dec;15(12):1053-66

(ii). McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, Loo V, Shaklee Sammons J, Sandora TJ, Wilcox MH. 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). Clin Infect Dis. 2018 Mar 19;66(7)

(iii). Ramirez JA, Angulo FJ, Carrico RM, Furmanek S, Oliva SP, Zamparo JM, Gonzalez E, Zhang P, Parrish LAW, Marimuthu S, Pride MW, Gray S, Matos Ferreira CS, Arnold FW, Istúriz RE, Minarovic N, Moïsi JC, Jodar L. Misdiagnosis of Clostridioides difficile Infections by Standard-of-Care Specimen Collection and Testing among Hospitalized Adults, Louisville, Kentucky, USA, 2019-20201. Emerg Infect Dis. 2023 May;29(5):919-928