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Why did a 10-year-old girl with spina bifida and neurogenic bowel suddenly develop severe voluminous diarrhea? That was the diagnostic challenge a team reported in .

The child presented with severe abdominal pain; she was dehydrated and experiencing watery diarrhea more than 20 times each day. She had been recently diagnosed with strep throat and treated with amoxicillin. Her gastrointestinal symptoms had developed 5 days after she completed the prescribed course of antibiotic treatment.

Tests for gastrointestinal pathogens using a panel that included 18 bacterial, viral, and parasitic pathogens were all negative, reported Maribeth Nicholson, MD, MPH, of Monroe Carell Jr. Children's Hospital at Vanderbilt in Nashville, Tennessee, and Curtis Donskey, MD, of the Cleveland VA Medical Center.

Polymerase chain reaction (PCR) testing of a stool sample was positive for Clostridioides difficile; however, enzyme immunoassay (EIA) testing for C. difficile toxins A and B results were negative.

After considering these findings, the team determined that the child should receive empirical treatment with antibiotics for C. difficile infection (CDI). Given that the patient had developed significant diarrhea after a recent course of antibiotics, they considered that she had a high pretest probability for CDI. "Therefore, her positive PCR test result and negative toxin EIA result were unlikely to be due to C. difficile colonization, and treatment for CDI was warranted," they explained.

Clinicians prescribed a 10-day course of treatment with oral vancomycin. Within 2 days, her diarrhea and abdominal pain had improved, and symptoms had resolved by the end of the course of antibiotic treatment.

However, 1 week later, the patient had a recurrence of extensive diarrhea, became severely dehydrated, and required hospitalization. Stool test results returned positive for C. difficile PCR and negative for toxin EIA. Given the probability that symptoms were due to a recurrence of CDI, clinicians prescribed fidaxomicin (Dificid), 200 mg twice daily. Within 2 days, her diarrhea had improved, with complete resolution after 10 days of fidaxomicin. At her most recent follow-up visit 2 months after her initial presentation, the patient had not experienced any further recurrences.

Discussion

Nicholson and Donskey noted that there is little data to guide best methods for diagnosis of CDI in children. A reported 3% to 40% of children under age 3 and 3% to 26% of hospitalized children and adults are colonized with toxigenic and nontoxigenic C. difficile, they noted. This highlights the importance of considering of diarrhea, such as laxative use, viral infections, and prior antibiotic use.

Authors presented a table summarizing diagnostic stool tests commonly used to detect CDI, explaining that nucleic acid amplification tests (NAAT), e.g., PCR, "detect genes that encode for toxins produced by toxigenic C. difficile." EIA for glutamate dehydrogenase (GDH) antigen tests for GDH protein, which is found in both toxigenic and nontoxigenic C. difficile.

"NAAT and GDH antigen tests have high sensitivity (96% and 94%, respectively) for detection of C. difficile, but lower specificity (94% and 90%, respectively) because they do not detect C. difficile toxin," Nicholson and Donskey explained. EIAs are highly specific (99%) for C. difficile toxins A and B, but the authors noted these should be accompanied by another test due to their low sensitivity for CDI (83%).

Multistep algorithms tend to include two tests: one that offers high sensitivity, such as a NAAT or GDH antigen test, and one with high specificity, like toxin EIA. Multistep algorithm testing is more effective than NAAT or GDH antigen testing alone in distinguishing CDI from C. difficile colonization, the authors said, thus "may facilitate avoiding unnecessary antibiotics."

"Negative screening have high negative predictive value (>98% at CDI prevalence of 5% to 10%) and reliably exclude CDI," they said. Patients who test positive for EIA toxin are considered likely to have CDI, they said, "although some may be asymptomatic carriers of toxigenic C. difficile."

Multistep screening can produce conflicting results -- such as a positive finding on a NAAT or GDH antigen test and a negative result on toxin EIA -- in patients with CDI or asymptomatic C. difficile, the authors noted. In those who test positive for GDH antigen and negative for toxin EIA, NAAT testing can determine whether they have a toxigenic strain of C. difficile. Among patients who have discordant multistep screening test results along with risk factors for C. difficile and symptoms that suggest CDI, authors noted that receive antibiotic treatment for CDI.

"Compared with patients who have positive results on both C. difficile multistep screening tests, patients with have less severe illness, reduced recurrence rates, and a lower mortality rate, although fulminant CDI can occur," Nicholson and Donskey wrote. Thus, cases that raise a high clinical suspicion of CDI should receive treatment.

Authors suggested that "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."

Alternative Diagnostic Testing Approaches

The Infectious Diseases Society of America's 2017 CDI advised that CDI testing can be performed with NAAT on its own, "in hospitals with a diagnostic stewardship program that educates clinicians and laboratory personnel to perform NAAT only for unexplained new-onset diarrhea (≥3 unformed stools in 24 hours) in patients not taking laxatives." They noted that "cell cytotoxicity neutralization assay for toxin and toxigenic culture are the reference tests for C. difficile. Nevertheless, the delay of several days in obtaining results means they're rarely used in clinical laboratories."

The clinical bottom line? "Multistep CDI testing may help distinguish CDI vs colonization, potentially avoiding unnecessary antibiotics compared with NAAT or GDH antigen testing alone," Nicholson and Donskey concluded.

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