VAIL, COLO. – The worldly private eye in many a film noir has cautioned a potential client, "It’s best not to ask questions you’d rather not know the answer to."
That warning is apt as well when it comes to Clostridium difficile testing in infants with persistent diarrhea.
Dr. Samuel Dominguez
"We discourage testing of infants because we can’t actually distinguish colonization from C. difficile disease. I think that’s a big, complicated issue. And we get this question not infrequently: ‘What do we do with this positive test in a patient less than 1 year old?’ My answer is, ‘I don’t know. You shouldn’t test them in the first place,’ " Dr. Samuel R. Dominguez said at a conference on pediatric infectious diseases sponsored by the Children’s Hospital Colorado.
"Keep in mind that there are a lot of reasons other than C. difficile disease why an infant can have persistent diarrhea. I wouldn’t want anyone to be deluded by a positive C. difficile test. So I would have great caution in testing anyone under 1 year of age. It is true that you can have C. difficile infection under 1 year of age that can cause disease, but it is a rare event, not a common one," stressed Dr. Dominguez, a pediatric infectious diseases specialist at the hospital and the University of Colorado, Denver.
Unlike C. difficile disease, asymptomatic C. difficile colonization is extremely common in infants. For example, a French study involving stool testing of 85 asymptomatic infants in two day-care centers found a C. difficile carriage prevalence of 36% at age 2-6 months, climbing to 67% at 7-9 months, then peaking at 75% at 10-12 months, at which point 19% of the children harbored toxigenic strains. Yet none of the children had clinical disease at any point. After 12 months of age, the carriage rate declined steadily to 6% at 24-36 months (Clin. Infect. Dis. 2012;55:1209-15), which is comparable to the asymptomatic carriage rate in adults.
The significance of the high rate of C. difficile colonization in infants is controversial and poorly understood. It’s known that breastfed infants are less likely to be colonized than formula-fed infants, and that maternal-fetal transmission is rarely the source of infant colonization. Infants have the same rates of colonization and toxin production regardless of whether they have diarrhea, he noted.
Among the hypotheses offered to explain the rarity of C. difficile symptomatic disease in infants despite their high colonization rate is the observation that the gut microbial flora early in life is still in the process of formation. Its composition doesn’t approach that of the adult microbiome until about 1 year of age. Also, the infant immune system is immature. It is possible, although speculative, that the high rate of infant colonization is the result of a lack of protective gut bacteria early in life, while the rarity of symptomatic disease is a consequence of the immature immune system’s inability to recruit neutrophils, or alternatively is perhaps due to an absence of C. difficile receptors in the infant intestine.
Dr. Dominguez’ caution against testing for C. difficile in infants mirrors that of a recent American Academy of Pediatrics policy statement (Pediatrics 2013;131:196-200), which declared "it is prudent" to avoid testing in children under age 1 year. The AAP recommends first looking for other possible causes of diarrhea, especially viral pathogens, before testing for C. difficile in 1- to 3-year-olds. In symptomatic children over age 3, a positive test indicates probable infection.
An intriguing speculation recently raised in the literature is that colonized children might pose a risk to adults, serving as a reservoir for infection in much the same way they act as a reservoir for respiratory pathogens including influenza and pneumococcus (Clin. Infect. Dis. 2013;57:9-12). There is, however, no evidence as yet for this notion, Dr. Dominguez noted.
Current practice guidelines from the American College of Gastroenterology (Am. J. Gastroenterol. 2013;108:478-98) and Infectious Diseases Society of America (Infect. Control Hosp. Epidemiol. 2010;31:431-55) recommend PCR for C. difficile toxin genes as the standard diagnostic test. The guidelines list as an acceptable alternative a two-step method using a glutamate dehydrogenase test as a screen; if positive, it is to be followed by PCR or enzyme immunoassay. Dr. Dominguez indicated he has a problem with this recommendation because the glutamate dehydrogenase test has what he considers unacceptably high false-positive and -negative rates.
Enzyme immunoassay for toxins A and B is not endorsed as a stand-alone test in the latest guidelines because of its lack of sensitivity.