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Clostridium difficile Diarrheal Disease in Children
Abstract & Commentary
By Ellen Jo Baron, MD, PhD, D(ABMM), Professor of Pathology and Medicine, Stanford University; Clinical Microbiology and Virology Laboratories, Stanford University Medical Center. Dr. Baron reports no financial relationships relevant to this field of study. This article originally appeared in the November 2009 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, and peer reviewed by Connie Price, MD. Dr. Deresinski is Clinical Professor of Medicine, Stanford University; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Price is Assistant Professor, University of Colorado School of Medicine. Dr. Deresinski serves on the speaker's bureau for Merck, Pharmacia, GlaxoSmithKline, Pfizer, Bayer, and Wyeth, and does research for Merck, and Dr. Price reports no financial relationships relevant to this field of study.
The diagnosis of C. difficile-related disease (CDD) in children is controversial, as recently reviewed.1 Do children < 1-year-old actually develop diarrhea due to C. difficile? What should be the patient age cutoff below which laboratories should reject any stools for C. difficile testing? How will the new state-of-the-art molecular tests influence the interpretation of results in children?
The situation for rejecting stools for C. difficile testing from children < 2-years-old is similar to the reasoning used by microbiologists to reject sputum containing too many squamous epithelial cells (originating from upper airway secretions) for culture. Even if a potential pathogen is recovered in culture from a sputum containing > 10 squamous epithelial cells per low power field, as enumerated on Gram stain, the involvement of that pathogen in lower lung disease cannot be unequivocally determined. The isolate could be colonizing the upper airway without contributing to the patient's pneumonia at all. The laboratory cannot come to any conclusion; therefore, to avoid inappropriate interpretations, it chooses not to perform the test.2 This rejection criterion is actually a requirement for laboratory accreditation by the College of American Pathologists. Diagnosis of C. difficile disease in young children is equally difficult because of the large number of asymptomatic infants that carry toxin-producing and non-toxin-producing strains in their feces.3,4 The commercial molecular tests (today's best tests, as reviewed in September, 2008 Infectious Disease Alert) all have an FDA-required, two-year age limitation below which test results have not been validated, as stated in their product inserts (Prodesse, Milwaukee, WI; BD, Franklin Lakes, NJ; Cepheid, Sunnyvale, CA). In the future, perhaps the age cutoff for accepting stool for testing should be lowered to one year for reasons outlined below.
Epidemiological studies report incidences of asymptomatic colonization that varies from 50%-90% immediately after birth, with an average of 50% during the first year, falling to around 3%-6% during the second year.1,3-8 Studies looking for the organism in newborns on a daily basis found colonization rates as high as 52%, tracked to acquisition from the environment, not from the mothers.3,9 Although not reported in all studies, it seems that acquisition of C. difficile in newborns was not associated with gastrointestinal symptoms, but the percentage of strains producing toxin varies among studies.3,6 Some studies even showed that children with C. difficile had a lower incidence of diarrhea than non-colonized controls.7 However, colonized children can serve as a source of disease in others.10,11 Reading these numerous studies linking colonization to the environment in the hospital suggests to me that effective disinfection (using bleach or more aggressive techniques) and assiduous infection control practices for newborn nurseries and NICUs might significantly decrease colonization rates in infants and, perhaps, lower disease rates in associated adults. Could at least some of our growing epidemic of CDD be traced to an uncontained reservoir in our pediatric facilities?
Why some infants carrying fecal toxigenic C. difficile do not become ill is still a mystery, but a pattern is emerging. Hospital discharge records from 22 children's hospitals in the United States were surveyed to determine the incidence of C. difficile-associated disease reported on children age 1-18.12 A rise from 2.6 to 4.0 cases per 1,000 admissions was seen from 2001 to 2006, even when numbers of test requests were evaluated. This study, as well as others to be reviewed, noted that 67% of the CDD seen in children was associated with chronic underlying conditions.
Children < 1 year of age, and particularly those with complicating gastrointestinal conditions, clearly can develop CDD. C. difficile-associated gastroenteritis in patients with Hirschsprung's disease, inflammatory bowel disease, and necrotizing enterocolitis has been studied.13,14 Back in 1986, workers showed that C. difficile could be found in stool cultures from Hirschsprung's syndromic children < 3-years-old with colitis (77%) significantly more often than in normal children with or without diarrhea.15 A group in Canada surveyed 200 children > 1-year-old with C. difficile-associated diarrhea over a three-year period, basing their diagnosis on cell-culture cytotoxicity. They found a high proportion of the patients had Crohn's disease, chemotherapy treatment, immunotherapy and/or antibiotics post-transplantation, or immunodeficiency.16 In total, 74.5% of the patients had received antibiotics and 55% had healthcare exposure in the preceding month, although these risks are not universally observed.
Pascarella et al studied C. difficile in association with pediatric inflammatory bowel disease (IBD), including Crohn's disease, ulcerative colitis, and colitis of indeterminate cause, as determined by radiology, histopathology, endoscopy, and clinical criteria.17 C. difficile toxin was detected by a lateral flow enzyme immunoassay for toxins A and B in 24.7% of the 81 patients with IBD and only 8.9% of the 112 without IBD. Unlike other studies, association of C. difficile colonization and pre-existing risk factors (antibiotic exposure, immunosuppression, chemotherapeutic agents, proton-pump inhibitors) was not seen. Of course, given the relative insensitivity of toxin assays, the prevalence of toxigenic C. difficile in both populations is likely to have been underestimated.18
The incidence of CDD in children without confounding comorbidities has been low, but outbreaks in daycare centers, for example, have been identified.11 A study from Taiwan suggests that serious complications of CDD in children (average age 26 months) is also rare. Over the course of a year, 20 children developed toxic megacolon at their institution.19 Pathogens were isolated from the stools of 13 patients, 12 Salmonella and only one C. difficile. Along with the rise of 027/NAP1/BI strain in the U.S. and Europe, however, infections in children may also be increasing.8 The regular risk factors, including treatment with antibiotics and healthcare exposure, are not as common as would be expected.20
Although the results of some epidemiological studies in children appear compelling on the surface, they are usually marred by failure to explore potential other causes of diarrhea, including rotavirus, in the majority of cases. However, a group from the United Kingdom did use electron microscopy to detect viruses, along with routine tests for bacteria and parasites, to examine stools from children < 2-years-old admitted to the hospital for gastrointestinal symptoms.21 In addition, 390 infants and 118 controls were tested for C. difficile by both culture and cell culture cytotoxicity neutralization assay. Half of the children with gastroenteritis and one-third of the controls carried C. difficile in their feces. Only 19 (4.9%) of the children with gastroenteritis and 2.5% of the controls from whom C. difficile was isolated also had cytotoxin detected. Thirteen of these 19 patients had another fecal pathogen, usually an enteric virus, detected along with C. difficile. The control group was actually more likely to have received recent antibiotic treatment. Ellis and others concluded that C. difficile was a pathogen in their children with gastroenteritis; however their data alone, particularly regarding the role of the co-pathogens, do not support such a definitive conclusion. Other reports may provide support for their conclusion, however. Workers from Finland reported on the association of CDD and viral gastroenteritis, suggesting that virus infection may exacerbate the effects of toxin.22 New epidemiologic studies of C. difficile utilizing the best molecular tests, complete studies for other stool pathogens (such as a microarray platform), and thorough clinical evaluations will be needed to fully determine the role of C. difficile in gastroenteritis of children and infants.
In summary, C. difficile is clearly extending its pathogenic reach into lower age groups. The organism is more likely to be a pathogen in children with comorbidities, with Hirschsprung's disease demonstrating the most convincing association. Laboratories may wish to validate their tests and then lower the age to one year below which samples should be rejected, and microbiologists should continue to insist that specimens not be tested if they are not clearly diarrhea (take the shape of the container, more than three loose stools per day) unless the diagnosis of toxic megacolon is suggested.
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