C. difficile Infection in Children May Be on the Rise

March 07, 2013

By Lorraine L. Janeczko

NEW YORK (Reuters Health) Mar 07 - Rates of Clostridium difficile infection (CDI) may be rising, even in children thought to be at low risk, new research suggests.

"The incidence of C. difficile infection is increasing significantly in children, while previously it was thought to infect the elderly and be rare in children," said study author Dr. Sahil Khanna from the Mayo Clinic in Rochester, Minnesota, in an email to Reuters Health.

Although CDI in children remains uncommon, there was a more than 12-fold increase in cases from 1991 to 2009, with a sharp increase from 2006 onwards, according to the study published online February 13 in Clinical Infectious Diseases.

However, at least one expert not involved in the study questioned whether the spike might be due at least in part to a change in testing methods.

While most prior studies involved inpatients with hospital-acquired CDI, this one looked instead at people in Olmsted County communities and found that "the majority of CDI cases in children occurred in outpatients," said senior investigator Dr. Darrell S. Pardi, also from the Mayo Clinic, in an email.

"Estimates of the incidence of CDI that include only hospitalized children may significantly underestimate the burden of disease in children," the authors said in their report.

In the first population-based study describing the epidemiology of CDI in children, Dr. Pardi and his team investigated the incidence, severity, treatment responses and outcomes of CDI in children up to 18 years of age, from 1991 to 2009.

Consulting the centralized medical records of Olmsted county residents from the Rochester Epidemiology Project, they identified 99 possible patients and excluded seven due to non-CDI-caused diarrhea or lack of diarrhea.

Of the 92 CDI cases they studied, the median age was 2.3 years (range, one month to 17.6 years). Most cases (75%) were community-acquired and most (54%) occurred in males.

The overall age- and sex-adjusted CDI incidence was 13.8 per 100,000 persons, which increased 12.5 fold, from 2.6 (1991 to 1997) to 32.6 per 100,000 (2004 to 2009), over the study period (p<0.0001).

Community-acquired CDI incidence was 10.3 per 100,000 persons, which increased 10.5 fold, from 2.2 (1991 to 1997) to 23.4 per 100,000 (2004 to 2009), (p<0.0001). Severe, severe-complicated, and recurrent CDI occurred in a total of 32% of cases.

Dr. Khanna told Reuters Health that metronidazole (Flagyl) is used for mild-to-moderate first infection, although it's not approved by the FDA for this indication. Vancomycin is FDA approved and is used to treat severe and recurrent infection.

Of the 82% of cases initially treated with metronidazole, 18% had treatment failure. By contrast, of the 8% of cases initially treated with vancomycin, no treatments failed.

Among all cases, eight (8.7%) were severe and four (4.2%) were severe-complicated cases. Severe infection was more common in the hospital-acquired group than in the community-acquired group.

One death occurred in a child with metastatic rhabdomyosarcoma. Of the eight severe cases, six were initially treated with metronidazole, one with vancomycin, and one received no documented treatment.

The overall recurrence rate was 19.6% (21.3% in children taking metronidazole and 0% in children taking vancomycin, p=0.07). No difference in recurrence was seen with severe CDI compared to mild-to-moderate CDI.

"Primary care physicians and specialists need to be astutely aware of the risk for C. difficile infection as a cause of diarrhea and specifically test for it," observed Dr. Mitchell B. Cohen, director of gastroenterology, hepatology and nutrition at Cincinnati Children's Hospital Medical Center in Ohio, in an email to Reuters Health. Dr. Cohen was not involved in the study.

Dr. Khanna noted that fecal transplants are used to treat refractory C. difficile in adults but are not widely used in children.

Dr. Markus Agito of Akron General Medical Center in Akron, Ohio explained in an email, "Fecal transplantation is usually considered a last resort for patients with severe, recurrent C. difficile infections who failed multiple antibiotic treatments."

"Unlike adults," he said, "children tend to respond better with initial antibiotic treatment because their gut immunity is naive and less exposed to agents that may damage the normal gut flora."

"Given that children have excellent response to initial antibiotic therapy, fecal transplantation may be avoided if not necessary," he added. Dr. Agito was not involved in the study.

Furthermore, Dr. Cohen said, "We still don't know the long term risks of transplanting someone's intestinal bacteria into another person. Specifically, we don't know whether this puts them at risk for diseases in which it is becoming clear that there are altered intestinal bacteria, such as obesity, autoimmune diseases, etc."

The authors noted the need for larger, randomized, blinded studies stratified by severity to evaluate possible differences in treatment outcomes between metronidazole and vancomycin in children.

Dr. Mark Wilcox of Leeds Teaching Hospitals and University of Leeds, UK noted in an email that the study may suffer from ascertainment bias because although 67% of the 92 cases occurred in the last three years of the study, that is "when the method for CDI testing changed from enzyme immunoassay (EIA) to polymerase chain reaction (PCR). ... PCR testing over-diagnoses CDI potentially by about 40-70%."

Dr. Wilcox, who was not involved in the study, added that "the authors do not state whether the rate of CDI testing changed. In other words, did clinicians start to request a CDI test more frequently? ... This increased awareness/testing could have exacerbated the ascertainment bias introduced by the recent change in testing method."

"This study reinforces the need for robust studies to examine the wide range of potential causes for diarrhea in children and to use appropriate C. difficile testing methods to determine the true extent of CDI in children," he concluded.

Dr. Khanna advised that "infection control, judicious antibiotic use and hand hygiene form the cornerstone of CDI prevention."

This study received funding from the National Institute on Aging of the National Institutes of Health and ViroPharma. Dr. Wilcox has received financial support from ViroPharma.

SOURCE: http://bit.ly/YDNdC6

Clin Infect Dis 2013.