Clostridioides difficile infection

Definitions of C. difficile disease and colonization

C. difficile disease is defined as new-onset of diarrhea (at least three unformed stools in less than a 24-hour period) and a positive diagnostic test result for C. difficile in stool, or colonoscopic or histopathologic evidence of pseudomembranous colitis. Because the probability of colonization is higher in younger children (usually those younger than 2 years), it is important to consider other common infectious and noninfectious etiologies of diarrhea even when C. difficile testing results are positive. There is no accepted definition for severe C. difficile disease. The presence of a complication of C. difficile disease or at least two abnormal laboratory findings ( Table 34.1 ) has been used in previous research studies, ^, but validation of this proposed scoring system is still required.

Several studies noted an increase in the rates of C. difficile disease among children. ^, A retrospective study of more than 20 children’s hospitals in the United States reported that the rates of pediatric C. difficile disease doubled between 2001 and 2006. Another study analyzing secondary data from more than 30,000 pediatric patients noted an increase in the rates of C. difficile disease diagnosed by toxin assay between 1999 and 2006, and a decrease in rates of C. difficile disease between 2006 and 2010. Molecular diagnostics have altered surveillance. The increased sensitivity of molecular assays has limited the ability to make comparisons between rates of colonization and disease calculated using toxin assays with those calculated using molecular diagnostics.

A retrospective study of 200 children with C. difficile disease reported that 38 (19%) had underlying conditions that increased their risk of infection, and 149 (75%) had received antibiotics in the 2 months before the episode. Risk factors for the development of C. difficile disease in children include younger age (1 to 4 years), prolonged hospitalization, feeding via gastrostomy or jejunostomy, use of broad-spectrum antibiotics, HSCT, SOT, cancer, immunodeficiency, and human immunodeficiency virus (HIV) infection, fungal infections, viral gastroenteritis, cystic fibrosis, and inflammatory bowel disease. A nested case-control study in children identified the following risk factors for CDI: SOT, lack of hospitalization, presence of gastrostomy or jejunostomy, and receipt of fluoroquinolones or nonquinolone antibiotics in the 4 weeks before C. difficile disease.

C. difficile infection in pediatric SOT recipients

The estimated prevalence of C. difficile disease among pediatric SOT recipients is 12%, varying by transplanted organ. The rates of C. difficile disease among pediatric SOT recipients ranges between 5% and 16% for kidney recipients; between 11% and 12.9% for heart recipients; between 11% and 18% for liver recipients; between 11.5% and 9% for lung recipients ; between 3% and 7% for pancreas recipients ^, ; and 20% for small bowel transplant recipients. A study that evaluated secondary data from more than 50,000 hospitalized adult SOT recipients reported that those with C. difficile disease had higher mortality rates, longer hospital stays, higher costs, more colectomies, and higher rates of complications associated with the transplanted organ compared with those patients without C. difficile disease.

Among pediatric kidney transplant recipients, young age (younger than 5 years), female gender, treatment with monoclonal antibodies, antibiotic use, and intraabdominal placement of the graft were associated with the development of C. difficile disease. Other risks factors for the development of C. difficile disease described for adult SOT recipients include recent hospitalization, augmentation of steroid dose, use of steroids before transplant, ganciclovir prophylaxis, the use of antithymocyte globulin, and transplant other that kidney alone.

C. difficile infection in pediatric HSCT recipients

The rates of C. difficile disease are similar in pediatric and adult HSCT patients, although some studies have found even higher rates in children compared with adults. The rate of C. difficile disease among pediatric allogeneic HSCT recipients was 17% compared with 11% among adult patients in the same institution. Infection with C. difficile is more common in adult patients undergoing allogeneic (9% to 27%) than autologous (7% to 9%) transplants, respectively. Differing rates of posttransplant C. difficile disease has been noted in several observational studies. Recipients of allogenic HSCTs are subject to prolonged use of broad-spectrum antibiotics, a higher immunosuppressive state, and an increased risk for graft-versus-host disease (GVHD), all of which are risk factors for C. difficile disease. Another contributing factor may be higher colonization rates with C. difficile before allogenic transplantation, a factor that has been reported among adult and pediatric allogenic HSCT recipients.

A nested case-control study with a multivariate analysis comparing 62 adult allogeneic HSCT recipients with 123 controls matched by graft type demonstrated that receipt of chemotherapy before conditioning, exposure to broad-spectrum antibiotics after transplant, and vancomycin-resistant enterococci colonization were associated with the development of C. difficile disease. Cord blood as the source of the stem cells, acute GVHD, and total body irradiation were associated with C. difficile disease among adult allogenic HSCT recipients.

C. difficile disease in pediatric oncologic patients

One-third of children younger than 3 years and one-fifth who are 3 years and older are colonized with C. difficile at the time of their first admission to the pediatric oncology ward. After 2 weeks of inpatient hospitalization, colonization rates increase to 90% for children younger than 3 years and 50% for those older than 3 years. Another surveillance study that used polymerase chain reaction (PCR) testing and culture, reported that 29% of asymptomatic pediatric oncology patients were colonized with C. difficile at the time of admission to an inpatient unit. Slightly more than half (55%) of those who had a history of C. difficile disease had positive results for stool sampling by molecular testing or culture noted intermittently for over 20 weeks, sometimes with different C. difficile strains. The high prevalence of colonization, gut dysbiosis, gastrointestinal effects of chemotherapy regimens, antibiotic exposure, other infections, and underlying conditions make the diagnosis of C. difficile disease challenging in pediatric oncologic patients.

Cancer has been reported as the most common comorbidity in pediatric C. difficile disease, with 25% of infections reported among children whose data was collected in administrative databases. ^, According to these databases, the rate of C. difficile disease is 10 times higher in pediatric patients with cancer compared with children without cancer. A multicenter retrospective cohort study evaluating children with acute myeloid leukemia reported that 37 (11%) developed diarrhea and had positive test results for C. difficile toxin while receiving chemotherapy.

A study that evaluated the risk factors associated with C. difficile disease among children with cancer reported that exposure to aminoglycosides, third- and fourth-generation cephalosporins, and proton pump inhibitors in the week before admission, and chemotherapy in the 8 to 14 days before admission were associated with the development of C. difficile disease. Another retrospective cohort study in children with acute myeloid leukemia reported that the duration of broad-spectrum antibiotics and infection of a sterile site were independently associated with C. difficile disease.