Challenges in the Diagnosis and Management of Recurrent and Severe Clostridioides difficile Infection in Children.

Children with Clostridioides difficile infection (CDI) can experience recurrent or severe disease. Recurrent CDI occurs in 20%-30% of children with an initial CDI episode. A careful clinical evaluation is important to distinguish recurrent CDI from other disorders that cause recurring gastrointestinal symptoms. Multiple treatment options exist for recurrent CDI, but the optimal therapeutic approach remains undefined. Severe or fulminant CDI can result in poor outcomes and significant morbidity in children. Since there is not a validated definition for severe CDI in children, physicians must use their clinical judgment to identify patients with severe CDI to institute appropriate therapy. In this review, we describe the diagnostic and management challenges in caring for children with recurrent and severe CDI.

Recent advances in Clostridioides difficile infection epidemiology, diagnosis and treatment in children.

PURPOSE OF REVIEW: The US Centers for Disease Control and Prevention (CDC) classified Clostridioides difficile as an 'urgent' public health threat that requires 'urgent and aggressive action'. This call to action has led to new discoveries that have advanced C. difficile infection (CDI) epidemiology, diagnosis and treatment, albeit predominantly in adults. In 2017, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America published clinical practice guidelines for both adults and children. At that time, recommendations in children were generally limited to relatively low-quality evidence. RECENT FINDINGS: Since publication of this guidance, there have been many advancements in the understanding of CDI in children. These include better understanding of healthcare settings as uncommon sources of C. difficile acquisition in children; risk factors for recurrent and community-associated CDI; performance of diagnostic tests in children and strategies for optimizing their use; and a more rigorous evidence base for CDI treatment in children, including the first-ever randomized controlled trial of CDI treatment in children and the largest study of fecal microbiota transplantation in children. SUMMARY: This review highlights the most recent salient advancements in paediatric CDI knowledge and practice that supplement published clinical guidance provided prior to these advancements.

Hyperammonemic Encephalopathy due to Ureaplasma parvum Infection in an Immunocompromised Child.

Idiopathic hyperammonemia is a rare complication with a high mortality rate that occurs in persons with hematologic malignancies or hematopoietic stem cell or solid organ transplant. Patients present with encephalopathy and hyperammonemia in the absence of liver disease or inborn errors of metabolism. Several etiologies have been proposed, including chemotherapeutic agents, medications, and a catabolic state with an elevated nitrogen load in the setting of acute illness. Recently, cases of hyperammonemia in adult lung transplant recipients have been attributed to infection from Ureaplasma parvum or U urealyticum Herein, we report a 12-year-old girl with acute myeloid leukemia and neutropenic fever who developed acute encephalopathy. Laboratory testing revealed severe hyperammonemia (blood ammonia level >1609 µmol/L) with normal liver function studies. U parvum was detected in blood, urine, and respiratory specimens by polymerase chain reaction testing. After antibiotic therapy directed against U parvum, blood ammonia levels normalized, the infection was eradicated, and the patient recovered. We propose that clinicians should test for invasive infection from Ureaplasma species in immunocompromised children with unexplained hyperammonemia.

Risk Factors for Surgical Site Infections Following Vertical Expandable Prosthetic Titanium Rib (VEPTR) Surgery in Children.

STUDY DESIGN: Case-control study. OBJECTIVES: To identify risk factors for surgical site infections (SSIs) following vertical expandable prosthetic titanium rib (VEPTR) surgery in children. SUMMARY OF BACKGROUND DATA: VEPTR surgery is a growth-sparing approach for early-onset scoliosis and chest or rib abnormalities. SSIs are an important complication following VEPTR surgery. We aimed to identify modifiable risk factors for SSIs following VEPTR surgery. METHODS: Children who underwent VEPTR surgery at a tertiary-care children's hospital from January 2010 through November 2014 were included. SSIs following VEPTR implant or revision surgeries were identified. For each case patient, three control subjects matched by procedure type were randomly selected among those without infection. Patient and surgery-related risk factors were analyzed using conditional logistic regression. RESULTS: Twenty-six infections occurred in 22 subjects following 326 VEPTR surgeries (SSI rate: 8.0%). The infection rate was greater among implant than revision surgeries (15.5% vs. 4.5%; p<.001). Methicillin-susceptible Staphylococcus aureus was the most common pathogen (50% of infections). On multivariate analysis, VEPTR SSI infections were associated with male gender (OR 3.5, 95% CI 0.9-13.2), assisted feeding (OR 4.5, 95% CI 1.0-20.3), administration of preoperative antibiotics more than 30 minutes before surgery (or >60 minutes for vancomycin) (OR 6.9, 95% CI 1.2-39.0), and an intraoperative temperature less than 35.0°C (OR 4.3, 95% CI 0.8-23.7). CONCLUSIONS: Administration of preoperative antibiotics closer to the time of surgery may reduce the risk of SSI in children undergoing VEPTR surgery. Further study is needed to determine the optimal timing of antibiotic prophylaxis for children undergoing spinal surgery. LEVEL OF EVIDENCE: Level III.

Recurrent Clostridium difficile Infection in Children: Patient Risk Factors and Markers of Intestinal Inflammation.

BACKGROUND: The management of Clostridium difficile infection (CDI) in children is complicated by recurrence rates of 20%-30%. The identification of risk factors associated with recurrent disease might allow early recognition of those children at highest risk. METHODS: Pediatric patients with CDI were identified through clinical laboratory records at 2 tertiary-care children's hospitals from March 2013 through May 2014. Subjects were enrolled and followed for 60 days to assess for recurrent CDI (rCDI). Blood samples were obtained at enrollment to evaluate host interleukin (IL)-8 polymorphisms and anti-toxin A antibody levels; stool samples were obtained for inflammatory markers (lactoferrin, calprotectin, IL-8) and C. difficile ribotype 027 strain status. Thirty days post enrollment, another serum sample was obtained to compare antibody responses. RESULTS: Of the 28 pediatric patients enrolled, 27 completed follow-up and 8 (30%) experienced rCDI. At enrollment, children with malignancy had significantly lower stool calprotectin, lactoferrin and IL-8 than those without malignancy. There was a trend toward increased stool inflammatory markers in those who later developed rCDI. The IL-8 A/A genotype was not associated with recurrent disease. No patients were found to have ribotype 027 or an antibody increase to toxin A. CONCLUSIONS: The rate of rCDI in our pediatric cohort was 30%. Children with rCDI had a trend toward higher fecal inflammatory markers with the initial infection, and these values were lower in children with malignancy. Fecal lactoferrin, calprotectin and IL-8 should be further studied to determine their value in predicting the risk of rCDI in children.

Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection.

Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile-associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.

Risk Factors for Community-associated Clostridium difficile-associated Diarrhea in Children.

BACKGROUND: Clostridium difficile-associated diarrhea (CDAD) is increasingly diagnosed in children in community settings. This study aims to assess recent antibiotic use and other risk factors in children with community-associated (CA-) CDAD compared with children with other diarrheal illnesses in a tertiary care setting. METHODS: Children with CA-CDAD evaluated at Texas Children's Hospital (Houston, TX) from January 1, 2012 to June 30, 2013 were identified. Two control subjects with community-associated diarrhea who tested negative for C. difficile were matched to case subjects. Data on demographics, medication exposure and outpatient healthcare encounters were collected from medical records. Multivariate logistic regression was performed to identify predictors of pediatric CA-CDAD. RESULTS: Of 69 CA-CDAD cases, most (62.3%) had an underlying chronic medical condition and 40.6% had antibiotic exposure within 30 days of illness. However, no traditional risk factor for CDAD was identified in 23.2% and 15.9% of CA-CDAD cases within 30 and 90 days of illness onset, respectively. Outpatient healthcare encounters within 30 days were more common among CA-CDAD cases than control subjects (66.7% vs. 48.6%; P = 0.01). In the final multivariate model, CA-CDAD was associated with cephalosporin use within 30 days [odds ratio: 3.32; 95% confidence interval: 1.10-10.01] and the presence of a gastrointestinal feeding device (odds ratio: 2.59; 95% confidence interval: 1.07-6.30). CONCLUSIONS: Recent use of cephalosporins and the presence of gastrointestinal feeding devices are important risk factors for community- associated CDAD in children. Reduction in the use of outpatient antibiotics may decrease the burden of CA-CDAD in children.

A hospital-based study of the clinical characteristics of Clostridium difficile infection in children.

BACKGROUND: Clostridium difficile infection (CDI) is an increasingly important cause of morbidity in hospitalized children. We describe the recent epidemiology of pediatric CDI at a children's hospital, compare community-associated (CA) and hospital-associated (HA) infections and identify risk factors for severe disease. METHODS: Children with CDI at Texas Children's Hospital were identified from February 1, 2011, to October 31, 2011. Severe CDI was defined as the presence of a CDI-related complication or ≥2 clinical features: fever, bloody stools, leukocytosis, hypoalbuminemia or elevated creatinine. Standard epidemiologic definitions were used. RESULTS: One-hundred and nine unique patients 1-21 years of age with CDI were identified throughout the study period. The proportions of CA-CDI (41%) and HA-CDI (46%) were similar, whereas community-onset indeterminate CDI (13%) was less common. Children with malignancy or solid organ transplantation were more likely to have HA-CDI. Conversely, all children with inflammatory bowel disease had CA-CDI. Twenty-three patients (21%) met criteria for severe disease and 8 experienced a CDI-related complication, including 1 death attributable to CDI. On multivariate analysis, the presence of a gastrostomy tube (adjusted odds ratio: 3.09; 95% confidence interval: 1.07-8.94) and having community-onset indeterminate disease (adjusted odds ratio: 4.62; 95% confidence interval: 1.28-16.67) were found to be associated with severe CDI. CONCLUSIONS: A substantial proportion of pediatric CDI is CA and there are clinical differences between children with CA-CDI and HA-CDI. Children with CDI frequently experience severe disease, whereas complications are uncommon. Early identification and treatment of CDI should be pursued in children with gastrostomy tube and recent hospitalization.

Sustained improvement in hand hygiene at a children's hospital.

A quality improvement project was conducted to improve hand hygiene at a children's hospital. Interventions included education, performance feedback, an incentive program, and a marketing campaign. There were 9,322 observations performed over a 5-year period. Hospital-wide adherence increased from 39.9% to 97.9%. Adherence of 95% or greater was sustained for over 3 years.

Clostridium difficile: an emerging pathogen in children.

Clostridium difficile is emerging as an important enteric pathogen in children. Historically considered as an asymptomatic colonizer of the gastrointestinal tract, C. difficile infection (CDI) has not been well-studied in pediatric populations. While asymptomatic carriage remains high among infants, recent epidemiological surveillance has demonstrated a rise in the prevalence of CDI in both healthcare and community settings, particularly in children 1-5 years of age. The pathogenesis of pediatric CDI, including the factors underlying the absence of toxin-mediated effects among colonized infants, remains ill-defined. Studies suggest that traditional adult CDI risk factors such as antibiotic and healthcare exposure may not be as important for children who acquire CDI in the community. As recognition of the significant impact of CDI in children increases, the pressing need for deepening our understanding of this disease and identifying optimal therapeutic and preventative strategies is becoming apparent.