P it fa lls in D i ag n o s i s o f Pediatric Clostridium d iffic ile I n f e c t i o n Julia S. Sammons,

MD, MSCE

a,

*, Philip Toltzis,

MD

b

KEYWORDS  Clostridium difficile  Diagnosis  Diarrhea  Pediatrics KEY POINTS  Clostridium difficile testing should only be performed in children with diarrhea and prioritized to those with known risk factors for C difficile infection (CDI).  C difficile testing is most appropriate in children older than 2 years; for children younger than 2, C difficile testing should be pursued only if symptoms persist in the absence of alternative diagnoses or if the clinical presentation is severe or CDI-consistent.  For otherwise healthy children with diarrhea in the community and no known exposures or risk factors for CDI, C difficile testing is likely rarely indicated, particularly if diarrhea is mild.  Efforts should be made to remove the inciting agent or identify alternative diagnoses before pursuing testing or treatment.  C diffiicle testing should be sought only in the child with persistent symptoms despite these interventions and when no alternative pathogens have been identified.

Clostridium difficile is the most common identifiable cause of health care–associated diarrhea in North America and Europe1,2 and is now the most common health care– associated infection in the United States.3,4 The pathogenicity of C difficile results from expression of 2 homologous enterotoxins labeled toxins A and B, which undermine the integrity of the cytoskeleton of colonic epithelial cells5; this in turn produces intense inflammation and often profound and prolonged diarrhea. Strains of C difficile that do not encode these toxins do not produce disease. Outside the body, the organisms sporulate, rendering them resistant to many disinfectants and enabling them to survive on inanimate surfaces for prolonged periods of time.6,7 Inadvertent ingestion of even small numbers of spores, especially in patients with a disturbed colonic microbiome as occurs after antibiotic exposure,8,9 can result in symptomatic infection.

a Division of Infectious Diseases, Department of Infection Prevention and Control, The Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; b Division of Pediatric Critical Care, Rainbow Babies and Children’s Hospital, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA * Corresponding author. E-mail address: [email protected]

Infect Dis Clin N Am - (2015) -–http://dx.doi.org/10.1016/j.idc.2015.05.010 0891-5520/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

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Sammons & Toltzis

Given the prominence of this pathogen and its propensity to spread within closed environments, accurate and expeditious diagnosis is important. However, the diagnosis of CDI in adults is beset with dilemmas, and these are compounded in children. The tests that are available for the diagnosis of C difficile infection (CDI) in children are the same as in adults, with similar sensitivities and specificities. However, the diagnosis of CDI in children has a number of pitfalls. Of particular importance is the issue of specificity and the resultant low positive predictive value (PPV; the ratio of true positives to the sum of true positives and false positives) in populations with low CDI prevalence, as is common in many groups of tested children. Furthermore, many persons (particularly young infants) become colonized asymptomatically after exposure to C difficile spores, but may excrete detectable quantities of toxigenic C difficile, making the interpretation of test results and diagnosis of clinical disease challenging. This leads to the possibility of identifying “biological false positives,” where false positivity is not related to the intrinsic characteristics of the test, but to identification of organisms in circumstances in which they are irrelevant clinically. Thus, when used indiscriminately in children, the PPV of C difficile tests can be unacceptably low. As a consequence, a falsely positive test may prompt the ordering of isolation precautions and antimicrobial treatment, which are unnecessary and costly and may distract caregivers away from more important alternative diagnoses. This article discusses these issues in detail. CHANGING EPIDEMIOLOGY OF C DIFFICILE INFECTION Increased Incidence of C difficile Infection

The epidemiology of CDI has changed dramatically in recent years. Between 2000 and 2010, the incidence of CDI more than doubled in adults and CDI-related hospitalizations increased by nearly 300%.10 The changing epidemiology of CDI is likely multifactorial, owing in part to the emergence of an epidemic strain of C difficile, the North American pulsed-field gel electrophoresis type 1 (NAP1) strain, which has been associated with increased morbidity and mortality11,12 and linked with outbreaks in North America, Europe, and Asia.1 Increased antibiotic use, growing awareness of CDI among clinicians, and the emergence of highly sensitive detection methods for C difficile likely also have contributed to the changing landscape.13 CDI is now the most common cause of health care–associated infection in the United States, with excess health care costs approaching $5 billion.3,4,14 Recent data from active population- and laboratory-based surveillance by the Emerging Infections Program in 2011 estimated the number of incident cases of CDI in the United States at 453,000 with 29,300 deaths.13 These estimates may include some patients with asymptomatic colonization owing to use of a case definition based solely on positive results from C difficile stool testing, but signal a significant national burden of disease. Similar to the findings in adults, several pediatric studies have shown that the incidence of CDI has risen among children15–21 and CDI is increasingly recognized as an important pathogen among pediatric patients.17,22 The majority of studies have used administrative data to evaluate the incidence of CDI-related hospitalizations among multicenter cohorts of hospitalized children.15,17,19 One of the first and largest of these studies evaluated incidence of CDI among 4895 hospitalized children at 22 US children’s hospitals using a combination of discharge diagnosis codes and charges for C difficile tests and treatment; in this study, Kim and colleagues15 found an increase from 2.6 to 4 cases per 1000 admissions from 2001 to 2006, whereas the rates of C difficile testing remained stable. More recently, data from population-based surveillance of CDI among children in the United States have revealed similar findings.21,23 Khanna and colleagues21 performed a population-based cohort study of CDI among children

Pediatric C difficile Diagnosis

residing in Olmsted County, Minnesota, from 1991 to 2009 and identified an increased incidence of CDI from 2.6 (1991–1997) to 32.6 per 100,000 (2004–2009; P

Pitfalls in Diagnosis of Pediatric Clostridium difficile Infection.

The incidence of Clostridium difficile infection (CDI) has risen among children and C difficile is increasingly recognized as an important cause of he...
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