INTRODUCTION — Clostridioides difficile is an important cause of antibiotic-associated diarrhea and one of the most common health care-associated pathogens [1]. Its clinical manifestations range from asymptomatic colonization or mild diarrhea to fulminant disease characterized by ileus, toxic megacolon, hypotension, or shock. C. difficile infection is less common in children than adults, but the incidence of C. difficile infection in children is increasing [2-5].
The microbiology, pathogenesis, and epidemiology of C. difficile infection in children will be discussed below. The clinical features, diagnosis, treatment, and prevention of C. difficile infection in children are discussed separately. (See "Clostridioides difficile infection in children: Clinical features and diagnosis" and "Clostridioides difficile infection in children: Treatment and outcome" and "Clostridioides difficile infection: Prevention and control".)
C. difficile infection in adults also is discussed separately. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology" and "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridioides difficile infection in adults: Treatment and prevention".)
MICROBIOLOGY
Organism — C. difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus. It exists in spore form in the environment. The spores are metabolically dormant and resistant to heat, acid, antibiotics, and most disinfectants. After C. difficile spores reach the intestine, they germinate into the vegetative form, which is capable of producing toxins and is susceptible to killing by antimicrobial agents.
C. difficile is widely distributed in nature. It has been found in water, soil, food products, domestic and farm animals, and households [6-10]. Within health care facilities, C. difficile has been cultured from the hands of patients and health care personnel, hospital surfaces, medical equipment, and hospital pet therapy dogs [11,12]. C. difficile can persist on hospital surfaces for months [11].
Toxins — Toxins A and B are the major virulence factors of C. difficile. They are encoded by genes (tcdA and tcdB) located on a pathogenicity locus that also contains three regulatory genes. Nontoxigenic strains lack the tcdA and tcdB genes and are nonpathogenic. Toxins A and B mediate disease by disrupting the cytoskeletal structure of intestinal epithelial cells, resulting in inflammation and cell death [13]. Toxin A ("enterotoxin") causes inflammation leading to mucosal injury and intestinal fluid secretion [14]. Toxin B ("cytotoxin") is essential for the virulence of C. difficile and is more potent than toxin A in mediating colonic mucosal damage [15,16]. Thus, strains lacking toxin A can be as virulent as strains with both toxins [17,18]. Fecal toxin levels may correlate with disease severity [19]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Toxins'.)
The NAP1/BI/027 strain has unique characteristics: It possesses a deletion in the tcdC gene (a negative regulator of toxin production), produces a third toxin (binary toxin), and is resistant to fluoroquinolones [20]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'PCR ribotype 027 strain'.)
PATHOGENESIS — The pathogenesis of C. difficile disease is incompletely understood. However, disease expression is known to involve [21,22] (see "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Pathophysiology'):
●Alteration of the colonic microbiota (usually, but not always, following antibiotic therapy)
●Ingestion, colonization, and overgrowth of C. difficile
●Production of C. difficile toxin(s) (necessary but not sufficient to cause clinical disease)
●Injury to and inflammation of intestinal epithelium
Other factors may include:
●Production of antitoxin antibodies – Adults colonized with C. difficile who have low or undetectable levels of antibody against toxin A are more likely to develop diarrhea than those with detectable antibody [23]. Production of antitoxin antibodies following a primary C. difficile infection is associated with protection against recurrent disease [24]. In addition, in randomized trials in adults with C. difficile infection, bezlotoxumab, a monoclonal antibody against toxin B, lowered the risk of recurrent disease [25].
●Colonization with nontoxigenic strains, which may afford protection against disease from toxigenic C. difficile [26,27].
●Variable expression of intestinal toxin receptors – As an example, newborn rabbits lack intestinal receptors for toxin A and are resistant to disease, whereas newborn pigs have receptors and are susceptible to C. difficile infection [28,29].
EPIDEMIOLOGY
Incidence — In 2019, active population-based surveillance in the United States estimated that the incidence of C. difficile infection in children <18 years was 34.8 cases per 100,000 population; approximately three-quarters of cases were community associated (stool sample collected on an outpatient basis or within three days after hospital admission in a person with no documented overnight stay in a health care facility in the preceding 12 weeks) [30].
In the early 2000s, an increase in the frequency and severity of C. difficile infection in adults was observed in several hospitals in North America [20,31]. These hospital outbreaks were largely attributed to the NAP1/BI/027 strain [20]. Since then, the incidence of C. difficile infection has increased considerably. In the United States, the incidence of C. difficile-related hospitalizations more than doubled between 2000 and 2009 [32]. (See "Clostridioides difficile infection in adults: Epidemiology, microbiology, and pathophysiology", section on 'Epidemiology'.)
Increased frequency of C. difficile infection has also been documented for children [2-5,33]. The highest incidence of C. difficile infection occurs in children one to five years old [2,3,5].
The majority of C. difficile infections in children are community associated. Population-based studies suggest that 70 to 75 percent of pediatric C. difficile infections are community associated [33-35]. Children with community-associated infection tend to be healthier and have lower rates of exposure to antibiotics and acid suppressants than children with health care-associated disease [36,37].
Severe disease — Children can experience severe disease and complications from C. difficile infection, although with significantly lower frequency than adults. Data on the frequency of severe disease in children are limited by the absence of a validated definition. Estimation of disease severity in children is inaccurate when adult criteria for severe C. difficile disease are applied to children [38,39].
Studies report that 3 to 7 percent of children with C. difficile develop a fulminant disease – hypotension or shock, ileus, or toxic megacolon [37-40]. No temporal change in the incidence of colectomy or death has been noted in hospitalized children with C. difficile despite the increased incidence of C. difficile infection [2,4,5].
Colonization — Asymptomatic intestinal colonization with toxigenic C. difficile is common in the neonatal period and infancy [41-43]. This phenomenon has two important implications:
●C. difficile may be an incidental finding in neonates and infants with diarrhea.
●Neonates and infants may be a reservoir of C. difficile.
Neonates and infants — Colonization with toxigenic or nontoxigenic C. difficile is common during the first year of life. Early acquisition during the neonatal period and acquisition later in infancy has been described [44]. Colonization generally persists for a few months, though it can persist for up to 12 months or longer [44-46]. Shifts between toxigenic and nontoxigenic strains over time have been observed [47].
The rate of colonization reported in the literature varies widely due to differences in the testing method employed and the population studied. In a meta-analysis of observational studies, the estimated proportion of colonization with toxigenic or nontoxigenic C. difficile increased from 15 percent (95% CI 7-25 percent) in infants <7 days of age to 41 percent (95% CI 32-50 percent) in those 6 to 12 months of age, the peak age for asymptomatic colonization [47]. The estimated proportion of colonization with toxigenic C. difficile increased from ≤6 percent in infants <3 months of age to 14 percent (95% CI 8-21 percent) in infants 6 to 12 months of age.
The most common source of C. difficile acquisition among hospitalized neonates and infants is the hospital environment, and the risk of colonization increases with the duration of the hospital stay [43]. Maternal-infant transmission is only rarely described [42]. Various host factors influence C. difficile colonization rates during infancy. Higher rates of colonization are reported in infants who are formula fed (versus breast fed), preterm (versus term), hospitalized, and recently exposed to antibiotics [41,42,48]. Studies evaluating mode of delivery and colonization status have inconsistent findings [41,48].
Although neonates and infants frequently are colonized with toxigenic C. difficile, they rarely develop symptomatic disease [41]. High levels of C. difficile organisms and toxins (levels similar to those in adults with pseudomembranous colitis) can be found in the stools of healthy, asymptomatic neonates and infants [49,50]. The reasons for this paradox have not been fully elucidated. An absence of intestinal receptors for C. difficile toxins has been proposed. Additionally, in a prospective cohort study, colonization with toxigenic C. difficile during infancy was associated with antibody response against toxins A and B; whether these antibodies protect against C. difficile infection and how long they persist requires additional investigation [51]. (See 'Pathogenesis' above.)
Neonates and infants may be a reservoir of C. difficile for vulnerable individuals. Toxigenic strains known to circulate in adults have been detected from asymptomatic infants [44,46,48,52]. Additionally, in a case-control study among adults with community-associated diarrhea, individuals with C. difficile infection were more likely to report contact with children ≤2 years old [53].
Children — Beyond infancy, children have lower rates of colonization. By approximately two to three years of age, toxigenic strain colonization rates decrease to 6 to 8 percent, similar to rates in nonhospitalized adults [47]. Elevated colonization rates (17 to 30 percent) have been described among hospitalized children and children with malignancy, cystic fibrosis, or inflammatory bowel disease [54-57].
Transmission — In health care settings, C. difficile can be spread through human hands, contaminated with C. difficile spores, and through contamination of the health care environment [22,58,59]. Factors associated with health care acquisition of C. difficile include ward-level antibiotic use and assignment to a room in which a previous patient had C. difficile [22,60]. Although molecular studies suggest that symptomatic patients and asymptomatic carriers transmit C. difficile in the hospital setting [61-63], in studies from pediatric facilities, transmission from symptomatic patients appears to be uncommon [64,65]. Asymptomatic carriers may be an important source of C. difficile transmission without health care exposure [22,62].
C. difficile is increasingly acquired in the community by patients without prior health care exposure, antimicrobial treatment, or other established risk factors [35,66]. Asymptomatically colonized neonates and infants may be a source of C. difficile transmission to adults [53].
Hypervirulent strains — Data regarding the prevalence of infection with hypervirulent strains (NAP1/BI/027) in children are limited. No data have suggested outbreaks in children or increased severity associated with the NAP1/BI/027 strain. The proportion of pediatric C. difficile stool samples that are the NAP1/BI/027 strain has ranged from <1 to 23 percent [35,67,68].
RISK FACTORS
Antibiotic exposure — Exposure to antibiotics is the single-most important risk factor for both health care-associated and community-associated C. difficile infection [66,69-71]. Any antibiotic may predispose to C. difficile infection, though the risk varies across antibiotic classes [21,72]. Amoxicillin-clavulanate, cephalosporins, clindamycin, and fluoroquinolones are most frequently implicated [73]. Sulfonamides, tetracyclines [74], vancomycin, metronidazole, and aminoglycosides are infrequently implicated in children. In pediatric studies, exposure to multiple classes of antibiotics in the preceding 30 days has been associated with severe and recurrent C. difficile infection [40,75].
C. difficile infection, including severe disease, can occur in children without prior antibiotics [66,76]. In large observational studies, antimicrobial exposure was absent in >40 percent of cases of C. difficile in children [66].
Other risk factors — Proton pump inhibitors, and to a lesser extent histamine-2 receptor antagonists, have been associated with an increased risk of C. difficile infection in children and adults [66,77-80]. Gastrointestinal feeding devices (ie, gastrostomy or jejunostomy tubes) have also been associated with C. difficile infection in children [37,70].
Predisposing conditions — A number of medical conditions are associated with C. difficile infection in children.
●Malignancy – Malignancy is the most common chronic condition among hospitalized children with C. difficile infection, accounting for 20 to 25 percent of hospital-based cases [2,4,81]. Children with malignancy and C. difficile infection have longer lengths of stay and higher rates of in-hospital mortality compared with children with malignancy without C. difficile infection [82,83]. They also have increased rates of recurrence [84].
Several factors may predispose pediatric oncology patients to C. difficile infection: repeated exposures to broad-spectrum antibiotics, receipt of chemotherapy, and frequent visits to health care facilities. Variation in the risk of C. difficile infection has been reported across antibiotic classes for pediatric oncology patients [82,85]. As an example, in a multicenter cohort, among antipseudomonal antibiotics, cefepime and ceftazidime were independently associated with C. difficile infection, while antipseudomonal penicillins and carbapenems were not [85].
●Transplantation – Pediatric hematopoietic and solid organ transplant recipients have an increased risk of C. difficile infection [86]. C. difficile infection is common following hematopoietic transplantation. In a single-center study, 17 percent of pediatric hematopoietic transplant recipients were diagnosed with C. difficile infection during the 100 days posttransplant [87]. Among solid organ transplant recipients, the incidence of C. difficile infection varies with the transplanted organ. It is highest with pancreatic and intestinal transplantation and lowest with renal transplantation [88]. Calcineurin inhibitors and antibiotic exposure have been associated with C. difficile infection in pediatric solid organ transplant recipients [89,90].
●Inflammatory bowel disease – Children with inflammatory bowel disease (IBD) have a higher rate of symptomatic C. difficile infection and higher rate of recurrence than the general pediatric population [84,91-94]. Hospitalizations related to C. difficile infection are increasing among children with IBD [92]. Among children hospitalized with IBD, C. difficile infection is associated with longer stays, increased need for parenteral nutrition, and increased blood transfusions [92]. C. difficile infection also has been associated with exacerbations of IBD in children [91-93].
●Cystic fibrosis – Children with cystic fibrosis may be predisposed to C. difficile infection because of their increased exposure to antibiotics and health care settings. Asymptomatic carriage of toxigenic C. difficile appears to be common in children with cystic fibrosis and occurs more frequently than C. difficile infection [95]. However, severe C. difficile infection with typical findings of pseudomembranous colitis has been documented [57,96-98]. (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Distal intestinal obstruction syndrome'.)
●Hirschsprung disease – Children with Hirschsprung disease, and other disorders of gut motility, may be susceptible to C. difficile infection due to colonic stasis, changes in mucosal defense, and altered colonic flora. While it is not known definitively whether C. difficile contributes to Hirschsprung enterocolitis, the reports of pseudomembranous colitis occurring in infants with Hirschsprung disease suggest the relationship could be causal in some cases [99,100]. (See "Clostridioides difficile infection in children: Clinical features and diagnosis", section on 'Pseudomembranous colitis' and "Emergency complications of Hirschsprung disease", section on 'Enterocolitis'.)
●Structural or postoperative intestinal disorders – Severe C. difficile disease may occur in children with structural intestinal disorders and after intestinal operations, including placement of an ileostomy. Severe enteritis should prompt consideration of C. difficile disease in such children, in the immediate postoperative period and any time thereafter [101,102].
SUMMARY
●Microbiology – Clostridioides difficile is an anaerobic, gram-positive, spore-forming, toxin-producing bacillus. The spore form of C. difficile is resistant to heat, acid, antibiotics, and most disinfectants, and can persist in the hospital environment for several months. (See 'Organism' above.)
●Pathogenesis – The pathogenesis of C. difficile disease involves altered colonic microflora; C. difficile ingestion, colonization, and overgrowth; toxin production; and toxin injury of intestinal epithelial cells, resulting in inflammation and diarrhea. (See 'Pathogenesis' above.)
●Colonization – Asymptomatic C. difficile colonization is common among neonates and infants, peaking between 6 and 12 months of age. Given the high frequency of asymptomatic colonization, C. difficile may be an incidental finding in neonates and infants with diarrhea. (See 'Colonization' above.)
●Risk factors – Antibiotic use is the most important risk factor for C. difficile infection in children. The antibiotics most frequently implicated include clindamycin, cephalosporins, and fluoroquinolones. A minority of cases occur without prior antimicrobial exposure. (See 'Antibiotic exposure' above.)
Additional risk factors for C. difficile infection in children include gastric acid suppressants and gastrointestinal feeding devices. (See 'Other risk factors' above.)
●Predisposing conditions – Certain medical conditions may predispose to C. difficile infection, may increase the risk of severe C. difficile infection, or may be exacerbated by C. difficile infection. These include malignancy, hematopoietic cell or solid organ transplantation, inflammatory bowel disease, cystic fibrosis, and Hirschsprung disease. (See 'Predisposing conditions' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael Cooperstock, MD, MPH, who contributed to an earlier version of this topic review.
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